December 2, 2009
EXTON, PA.--(BUSINESS WIRE)--
Absorption Systems, a leader in drug safety and ADMET (absorption, distribution, metabolism, excretion and toxicity) testing, today announced the introduction of a more complete series of drug metabolism assays designed to support the pharmaceutical R&D process, from early-stage discovery through late-stage clinical development. The tests are intended to provide researchers with a more comprehensive picture of the role that metabolites, which are generally associated with the body's detoxification process, play in drug safety. If metabolites are not produced by and eliminated from the body in a timely fashion, a drug's active ingredients can accumulate and increase the potential for adverse reactions.
"This expanded series of assays helps our customers develop drugs with more desirable properties and fewer liabilities," commented Patrick M. Dentinger, president and CEO of Absorption Systems. "These offerings are in keeping with our mission to help our pharmaceutical and biotech clients by designing and performing studies that get them to the point of FDA submission as quickly as possible."
Absorption Systems is offering more than 20 new drug metabolism assays. Highlighted assays include:
Biomimetic Oxidation: Using an artificial test system, Absorption Systems can optimize reaction conditions to focus on metabolite(s) of interest. This system is an efficient and cost-effective way to produce sufficient quantities of oxidative metabolites for in vitro drug interaction testing.
Time Dependent Inhibition: This assay is used at an early stage to identify compounds that inhibit drug-metabolizing enzymes irreversibly. Such compounds can have powerful interactions with other drugs that are taken at the same time, leading to serious and unexpected adverse effects.
Metabolite Identification: This assay, implemented at an early stage of drug development, can flag potentially toxic drug metabolites and optimize preclinical safety testing. In addition, this assay is necessary to identify metabolites that may require their own separate safety testing.
About Absorption Systems, LP
Absorption Systems, founded in 1996, assists pharmaceutical and medical device companies in identifying and overcoming ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) barriers in the development of drugs and medical devices. The company's mission is to continually develop innovative research tools that can be used to accurately predict human outcomes or to explain unanticipated human outcomes when they occur. The CellPort Technologies™ platform, a suite of human cell-based tests systems for drug transporter characterization, exemplifies Absorption Systems' commitment to innovation and is soon to be an industry assay standard for in vitro drug interaction assessment. Absorption Systems has facilities near Philadelphia, PA and San Diego, CA, and serves customers throughout the world. For information on the company's comprehensive contract services and applied research programs, please visit http://www.seasiapublisentra.blogspot.com.
16 Desember 2009
PPD Launches New Global Biostatistics Technology Infrastructure
December 2, 2009
WILMINGTON, N.C.--(BUSINESS WIRE)--
PPD, Inc. (NASDAQ: PPDI) today announced it has launched a new global information technology infrastructure for analysis and reporting of clinical trial data. The biostatistics technology infrastructure (BTI) is a centralized computing platform that enhances the company's ability to deliver secure, quality reporting and data analysis to meet client timelines.
The virtual server environment allows PPD to deploy global teams of biostatisticians and programmers to projects on a single platform. The analysis processing environments are located in the same data centers as PPD's clinical data management systems, eliminating the need to move large quantities of data between file servers. Operating on this unified platform reduces bandwidth utilization, increases employee productivity and creates significant time savings.
"This new environment allows our employees around the world to work together, accessing the same data," said Susan Atkinson, senior vice president, global biometrics and technical operations for PPD. "Our investment in a global, innovative solution decreases our computer processing time and enhances our data security, giving us the ability to deliver more efficiently for our clients."
In addition, the BTI features a number of best practice global solutions such as code development, version control, output configuration, validation and delivery of production output. PPD has installed the BTI at its U.S. locations in Austin, Texas, and Research Triangle Park, N.C., as well as at its European headquarters in Cambridge, U.K.
PPD employs approximately 300 biostatisticians and programmers worldwide who provide study design, planning and reporting expertise across all phases of drug development. The company's reporting services range from Phase I trials through regulatory submission and post approval and include full support of the Clinical Data Interchange Standards Consortium data standards.
PPD is a leading global contract research organization providing discovery, development and post-approval services as well as compound partnering programs. Our clients and partners include pharmaceutical, biotechnology, medical device, academic and government organizations. With offices in 38 countries and more than 10,500 professionals worldwide, PPD applies innovative technologies, therapeutic expertise and a commitment to quality to help its clients and partners maximize returns on their R&D investments and accelerate the delivery of safe and effective therapeutics to patients. For more information, visit our Web site at http://www.seasiapublisentra.blogspot.com.
Except for historical information, all of the statements, expectations and assumptions contained in this news release, including expectations and assumptions about the value of the biostatistics technology infrastructure, are forward-looking statements that involve a number of risks and uncertainties. Although PPD attempts to be accurate in making these forward-looking statements, it is possible that future circumstances might differ from the assumptions on which such statements are based. In addition, other important factors which could cause results to differ materially include the following: rapid technological advances that make our products and services less competitive; the ability to attract and retain key personnel; competition within the outsourcing industry; risks associated with investments, such as impairments; success in sales growth; loss of large contracts; increased cancellation rates; economic conditions and outsourcing trends in the pharmaceutical, biotechnology, medical device, academic and government industry segments; risks associated with and dependence on collaborative relationships; risks associated with the development and commercialization of drugs, including earnings dilution and obtaining regulatory approval; risks that we may not continue our dividend policy; and the other risk factors set forth from time to time in the SEC filings for PPD, copies of which are available free of charge upon request from the PPD investor relations department.
WILMINGTON, N.C.--(BUSINESS WIRE)--
PPD, Inc. (NASDAQ: PPDI) today announced it has launched a new global information technology infrastructure for analysis and reporting of clinical trial data. The biostatistics technology infrastructure (BTI) is a centralized computing platform that enhances the company's ability to deliver secure, quality reporting and data analysis to meet client timelines.
The virtual server environment allows PPD to deploy global teams of biostatisticians and programmers to projects on a single platform. The analysis processing environments are located in the same data centers as PPD's clinical data management systems, eliminating the need to move large quantities of data between file servers. Operating on this unified platform reduces bandwidth utilization, increases employee productivity and creates significant time savings.
"This new environment allows our employees around the world to work together, accessing the same data," said Susan Atkinson, senior vice president, global biometrics and technical operations for PPD. "Our investment in a global, innovative solution decreases our computer processing time and enhances our data security, giving us the ability to deliver more efficiently for our clients."
In addition, the BTI features a number of best practice global solutions such as code development, version control, output configuration, validation and delivery of production output. PPD has installed the BTI at its U.S. locations in Austin, Texas, and Research Triangle Park, N.C., as well as at its European headquarters in Cambridge, U.K.
PPD employs approximately 300 biostatisticians and programmers worldwide who provide study design, planning and reporting expertise across all phases of drug development. The company's reporting services range from Phase I trials through regulatory submission and post approval and include full support of the Clinical Data Interchange Standards Consortium data standards.
PPD is a leading global contract research organization providing discovery, development and post-approval services as well as compound partnering programs. Our clients and partners include pharmaceutical, biotechnology, medical device, academic and government organizations. With offices in 38 countries and more than 10,500 professionals worldwide, PPD applies innovative technologies, therapeutic expertise and a commitment to quality to help its clients and partners maximize returns on their R&D investments and accelerate the delivery of safe and effective therapeutics to patients. For more information, visit our Web site at http://www.seasiapublisentra.blogspot.com.
Except for historical information, all of the statements, expectations and assumptions contained in this news release, including expectations and assumptions about the value of the biostatistics technology infrastructure, are forward-looking statements that involve a number of risks and uncertainties. Although PPD attempts to be accurate in making these forward-looking statements, it is possible that future circumstances might differ from the assumptions on which such statements are based. In addition, other important factors which could cause results to differ materially include the following: rapid technological advances that make our products and services less competitive; the ability to attract and retain key personnel; competition within the outsourcing industry; risks associated with investments, such as impairments; success in sales growth; loss of large contracts; increased cancellation rates; economic conditions and outsourcing trends in the pharmaceutical, biotechnology, medical device, academic and government industry segments; risks associated with and dependence on collaborative relationships; risks associated with the development and commercialization of drugs, including earnings dilution and obtaining regulatory approval; risks that we may not continue our dividend policy; and the other risk factors set forth from time to time in the SEC filings for PPD, copies of which are available free of charge upon request from the PPD investor relations department.
Javelin Pharmaceuticals Submits Dyloject New Drug Application To FDA For Management Of Acute Moderate-To-Severe Pain In Adults
December 2, 2009
CAMBRIDGE, MASS.--(BUSINESS WIRE)--
Javelin Pharmaceuticals, Inc. (NYSE Amex: JAV), a leading developer and marketer of specialty pharmaceutical products for pain management, today announced that it has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for its investigational product candidate, Dyloject™ (diclofenac sodium) Injection, for the management of acute moderate-to-severe pain in adults. If approved, Dyloject will be the first IV non-steroidal anti-inflammatory drug (NSAID) marketed in the United States as a single agent for the management of acute moderate-to-severe pain in adults since ketorolac in 1990.
"Our NDA submission for Dyloject is a significant milestone for Javelin. It reflects our commitment to patients suffering from acute moderate-to-severe pain, whose need for effective and safe analgesia in both the inpatient and day surgery settings is currently underserved," stated Martin J. Driscoll, CEO of Javelin Pharmaceuticals, Inc. "I am proud of my fellow colleagues who worked diligently to complete today's NDA submission and the many investigators who participated in our Dyloject clinical development program."
Javelin's comprehensive submission includes 16 clinical studies evaluating over 2000 subjects dosed with Dyloject. It includes over 1300 US patients in two multi-dose, multiple-day placebo-controlled Phase 3 pivotal efficacy studies and one multi-dose, multiple-day open label safety study. As previously reported, patient populations included the elderly (65 years of age and older) and patients with mild-to-moderate renal or mild hepatic insufficiency. In addition, over 400 Dyloject-treated patients received blood thinning agents during routine post-operative care. The two major efficacy trials for Dyloject achieved their primary endpoints (summary of pain intensity differences over the duration of the trial) and also showed reductions in postoperative opioid consumption of 43.5% and 61.5% compared to placebo. Moreover, the NDA submission includes pharmacovigilance data on Dyloject® from the UK, where it has been marketed following its approval in the fourth quarter of 2007.
Diclofenac sodium, the active pharmaceutical ingredient in Dyloject is one of the most widely prescribed NSAIDs. Since its initial approval in the 1980s approximately 1 billion patient days of treatment with diclofenac are estimated worldwide. It is approved and marketed in a variety of forms in the US including several oral formulations, a topical gel, patch and ophthalmic drops. However, an injectable formulation is not yet available in the United States.
The Company believes there is a significant unmet medical need for non-opioid agents for the management of pain in patients with acute moderate-to-severe pain. Opioids such as morphine may cause undesirable side effects including nausea, vomiting, constipation, sedation, cognitive impairment and respiratory depression. Decreasing or eliminating the need for opioid medication can reduce many of these side effects.
About Dyloject:
Dyloject has the potential to provide a novel alternative for the management of acute moderate-to-severe pain as a single agent. In clinical studies it reduced the need for morphine or other opioids. It is well established that a reduction in opioid requirements by at least 30% is necessary to effect a decrease in opioid-related side effects. Combining different types of pain medicines ("multimodal analgesia") is the most commonly advocated approach to postoperative pain management. Numerous studies of multimodal analgesia have shown that this strategy for maintaining effective pain relief while reducing opioid dose requirements often decreases the incidence of opioid related adverse events.
About Javelin
With corporate headquarters in Cambridge, MA, Javelin applies innovative proprietary technologies to develop new drugs and improved formulations of existing drugs to target unmet and underserved medical needs in the acute pain management market. The Company has one approved drug in the UK, a submitted NDA for Dyloject and two drug candidates in US Phase III clinical development.
Forward Looking Statement
This news release contains forward-looking statements. Such statements are valid only as of today, and we disclaim any obligation to update this information. These statements are subject to known and unknown risks and uncertainties that may cause actual future experience and results to differ materially from the statements made. These statements are based on our current beliefs and expectations as to future outcomes. Forward-looking statements include statements regarding the potential for FDA to accept our filing and approve our NDA for Dyloject, our belief in the strength of the data supporting the NDA for Dyloject, and statements regarding unmet medical needs and Dyloject's commercial and therapeutic potential. The inclusion of forward-looking statements should not be regarded as a representation by Javelin that its past and future plans will be achieved. Actual results may be materially different from those included in this press release, past press releases and other public filings due to the high degree and inherent risks involved in drug discovery, development and commercialization.
Drug discovery, development and commercialization involve a high degree of risks and uncertainties, including: The materiality of Dyloject's success to Javelin, and uncertainty as to whether Dyloject and/or our other drug candidates Rylomine and Ereska, will receive regulatory approvals or be successfully commercialized; the potential that the FDA may not accept Dyloject's NDA for review in a timely fashion, or that the clinical data and other submission materials included in the Company's NDA for Dyloject may not support our product candidate's safety and efficacy; that the incidence, frequency and severity of adverse side effects associated with this product candidate may be greater than anticipated, which could significantly delay or prevent its US regulatory approval; that the FDA may require the Company to perform additional non-clinical or clinical studies; the potential that the FDA may introduce additional requirements that need to be completed before or after regulatory approval; that the Companies manufacturing process for Dyloject does not meet all regulatory requirements; that our reliance on third parties to conduct clinical trials, regulatory submissions, manufacturing, and other vital elements of Dyloject's and our other product candidates development programs and the risk that third party performance, if found to be substandard, could delay or prevent the approval of Dyloject or our other product candidates.
In addition, other factors that might cause additional material differences to our business include, among others; uncertainties related to the ability to attract and retain development and commercialization partners for our technologies, the identification of lead compounds, the successful preclinical development thereof, the completion of clinical trials, the FDA review process and other governmental regulation, our ability to obtain working capital, our ability to successfully develop and commercialize drug candidates, and inherent competition from other pharmaceutical companies.
CAMBRIDGE, MASS.--(BUSINESS WIRE)--
Javelin Pharmaceuticals, Inc. (NYSE Amex: JAV), a leading developer and marketer of specialty pharmaceutical products for pain management, today announced that it has submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for its investigational product candidate, Dyloject™ (diclofenac sodium) Injection, for the management of acute moderate-to-severe pain in adults. If approved, Dyloject will be the first IV non-steroidal anti-inflammatory drug (NSAID) marketed in the United States as a single agent for the management of acute moderate-to-severe pain in adults since ketorolac in 1990.
"Our NDA submission for Dyloject is a significant milestone for Javelin. It reflects our commitment to patients suffering from acute moderate-to-severe pain, whose need for effective and safe analgesia in both the inpatient and day surgery settings is currently underserved," stated Martin J. Driscoll, CEO of Javelin Pharmaceuticals, Inc. "I am proud of my fellow colleagues who worked diligently to complete today's NDA submission and the many investigators who participated in our Dyloject clinical development program."
Javelin's comprehensive submission includes 16 clinical studies evaluating over 2000 subjects dosed with Dyloject. It includes over 1300 US patients in two multi-dose, multiple-day placebo-controlled Phase 3 pivotal efficacy studies and one multi-dose, multiple-day open label safety study. As previously reported, patient populations included the elderly (65 years of age and older) and patients with mild-to-moderate renal or mild hepatic insufficiency. In addition, over 400 Dyloject-treated patients received blood thinning agents during routine post-operative care. The two major efficacy trials for Dyloject achieved their primary endpoints (summary of pain intensity differences over the duration of the trial) and also showed reductions in postoperative opioid consumption of 43.5% and 61.5% compared to placebo. Moreover, the NDA submission includes pharmacovigilance data on Dyloject® from the UK, where it has been marketed following its approval in the fourth quarter of 2007.
Diclofenac sodium, the active pharmaceutical ingredient in Dyloject is one of the most widely prescribed NSAIDs. Since its initial approval in the 1980s approximately 1 billion patient days of treatment with diclofenac are estimated worldwide. It is approved and marketed in a variety of forms in the US including several oral formulations, a topical gel, patch and ophthalmic drops. However, an injectable formulation is not yet available in the United States.
The Company believes there is a significant unmet medical need for non-opioid agents for the management of pain in patients with acute moderate-to-severe pain. Opioids such as morphine may cause undesirable side effects including nausea, vomiting, constipation, sedation, cognitive impairment and respiratory depression. Decreasing or eliminating the need for opioid medication can reduce many of these side effects.
About Dyloject:
Dyloject has the potential to provide a novel alternative for the management of acute moderate-to-severe pain as a single agent. In clinical studies it reduced the need for morphine or other opioids. It is well established that a reduction in opioid requirements by at least 30% is necessary to effect a decrease in opioid-related side effects. Combining different types of pain medicines ("multimodal analgesia") is the most commonly advocated approach to postoperative pain management. Numerous studies of multimodal analgesia have shown that this strategy for maintaining effective pain relief while reducing opioid dose requirements often decreases the incidence of opioid related adverse events.
About Javelin
With corporate headquarters in Cambridge, MA, Javelin applies innovative proprietary technologies to develop new drugs and improved formulations of existing drugs to target unmet and underserved medical needs in the acute pain management market. The Company has one approved drug in the UK, a submitted NDA for Dyloject and two drug candidates in US Phase III clinical development.
Forward Looking Statement
This news release contains forward-looking statements. Such statements are valid only as of today, and we disclaim any obligation to update this information. These statements are subject to known and unknown risks and uncertainties that may cause actual future experience and results to differ materially from the statements made. These statements are based on our current beliefs and expectations as to future outcomes. Forward-looking statements include statements regarding the potential for FDA to accept our filing and approve our NDA for Dyloject, our belief in the strength of the data supporting the NDA for Dyloject, and statements regarding unmet medical needs and Dyloject's commercial and therapeutic potential. The inclusion of forward-looking statements should not be regarded as a representation by Javelin that its past and future plans will be achieved. Actual results may be materially different from those included in this press release, past press releases and other public filings due to the high degree and inherent risks involved in drug discovery, development and commercialization.
Drug discovery, development and commercialization involve a high degree of risks and uncertainties, including: The materiality of Dyloject's success to Javelin, and uncertainty as to whether Dyloject and/or our other drug candidates Rylomine and Ereska, will receive regulatory approvals or be successfully commercialized; the potential that the FDA may not accept Dyloject's NDA for review in a timely fashion, or that the clinical data and other submission materials included in the Company's NDA for Dyloject may not support our product candidate's safety and efficacy; that the incidence, frequency and severity of adverse side effects associated with this product candidate may be greater than anticipated, which could significantly delay or prevent its US regulatory approval; that the FDA may require the Company to perform additional non-clinical or clinical studies; the potential that the FDA may introduce additional requirements that need to be completed before or after regulatory approval; that the Companies manufacturing process for Dyloject does not meet all regulatory requirements; that our reliance on third parties to conduct clinical trials, regulatory submissions, manufacturing, and other vital elements of Dyloject's and our other product candidates development programs and the risk that third party performance, if found to be substandard, could delay or prevent the approval of Dyloject or our other product candidates.
In addition, other factors that might cause additional material differences to our business include, among others; uncertainties related to the ability to attract and retain development and commercialization partners for our technologies, the identification of lead compounds, the successful preclinical development thereof, the completion of clinical trials, the FDA review process and other governmental regulation, our ability to obtain working capital, our ability to successfully develop and commercialize drug candidates, and inherent competition from other pharmaceutical companies.
14 Desember 2009
I enclose details of our Outlook for Medical Devices in South East Asia.
The eight Asian countries in this report represent a total market of 588 million people and a combined GDP of US$2.8 trillion in 2008
Business opportunities in Asian medical device equipment supply markets are very different from a few years ago. The traditional tiger economies, characterised by economic growth, free market environment, developed industry and investment in health and health infrastructure have had a long haul back from the financial instability and economic downturn in the 1990's.
Tiger Cubs?
At the same time, markets that had hitherto excited little industry or investor interest, have emerged as real areas of opportunity for suppliers and service companies alike. Diverse influences - from deregulation and better trade links to improved access and the rise of medical tourism - are seeing markets such as Malaysia and Vietnam take an increasingly important role in the region.
Sustained growth
With established western markets maturing, serious attention is being paid to the countries where manufacturers can see significant long-term growth. However, effective planning is vital, and impartial, thoroughly researched business data is essential to fully appreciate the current market status as a basis for future development.
These quarterly updated reports analyse the issues
The Outlook for Medical Devices in South East Asia to 2013. Each report provides individual and highly-detailed analysis of each market, looking at the key regulatory, political, economic and corporate developments in the wider context of market structure, service and access. The reports are available individually or as a discounted collection, and prices include 4 completely updated reports sent quarterly plus a comprehensive annual review.
Executive Summary
8 Markets Covered!
Indonesia Philippines South Korea Thailand
Malaysia Singapore Taiwan Vietnam
Highlights from the report
INDONESIA
The Indonesian market for medical equipment and supplies was valued at US$146 million in 2008, equal to just US$0.6 per capita. In overall market terms the total is similar to Kuwait, in per capita terms the total is similar to India and Bangladesh. Indonesia spends roughly 1.1% of total health expenditure on medical devices, equal to 0.03% of total GDP. The market accounts for around 0.07% of the total world market. Only the basic medical items are produced locally and the country is reliant on imports.
MALAYSIA
The Malaysian government is keen to develop its medical device manufacturing capability in order to remain competitive, but the country is still heavily reliant on imports, which have nearly doubled over the last five years. This trend is expected to continue in the foreseeable future, despite the government's ambitious plans to promote the manufacture of medical devices at the higher end of the technology scale. The Malaysian market for medical equipment and supplies is estimated at US$614 million in 2008, and recent trends suggest a positive outlook leading to 2013.
PHILIPPINES
The Philippines will continue to rely heavily on imported medical equipment, and some of the key areas of growth, based on recent trends, are ophthalmic instruments and appliances, syringes needles and catheters, X-ray equipment, orthopaedic and prosthetic appliances, and surgical gloves. The Philippines medical device market is expected to grow at a rate of 4.1% from 2008 to 2013. This growth will be spearheaded by the private sector, medical tourism and a steady economy.
SINGAPORE
The Singapore market for medical equipment and supplies was estimated at US$215 million in 2008, equal to US$49 per capita. Singapore's medical device market has been fairly resilient, with growth continuing throughout the period of financial instability towards the end of the last decade. Stable device import figures underline the fundamental strength of the market. Moreover, strong trade links with the US and EU have played a large part in this industry buoyancy. Owing to impressive import growth, a fairly steady economy and an ageing population, Espicom estimates the Singaporean market to exhibit annual average growth of around 13.1%.
SOUTH KOREA
Market demand for advanced and innovative medical devices is forecast to remain strong in 2008 and over the next several years as Korea's hospitals continue to purchase technology intensive products from abroad and increasing numbers of elderly Korean patients require sophisticated medical procedures. Espicom estimates the Korean market to exhibit annual average growth of 7.0%. Based on this rate, the market will be worth US$4.0 billion by 2013. Even so, the government continues to put pressure on medical equipment costs.
TAIWAN
Along with South Korea, Taiwan is one of the richer 'Asian Tiger' economies. Per capita GDP is similar to New Zealand, and behind only Japan, Singapore, Hong Kong and Australia in the Asia-Pacific region. The economy contracted in the wake of the more general slowdown in 2001, but has since performed well again. A heavily used and under funded health insurance scheme has caused the government to initiate unpopular cost control reforms.
THAILAND
Recovery of the Thai medical device market since the economic crisis has been gradual, with 2001 imports around a third below pre-crisis levels. Since then, imports have nearly doubled leading to 2005, and the prospects for growth remain encouraging. In 2008, the market is valued at US$492 million, and is expected to continue to grow at a real average of 7.7% over the next five years.
VIETNAM
The medical device and supplies market is expected to expand steadily in Vietnam over the next few years, in line with the increasing value of imports, which account for just under 80% of the market. It is expected that the device market will continue to expand at an average rate of 10.4% per annum. ..... FOR EVERY MARKET,
Business opportunities in Asian medical device equipment supply markets are very different from a few years ago. The traditional tiger economies, characterised by economic growth, free market environment, developed industry and investment in health and health infrastructure have had a long haul back from the financial instability and economic downturn in the 1990's.
Tiger Cubs?
At the same time, markets that had hitherto excited little industry or investor interest, have emerged as real areas of opportunity for suppliers and service companies alike. Diverse influences - from deregulation and better trade links to improved access and the rise of medical tourism - are seeing markets such as Malaysia and Vietnam take an increasingly important role in the region.
Sustained growth
With established western markets maturing, serious attention is being paid to the countries where manufacturers can see significant long-term growth. However, effective planning is vital, and impartial, thoroughly researched business data is essential to fully appreciate the current market status as a basis for future development.
These quarterly updated reports analyse the issues
The Outlook for Medical Devices in South East Asia to 2013. Each report provides individual and highly-detailed analysis of each market, looking at the key regulatory, political, economic and corporate developments in the wider context of market structure, service and access. The reports are available individually or as a discounted collection, and prices include 4 completely updated reports sent quarterly plus a comprehensive annual review.
Executive Summary
8 Markets Covered!
Indonesia Philippines South Korea Thailand
Malaysia Singapore Taiwan Vietnam
Highlights from the report
INDONESIA
The Indonesian market for medical equipment and supplies was valued at US$146 million in 2008, equal to just US$0.6 per capita. In overall market terms the total is similar to Kuwait, in per capita terms the total is similar to India and Bangladesh. Indonesia spends roughly 1.1% of total health expenditure on medical devices, equal to 0.03% of total GDP. The market accounts for around 0.07% of the total world market. Only the basic medical items are produced locally and the country is reliant on imports.
MALAYSIA
The Malaysian government is keen to develop its medical device manufacturing capability in order to remain competitive, but the country is still heavily reliant on imports, which have nearly doubled over the last five years. This trend is expected to continue in the foreseeable future, despite the government's ambitious plans to promote the manufacture of medical devices at the higher end of the technology scale. The Malaysian market for medical equipment and supplies is estimated at US$614 million in 2008, and recent trends suggest a positive outlook leading to 2013.
PHILIPPINES
The Philippines will continue to rely heavily on imported medical equipment, and some of the key areas of growth, based on recent trends, are ophthalmic instruments and appliances, syringes needles and catheters, X-ray equipment, orthopaedic and prosthetic appliances, and surgical gloves. The Philippines medical device market is expected to grow at a rate of 4.1% from 2008 to 2013. This growth will be spearheaded by the private sector, medical tourism and a steady economy.
SINGAPORE
The Singapore market for medical equipment and supplies was estimated at US$215 million in 2008, equal to US$49 per capita. Singapore's medical device market has been fairly resilient, with growth continuing throughout the period of financial instability towards the end of the last decade. Stable device import figures underline the fundamental strength of the market. Moreover, strong trade links with the US and EU have played a large part in this industry buoyancy. Owing to impressive import growth, a fairly steady economy and an ageing population, Espicom estimates the Singaporean market to exhibit annual average growth of around 13.1%.
SOUTH KOREA
Market demand for advanced and innovative medical devices is forecast to remain strong in 2008 and over the next several years as Korea's hospitals continue to purchase technology intensive products from abroad and increasing numbers of elderly Korean patients require sophisticated medical procedures. Espicom estimates the Korean market to exhibit annual average growth of 7.0%. Based on this rate, the market will be worth US$4.0 billion by 2013. Even so, the government continues to put pressure on medical equipment costs.
TAIWAN
Along with South Korea, Taiwan is one of the richer 'Asian Tiger' economies. Per capita GDP is similar to New Zealand, and behind only Japan, Singapore, Hong Kong and Australia in the Asia-Pacific region. The economy contracted in the wake of the more general slowdown in 2001, but has since performed well again. A heavily used and under funded health insurance scheme has caused the government to initiate unpopular cost control reforms.
THAILAND
Recovery of the Thai medical device market since the economic crisis has been gradual, with 2001 imports around a third below pre-crisis levels. Since then, imports have nearly doubled leading to 2005, and the prospects for growth remain encouraging. In 2008, the market is valued at US$492 million, and is expected to continue to grow at a real average of 7.7% over the next five years.
VIETNAM
The medical device and supplies market is expected to expand steadily in Vietnam over the next few years, in line with the increasing value of imports, which account for just under 80% of the market. It is expected that the device market will continue to expand at an average rate of 10.4% per annum. ..... FOR EVERY MARKET,
11 Desember 2009
10 Desember 2009
Canada’s Top 100 Corporate R&D Spenders List 2009 Analysis
R&D Spending in the Doldrums
Corporate R&D spending remained essentially unchanged in Fiscal 2008 compared with the previous year. Spending on research by the Top 100 Corporate R&D Spenders totalled $10.09 billion, a slight decline of-0.2% from Fiscal 2007. With Nortel Networks, Canada’s perpetual but soon-to-be-extinct R&D leader removed from the equation, spending by the remaining 99 firms eked out a 1.9% increase.
Research intensity – R&D spending as a share of revenues – was 2.7% down from 3.2% the year before. Excluding Nortel’s results research intensity was 2.3% compared with 2.7% the previous year. A sharp 12.3% growth in corporate revenues over the period amplified the decline in research intensity. (We calculated research intensity for the 94 firms that supplied income data.)
Overall, 59 companies achieved positive R&D growth, 40 firms spent less on research and one company was static. These figures are comparable with those in previous years.
The $100 Million Club
In Fiscal 2008, 19 companies qualified for RE$EARCH Infosource’s $100 Million Club – the elite group of firms that spent $100 million or more on research. This is the same number of firms as in Fiscal 2007, but down from the 24 firms in Fiscal 2006. Among the Club members were 12 Canadian companies and 7 foreign subsidiaries.
Returning to the $100 Million Club this year were TELUS, Open Text and CAE; and new to the Club was Aastra Technologies. Two former Club members fell off the list this year because their spending declined below $100 million.
Among the 19 Club members, 12 companies increased their R&D spending, while 6 firms had negative R&D spending growth and 1 firm reported no growth.
The $100 Million Club was dominated by 9 companies in the Information and Communication Technology sector. Next in prominence were 4 Pharmaceutical/biotechnology companies, followed by 3 firms in the Aerospace sector.
Club members accounted for 67% of total Top 100 companies’ R&D spending ($6.8 billion), the same share as in the year before.
Industry Performance
Eleven companies in the Communications/telecommunications equipment sector dominated Top 100 spending again this year. These firms accounted for 27% of total Top 100 spending, a slight 1.5% increase over Fiscal 2007. But if Nortel Networks’ results are omitted, the remaining 10 Communications/telecommunications equipment firms posted an extremely strong 26.3% gain in their combined R&D spending over the period.
Next in total spending were 31 firms in the Pharmaceuticals/biotechnology sector, which among them accounted for 19% of total spending – similar to the previous year. Four companies in the Telecommunications services sector were responsible for 13% of Top 100 spending, but declined -9.6% from the year before.
Companies in 4 sectors – Engineering services (14.5%), Software and computer services (7.9%), Aerospace (5.6%) and Energy/oil and gas (4.1%) – showed strong or moderate gains in research spending, while their counterparts in other sectors had declines in their spending. Between Fiscal 2007 and Fiscal 2008, total R&D spending increased in 5 of the 9 leading sectors represented by the Top 100 R&D spenders.
The Top 10 R&D Intensive Firms
The 10 most research intensive companies on the Top 100 list spend a large proportion of revenues on research. In the case of 8 of the 10 firms, spending on research was far in excess of revenues. This typically indicates companies that are in a startup or early growth phase in which research spending is high and revenues are low.
Not surprisingly, almost all of the companies on the list this year were Pharmaceuticals/biotechnology companies. These firms normally have long product development cycles, which are characterized by deferred revenues; hence, their high levels of research intensity.
Gainers and Losers
Ten companies on the Top 100 list exhibited strong gains in research spending, increasing their R&D by 60% or more between Fiscal 2007 and Fiscal 2008. This year’s list of gainers included a mix of technology, resources and pharma/bio firms.
Leading the list was Allen-Vanguard, which had a strong 263.5% increase in research spending. Mining and metals company ArcelorMittal Dofasco was next with a sharp 151.9% increase in R&D spending. Telecom services giant TELUS boosted its R&D spending by a hefty 147.1%. Husky Energy expanded its spending by 122.2%, while Pharmaceuticals/biotechnology company Cangene grew its R&D by 104.7%.
Not all firms managed increases in their research spending in Fiscal 2008. A group of 10 firms posted strong pull-backs in R&D. Among the well-known firms where spending declined, were Ballard Power Systems (-37.0%), QLT (-36.8%), Tembec (-29.9%), and Teck Resources (-28.1%).
Looking Ahead
Last year we wrote that “Companies are bracing for the impact of world financial and stock market meltdowns as this analysis is being written. Suffice to say that there are bound to be major repercussions for corporate R&D spending next year. At this time everything is up for grabs. A number of leading firms may not be in existence next year.”
Based on the Fiscal 2008 results Canada’s Top 100 Corporate R&D Spenders avoided an R&D wipe-out. Total spending declined by -0.2% (up 1.9% without Nortel Networks), which under the circumstances could be seen to be a minor miracle. Perhaps, though, the so-so 2008 results simply reflected a delayed reaction on the part of firms to their dire business circumstances. Undoubtedly, the less-than-expected R&D spending decline was cushioned by the strong growth of revenues of 12.3% for the Top 100 R&D Spenders.
While the overall Top 100 result held up well (in the circumstances), that could not be said for all individual company results. Forty firms experienced negative R&D growth against 59 firms where spending increased.
The full effect of the deteriorating world economy will be reflected in next year’s Fiscal 2009 corporate R&D spending results. It is hard to envisage better overall performance than in 2008. For one thing, it appears that Canada’s perpetual R&D spending leader (Nortel Networks) will be absent from the list in 2009. In consequence, total corporate R&D spending will undoubtedly be affected – in a downward direction.
New measures are needed to reinvigorate corporate research and innovation in Canada. As we have written elsewhere (Canada Needs New Paradigm for Research and Innovation. Toronto Star, 26 August 2009), there are concrete steps that can be taken today, many with little or no net cost, to boost research and innovation:
• Create a research strategy to commercialize our vast services potential.
• Shift a large part of corporate research funding from the tax system to direct support of research through programs such as the National Research Council's Industrial Research Assistance Program (IRAP).
• Strengthen our areas of traditional comparative advantage: agriculture, forestry, mining, mineral processing, energy production and so forth.
• Develop a national strategy to support companies developing instrumentation.
• Modernize procurement policies to allow governments to acquire promising new technologies.
• Reinstate the "unsolicited proposal" program that allowed companies to get support for novel ideas that could be used by government.
• Shift “technology push” resources to “demand pull” - to companies that have identified a market opportunity and need help to pay universities to develop their ideas.
• Automatically give intellectual property rights to companies that pay for or perform government research.
• Consolidate the alphabet soup of federal and provincial funding programs and make it easier for companies and individual researchers to navigate the program maze.
Develop broad university and college "business engagement strategies" and not simply narrow "commercialization strategies."
• Develop a national software strategy. Canada is an international software powerhouse, producing everything from gaming to financial modelling software.
• Compensate for low levels of venture capital funding by applying the flow-through share model common in the energy sector to research-based companies.
Meanwhile, let’s see how well Canada will ride out the global economic downturn.
Corporate R&D spending remained essentially unchanged in Fiscal 2008 compared with the previous year. Spending on research by the Top 100 Corporate R&D Spenders totalled $10.09 billion, a slight decline of-0.2% from Fiscal 2007. With Nortel Networks, Canada’s perpetual but soon-to-be-extinct R&D leader removed from the equation, spending by the remaining 99 firms eked out a 1.9% increase.
Research intensity – R&D spending as a share of revenues – was 2.7% down from 3.2% the year before. Excluding Nortel’s results research intensity was 2.3% compared with 2.7% the previous year. A sharp 12.3% growth in corporate revenues over the period amplified the decline in research intensity. (We calculated research intensity for the 94 firms that supplied income data.)
Overall, 59 companies achieved positive R&D growth, 40 firms spent less on research and one company was static. These figures are comparable with those in previous years.
The $100 Million Club
In Fiscal 2008, 19 companies qualified for RE$EARCH Infosource’s $100 Million Club – the elite group of firms that spent $100 million or more on research. This is the same number of firms as in Fiscal 2007, but down from the 24 firms in Fiscal 2006. Among the Club members were 12 Canadian companies and 7 foreign subsidiaries.
Returning to the $100 Million Club this year were TELUS, Open Text and CAE; and new to the Club was Aastra Technologies. Two former Club members fell off the list this year because their spending declined below $100 million.
Among the 19 Club members, 12 companies increased their R&D spending, while 6 firms had negative R&D spending growth and 1 firm reported no growth.
The $100 Million Club was dominated by 9 companies in the Information and Communication Technology sector. Next in prominence were 4 Pharmaceutical/biotechnology companies, followed by 3 firms in the Aerospace sector.
Club members accounted for 67% of total Top 100 companies’ R&D spending ($6.8 billion), the same share as in the year before.
Industry Performance
Eleven companies in the Communications/telecommunications equipment sector dominated Top 100 spending again this year. These firms accounted for 27% of total Top 100 spending, a slight 1.5% increase over Fiscal 2007. But if Nortel Networks’ results are omitted, the remaining 10 Communications/telecommunications equipment firms posted an extremely strong 26.3% gain in their combined R&D spending over the period.
Next in total spending were 31 firms in the Pharmaceuticals/biotechnology sector, which among them accounted for 19% of total spending – similar to the previous year. Four companies in the Telecommunications services sector were responsible for 13% of Top 100 spending, but declined -9.6% from the year before.
Companies in 4 sectors – Engineering services (14.5%), Software and computer services (7.9%), Aerospace (5.6%) and Energy/oil and gas (4.1%) – showed strong or moderate gains in research spending, while their counterparts in other sectors had declines in their spending. Between Fiscal 2007 and Fiscal 2008, total R&D spending increased in 5 of the 9 leading sectors represented by the Top 100 R&D spenders.
The Top 10 R&D Intensive Firms
The 10 most research intensive companies on the Top 100 list spend a large proportion of revenues on research. In the case of 8 of the 10 firms, spending on research was far in excess of revenues. This typically indicates companies that are in a startup or early growth phase in which research spending is high and revenues are low.
Not surprisingly, almost all of the companies on the list this year were Pharmaceuticals/biotechnology companies. These firms normally have long product development cycles, which are characterized by deferred revenues; hence, their high levels of research intensity.
Gainers and Losers
Ten companies on the Top 100 list exhibited strong gains in research spending, increasing their R&D by 60% or more between Fiscal 2007 and Fiscal 2008. This year’s list of gainers included a mix of technology, resources and pharma/bio firms.
Leading the list was Allen-Vanguard, which had a strong 263.5% increase in research spending. Mining and metals company ArcelorMittal Dofasco was next with a sharp 151.9% increase in R&D spending. Telecom services giant TELUS boosted its R&D spending by a hefty 147.1%. Husky Energy expanded its spending by 122.2%, while Pharmaceuticals/biotechnology company Cangene grew its R&D by 104.7%.
Not all firms managed increases in their research spending in Fiscal 2008. A group of 10 firms posted strong pull-backs in R&D. Among the well-known firms where spending declined, were Ballard Power Systems (-37.0%), QLT (-36.8%), Tembec (-29.9%), and Teck Resources (-28.1%).
Looking Ahead
Last year we wrote that “Companies are bracing for the impact of world financial and stock market meltdowns as this analysis is being written. Suffice to say that there are bound to be major repercussions for corporate R&D spending next year. At this time everything is up for grabs. A number of leading firms may not be in existence next year.”
Based on the Fiscal 2008 results Canada’s Top 100 Corporate R&D Spenders avoided an R&D wipe-out. Total spending declined by -0.2% (up 1.9% without Nortel Networks), which under the circumstances could be seen to be a minor miracle. Perhaps, though, the so-so 2008 results simply reflected a delayed reaction on the part of firms to their dire business circumstances. Undoubtedly, the less-than-expected R&D spending decline was cushioned by the strong growth of revenues of 12.3% for the Top 100 R&D Spenders.
While the overall Top 100 result held up well (in the circumstances), that could not be said for all individual company results. Forty firms experienced negative R&D growth against 59 firms where spending increased.
The full effect of the deteriorating world economy will be reflected in next year’s Fiscal 2009 corporate R&D spending results. It is hard to envisage better overall performance than in 2008. For one thing, it appears that Canada’s perpetual R&D spending leader (Nortel Networks) will be absent from the list in 2009. In consequence, total corporate R&D spending will undoubtedly be affected – in a downward direction.
New measures are needed to reinvigorate corporate research and innovation in Canada. As we have written elsewhere (Canada Needs New Paradigm for Research and Innovation. Toronto Star, 26 August 2009), there are concrete steps that can be taken today, many with little or no net cost, to boost research and innovation:
• Create a research strategy to commercialize our vast services potential.
• Shift a large part of corporate research funding from the tax system to direct support of research through programs such as the National Research Council's Industrial Research Assistance Program (IRAP).
• Strengthen our areas of traditional comparative advantage: agriculture, forestry, mining, mineral processing, energy production and so forth.
• Develop a national strategy to support companies developing instrumentation.
• Modernize procurement policies to allow governments to acquire promising new technologies.
• Reinstate the "unsolicited proposal" program that allowed companies to get support for novel ideas that could be used by government.
• Shift “technology push” resources to “demand pull” - to companies that have identified a market opportunity and need help to pay universities to develop their ideas.
• Automatically give intellectual property rights to companies that pay for or perform government research.
• Consolidate the alphabet soup of federal and provincial funding programs and make it easier for companies and individual researchers to navigate the program maze.
Develop broad university and college "business engagement strategies" and not simply narrow "commercialization strategies."
• Develop a national software strategy. Canada is an international software powerhouse, producing everything from gaming to financial modelling software.
• Compensate for low levels of venture capital funding by applying the flow-through share model common in the energy sector to research-based companies.
Meanwhile, let’s see how well Canada will ride out the global economic downturn.
04 Desember 2009
PHARMA HISTORY III
Drug disasters - DES
Tragically, most modern drug disasters have been associated with therapies delivered to pregnant women. In 1938, the British scientist, Edward Dodds (1899-1973), discovered a synthetic oestrogen hormone called diethylstilboestrol (DES). It was prescribed to pregnant women believed to be at risk of miscarriages. An estimated 5-10 million women in Europe and America took the drug between 1938-1971 when it was banned for use in pregnancy because of an association with a rare cancer of the vagina and cervix in their daughters. The risks of `DES daughters' developing this cancer were estimated to be 1 in 10,000. However, both DES daughters and sons were found to have a higher than average incidence of other abnormalities of the reproductive system.
Drug disasters - thalidomide
Thalidomide was introduced as a sedative in 1956, and marketed for use in pregnancy to control sickness. It was withdrawn in 1961 by which time 12,000 severely disabled children had been born in 46 countries including Britain, Europe, Australia, Canada, and Japan (the drug was never marketed in the United States). Only 8000 survived. Mothers who took thalidomide during the first 3 months of pregnancy when the foetal limbs were forming, gave birth to babies with distinctive deformities. During the 1960s, however, thalidomide was found to be effective in treating the skin disorders of leprosy, and in 1998, the drug was approved in the United States for this purpose. Studies also revealed its potential value in treating ulcers in AIDS, inflammatory bowel disease, and some types of cancers. It is thought to prevent tumours from growing new blood vessels which allow them to increase in size.
Drug disasters - thalidomide
Thalidomide was introduced as a sedative in 1956, and marketed for use in pregnancy to control sickness. It was withdrawn in 1961 by which time 12,000 severely disabled children had been born in 46 countries including Britain, Europe, Australia, Canada, and Japan (the drug was never marketed in the United States). Only 8000 survived. Mothers who took thalidomide during the first 3 months of pregnancy when the foetal limbs were forming, gave birth to babies with distinctive deformities. During the 1960s, however, thalidomide was found to be effective in treating the skin disorders of leprosy, and in 1998, the drug was approved in the United States for this purpose. Studies also revealed its potential value in treating ulcers in AIDS, inflammatory bowel disease, and some types of cancers. It is thought to prevent tumours from growing new blood vessels which allow them to increase in size.
By 2000, thalidomide was available in Britain only on a `named patient' basis.
Thalidomide - the aftermath
The thalidomide tragedy resulted in more stringent testing of drugs, and extensive clinical trials prior to the launch of a new product. Typically, a prescribed only medication (POM) requires evaluation for toxicity and effects on fertility. If the drug is to administered to women of child-bearing age, it must also be tested for potential foetal malformation (teratogenicity). All toxicity studies are carried out in animals. Toxicity tests are followed by Phase I studies, usually on healthy human volunteers, sometimes patients. These determine common side effects. Phase II and III studies investigate efficacy on 1000-2000 patients, and also look for adverse reactions. These are early clinical trials. The time span between the beginning of Phase I and the end of Phase III may be as long as 5 years.
The Medicines Control Agency (MCA) in Britain, and the Food and Drug Administration (FDA) in the US, act both as regulatory bodies and licensing authorities. In Britain, by the 1980s, all newly licensed drugs were identified with a black triangle. In addition, the `Yellow Card' system was introduced in 1964 so that doctors could report adverse reactions to new and established drugs directly to the Committee on Safety of Medicines. By 1989, the annual number of reports was about 20,000. In the United Kingdom and Europe, only medically confirmed suspected adverse reactions were reported to regulatory authorities. In the United States, reports by patients, nurses and pharmacists were given similar consideration to those made by doctors. Pharmaceutical companies also began to establish drug surveillance units which monitored reports of adverse reactions to their products on a worldwide basis.
National Poisons Information Service
The doctors of ancient Greece believed that all substances were potentially poisonous. The only thing which distinguished a poison from a remedy was the dosage. By the 19th century, this was an accepted fact and the investigation of poisons became known as toxicology. During the 1960s, the Department of Health in Britain, established a Poisons Information Service. This gave doctors 24-hour telephone access to expert advice on the diagnosis, treatment, and management of patients who may have been poisoned. The term `poison' covered a wide range of substances including drugs, plants, household products, and snake venom. By 2000, there were 6 regional poisons centres and one national centre for complex cases. As well as answering telephone queries, these units also supported toxicology laboratories which analysed samples from cases of suspected poisoning.
This work was important not only to the medical profession but also to police, industry, and the legal profession. The American Association of Poison Control Centers offers a similar service in the United States. The European Association of Poisons Centres and Clinical Toxicologists was established in 1964 to advance knowledge and understanding of the diagnosis and treatment of all forms of poisoning.
Pharmacy comes of age
The American doctor of the late 19th century was said to get by with calomel (a mercury compound used as a purgative), opium, quinine, buchu (a diuretic), ipecac (an emetic), and Dover's powder (an opium preparation). The therapeutic range of the British general practitioner was little different. The therapeutic revolution of the second half of the 20th century changed everything. Restrictive legislation on medicines sold over the counter was first passed in Britain in 1860 when prescription-only drugs came into being. In 1948, when the National Health Service was established, a general practitioner's average prescription costs were 72 pence per patient a year. Fifty years later, this had risen to œ90 per patient a year. In 1988, there were 106 pharmaceutical companies manufacturing prescribed-only medications, and 147 supplying over-the-counter products. Gone were the days when aspirin simply meant `acetylsalicylic acid'.
A British general practitioner in 1991 could choose between 15 different brands of aspirin, 30 brands of paracetamol, 29 brands of contraceptive pill, 29 brands of insulin, and 21 brands of penicillin antibiotics. The manufacture of `me-too' drugs became a phenomenon of the late 20th century as pharmaceutical companies played around with molecules in order to come up with a variation on a theme. If the end result turned out to be a `me-too', the packaging could make or break the product. The retail pharmacist became the local drugs `expert' and acted as an important intermediary between doctor and patient. In July 2000, the British government published its NHS Plan which included new roles for community pharmacists.
Addiction - how it began
The concept of `addiction' or `substance abuse' as a social evil was largely a 20th century creation although the `medicalisation' of intoxication began in the 18th century. Throughout history, psychoactive substances have played a major role in ritual, recreation, medical treatment, and pain relief. The ancient Egyptians used opium to stop children crying and send them to sleep. The Roman emperor, *Marcus Aurelius (CE 121-180) began each day with a portion dissolved in wine, prescribed by his physician, *Galen (CE 129-c. 200/216). Both the Greeks and the Romans enjoyed wine and beer, often to excess. Hemp was used in ancient India, Mesopotamia, Egypt, western Europe, and Britain. Coca leaves were chewed by Andean Indians from the third century BCE. Its use was a court privilege as well as a religious observance.
It was also an important source of revenue during Spanish colonialism as well as sustaining the miners of Bolivia and Peru who worked in conditions of great hardship. Cacao (cocoa) was used as a stimulant by the *Aztecs of Mexico, coffee was discovered in Arabia sometime after the 10th century, and tea belonged to China. Tobacco had long been known to *American Indians when Europeans began colonisation of the New World in the 16th century. Spain and Portugal became the first countries to introduce tobacco smoking (initially, for medicinal purposes) but most other countries followed by about 1600. At first, the Spanish *Inquisition considered tobacco smoking to be a mark of possession since only Satan could confer upon humans the power to exhale smoke through the mouth.
Addiction - creating the alcoholic
Drunkenness commanded the attention of religious authorities throughout the Middle Ages but was scarcely mentioned in medical writing except to warn against the use of drink to relieve melancholia. In 1684, the English physician, Thomas Willis (1621-1675), suggested that habitual drunkenness resulted in `stupidity' but physicians frequently prescribed wine, beer, and spirits as medicines. The 18th century was particularly renowned for its excesses, and habitual drunkenness came to be seen as a disease. The American physician, Benjamin Rush (1745-1813), concocted a rum and tartar emetic which he used as aversion therapy for men who preferred the tavern to domestic society. Doctors began to associate drink with insanity. The term `delirium tremens' (DTs) was first used in 1813 by English physician, Thomas Sutton.
An episode of DTs was sufficient reason for admission to a lunatic asylum and there was a common belief that habitual drunkenness resulted in dementia. A study of 668 men admitted to a London lunatic asylum between 1880-1920 revealed that `drink' was considered a cause of insanity in 22% of cases. There were no admissions associated with opium or other drugs. Drunkenness officially achieved disease status in 1852 when Swedish physician, Magnus Huss (1807-1890) introduced the term ` chronic alcoholism'. In England, Charles Mercier and Henry Maudsley (1835-1918) classified alcoholic insanity as a distinct disease. Alcoholism was also seen as a social evil and there began a movement in Britain and America to establish `inebriate reformatories' for habitual drunkards. In England, the Reverend Harold Nelson Burden (1860-1930) and his wife, Kate (c.1856-1919) established 617 homes by 1907.
Addiction - opium
Opium was the most important and powerful drug in the doctor's bag. The English physician, Thomas Sydenham (1624-1689), formulated 'Sydenham's Laudanum' which was opium diluted in Malaga wine with saffron, cinnamon, and cloves. Both he and the Dutch physician, Hermann Boerhaave (1668-1738) maintained that opium was a gift from God to alleviate the sufferings of man. Physicians were divided on the relationship between opiates and insanity. The English physician, Thomas Willis (1621-1675) believed that opium dulled the mind although he recommended it as a remedy against insanity. Between 1814-1818, opium accounted for one third of all export trade from Bengal in British India to China and the East Indies. It was known to be habit-forming but until the 19th century, there was no culture of 'drug abuse' to heap shame or secrecy on users.
Opium was used regularly by monarchs, writers, poets, and artists, not only as a 'recreational' drug but also to ease pain or relieve the symptoms of chronic disease. Thus, the English poet, John Keats (1795-1821), used it to treat his tuberculosis, and Elizabeth Barrett Browning (1806-1861) swallowed laudanum (opium dissolved in spirits) to suppress the agony of an injured spine. In England, at mid-19th century, it could be bought from any chemist, druggist, or grocer for one penny an ounce. A palatable opium mixture, given to children, was Godfrey's cordial which contained opium, sweet treacle, water and spices. During the 1860s, a Manchester druggist was selling half a gallon a week. Other brands were called Steedman's Powder and Atkinson's Royal Infants Preservative.
Addiction - creating addicts
In 1898, the German pharmaceutical company, Bayer, launched a `safer' derivative of morphine which they named heroin because of its stimulant properties. Heroin was advertised as a `cure' for morphine and opium addiction. When Bayer introduced Aspirin in 1899, it was sold in a double package with heroin. Between 1911-1914, England exported 40 tons of morphine, and Germany 10 tons of heroin, to China and the Far East in an attempt to rehabilitate the estimated 13.5 million Chinese (27% of all adult males) who were addicted to opium, largely through British exports from India. From the mid-20th century, a synthetic drug called methadone which resembled morphine, was being used to rehabilitate heroin addicts. Cocaine, an alkaloid of coca, was isolated by Albert Niemann (1834-1861) in 1860, and recommended as a nerve tonic and an antidepressant.
In 1876, Sir Clifford Allbutt (1836-1925), later Regius Professor of Medicine at Cambridge University, took coca leaves on a walking tour of the Alps. The Austrian neurologist, Sigmund Freud (1856-1939), began a research project on cocaine which included self-experimentation. In the same year, the American surgeon, William Stewart Halsted (1852-1922), began experimenting with cocaine to determine whether it could be used for lumbar anaesthesia. He became addicted and was sent off for therapy which involved replacing cocaine with morphine, supposedly a `cure' for drug dependency. By the 1890s, there were more than 100 beverages containing coca extracts or pure cocaine. In 1885, JS Pemberton, an American druggist, registered `Coca-Cola', which contained cocaine, cola nuts (a source of caffeine), and citrus juices.
Addiction - controlling drugs
The identification, by chemical analysis, of the active principle in psychoactive substances, often heightened their appeal. Peyote, an hallucinogenic plant used for centuries in Mexico, achieved new popularity after 1888 when its active principle, mescaline, was isolated. Afficionados were Irish poet, William Butler Yeats (1865-1939), American dramatist, Eugene O'Neill (1888-1953), and English physician, Henry Havelock Ellis (1859-1939). The cause of addiction to drugs and alcohol was related to weakness of character rather than substance availability so there was little incentive to regulate supply. In any case, about 65% of morphine addicts at the end of the 19th century were health professionals and their relatives who had access to any number of psychoactive drugs.
These included chloroform and ether, first used as anaesthetics during the 1840s but soon acquiring a following amongst the poor of Europe because they were cheaper than alcohol. The French writer, Guy de Maupassant (1850-1893) was an ether addict. By the beginning of the 20th century, doctors, pharmacists, politicians, and reformers in the United States, Britain, and Europe, were suggesting that drugs could be destructive unless dispensed by qualified health professionals. Doctors and psychiatrists defined an `addict type' and addiction was defined as a disease. In the United States, the Pure Food and Drug Act (1906) created the Food and Drug Administration (FDA) to regulate manufacture and sale of medicines. The Act also ended the availability of over-the-counter narcotics.
Addiction - controlling people
In Britain, the Dangerous Drugs Act (1920) was an attempt to control the supply of cocaine and opiates by making them available only through a doctor's prescription. Gradually, other drugs such as the barbiturates, developed during the early 20th century, came under the `controlled' list. Cannabis was made illegal in 1928. The Misuse of Drugs Act (1971) classified controlled drugs into 3 classes with the opioids in Class A, and benzodiazepines in Class C. Cannabis and codeine were slotted into Class B. In 1973, doctors were required to report suspected drug addicts to the Chief Medical Officer at the Home Office. Medical practitioners required a special licence issued by the Home Secretary to prescribe certain drugs to addicts. The Misuse of Drugs Regulations (1985) created 5 schedules of drugs, each of which had a set of regulations governing (amongst other things) supply, possession, and prescribing.
People using drugs listed in Schedules 2 and 3 were not allowed to travel abroad with more than 15 days supply without a licence. In the United States, the term `drug addiction' appeared in the 1934 American Psychiatric Association's diagnostic handbook, and 3 years later, the Marijuana Tax Act, illegalised cannabis. In 1971, President Richard Nixon (1913-1994) declared drug abuse to be `Public Enemy No 1'. His `war on drugs' campaign led to the arrest, during the 1980s, of 300,000 Americans a year on cannabis charges. The campaign against smoking was not so vociferous, and legislation was slow to be enacted. In 1950, epidemiologists, Richard Doll (b. 1912) and Austin Bradford Hill (1897-1991) published a report in the British Medical Journal entitled `Smoking and carcinoma of the lung'. Six years later, they showed that lung cancer deaths among doctors who smoked 25 or more cigarettes a day were 20 times higher than non-smokers.
Tragically, most modern drug disasters have been associated with therapies delivered to pregnant women. In 1938, the British scientist, Edward Dodds (1899-1973), discovered a synthetic oestrogen hormone called diethylstilboestrol (DES). It was prescribed to pregnant women believed to be at risk of miscarriages. An estimated 5-10 million women in Europe and America took the drug between 1938-1971 when it was banned for use in pregnancy because of an association with a rare cancer of the vagina and cervix in their daughters. The risks of `DES daughters' developing this cancer were estimated to be 1 in 10,000. However, both DES daughters and sons were found to have a higher than average incidence of other abnormalities of the reproductive system.
Drug disasters - thalidomide
Thalidomide was introduced as a sedative in 1956, and marketed for use in pregnancy to control sickness. It was withdrawn in 1961 by which time 12,000 severely disabled children had been born in 46 countries including Britain, Europe, Australia, Canada, and Japan (the drug was never marketed in the United States). Only 8000 survived. Mothers who took thalidomide during the first 3 months of pregnancy when the foetal limbs were forming, gave birth to babies with distinctive deformities. During the 1960s, however, thalidomide was found to be effective in treating the skin disorders of leprosy, and in 1998, the drug was approved in the United States for this purpose. Studies also revealed its potential value in treating ulcers in AIDS, inflammatory bowel disease, and some types of cancers. It is thought to prevent tumours from growing new blood vessels which allow them to increase in size.
Drug disasters - thalidomide
Thalidomide was introduced as a sedative in 1956, and marketed for use in pregnancy to control sickness. It was withdrawn in 1961 by which time 12,000 severely disabled children had been born in 46 countries including Britain, Europe, Australia, Canada, and Japan (the drug was never marketed in the United States). Only 8000 survived. Mothers who took thalidomide during the first 3 months of pregnancy when the foetal limbs were forming, gave birth to babies with distinctive deformities. During the 1960s, however, thalidomide was found to be effective in treating the skin disorders of leprosy, and in 1998, the drug was approved in the United States for this purpose. Studies also revealed its potential value in treating ulcers in AIDS, inflammatory bowel disease, and some types of cancers. It is thought to prevent tumours from growing new blood vessels which allow them to increase in size.
By 2000, thalidomide was available in Britain only on a `named patient' basis.
Thalidomide - the aftermath
The thalidomide tragedy resulted in more stringent testing of drugs, and extensive clinical trials prior to the launch of a new product. Typically, a prescribed only medication (POM) requires evaluation for toxicity and effects on fertility. If the drug is to administered to women of child-bearing age, it must also be tested for potential foetal malformation (teratogenicity). All toxicity studies are carried out in animals. Toxicity tests are followed by Phase I studies, usually on healthy human volunteers, sometimes patients. These determine common side effects. Phase II and III studies investigate efficacy on 1000-2000 patients, and also look for adverse reactions. These are early clinical trials. The time span between the beginning of Phase I and the end of Phase III may be as long as 5 years.
The Medicines Control Agency (MCA) in Britain, and the Food and Drug Administration (FDA) in the US, act both as regulatory bodies and licensing authorities. In Britain, by the 1980s, all newly licensed drugs were identified with a black triangle. In addition, the `Yellow Card' system was introduced in 1964 so that doctors could report adverse reactions to new and established drugs directly to the Committee on Safety of Medicines. By 1989, the annual number of reports was about 20,000. In the United Kingdom and Europe, only medically confirmed suspected adverse reactions were reported to regulatory authorities. In the United States, reports by patients, nurses and pharmacists were given similar consideration to those made by doctors. Pharmaceutical companies also began to establish drug surveillance units which monitored reports of adverse reactions to their products on a worldwide basis.
National Poisons Information Service
The doctors of ancient Greece believed that all substances were potentially poisonous. The only thing which distinguished a poison from a remedy was the dosage. By the 19th century, this was an accepted fact and the investigation of poisons became known as toxicology. During the 1960s, the Department of Health in Britain, established a Poisons Information Service. This gave doctors 24-hour telephone access to expert advice on the diagnosis, treatment, and management of patients who may have been poisoned. The term `poison' covered a wide range of substances including drugs, plants, household products, and snake venom. By 2000, there were 6 regional poisons centres and one national centre for complex cases. As well as answering telephone queries, these units also supported toxicology laboratories which analysed samples from cases of suspected poisoning.
This work was important not only to the medical profession but also to police, industry, and the legal profession. The American Association of Poison Control Centers offers a similar service in the United States. The European Association of Poisons Centres and Clinical Toxicologists was established in 1964 to advance knowledge and understanding of the diagnosis and treatment of all forms of poisoning.
Pharmacy comes of age
The American doctor of the late 19th century was said to get by with calomel (a mercury compound used as a purgative), opium, quinine, buchu (a diuretic), ipecac (an emetic), and Dover's powder (an opium preparation). The therapeutic range of the British general practitioner was little different. The therapeutic revolution of the second half of the 20th century changed everything. Restrictive legislation on medicines sold over the counter was first passed in Britain in 1860 when prescription-only drugs came into being. In 1948, when the National Health Service was established, a general practitioner's average prescription costs were 72 pence per patient a year. Fifty years later, this had risen to œ90 per patient a year. In 1988, there were 106 pharmaceutical companies manufacturing prescribed-only medications, and 147 supplying over-the-counter products. Gone were the days when aspirin simply meant `acetylsalicylic acid'.
A British general practitioner in 1991 could choose between 15 different brands of aspirin, 30 brands of paracetamol, 29 brands of contraceptive pill, 29 brands of insulin, and 21 brands of penicillin antibiotics. The manufacture of `me-too' drugs became a phenomenon of the late 20th century as pharmaceutical companies played around with molecules in order to come up with a variation on a theme. If the end result turned out to be a `me-too', the packaging could make or break the product. The retail pharmacist became the local drugs `expert' and acted as an important intermediary between doctor and patient. In July 2000, the British government published its NHS Plan which included new roles for community pharmacists.
Addiction - how it began
The concept of `addiction' or `substance abuse' as a social evil was largely a 20th century creation although the `medicalisation' of intoxication began in the 18th century. Throughout history, psychoactive substances have played a major role in ritual, recreation, medical treatment, and pain relief. The ancient Egyptians used opium to stop children crying and send them to sleep. The Roman emperor, *Marcus Aurelius (CE 121-180) began each day with a portion dissolved in wine, prescribed by his physician, *Galen (CE 129-c. 200/216). Both the Greeks and the Romans enjoyed wine and beer, often to excess. Hemp was used in ancient India, Mesopotamia, Egypt, western Europe, and Britain. Coca leaves were chewed by Andean Indians from the third century BCE. Its use was a court privilege as well as a religious observance.
It was also an important source of revenue during Spanish colonialism as well as sustaining the miners of Bolivia and Peru who worked in conditions of great hardship. Cacao (cocoa) was used as a stimulant by the *Aztecs of Mexico, coffee was discovered in Arabia sometime after the 10th century, and tea belonged to China. Tobacco had long been known to *American Indians when Europeans began colonisation of the New World in the 16th century. Spain and Portugal became the first countries to introduce tobacco smoking (initially, for medicinal purposes) but most other countries followed by about 1600. At first, the Spanish *Inquisition considered tobacco smoking to be a mark of possession since only Satan could confer upon humans the power to exhale smoke through the mouth.
Addiction - creating the alcoholic
Drunkenness commanded the attention of religious authorities throughout the Middle Ages but was scarcely mentioned in medical writing except to warn against the use of drink to relieve melancholia. In 1684, the English physician, Thomas Willis (1621-1675), suggested that habitual drunkenness resulted in `stupidity' but physicians frequently prescribed wine, beer, and spirits as medicines. The 18th century was particularly renowned for its excesses, and habitual drunkenness came to be seen as a disease. The American physician, Benjamin Rush (1745-1813), concocted a rum and tartar emetic which he used as aversion therapy for men who preferred the tavern to domestic society. Doctors began to associate drink with insanity. The term `delirium tremens' (DTs) was first used in 1813 by English physician, Thomas Sutton.
An episode of DTs was sufficient reason for admission to a lunatic asylum and there was a common belief that habitual drunkenness resulted in dementia. A study of 668 men admitted to a London lunatic asylum between 1880-1920 revealed that `drink' was considered a cause of insanity in 22% of cases. There were no admissions associated with opium or other drugs. Drunkenness officially achieved disease status in 1852 when Swedish physician, Magnus Huss (1807-1890) introduced the term ` chronic alcoholism'. In England, Charles Mercier and Henry Maudsley (1835-1918) classified alcoholic insanity as a distinct disease. Alcoholism was also seen as a social evil and there began a movement in Britain and America to establish `inebriate reformatories' for habitual drunkards. In England, the Reverend Harold Nelson Burden (1860-1930) and his wife, Kate (c.1856-1919) established 617 homes by 1907.
Addiction - opium
Opium was the most important and powerful drug in the doctor's bag. The English physician, Thomas Sydenham (1624-1689), formulated 'Sydenham's Laudanum' which was opium diluted in Malaga wine with saffron, cinnamon, and cloves. Both he and the Dutch physician, Hermann Boerhaave (1668-1738) maintained that opium was a gift from God to alleviate the sufferings of man. Physicians were divided on the relationship between opiates and insanity. The English physician, Thomas Willis (1621-1675) believed that opium dulled the mind although he recommended it as a remedy against insanity. Between 1814-1818, opium accounted for one third of all export trade from Bengal in British India to China and the East Indies. It was known to be habit-forming but until the 19th century, there was no culture of 'drug abuse' to heap shame or secrecy on users.
Opium was used regularly by monarchs, writers, poets, and artists, not only as a 'recreational' drug but also to ease pain or relieve the symptoms of chronic disease. Thus, the English poet, John Keats (1795-1821), used it to treat his tuberculosis, and Elizabeth Barrett Browning (1806-1861) swallowed laudanum (opium dissolved in spirits) to suppress the agony of an injured spine. In England, at mid-19th century, it could be bought from any chemist, druggist, or grocer for one penny an ounce. A palatable opium mixture, given to children, was Godfrey's cordial which contained opium, sweet treacle, water and spices. During the 1860s, a Manchester druggist was selling half a gallon a week. Other brands were called Steedman's Powder and Atkinson's Royal Infants Preservative.
Addiction - creating addicts
In 1898, the German pharmaceutical company, Bayer, launched a `safer' derivative of morphine which they named heroin because of its stimulant properties. Heroin was advertised as a `cure' for morphine and opium addiction. When Bayer introduced Aspirin in 1899, it was sold in a double package with heroin. Between 1911-1914, England exported 40 tons of morphine, and Germany 10 tons of heroin, to China and the Far East in an attempt to rehabilitate the estimated 13.5 million Chinese (27% of all adult males) who were addicted to opium, largely through British exports from India. From the mid-20th century, a synthetic drug called methadone which resembled morphine, was being used to rehabilitate heroin addicts. Cocaine, an alkaloid of coca, was isolated by Albert Niemann (1834-1861) in 1860, and recommended as a nerve tonic and an antidepressant.
In 1876, Sir Clifford Allbutt (1836-1925), later Regius Professor of Medicine at Cambridge University, took coca leaves on a walking tour of the Alps. The Austrian neurologist, Sigmund Freud (1856-1939), began a research project on cocaine which included self-experimentation. In the same year, the American surgeon, William Stewart Halsted (1852-1922), began experimenting with cocaine to determine whether it could be used for lumbar anaesthesia. He became addicted and was sent off for therapy which involved replacing cocaine with morphine, supposedly a `cure' for drug dependency. By the 1890s, there were more than 100 beverages containing coca extracts or pure cocaine. In 1885, JS Pemberton, an American druggist, registered `Coca-Cola', which contained cocaine, cola nuts (a source of caffeine), and citrus juices.
Addiction - controlling drugs
The identification, by chemical analysis, of the active principle in psychoactive substances, often heightened their appeal. Peyote, an hallucinogenic plant used for centuries in Mexico, achieved new popularity after 1888 when its active principle, mescaline, was isolated. Afficionados were Irish poet, William Butler Yeats (1865-1939), American dramatist, Eugene O'Neill (1888-1953), and English physician, Henry Havelock Ellis (1859-1939). The cause of addiction to drugs and alcohol was related to weakness of character rather than substance availability so there was little incentive to regulate supply. In any case, about 65% of morphine addicts at the end of the 19th century were health professionals and their relatives who had access to any number of psychoactive drugs.
These included chloroform and ether, first used as anaesthetics during the 1840s but soon acquiring a following amongst the poor of Europe because they were cheaper than alcohol. The French writer, Guy de Maupassant (1850-1893) was an ether addict. By the beginning of the 20th century, doctors, pharmacists, politicians, and reformers in the United States, Britain, and Europe, were suggesting that drugs could be destructive unless dispensed by qualified health professionals. Doctors and psychiatrists defined an `addict type' and addiction was defined as a disease. In the United States, the Pure Food and Drug Act (1906) created the Food and Drug Administration (FDA) to regulate manufacture and sale of medicines. The Act also ended the availability of over-the-counter narcotics.
Addiction - controlling people
In Britain, the Dangerous Drugs Act (1920) was an attempt to control the supply of cocaine and opiates by making them available only through a doctor's prescription. Gradually, other drugs such as the barbiturates, developed during the early 20th century, came under the `controlled' list. Cannabis was made illegal in 1928. The Misuse of Drugs Act (1971) classified controlled drugs into 3 classes with the opioids in Class A, and benzodiazepines in Class C. Cannabis and codeine were slotted into Class B. In 1973, doctors were required to report suspected drug addicts to the Chief Medical Officer at the Home Office. Medical practitioners required a special licence issued by the Home Secretary to prescribe certain drugs to addicts. The Misuse of Drugs Regulations (1985) created 5 schedules of drugs, each of which had a set of regulations governing (amongst other things) supply, possession, and prescribing.
People using drugs listed in Schedules 2 and 3 were not allowed to travel abroad with more than 15 days supply without a licence. In the United States, the term `drug addiction' appeared in the 1934 American Psychiatric Association's diagnostic handbook, and 3 years later, the Marijuana Tax Act, illegalised cannabis. In 1971, President Richard Nixon (1913-1994) declared drug abuse to be `Public Enemy No 1'. His `war on drugs' campaign led to the arrest, during the 1980s, of 300,000 Americans a year on cannabis charges. The campaign against smoking was not so vociferous, and legislation was slow to be enacted. In 1950, epidemiologists, Richard Doll (b. 1912) and Austin Bradford Hill (1897-1991) published a report in the British Medical Journal entitled `Smoking and carcinoma of the lung'. Six years later, they showed that lung cancer deaths among doctors who smoked 25 or more cigarettes a day were 20 times higher than non-smokers.
PHARMA HISTORY II
Physic gardens - gathering world medicines
*Aristotle (384-322 BCE), the Greek natural philosopher and tutor of *Alexander the Great (reigned 336-323 BCE), created a botanic garden which was tended by Theophrastus of Eresos (370-285 BCE). Theophrastus's botanical lectures in the Lyceum included descriptions of the plants seen by his pupil's armies as they travelled through India and the Persian Gulf. The spread of Christianity throughout Europe from the beginning of the 4th century resulted in a proliferation of monasteries, which became the centres of organised learning. Monks often tended the sick and grew medicinal plants in dedicated physic gardens. Some of these plants were imported, and Benedictine monks were largely responsible for bringing Roman horticultural techniques from Italy to the rest of Europe.
The first British and European universities grew out of the monastic schools. These initially instructed scholars for vocations in the Church, but by the 14th century they were training students for the professions of law and medicine. In the medical faculties, it was important to teach students how to distinguish the many plants used in remedies and the idea arose of growing them side by side in a systematic way. The discovery of America in the late 15th century provided a further impulse towards the creation of large, formal physic gardens whose purpose was to gather plants from all over the world.
Physic gardens - the recreation of Eden
In 1543, a physic garden was established at the University of Pisa, Italy, under the guidance of Luca Ghini (1490-1556), Professor of Botany at Bologna. He had already created his own private garden at Bologna and invented the `herbarium', portable bound volumes of dried, pressed, and labelled plant specimens which botanists carried on field trips. Two other Italian universities, Florence and Padua, founded physic gardens in 1545. Plants were labelled and arranged in formal beds. At Padua, an attempt was made to divide the garden into 4 sections representing the flora of Europe, Africa, America, and Asia. Other gardens emulated this idea. The garden at Padua also contained statues of Aesculapius, *Hippocrates, *Galen, and Mithridates. In 1587, a physic garden was established at Leiden University in the Netherlands.
This became one of the most important botanical centres in Europe, pioneering the cultivation in greenhouses of tropical and subtropical plants. This became one of the most important botanical centres in Europe, pioneering the cultivation in greenhouses of tropical and subtropical plants. By the end of the 16th century, there were physic gardens at the important medical universities of Heidelberg in Germany and Montpellier in France. Montpellier cultivated an outstanding collection of alpine plants. The first physic garden in England was established by the Earl of Danby ( 1573-1649) at Oxford in 1621. His wish was to improve the teaching of medicine at the university. Its first curator, Jacob Bobart (1600-1680), was appointed in 1642. He encouraged botanists travelling to remote parts of the world to contribute to the garden's collection.
The Chelsea Physic Garden
The Chelsea Physic Garden, a 3.5 acre site originally on the banks of the River Thames, was founded in 1673 by the Worshipful Society of Apothecaries of London for the botanical instruction of their members and apprentices. Chelsea was then a rural area so it was important for the apothecaries to select a riverside site since students could visit the garden by boat. The first exchange visits began in 1683 when Paul Hermann, Professor of Botany at Leiden University in Holland, visited Chelsea to exchange plants and seeds with John Watts, the Gardener. At that time, Chelsea had an underfloor-heated glasshouse, probably the first in the world. In 1722, the physician, Sir Hans Sloane (1660-1753), who had studied at the garden and subsequently purchased the Manor of Chelsea, leased the Physic Garden to the Society of Apothecaries for œ5 a year in perpetuity on condition that it always be maintained as a physic garden.
The terms of the lease required that 50 plant specimens a year be donated to the Royal Society (of which Sloane was president) until 2000 had been received. By 1796, the total had reached 3750. In 1736, the great Swedish botanist, Carl *Linnaeus (1707-1778) visited Chelsea during the tenure of Philip Miller, Gardener from 1722-1771. Miller was eventually persuaded to adopt Linnaeus' binomial nomenclature in the 8th edition of his Gardeners' dictionary, one of the first encyclopaedias of horticulture. During these years, Chelsea sent *cotton seeds to Georgia, the newly founded English colony in America where cotton became the staple crop. In return, Miller received seeds of new species. Sir Joseph *Banks (1743-1820, who also helped develop the Royal Botanic Gardens at Kew), donated seeds from his travels around the world with Captain James Cook (1728-1729).
The rise of chemical medicines
The 18th century was marked by the growing respectability of iatrochemistry (chemistry applied to medicine), which had gradually become popular after the death of Paracelsus (1493-1541) who had considered disease to be an imbalance in the human body of the chemical elements, mercury, sulphur, and salt. The work of British chemist, Robert *Boyle (1627-1691) in the 17th century put the preparation of chemical compounds on a more scientific basis. Research into how the body worked (physiology) helped provide a foundation for the science of drug action. Swiss physician, Albrecht von Haller (1708-1777) studied the effects of alcohol, silver nitrate, antimony chloride, and other chemicals, on animal tissues which helped formulate his theory of muscle excitability. He contributed a preface to the Pharmacopoeia Helvetica (1771).
Swedish pharmacist, Carl Wilhelm *Scheele (1742-1786), and French chemist, Antoine Laurent *Lavoisier (1743-1794), developed chemical methods of purifying the active principles of crude drugs by crystallisation. Experiments on animals by the French investigators, Xavier Bichat (1771-1802) and François Magendie (1783-1855), enabled the effects of potent drugs to be measured. Popular mineral-based drugs included mercury which was the favoured treatment for syphilis, and calomel, a mercury compound used as a purgative. Antimony was favoured as a febrifuge (for reducing fevers). Patented by Dr Robert James as `Dr James's Fever Powders', it was given unconventional publicity in the children's story, Goody Two-Shoes, published by James' agent, John Newbery (1713-1767). The heroine's father died because he was seized with a fever in a locality where `Dr James's Fever Powders' were not available.
Quackery was entrepreneurial medicine writ large and its practitioners medically unqualified. Some were itinerant traders, doing the rounds of fairs, circuses, and markets. Others, such as the Scottish empiric, James Graham (1745-1794), who had worked the American circuits, were `big names' with ostentatious premises. Graham's Temple of Health opened in Pall Mall, London, in 1780. The entrance fee was 6 guineas, a phenomenal sum. Clients were lectured on sexual rejuvenation, during which a scantily clad `Hebe Vestina, Rosy Goddess of Health and Hymen' would rise through a trap door to distribute bottles of `aethereal balm'. Hebe Vestina, was supposedly played by Emma Lyon, who became more famous as Lady *Hamilton (1761-1815), the mistress of Lord *Nelson (1758-1805).
A feature of the Temple was its blue satin `Celestial Bed' which guaranteed fruitfulness to couples who spent a night in it, the cost of which was 100 guineas including breakfast. In 1782, Graham reputedly earned œ30,000. A feature of the Temple was its blue satin `Celestial Bed' which guaranteed fruitfulness to couples who spent a night in it, the cost of which was 100 guineas including breakfast. In 1782, Graham reputedly earned œ30,000. Another wealthy empiric was Joanna Stephens (d. 1774) whose successful remedy for dissolving bladder stones (very common at the time) was purchased by Parliament for œ5000. The Reverend Stephen *Hales (1677-1761), awarded the Royal Society's *Copley Medal in 1739 for his analysis of bladder stones, investigated her secret formula. Of all the ingredients, he believed that it was the lye used in soap making, and lime from eggshells which dissolved the stones.
Quack medicines
Quack medicines were often claimed to cure conditions untreatable by doctors including cancer, the pox (syphilis), tuberculosis, ageing, or impotence. Nevertheless, some empirical nostrums were as effective as any prescribed by doctors. Husson's Eau médicinale, a widely advertised gout remedy, contained colchicum, an alkaloid of the Meadow saffron (Colchicum autumnale), particularly effective for pain and inflammation in acute gout. Quack cures generally came in fancy packaging, accompanied by flashy advertising, mail order, free gifts, special offers, endorsement by famous names, and money-back-guarantees. They were an important part of the national economy, particularly in Britain where empirics from the Continent could purchase royal privileges to practise, and all quack medicines were subject to stamp duty.
Britain's philosophy of free trade viewed quackery with lenience although it did not have the same freedom in other European countries, particularly France which attempted to limit empirical remedies and charlatan practice through the Société Royale de M‚dicine. By the end of the 18th century, however, as the medical and pharmaceutical professions became organised and regulated, quacks and other `alternative' practitioners began to be pushed out of the medical marketplace.
New drugs for old
As the range of new drugs increased, medication gradually became more central to healing, doctors claimed a superior knowledge of medicines over quacks or self-prescribers, and pharmacy became organised into guilds and companies. There arose a new professional group of manufacturing druggists like the London chemist, Thomas Corbyn (1711-1791), who traded with Europe and the Americas, and supplied wholesale medicines to hospitals and the colonies. Whilst the Leiden Pharmacopoeia Leodiensis (1741) listed oil of earthworms amongst its remedies, the fifth edition of the London Pharmacopoeia (1746) omitted spider's webs, human fat, moss from human skulls, and unicorn's horn. Wood-lice, pearls, bezoars, vipers, coral, and theriac were, nevertheless, retained.
In 1745, the English physician, William Heberden (1710-1801), censured the continuing use of theriac, and by the sixth edition in 1788, most of these had disappeared. New drugs and compounds included aconite, castor oil, magnesia, ether, tartrate of iron, oxide of zinc, sarsaparilla, paregoric (liquid opium), and various patent preparations including Dr James's Fever Powders (contained antimony), Dover's powder (an opium mixture), and Huxham's tincture. In 1763, it was discovered that the bark of the English willow tree (Salix species), reduced fevers in a similar manner to the expensive imported remedy, cinchona (Peruvian bark).
Digitalis - foxglove tea
Foxglove tea, prepared from the leaves of the foxglove (Digitalis purpurea), was an English folk remedy for treating swollen hands, legs, and feet. William Withering (1741-1799), a physician working in Birmingham, learned about it from a country woman in Shropshire and a carpenter in Oxford. Being an ardent medical botanist, he made a study of the foxglove during 1775-1785 and published his findings in 1785. He recognised that it increased the flow of urine, reduced dropsy (excess body fluid), and had a powerful action on the heart. As digitalis, the drug appeared in the London Pharmacopoeia of 1809. Nevertheless, its use in dropsy declined possibly because dropsy due to heart failure was not easy to distinguish from dropsy due to kidney disease. The circulation of the blood was known because it had been discovered by William *Harvey (1578-1657) in the 1620s, but its role in transporting water was not.
In 1835, a French physician, J-B Bouillaud, noted that digitalis slowed the heart beat. He administered it by blistering the chest over the heart (precordium) and covering the area with powdered drug. He described its effect as `an opium for the heart'. In 1873, FT Roberts found that digitalis relieved the symptoms of palpitations caused by disease of the heart's mitral valve (usually a result of rheumatic fever which was common at that time). In 1908, the English general practitioner, James Mackenzie (1853-1925), published his 10-year study of the heart's rhythm in health and disease. He showed that digitalis was valuable when heart failure was due to the excessive pumping action of the ventricles (the main pumping chambers of the heart) which exhausted the heart. It slowed the heart rate and allowed the ventricles to fill with blood before they contracted. He noted that `the effect of the drug was at times phenomenal'.
Homeopathy
In 1796, the German physician, Samuel Hahnemann (1755-1843), published his system of treating disease which he named `homeopathy' from the Greek, homoios, meaning similar. Hahnemann conceived the idea for homeopathy after translating a work on medicines by Scottish physician, William Cullen (1710-1790). He believed that Cullen's ideas on the action of drugs was vague. From his self-experimentation with cinchona, the remedy for intermittent fever, he concluded that the drug caused the same symptoms as the illness, and worked by mobilising and redirecting the body's vital forces to overpower and suppress it. Physicians, therefore, needed to use a medicine which induced artificial disease, a principle he called similia similibus curantur or `like cures like'.
Hahnemann contrasted this with the principle of opposites, contraria contrariis curantur, employed by most physicians in their aim to rid the body of so-called `morbid' substances which they associated with the cause of disease. He called this type of therapy, `allopathic', from the Greek àllos, meaning different. He believed that allopathic medicines created new, artificial diseases alongside the original illness which made the patient worse and more incurable. Physicians then piled on larger and stronger doses of medicines, often mixing a considerable number of drugs. These sometimes resulted in temporary suppression of the symptoms or illness which then had to be kept at bay with larger and more frequent doses. Hahnemann used the example of the pain-killer, morphine, to prove this point. Sometimes, it was the medicine and not the disease which eventually killed the patient.
Pharmacy, pharmacology, and toxicology
The emerging professions of pharmacy and pharmacology combined the skills of apothecaries, botanists, chemists, and physiologists. In 1806, a German apothecary's assistant, Friedrich Sertürner (1783-1841), isolated morphine from opium. This was one of the first `alkaloids', so-called because they were drugs which formed salts with acids (like inorganic salts). The French physiologist, François Magendie (1783-1855) collaborated with pharmacist, Pierre Joseph Pelletier (1788-1842) to study the effects of poisonous plants. They isolated the substance in ipecacuanha which caused vomiting, and named it emetine. From the seeds of the Indian tree, Strychnos nux-vomica, they prepared strychnine, a poison which caused convulsions, but in minute doses was a popular ingredient of `tonic' medicines.
Between 1817-1821, Pelletier and Joseph Bienaimé Caventou (1793-1877) isolated a range of alkaloids including veratrine from hellebore, caffeine from coffee beans, and quinine from cinchona. Many European medicines depended on natural products from the tropical regions of the world. Cinchona plantations were established in Dutch Java and British India during the mid-19th century. In India, there were important botanic gardens at Calcutta (1793), Saharanpur (1818), Darjeeling, and Mussoorie which grew medicinal plants such as belladonna, digitalis, senna, and valerian. The first university department of pharmacology was established at Dorpat (now Tartu, Estonia) under Rudolf Buchheim (1820-1879) who had been trained at Leipzig.
Kill or cure
The ancient Egyptians used opium to stop children crying and send them to sleep. It was still being used for the same purpose at mid-19th century and could be bought from any chemist or druggist for one penny an ounce. A more palatable version was Godfrey's cordial which contained opium, sweet treacle, water and spices. During the 1860s, a Manchester druggist was selling half a gallon a week. Other brands were called Steedman's Powder and Atkinson's Royal Infants' Preservative. Arsenic, from the Greek word `arsenikon' meaning `potent', was used by the Greeks and Romans as a treatment for cleaning wounds and ulcers. It was also used as a poison by the Roman emperor, Nero (CE 15-68), and the notorious 15th century *Borgia family of Italy. During the 18th century, arsenic was favoured as a remedy for ague, headaches, blood disorders, and rheumatism.
Patent medicines which contained arsenic, such as Thomas Wilson's `ague drops', and Fowler's Solution, remained popular through the 19th century. Nevertheless, doctors and apothecaries became increasingly concerned about the ready availability of potentially lethal substances. In the medical hierarchy, apothecaries were the forerunners of general practitioners and prescribed medicines for illnesses which they themselves had diagnosed. Chemists and druggists, on the other hand, were retail and wholesale pharmacists who often indulged in fierce undercutting of apothecaries' prices. The publicity given to `spectacular' poisonings emphasised the significant role played by chemists and druggists in the sale of poisons. Between 1839-1849, 70 people in England were convicted of murder by poisoning but others certainly got away with it.
Opium - a gift from God
Opium, extracted from the poppy (Papaver somniferum), was known to the Minoans and Egyptians in about 1300 BCE. In Egypt, one of its uses was to quieten a crying child. The Greek physician, *Galen (CE 129-c. 216), prescribed opium for the emperor, *Marcus Aurelius (CE 121-180), although he was apparently aware of its addictive properties. The Swiss physician, Paracelsus (1493-1541) invented a secret remedy which he named laudanum, which was probably opium dissolved in wine. In terms of its pain-relieving properties, opium was arguably the most important and powerful drug in the doctor's bag. In England, Thomas Sydenham (1624-1689), formulated `Sydenham's Laudanum' which was opium diluted in Malaga wine with saffron, cinnamon, and cloves. Both he and the Dutch physician, Hermann Boerhaave (1668-1738) maintained that opium was a gift from God to alleviate the sufferings of man.
Opium - the Opium Wars
The opium trade between India and China was developed by the *East India Company which, by the 1760s, not only had a statutory monopoly of trade between England and India, but had assumed powers of government. In 1772, Warren Hastings (1732-1818), was appointed Governor of Bengal, and the following year became first Governor General of India. Hastings encouraged the export of opium to China largely because of a need to increase the revenue of the Company. By the end of the 18th century, there were serious addiction problems in China, and authorities in Peking declared the trade to be illegal. The East India Company ignored these declarations, and because they monopolised opium in Bengal, they were able to sell it to the Chinese by bribing local officials. Between 1814-1818, opium accounted for one third of all export trade from Bengal to China and the East Indies.
Opium - the Opium Wars
The opium trade between India and China was developed by the *East India Company which, by the 1760s, not only had a statutory monopoly of trade between England and India, but had assumed powers of government. In 1772, Warren Hastings (1732-1818), was appointed Governor of Bengal, and the following year became first Governor General of India. Hastings encouraged the export of opium to China largely because of a need to increase the revenue of the Company. By the end of the 18th century, there were serious addiction problems in China, and authorities in Peking declared the trade to be illegal. The East India Company ignored these declarations, and because they monopolised opium in Bengal, they were able to sell it to the Chinese by bribing local officials. Between 1814-1818, opium accounted for one third of all export trade from Bengal to China and the East Indies.
In 1839, the Peking government tried to enforce the opium ban to which the British responded by defending the principle of `free trade'. In the ensuing `Opium War' (1840-1842), the port of Canton was bombarded, and China was forced to surrender. Under the treaty of Nanking, Canton, Shanghai and 3 other ports were once again opened to trade, and China ceded the island of Hong Kong to the British. The Second Opium War (1857-1860) resulted in further losses of Chinese sovereignty and the country was opened to foreign residents and Christian missionaries. By 1895, however, China was producing 85% of its internal demand for opium, and by 1906, it was estimated that 13.5 million Chinese, or 27% of the adult males, smoked opium. In that year, the Chinese Government forbad the consumption of opium and the cultivation of the opium poppy in China.
John Bell & Co, a London chemist
In 1798, John Bell opened his chemist and druggist shop at number 338 Oxford Street, in the heart of London's West End. Behind its plate glass windows were the trademark symbols of the retail chemist - glowing glass bottles filled with yellow, red, and blue liquid. Bell's was a high-class establishment with its own laboratory on the premises and a full staff of counter assistants, servants, porters, and errand boys. It sold not only to the public, but dispensed medicines from physicians' prescriptions as well as supplying drugs and chemicals to hospitals and dispensaries. Like many successful chemists and druggists of the time, the Bell family were *Quakers with a wide network of Quaker Friends and business associates. As non-conformists, Quakers were barred from holding public office or entering the established universities, so they trained and apprenticed their own.
Bell's shop became a private school of pharmacy not only for indentured apprentices but also for medical students training to be surgeon-apothecaries. The Apothecaries Act (1815) required the Society of Apothecaries to set a qualifying examination for surgeon-apothecaries who later became known as general practitioners. It was the first government attempt to establish a standard of professional medical education. Nevertheless, many people continued to seek advice from chemists, often because they could not afford to pay doctors' or apothecaries' fees, and patent medicines were generally cheaper than prescription drugs. Large establishments like Bell's would supply medicine chests, veterinary supplies, spectacles, leeches, pills, powders, liniments, lotions, bandages, drops, gargles, and plasters.
Jacob Bell and the Pharmaceutical Society
During the first half of the 19th century, the medical profession made concerted efforts to raise its professional status. At the same time, there was a growing interest in drug analysis and the effects of drugs on the body. This gave retail chemists and druggists the impetus to prove themselves as skilled practitioners rather than be labelled shop-keepers. The first journal for druggists, The Chemist, was launched in January 1840, by which time John Bell's son, Jacob (1810-1859), was a partner in John Bell & Co although he had long abandoned the Quaker speech and dress. In February 1841, government drafted a Bill which would bring chemists and druggists under the control of apothecaries and make over-the-counter prescribing illegal. Fines of œ20 were inflicted on druggists who flouted this ruling.
On 17 March, Bell met with a group of retail chemists and formed the Pharmaceutical Society which by September had 450 members. The Society was open to all bone-fide chemists and druggists but it was envisaged that, in the future, none would be admitted without a qualifying examination. By May 1842, the Society's membership was just under 2000 and in 1843, it received a Royal charter, becoming the Royal Pharmaceutical Society. The Pharmaceutical Times was launched in 1846, and Peter Squire (1798-1884), who owned a shop near the Bell's, became the first chemist and druggist to replace an apothecary in supplying medicines to the Royal Family.
Jacob Bell and the Pharmacy Act
Jacob Bell (1810-1859), of John Bell & Co, moved in high circles. A talented artist himself, he was a fervent patron of the arts, and commissioned William Powell *Frith (1819-1909) to paint Derby Day which was completed in 1858. Bell also found all the models for the painting. He was a very close friend of Sir Edwin *Landseer (1802-1873), Queen Victoria's favourite painter, and best known for his animal subjects. For Shoeing, exhibited at the Royal Academy in 1844, Jacob supplied his mare, `Old Betty', his bloodhound, `Laura', and even his farrier. The model for The Sleeping Bloodhound was an animal which had died after falling from a parapet at John Bell's house in Wandsworth. By the late 1840s, Jacob realised that the pharmaceutical industry could only be regulated through an Act of Parliament.
Unable to find a Member of Parliament willing to take up his cause, Jacob decided to enter Parliament himself, although as a non-conformist, he stood little chance of being elected. However, in 1850, the Member of Parliament for St Albans in Hertfordshire, died, and Jacob was informed that most of the electorate would be willing to sell their votes, as they regularly did. Accordingly, he spent œ2500 in securing his seat as a Liberal MP and beat his opponent by 276 votes. Jacob worked feverishly to push his private member's Pharmacy Bill through Parliament and succeeded by the skin of his teeth. On 2 February 1852, the St Albans Bribery Commission published its findings against Jacob, and on 3 May the Borough of St Albans was disenfranchised. He remained in the House of Commons until July when Parliament was dissolved after the fall of the Liberal government.
Medicines from plants and coal
By the mid-19th century, chemists had isolated the active principles from many plants used in medicine. These included codeine (1832) and papaverine (1850) from the opium poppy (Papaver somniferum); aconitine from aconite or common monkshood (Aconitum napellus); atropine from deadly nightshade (Atropa bella-donna); colchicine from the Autumn crocus or meadow saffron (Colchicum Autumnale); hyoscyamine from henbane (Hyoscyamus niger); daturine from thornapple (Datura stramonium); and cocaine from coca (Erythroxylum species). Newly discovered soporifics included ether, chloroform, and nitrous oxide.
Another important raw material was coal. In 1825, the English chemist, Michael *Faraday (1791-1867), isolated benzene from coal tar which was produced commercially as a fuel. Industrial chemists investigated coal tar for medicinal compounds and developed the analgesics, phenacetin and paracetamol. In the 1850s, another English chemist, William Henry *Perkins (1838-1907), attempted to synthesise quinine from coal tar but instead, produced the first synthetic dye, mauvein (mauve). This not only established the synthetic dyestuffs industry but was an important milestone on the road to antimicrobial medicines, antiseptics, and tissue stains for microscope specimens.
Rise of the pharmaceutical industry
In 1858, ER Squibb opened a laboratory to supply medicines to the United States army, and went on to manufacture chloroform and ether. Parke, Davis & Company was founded in 1867, and Eli Lilly in 1876. In 1880, Burroughs Wellcome brought mass-produced, machine-made tablets to England from America, and the German company, Merck, opened an American division in 1891. In 1763, it had been discovered that the bark of the English willow tree (Salix species) reduced fevers in a similar manner to cinchona. After the extraction of quinine from cinchona, chemists looked for the active principle in willow. Salicin (which is converted to salicylic acid in the body) was isolated in 1830, and salicylic acid synthesised in 1852. For many years, it was used as a treatment for rheumatic diseases until the German pharmaceutical company, Bayer, produced acetylsalicylic acid in 1899. It was given the trade name Aspirin and became the world's most popular drug.
Bayer sold Aspirin in a double package with heroin, a morphine-derived substance isolated in 1883. Heroin was so called because of its energetic properties which supposedly calmed all fears, stopped coughs (including those of tuberculosis), and cured morphine addiction. The sleeping potion, chloral hydrate, was introduced in 1869, but soon found to be addictive. It was followed in 1888 by an even more potent drug called sulfonal. In 1903, Bayer produced its first barbiturate, `Veronal', which was followed by `Luminal' in 1912. These were all habit-forming drugs. Once the structure of a drug was identified, the chemistry could be manipulated to produce compounds which had more effective or safer properties. The local anaesthetic, `Novocain' or procaine, synthesised in 1899, was modelled on cocaine but was less hazardous and had a simpler chemical structure.
Bromides
Bromide of potassium was first used during the 1850s to control `hysterical' epilepsy in young women. The English physician, Sir Charles Locock (1799-1875), conceived the idea of its use in this way from a German report which suggested that it caused temporary impotence in men. Since hysteria was believed to be related to sexual disorders (the Greek word hystera means `womb'), the remedy seemed appropriate. It was found to be successful and for some years was confined to use in women who suffered epileptic fits during menstruation. Other physicians preferred to continue with an old remedy, tincture of henbane. The popularity of bromide of potassium rose during the 1860s when physician Samuel Wilks (1824-1911) used it successfully in patients with general paralysis of the insane (syphilis affecting the brain). These patients suffered uncontrollable seizures during the late stage of their disease.
Eventually, by the mid-1870s, it came to be used in all types of epilepsy. It proved so successful that the National Hospital for Paralysis and Epilepsy in London (now the National Hospital for Neurology and Neurosurgery) used 2.5 tons of bromide a year. Unfortunately, its side effects included severe skin rashes and abscesses. Bromide of potassium remained the mainstay of treatment for epilepsy until 1912 when the barbiturate sedative, phenobarbital (Luminal), was introduced. Nevertheless, by 1915, the National Hospital was still using 1.5 tons of bromide a year.
The dried leaves of the coca (Erythroxylum species) bush were chewed by native *American Indians in the Andes from the third century BCE. When the *conquistadors discovered the *Inca Empire of Peru in the 1530s, the use of coca was a court privilege as well as a religious observance. Priests chewed coca during religious ceremonies in order to appease the gods, and the leaves were burned to produce sacred smoke at sacrifices. Coca was an important source of revenue during the period of Spanish colonialism as well as sustaining the miners of Bolivia and Peru who worked in conditions of great hardship. Cocaine, an alkaloid of coca, was isolated by Albert Niemann (1834-1861) in 1860, and recommended as a nerve tonic and an anti-depressant. In 1876, Sir Clifford Allbutt (1836-1925), later Regius Professor of Medicine at Cambridge University, took coca leaves on a walking tour of the Alps.
The Austrian neurologist, Sigmund Freud (1856-1939), began a research project on cocaine which included self-experimentation. Having experienced its numbing sensation in the mouth, he suggested to his friend, Carl Koller (1857-1944), an eye surgeon, that it might be used as a local anaesthetic in the eye. Koller tried this successfully in 1884 and it was thereafter taken up by ophthalmologists throughout the world. In the same year, the American surgeon, William Stewart Halsted (1852-1922), who had spent time in Vienna, began experimenting with cocaine to determine whether it could be used for lumbar anaesthesia. In the course of his experiments he became addicted and was sent off for therapy which involved replacing cocaine with morphine, supposedly a `cure' for drug dependency.
Germ theory and magic bullets
The relationship between basic research in the medical sciences and the development of drugs was symbiotic. The French physiologist, Claude Bernard (1813-1878), showed that drugs did not act uniformly all over the body but at specific sites. For example, the paralysis caused by curare, the arrow poison used by South American Indians, was due to its effect on specialised tissue called the neuromuscular junction. Paul Ehrlich (1854-1914) of Germany, and the British physiologist, John Newport Langley (1852-1925), took this one stage further. Ehrlich investigated the dyes used for staining microscope specimens and noted how particular dyes fixed to specific types of tissue. He proposed that drugs acted on body organs by similar fixation and believed that they would not work unless they were fixed. He called this the `side chain theory'. Langley identified specialised sites of action in organs and nervous tissue.
These concepts developed into the `receptor' theory, which was used to explain the interaction of drugs with cells in all manner of living tissues. Ehrlich conceived the idea of the `magic bullet' whereby drugs might be produced which always found their way to the target. The most important targets discovered in the late 19th century were microorganisms. In France, Louis Pasteur (1822-1895) conceived of the germ theory of disease whereby minute living organisms (microbes) invaded the body. The German bacteriologist, Robert Koch (1843-1910), was the first to implicate bacteria in a disease, anthrax (1876), and went on to discover the organisms responsible for tuberculosis (1882) and cholera (1884). Between 1879-1900, the organisms responsible for major infectious diseases were discovered at the rate of one a year.
Hormones
Drug research was influenced by the increasing understanding of the body's complex nature. In 1883, the Swiss surgeon, Theodor Kocher (1841-1917), noted that patients whose thyroid glands had been removed because of goitre usually died. In animals it was found that death could be prevented by grafting a portion of thyroid gland into the abdomen. Research showed that the thyroid and other glands secreted substances or `chemical messengers' into the bloodstream which acted on distant organs and were essential to the overall function of the body. In 1905, the English physiologists, William Bayliss (1860-1924) and Ernest Starling (1866-1927), named these secretions `hormones' from the Greek word meaning `to excite'. As hormones were synthesised, they became important replacement drugs to treat deficiency of a natural secretion.
Adrenaline, isolated from adrenal glands in 1895, was the first hormone to be chemically isolated (1901). More than 30 corticosteroids were then isolated from the adrenals by researchers such as Tadeus Reichstein (b. 1897) of Switzerland, and the Americans Edward Kendall (1886-1972), and Philip Hench (1890-1965) who pioneered anti-inflammatory treatment with the corticosteroid, cortisone. All 3 won a Nobel Prize in 1950. Kendall also isolated thyroxine from the thyroid gland (1915). Testicular and ovarian hormones, isolated during the 1920s, included testosterone, oestrin, progesterone, oestriol, oestrone, and oestradiol. By 1928, Selmar Ascheim (1878-1979) and Bernhard Zondek (1891-1967) in Berlin, had developed a reliable pregnancy test based on levels of pregnancy hormones in urine.
Neuro-transmitters
The discovery of hormones as `chemical messengers' which relayed information from one part of the body to another prompted research into other kinds of messenger systems. During the 1920s, the Austrian pharmacologist, Otto Loewi (1873-1961), showed that chemical substances were released at nerve endings (hence their alternative name of neurotransmitters) which stimulated or inhibited other nerve cells, muscles, or glands. He and the British physiologist, Sir Henry Hallett Dale (1875-1968), identified one of these chemical or neuro-transmitters as acetylcholine. They shared a Nobel Prize in 1936. Another, noradrenaline, was identified by Ulf von Euler (1905-1983) from Sweden who was awarded a Nobel Prize in 1970.
The discovery of transmitters helped explain the action of certain drugs such as atropine (from Deadly nightshade), curare (the arrow poison from Strychnos toxifera), and eserine (from dried seeds of Physostigma venenosum). These drugs either stimulated or paralysed nerves and muscles. The synthesis of drugs which imitated transmitter activity included those for the treatment of Parkinson's disease, Huntington's chorea, anxiety and depression, eye disorders, gastric disorders, nausea and vomiting. In 1942, the Americans, HR Griffith (1894-1985) and GE Johnson, were the first to use curare as a muscle relaxant during surgery which made it easier for surgeons to operate on the abdomen.
Salvarsan - a treatment for syphilis
In 1905, Fritz Schaudinn (1871-1906) and Erich Hoffmann (1868-1959) in Germany discovered the micro-organism (Treponema pallidum) which caused syphilis. Since the arrival of syphilis in Europe following Christopher *Columbus' (1451-1506) voyage to the Americas, the most important therapy for the disease had been mercury. Patients treated with large doses of mercury often developed mercury poisoning, the symptoms of which included copious salivation (believed to remove the syphilitic poison from the body), loosening of the teeth, and softening of the bones. In 1909, the German immunologist, Paul Ehrlich (1854-1915), and his Japanese colleague, Sahachiro Hata (1873-1938), synthesised a `magic bullet' to seek out and destroy the treponema.
The drug was an arsenic compound which they named `Salvarsan' (salvation through arsenic) although it was also called `606' because it was the 606th arsenical which they had synthesised. Salvarsan was marketed by the German pharmaceutical company, Hoechst, which sent 65,000 free samples to doctors all over the world. Intravenous infusions of salvarsan were used with mercury rubs, but later it was used with bismuth. The minimum duration of treatment was 18 months. In 1908, Ehrlich won a Nobel Prize for salvarsan which became the most important treatment for syphilis until the discovery of penicillin. During the First World War, it was used to treat infected soldiers. A saying amongst them was that `606' was the treatment for syphilis but a bullet from a `303' was the cure!
A red dye kills germs
In 1935, Gerhard Domagk (1895-1964), research director at the German chemical company, IG Farbenindustrie, discovered that a bright red dye called Prontosil was effective in the treatment of streptococcal infection. When Prontosil was analysed by J Tréfouël (1897-1977) at the Pasteur Institute, Paris, it was discovered that the compound split into 2 parts in the body. Only one of the parts, later called sulphanilimide, was effective against the streptococcus bacteria. In fact, sulphanilimide had been synthesised in 1908 by Paul Gelmo at IG Farbenindustrie who found that it enhanced the colour-fastness of synthetic dyes. Seven years later, it was re-discovered by Charles Heidelberger in America who established that it killed bacteria in the test tube but was too toxic to be used on humans. It, therefore, remained as a dye ingredient for the next 20 years.
When sulphanilimide was finally produced as a drug during the mid-1930s, it was used on a group of patients with puerperal fever at Queen Charlotte's Maternity Hospital, London. It reduced the mortality rate from 20% to 4.7% and was hailed as a `miracle drug'. Sulphanilimide was a bacteriostatic compound and worked by preventing bacteria from reproducing. This allowed the body's natural defences to mobilise against the invading organism. Other sulpha drugs were soon synthesised which proved effective against pneumococcal infections. In Britain, the drug company, May & Baker, produced sulphapyridine which cured Winston *Churchill's (1874-1965) pneumonia at a critical stage of the Second World War.
Penicillin - Alexander Fleming
During the First World War, the Scottish bacteriologist, Alexander *Fleming (1881-1955) and his boss, Sir Almroth Wright (1861-1947), spent time in France investigating wounds and resistance to infection. They observed that the strong antiseptics used to clean wounds, which were largely based on Joseph *Lister's (1827-1912) carbolic acid, killed the body's natural defence mechanisms (leucocytes or white blood cells) faster than they killed bacteria. However, it was August 1928 before Fleming, returning from holiday to his laboratory at St Mary's Hospital, London, discovered that a mould had appeared on a culture dish containing staphylococci bacteria, the organisms responsible for boils, abscesses, and pneumonia. The staphylococci had been destroyed by the mould which he identified as a Penicillium species (Penicillium notatum).
Fleming discovered that Penicillium killed bacteria but was non-toxic to leucocytes. Using the simple procedures available at St Mary's, he was unable to concentrate the substance which he called `penicillin' because it was very unstable and easily destroyed. Although he tried it on a few patients with some success, he did not pursue his research because he was, in fact, working in a laboratory which produced vaccines and was not specifically interested in the mode of action of penicillin.
Penicillin - Florey and Chain
In 1938, Ernst Chain (1906-1979), a biochemist who had fled to England from Hitler's purge of German Jewish scientists, began working on penicillin at Oxford University. His boss was Professor Howard Florey (1898-1968). Chain began to purify penicillin out of scientific interest and not because he thought it would have any practical application. However, by May 1940, the Oxford team found that they had isolated a very powerful drug which was effective, not only against staphylococci bacteria but also against streptococci. In order to produce enough penicillin to try it on a patient, they were forced to grow it in milk churns, lemonade bottles, bedpans and a bath tub. Their first patient was a policeman dying of septicaemia following a scratch while pruning his roses. Even his urine was collected to recycle the drug. He improved remarkably after the fourth day but then the penicillin ran out and he died.
Florey and Chain then approached British pharmaceutical companies to take over production but the Second World War had just begun and they were all too busy supplying drugs for the war effort. In July 1941, the Oxford team turned to the United States where, in Peoria, Illinois, the Northern Regional Research Laboratory of the US Department of Agriculture, added a by-product from a corn milling process to the penicillin culture medium and increased the drug yield 10 times. Meanwhile, moulds from all over the world were sent to Peoria in the hope of finding others which would increase the yield even more. A local woman, Mary Hunt, contributed a mouldy cantaloupe bought from a fruit market. This proved so successful that the yield was doubled again. By 1943, British pharmaceutical companies had joined the mass-production of penicillin, and Florey showed that its treatment of war wounds was phenomenally successful.
Penicillin - creation of a legend
In 1945, Florey, Chain and Fleming were awarded a Nobel Prize for their discovery and production of the world's first antibiotic. Florey was created a baronet and the other two received knighthoods. In the aftermath of the war, there was much resentment in Britain regarding the `theft' of penicillin by the United States. The government was accused of `handing over' the manufacture of the antibiotic instead of taking control of a British invention. Even worse was the idea that the British manufacturers of penicillin would be forced to pay royalties to American pharmaceutical companies since they held all the patents for its production. Antagonism also developed between Fleming's team at St Mary's Hospital, London, and Florey and Chain at Oxford who considered that Fleming's glorification as the discoverer of the century's miracle drug was inappropriate.
In 1945, St Mary's Hospital launched an appeal to pay for post-war modernisation. A display entitled, `The Exhibition of Penicillin and Modern Medicine' was prepared for a visit by Queen Elizabeth (b. 1900, now Elizabeth, the Queen Mother) in June 1945. Afterwards, the exhibition toured south and south west England in a train loaned by the Great Western Railway. It stopped at 20 stations and was seen by 70,000 people. In 1944, Imperial Chemical Industries (ICI), one of the manufacturers of penicillin in Britain, launched a film about its discovery which `starred' Fleming, Chain, and Florey, and was shown at a cinema in central London. The film was perceived by its promoters as `a vital piece of national prestige propaganda'. When the National Health Service was formed in 1948, its first annual expenditure for drugs was œ17.5 millions which was œ6 millions higher than expected.
More antibiotics
The development of penicillin by Alexander Fleming (1881-1955), Ernst Chain (1906-1979), and Howard Florey (1898-1968), prompted the search for other antibiotics. In 1945, after penicillin had been introduced into medicine, an Italian professor, Giuseppi Brotzu, isolated a mould of Cephalosporium from a sewage outfall in Sardinia. He sent a specimen to Florey at Oxford University where it was discovered to contain a new penicillin, penicillin N. In 1953, penicillin N was found to contain another substance called cephalosporin C which was useful against staphylococci bacteria that had become resistant to penicillin. In 1964, the pharmaceutical company, Glaxo, introduced the first cephalosporin antibiotic into Britain. Second and third generation cephalosporins followed in 1978 and 1983 respectively.
In 1944, a Russian-American microbiologist, Selman Waksman (1888-1973), discovered a soil-based fungus called Streptomyces griseus from which the antibiotic, streptomycin, was isolated. Streptomycin proved effective against the bacillus causing tuberculosis (Mycobacterium tuberculosis) although the bacillus soon became resistant. The first ever clinical controlled trial was designed to establish the effectiveness of streptomycin in tuberculosis by comparing patients who received the drug with those who did not, and so acted as a `control' group. The trial was organised in 1948 by Austin Bradford Hill (1897-1991) at the Medical Research Council in Britain. In 1950, he and Richard Doll (b.1912) published their report implicating another drug, tobacco, with lung cancer.
Antibiotics to treat cancer
An important group of antibiotics, discovered during the 1950s, were found to stop cell division in cancer cells. These cytotoxic (meaning toxic to cells) antibiotics helped initiate the chemotherapeutic revolution. Mitomycin was discovered in 1956, and others followed. By the 1980s, the most commonly used cytotoxic antibiotics in Britain were doxorubicin (used to treat acute leukaemia, lymphomas, and a variety of solid tumours), actinomycin D (principally used to treat cancers in children), bleomycin (lymphomas and solid tumours), and mitomycin (stomach and breast cancer). By the year 2000, daunorubicin was being used to treat Kaposi's sarcoma, a rare skin cancer associated with Acquired Immune Deficiency Syndrome (AIDS), and mitoxantrone had been introduced for breast cancer.
However, it was well established that prolonged use of cytotoxic antibiotics resulted in cancer cells becoming resistant in the same way that bacteria became resistant to anti-bacterial drugs.
A pill for every ill
After the Second World War, the drugs industry initiated a therapeutic revolution. Important anti-bacterial research was soon joined by research into anti-viral substances, and then a whole range of compounds that regulate or adjust the body's defences. The hunt for drugs to kill viruses was complicated by the fact that these organisms take up residence within infected cells and become encoded into their genetic material. Vaccines for viral infections were being developed during the late 1940s. Polio vaccines were available in 1955 and 1960, measles in 1963, and a triple vaccine for measles, mumps and rubella (MMR) was launched in 1988. The anti-viral drugs, acylovir (herpes virus), ganciclovir (cytomegalovirus), and zidovudine (HIV virus) were also produced during the 1980s.
In 1960, the Australian scientist, Frank Macfarlane Burnet (1899-1985), and Peter Medawar (1915-1987) in Britain, won a Nobel Prize for their work on rejection in organ transplantation. This research led to the development of important immunosuppressant drugs such as azathioprine and cyclosporin without which kidney, heart, and liver transplants would not have progressed. The concept of peptic ulcer disease which many doctors believed was related to stress, resulted in a plethora of therapeutic agents including antacids, reflux suppressants, anti-flatulents, anti-spasmodics, H2 receptor blockers, proton pump inhibitors, cytoprotectants, and prostaglandin analogues. Treatment was often maintained for years until researchers in the 1990s discovered that a bacterium, Helicobacter pylori, caused 80% of stomach ulcers and over 90% of duodenal ulcers.
Cancer treatments
Important new chemotherapeutic agents for cancer were discovered in plant material. The Madagascar periwinkle (Vinca rosea, renamed Catharanthus roseus), first grown in the Chelsea Physic Garden in the 18th century, produced the vinca alkaloids, vincristine, vinblastine, and vindesin. These were used to treat leukaemia, lymphoma, and other cancers such as breast and lung. The bark of the slow-growing Pacific yew tree, a native of the forests of the Northwest Pacific, yielded an anti-cancer drug called Taxol (paclitaxel) which was first used in 1984 to treat women with advanced ovarian cancer. It was later approved for use in breast cancer, and in 1997, for Kaposi's sarcoma, an AIDS-related skin cancer. By 2000, the search for methods of synthesising Taxol became imperative because of its low yield in nature. Treatment for one patient required 60 pounds of bark, or 3, 100-year-old trees.
Tamoxifen, a drug used to treat breast cancer, was developed in Britain during the 1960s, and the first clinical trial was carried out at the Christie Hospital, Manchester, in 1970. In 1998, tamoxifen was also approved in the United States for women at high risk of developing breast cancer although it was also found to increase the risk of these women developing cancer of the womb lining (endometrium). By 2000, scientists in Nottingham were investigating a breast cancer treatment which combined tamoxifen and the plant, borage (Borago officinalis), also called the starflower because of its star-shaped blue flowers. The concentrated amounts of gamma linolenic acid (GLA) in borage were believed to inhibit the spread of tumours by restricting growth of blood vessels.
Medicines to change the mind - lithium
The 1950s brought a range of mind-altering (psychotropic) medicines onto the market. The first was lithium carbonate, first used in 1949 by Australian psychiatrist, John Cade, to treat patients with manic-depressive illness. An alkaline metal, lithium was discovered in 1817 by a student of the Swedish chemist, Johan Jakob Berzelius (1779-1848). It is present in nearly all mineral water. Early 20th century textbooks of psychiatry suggested that the mineral springs of Cornwall, Scotland, and Wales, helped to cure mania. Lithium salts were used in the 19th century to dissolve bladder stones formed by uric acid, and also to treat gout and rheumatism. In 1927, lithium bromide began to replace potassium bromide as a treatment for epilepsy because it had a greater sedative action, but was found to cause heart and kidney damage.
In 1951, French psychiatrists reported some success with lithium in the treatment of manic-depressive (bipolar) illness. However, it was a Danish psychiatrist, Mogens Schou, who persistently used lithium carbonate throughout the 1950s although he could persuade few colleagues to do so. From 1959-1963, there were only 15 publications citing lithium in the treatment of manic-depressive illness. Pharmaceutical companies were reluctant to commit to large-scale production of lithium for clinical use because the salts were readily available (`Dr Gustin's lithium salts' was a popular fizzy drink in France) and could not be patented. Eventually, by 1970, lithium was marketed for both the prevention and treatment of mood swings in manic-depressive illness, and by 1975, there were more than 3000 reports of its efficacy in the medical literature.
Medicines to change the mind - chlorpromazine
Chlorpromazine (Largactil) was synthesised in 1950 by the chemist, Paul Charpentier, working at the French pharmaceutical company, Rhône-Poulenc. It had powerful anti-histamine properties but its potential was not immediately appreciated so it was kept on a reserve shelf. Histamine, a chemical produced naturally in the body (discovered by English physiologist, Sir Henry Dale, 185-1968), had been implicated in a number of conditions such as asthma and allergy. The Swiss physiologist, Daniel Bovet (1907-1992), experimented with anti-histamine compounds to counteract the pathological effects of histamine. Anti-histamines were also shown to have a sedative effect. It was this property which interested the French neurosurgeon, Henri Laborit, who used antihistamine drugs to calm his patients before surgery. He had experienced some success with the antihistamine, promethiazine, but decided to try a more powerful version.
Rhône-Poulenc gave him a sample of chlorpromazine. He found that it induced a sense of `detachment' in his patients, and his colleagues considered its use in psychiatry. The first clinical trials on patients with schizophrenia were performed, in 1953, at the Val-de-Grâce Hospital, Paris. Within a decade, it was claimed that patients who had been confined to mental hospitals were able to leave, the padded cells were shut, and the strait waistcoats confined to cupboards. In reality, high doses of chlorpromazine caused symptoms similar to Parkinson's disease because it blocked production of the neurotransmitter, dopamine (patients with Parkinson's disease have reduced dopamine levels). It also caused other symptoms such as weight gain, hypersensitivity to sunlight, and tardive dyskinesia (TD), characterised by facial grimaces and other head movements.
Medicines to change the mind - benzodiazepines
During the 1960s, the tranquiliser, Librium (chlordiazepoxide), was the most prescribed drug in the world until overtaken in the 1970s by the chemically related Valium (diazepam). Both were discovered in 1958 by Hungarian-born chemist, Leo Sternbach, working at the American laboratory of Swiss pharmaceutical company, Hoffman-La Roche. Librium was an accidental discovery in that Sternbach synthesised 41 compounds during 1955, 40 of which were found to have no tranquilising properties. Sternbach and his team then went on to other work and the 41st compound lay on the laboratory shelf for two years. In 1957, it was `re-discovered' and found to possess quite different molecular properties than the 40 useless compounds.
The director of biological research at Hoffman-La Roche demonstrated its extraordinary tranquilising effect by commissioning a film which showed how wild animals including tigers, panthers, and pumas, could be approached and trained on `Librium'. For humans, the benzodiazepines were an important group of medicines because they had both a tranquilising and an anxiolytic effect. They helped people overcome excessive anxiety, fear, or worry. Nevertheless, by the 1980s, there were concerns that benzodiazepines were being over-prescribed, and were causing problems of dependence in some people. A study in Oxford revealed that, in 1978, benzodiazepines were used in 41% of drug overdose cases. By 1989, this had reduced to 17.2% in line with a reduction in prescribing. The benzodiazepines were, nevertheless, extremely valuable sedatives during minor medical and surgical procedures such as endoscopy and biopsies.
Medicines to change the mind - antidepressants
The first anti-depressant, imipramine (Tofranil), was developed during the mid-1950s by Swiss pharmaceutical company, Geigy. The company was actually looking for new compounds similar to that of chlorpromazine (Largactil) which had been used in the treatment of schizophrenia since 1952. At first, imipramine was thought to be considerably less active than chlorpromazine and was almost abandoned. However, in 1957, Swiss psychiatrist, Roland Kuhn, found that it lifted the mood of patients suffering from melancholia or depression. It was marketed as the first tricyclic antidepressant (so called because of its 3-ring structure). Tricyclics worked by prolonging the effects of the chemical neurotransmitters, noradrenaline and serotonin. A deficit of these transmitters was found to be associated with low mood.
Following the launch of imipramine, other tricyclics were developed which included sedative or stimulating properties. By 1989, there were 11 groups of tricyclic antidepressants available in Britain. Another group of antidepressants, the monoamine oxidase inhibitors (MOAIs) were discovered in 1957 by an American team which included psychiatrist, Nathan Kline. The discovery arose out of the observation that patients with tuberculosis who were treated with the anti-bacterial drug, isoniazid, sometimes showed an elevation of mood mounting to euphoria. It was found that isoniazid prevented the breakdown in the brain of monoamine neurotransmitters, a deficit of which caused lethargy and depression. The Swiss pharmaceutical company, Hoffman-La Roche, developed a MOAI suitable for treating depression which was marketed as Marsilid.
Medicines to change the mind - antidepressants
The first anti-depressant, imipramine (Tofranil), was developed during the mid-1950s by Swiss pharmaceutical company, Geigy. The company was actually looking for new compounds similar to that of chlorpromazine (Largactil) which had been used in the treatment of schizophrenia since 1952. At first, imipramine was thought to be considerably less active than chlorpromazine and was almost abandoned. However, in 1957, Swiss psychiatrist, Roland Kuhn, found that it lifted the mood of patients suffering from melancholia or depression. It was marketed as the first tricyclic antidepressant (so called because of its 3-ring structure). Tricyclics worked by prolonging the effects of the chemical neurotransmitters, noradrenaline and serotonin. A deficit of these transmitters was found to be associated with low mood.
Following the launch of imipramine, other tricyclics were developed which included sedative or stimulating properties. By 1989, there were 11 groups of tricyclic antidepressants available in Britain. Another group of antidepressants, the monoamine oxidase inhibitors (MOAIs) were discovered in 1957 by an American team which included psychiatrist, Nathan Kline. The discovery arose out of the observation that patients with tuberculosis who were treated with the anti-bacterial drug, isoniazid, sometimes showed an elevation of mood mounting to euphoria. It was found that isoniazid prevented the breakdown in the brain of monoamine neurotransmitters, a deficit of which caused lethargy and depression. The Swiss pharmaceutical company, Hoffman-La Roche, developed a MOAI suitable for treating depression which was marketed as Marsilid.
*Aristotle (384-322 BCE), the Greek natural philosopher and tutor of *Alexander the Great (reigned 336-323 BCE), created a botanic garden which was tended by Theophrastus of Eresos (370-285 BCE). Theophrastus's botanical lectures in the Lyceum included descriptions of the plants seen by his pupil's armies as they travelled through India and the Persian Gulf. The spread of Christianity throughout Europe from the beginning of the 4th century resulted in a proliferation of monasteries, which became the centres of organised learning. Monks often tended the sick and grew medicinal plants in dedicated physic gardens. Some of these plants were imported, and Benedictine monks were largely responsible for bringing Roman horticultural techniques from Italy to the rest of Europe.
The first British and European universities grew out of the monastic schools. These initially instructed scholars for vocations in the Church, but by the 14th century they were training students for the professions of law and medicine. In the medical faculties, it was important to teach students how to distinguish the many plants used in remedies and the idea arose of growing them side by side in a systematic way. The discovery of America in the late 15th century provided a further impulse towards the creation of large, formal physic gardens whose purpose was to gather plants from all over the world.
Physic gardens - the recreation of Eden
In 1543, a physic garden was established at the University of Pisa, Italy, under the guidance of Luca Ghini (1490-1556), Professor of Botany at Bologna. He had already created his own private garden at Bologna and invented the `herbarium', portable bound volumes of dried, pressed, and labelled plant specimens which botanists carried on field trips. Two other Italian universities, Florence and Padua, founded physic gardens in 1545. Plants were labelled and arranged in formal beds. At Padua, an attempt was made to divide the garden into 4 sections representing the flora of Europe, Africa, America, and Asia. Other gardens emulated this idea. The garden at Padua also contained statues of Aesculapius, *Hippocrates, *Galen, and Mithridates. In 1587, a physic garden was established at Leiden University in the Netherlands.
This became one of the most important botanical centres in Europe, pioneering the cultivation in greenhouses of tropical and subtropical plants. This became one of the most important botanical centres in Europe, pioneering the cultivation in greenhouses of tropical and subtropical plants. By the end of the 16th century, there were physic gardens at the important medical universities of Heidelberg in Germany and Montpellier in France. Montpellier cultivated an outstanding collection of alpine plants. The first physic garden in England was established by the Earl of Danby ( 1573-1649) at Oxford in 1621. His wish was to improve the teaching of medicine at the university. Its first curator, Jacob Bobart (1600-1680), was appointed in 1642. He encouraged botanists travelling to remote parts of the world to contribute to the garden's collection.
The Chelsea Physic Garden
The Chelsea Physic Garden, a 3.5 acre site originally on the banks of the River Thames, was founded in 1673 by the Worshipful Society of Apothecaries of London for the botanical instruction of their members and apprentices. Chelsea was then a rural area so it was important for the apothecaries to select a riverside site since students could visit the garden by boat. The first exchange visits began in 1683 when Paul Hermann, Professor of Botany at Leiden University in Holland, visited Chelsea to exchange plants and seeds with John Watts, the Gardener. At that time, Chelsea had an underfloor-heated glasshouse, probably the first in the world. In 1722, the physician, Sir Hans Sloane (1660-1753), who had studied at the garden and subsequently purchased the Manor of Chelsea, leased the Physic Garden to the Society of Apothecaries for œ5 a year in perpetuity on condition that it always be maintained as a physic garden.
The terms of the lease required that 50 plant specimens a year be donated to the Royal Society (of which Sloane was president) until 2000 had been received. By 1796, the total had reached 3750. In 1736, the great Swedish botanist, Carl *Linnaeus (1707-1778) visited Chelsea during the tenure of Philip Miller, Gardener from 1722-1771. Miller was eventually persuaded to adopt Linnaeus' binomial nomenclature in the 8th edition of his Gardeners' dictionary, one of the first encyclopaedias of horticulture. During these years, Chelsea sent *cotton seeds to Georgia, the newly founded English colony in America where cotton became the staple crop. In return, Miller received seeds of new species. Sir Joseph *Banks (1743-1820, who also helped develop the Royal Botanic Gardens at Kew), donated seeds from his travels around the world with Captain James Cook (1728-1729).
The rise of chemical medicines
The 18th century was marked by the growing respectability of iatrochemistry (chemistry applied to medicine), which had gradually become popular after the death of Paracelsus (1493-1541) who had considered disease to be an imbalance in the human body of the chemical elements, mercury, sulphur, and salt. The work of British chemist, Robert *Boyle (1627-1691) in the 17th century put the preparation of chemical compounds on a more scientific basis. Research into how the body worked (physiology) helped provide a foundation for the science of drug action. Swiss physician, Albrecht von Haller (1708-1777) studied the effects of alcohol, silver nitrate, antimony chloride, and other chemicals, on animal tissues which helped formulate his theory of muscle excitability. He contributed a preface to the Pharmacopoeia Helvetica (1771).
Swedish pharmacist, Carl Wilhelm *Scheele (1742-1786), and French chemist, Antoine Laurent *Lavoisier (1743-1794), developed chemical methods of purifying the active principles of crude drugs by crystallisation. Experiments on animals by the French investigators, Xavier Bichat (1771-1802) and François Magendie (1783-1855), enabled the effects of potent drugs to be measured. Popular mineral-based drugs included mercury which was the favoured treatment for syphilis, and calomel, a mercury compound used as a purgative. Antimony was favoured as a febrifuge (for reducing fevers). Patented by Dr Robert James as `Dr James's Fever Powders', it was given unconventional publicity in the children's story, Goody Two-Shoes, published by James' agent, John Newbery (1713-1767). The heroine's father died because he was seized with a fever in a locality where `Dr James's Fever Powders' were not available.
Quackery was entrepreneurial medicine writ large and its practitioners medically unqualified. Some were itinerant traders, doing the rounds of fairs, circuses, and markets. Others, such as the Scottish empiric, James Graham (1745-1794), who had worked the American circuits, were `big names' with ostentatious premises. Graham's Temple of Health opened in Pall Mall, London, in 1780. The entrance fee was 6 guineas, a phenomenal sum. Clients were lectured on sexual rejuvenation, during which a scantily clad `Hebe Vestina, Rosy Goddess of Health and Hymen' would rise through a trap door to distribute bottles of `aethereal balm'. Hebe Vestina, was supposedly played by Emma Lyon, who became more famous as Lady *Hamilton (1761-1815), the mistress of Lord *Nelson (1758-1805).
A feature of the Temple was its blue satin `Celestial Bed' which guaranteed fruitfulness to couples who spent a night in it, the cost of which was 100 guineas including breakfast. In 1782, Graham reputedly earned œ30,000. A feature of the Temple was its blue satin `Celestial Bed' which guaranteed fruitfulness to couples who spent a night in it, the cost of which was 100 guineas including breakfast. In 1782, Graham reputedly earned œ30,000. Another wealthy empiric was Joanna Stephens (d. 1774) whose successful remedy for dissolving bladder stones (very common at the time) was purchased by Parliament for œ5000. The Reverend Stephen *Hales (1677-1761), awarded the Royal Society's *Copley Medal in 1739 for his analysis of bladder stones, investigated her secret formula. Of all the ingredients, he believed that it was the lye used in soap making, and lime from eggshells which dissolved the stones.
Quack medicines
Quack medicines were often claimed to cure conditions untreatable by doctors including cancer, the pox (syphilis), tuberculosis, ageing, or impotence. Nevertheless, some empirical nostrums were as effective as any prescribed by doctors. Husson's Eau médicinale, a widely advertised gout remedy, contained colchicum, an alkaloid of the Meadow saffron (Colchicum autumnale), particularly effective for pain and inflammation in acute gout. Quack cures generally came in fancy packaging, accompanied by flashy advertising, mail order, free gifts, special offers, endorsement by famous names, and money-back-guarantees. They were an important part of the national economy, particularly in Britain where empirics from the Continent could purchase royal privileges to practise, and all quack medicines were subject to stamp duty.
Britain's philosophy of free trade viewed quackery with lenience although it did not have the same freedom in other European countries, particularly France which attempted to limit empirical remedies and charlatan practice through the Société Royale de M‚dicine. By the end of the 18th century, however, as the medical and pharmaceutical professions became organised and regulated, quacks and other `alternative' practitioners began to be pushed out of the medical marketplace.
New drugs for old
As the range of new drugs increased, medication gradually became more central to healing, doctors claimed a superior knowledge of medicines over quacks or self-prescribers, and pharmacy became organised into guilds and companies. There arose a new professional group of manufacturing druggists like the London chemist, Thomas Corbyn (1711-1791), who traded with Europe and the Americas, and supplied wholesale medicines to hospitals and the colonies. Whilst the Leiden Pharmacopoeia Leodiensis (1741) listed oil of earthworms amongst its remedies, the fifth edition of the London Pharmacopoeia (1746) omitted spider's webs, human fat, moss from human skulls, and unicorn's horn. Wood-lice, pearls, bezoars, vipers, coral, and theriac were, nevertheless, retained.
In 1745, the English physician, William Heberden (1710-1801), censured the continuing use of theriac, and by the sixth edition in 1788, most of these had disappeared. New drugs and compounds included aconite, castor oil, magnesia, ether, tartrate of iron, oxide of zinc, sarsaparilla, paregoric (liquid opium), and various patent preparations including Dr James's Fever Powders (contained antimony), Dover's powder (an opium mixture), and Huxham's tincture. In 1763, it was discovered that the bark of the English willow tree (Salix species), reduced fevers in a similar manner to the expensive imported remedy, cinchona (Peruvian bark).
Digitalis - foxglove tea
Foxglove tea, prepared from the leaves of the foxglove (Digitalis purpurea), was an English folk remedy for treating swollen hands, legs, and feet. William Withering (1741-1799), a physician working in Birmingham, learned about it from a country woman in Shropshire and a carpenter in Oxford. Being an ardent medical botanist, he made a study of the foxglove during 1775-1785 and published his findings in 1785. He recognised that it increased the flow of urine, reduced dropsy (excess body fluid), and had a powerful action on the heart. As digitalis, the drug appeared in the London Pharmacopoeia of 1809. Nevertheless, its use in dropsy declined possibly because dropsy due to heart failure was not easy to distinguish from dropsy due to kidney disease. The circulation of the blood was known because it had been discovered by William *Harvey (1578-1657) in the 1620s, but its role in transporting water was not.
In 1835, a French physician, J-B Bouillaud, noted that digitalis slowed the heart beat. He administered it by blistering the chest over the heart (precordium) and covering the area with powdered drug. He described its effect as `an opium for the heart'. In 1873, FT Roberts found that digitalis relieved the symptoms of palpitations caused by disease of the heart's mitral valve (usually a result of rheumatic fever which was common at that time). In 1908, the English general practitioner, James Mackenzie (1853-1925), published his 10-year study of the heart's rhythm in health and disease. He showed that digitalis was valuable when heart failure was due to the excessive pumping action of the ventricles (the main pumping chambers of the heart) which exhausted the heart. It slowed the heart rate and allowed the ventricles to fill with blood before they contracted. He noted that `the effect of the drug was at times phenomenal'.
Homeopathy
In 1796, the German physician, Samuel Hahnemann (1755-1843), published his system of treating disease which he named `homeopathy' from the Greek, homoios, meaning similar. Hahnemann conceived the idea for homeopathy after translating a work on medicines by Scottish physician, William Cullen (1710-1790). He believed that Cullen's ideas on the action of drugs was vague. From his self-experimentation with cinchona, the remedy for intermittent fever, he concluded that the drug caused the same symptoms as the illness, and worked by mobilising and redirecting the body's vital forces to overpower and suppress it. Physicians, therefore, needed to use a medicine which induced artificial disease, a principle he called similia similibus curantur or `like cures like'.
Hahnemann contrasted this with the principle of opposites, contraria contrariis curantur, employed by most physicians in their aim to rid the body of so-called `morbid' substances which they associated with the cause of disease. He called this type of therapy, `allopathic', from the Greek àllos, meaning different. He believed that allopathic medicines created new, artificial diseases alongside the original illness which made the patient worse and more incurable. Physicians then piled on larger and stronger doses of medicines, often mixing a considerable number of drugs. These sometimes resulted in temporary suppression of the symptoms or illness which then had to be kept at bay with larger and more frequent doses. Hahnemann used the example of the pain-killer, morphine, to prove this point. Sometimes, it was the medicine and not the disease which eventually killed the patient.
Pharmacy, pharmacology, and toxicology
The emerging professions of pharmacy and pharmacology combined the skills of apothecaries, botanists, chemists, and physiologists. In 1806, a German apothecary's assistant, Friedrich Sertürner (1783-1841), isolated morphine from opium. This was one of the first `alkaloids', so-called because they were drugs which formed salts with acids (like inorganic salts). The French physiologist, François Magendie (1783-1855) collaborated with pharmacist, Pierre Joseph Pelletier (1788-1842) to study the effects of poisonous plants. They isolated the substance in ipecacuanha which caused vomiting, and named it emetine. From the seeds of the Indian tree, Strychnos nux-vomica, they prepared strychnine, a poison which caused convulsions, but in minute doses was a popular ingredient of `tonic' medicines.
Between 1817-1821, Pelletier and Joseph Bienaimé Caventou (1793-1877) isolated a range of alkaloids including veratrine from hellebore, caffeine from coffee beans, and quinine from cinchona. Many European medicines depended on natural products from the tropical regions of the world. Cinchona plantations were established in Dutch Java and British India during the mid-19th century. In India, there were important botanic gardens at Calcutta (1793), Saharanpur (1818), Darjeeling, and Mussoorie which grew medicinal plants such as belladonna, digitalis, senna, and valerian. The first university department of pharmacology was established at Dorpat (now Tartu, Estonia) under Rudolf Buchheim (1820-1879) who had been trained at Leipzig.
Kill or cure
The ancient Egyptians used opium to stop children crying and send them to sleep. It was still being used for the same purpose at mid-19th century and could be bought from any chemist or druggist for one penny an ounce. A more palatable version was Godfrey's cordial which contained opium, sweet treacle, water and spices. During the 1860s, a Manchester druggist was selling half a gallon a week. Other brands were called Steedman's Powder and Atkinson's Royal Infants' Preservative. Arsenic, from the Greek word `arsenikon' meaning `potent', was used by the Greeks and Romans as a treatment for cleaning wounds and ulcers. It was also used as a poison by the Roman emperor, Nero (CE 15-68), and the notorious 15th century *Borgia family of Italy. During the 18th century, arsenic was favoured as a remedy for ague, headaches, blood disorders, and rheumatism.
Patent medicines which contained arsenic, such as Thomas Wilson's `ague drops', and Fowler's Solution, remained popular through the 19th century. Nevertheless, doctors and apothecaries became increasingly concerned about the ready availability of potentially lethal substances. In the medical hierarchy, apothecaries were the forerunners of general practitioners and prescribed medicines for illnesses which they themselves had diagnosed. Chemists and druggists, on the other hand, were retail and wholesale pharmacists who often indulged in fierce undercutting of apothecaries' prices. The publicity given to `spectacular' poisonings emphasised the significant role played by chemists and druggists in the sale of poisons. Between 1839-1849, 70 people in England were convicted of murder by poisoning but others certainly got away with it.
Opium - a gift from God
Opium, extracted from the poppy (Papaver somniferum), was known to the Minoans and Egyptians in about 1300 BCE. In Egypt, one of its uses was to quieten a crying child. The Greek physician, *Galen (CE 129-c. 216), prescribed opium for the emperor, *Marcus Aurelius (CE 121-180), although he was apparently aware of its addictive properties. The Swiss physician, Paracelsus (1493-1541) invented a secret remedy which he named laudanum, which was probably opium dissolved in wine. In terms of its pain-relieving properties, opium was arguably the most important and powerful drug in the doctor's bag. In England, Thomas Sydenham (1624-1689), formulated `Sydenham's Laudanum' which was opium diluted in Malaga wine with saffron, cinnamon, and cloves. Both he and the Dutch physician, Hermann Boerhaave (1668-1738) maintained that opium was a gift from God to alleviate the sufferings of man.
Opium - the Opium Wars
The opium trade between India and China was developed by the *East India Company which, by the 1760s, not only had a statutory monopoly of trade between England and India, but had assumed powers of government. In 1772, Warren Hastings (1732-1818), was appointed Governor of Bengal, and the following year became first Governor General of India. Hastings encouraged the export of opium to China largely because of a need to increase the revenue of the Company. By the end of the 18th century, there were serious addiction problems in China, and authorities in Peking declared the trade to be illegal. The East India Company ignored these declarations, and because they monopolised opium in Bengal, they were able to sell it to the Chinese by bribing local officials. Between 1814-1818, opium accounted for one third of all export trade from Bengal to China and the East Indies.
Opium - the Opium Wars
The opium trade between India and China was developed by the *East India Company which, by the 1760s, not only had a statutory monopoly of trade between England and India, but had assumed powers of government. In 1772, Warren Hastings (1732-1818), was appointed Governor of Bengal, and the following year became first Governor General of India. Hastings encouraged the export of opium to China largely because of a need to increase the revenue of the Company. By the end of the 18th century, there were serious addiction problems in China, and authorities in Peking declared the trade to be illegal. The East India Company ignored these declarations, and because they monopolised opium in Bengal, they were able to sell it to the Chinese by bribing local officials. Between 1814-1818, opium accounted for one third of all export trade from Bengal to China and the East Indies.
In 1839, the Peking government tried to enforce the opium ban to which the British responded by defending the principle of `free trade'. In the ensuing `Opium War' (1840-1842), the port of Canton was bombarded, and China was forced to surrender. Under the treaty of Nanking, Canton, Shanghai and 3 other ports were once again opened to trade, and China ceded the island of Hong Kong to the British. The Second Opium War (1857-1860) resulted in further losses of Chinese sovereignty and the country was opened to foreign residents and Christian missionaries. By 1895, however, China was producing 85% of its internal demand for opium, and by 1906, it was estimated that 13.5 million Chinese, or 27% of the adult males, smoked opium. In that year, the Chinese Government forbad the consumption of opium and the cultivation of the opium poppy in China.
John Bell & Co, a London chemist
In 1798, John Bell opened his chemist and druggist shop at number 338 Oxford Street, in the heart of London's West End. Behind its plate glass windows were the trademark symbols of the retail chemist - glowing glass bottles filled with yellow, red, and blue liquid. Bell's was a high-class establishment with its own laboratory on the premises and a full staff of counter assistants, servants, porters, and errand boys. It sold not only to the public, but dispensed medicines from physicians' prescriptions as well as supplying drugs and chemicals to hospitals and dispensaries. Like many successful chemists and druggists of the time, the Bell family were *Quakers with a wide network of Quaker Friends and business associates. As non-conformists, Quakers were barred from holding public office or entering the established universities, so they trained and apprenticed their own.
Bell's shop became a private school of pharmacy not only for indentured apprentices but also for medical students training to be surgeon-apothecaries. The Apothecaries Act (1815) required the Society of Apothecaries to set a qualifying examination for surgeon-apothecaries who later became known as general practitioners. It was the first government attempt to establish a standard of professional medical education. Nevertheless, many people continued to seek advice from chemists, often because they could not afford to pay doctors' or apothecaries' fees, and patent medicines were generally cheaper than prescription drugs. Large establishments like Bell's would supply medicine chests, veterinary supplies, spectacles, leeches, pills, powders, liniments, lotions, bandages, drops, gargles, and plasters.
Jacob Bell and the Pharmaceutical Society
During the first half of the 19th century, the medical profession made concerted efforts to raise its professional status. At the same time, there was a growing interest in drug analysis and the effects of drugs on the body. This gave retail chemists and druggists the impetus to prove themselves as skilled practitioners rather than be labelled shop-keepers. The first journal for druggists, The Chemist, was launched in January 1840, by which time John Bell's son, Jacob (1810-1859), was a partner in John Bell & Co although he had long abandoned the Quaker speech and dress. In February 1841, government drafted a Bill which would bring chemists and druggists under the control of apothecaries and make over-the-counter prescribing illegal. Fines of œ20 were inflicted on druggists who flouted this ruling.
On 17 March, Bell met with a group of retail chemists and formed the Pharmaceutical Society which by September had 450 members. The Society was open to all bone-fide chemists and druggists but it was envisaged that, in the future, none would be admitted without a qualifying examination. By May 1842, the Society's membership was just under 2000 and in 1843, it received a Royal charter, becoming the Royal Pharmaceutical Society. The Pharmaceutical Times was launched in 1846, and Peter Squire (1798-1884), who owned a shop near the Bell's, became the first chemist and druggist to replace an apothecary in supplying medicines to the Royal Family.
Jacob Bell and the Pharmacy Act
Jacob Bell (1810-1859), of John Bell & Co, moved in high circles. A talented artist himself, he was a fervent patron of the arts, and commissioned William Powell *Frith (1819-1909) to paint Derby Day which was completed in 1858. Bell also found all the models for the painting. He was a very close friend of Sir Edwin *Landseer (1802-1873), Queen Victoria's favourite painter, and best known for his animal subjects. For Shoeing, exhibited at the Royal Academy in 1844, Jacob supplied his mare, `Old Betty', his bloodhound, `Laura', and even his farrier. The model for The Sleeping Bloodhound was an animal which had died after falling from a parapet at John Bell's house in Wandsworth. By the late 1840s, Jacob realised that the pharmaceutical industry could only be regulated through an Act of Parliament.
Unable to find a Member of Parliament willing to take up his cause, Jacob decided to enter Parliament himself, although as a non-conformist, he stood little chance of being elected. However, in 1850, the Member of Parliament for St Albans in Hertfordshire, died, and Jacob was informed that most of the electorate would be willing to sell their votes, as they regularly did. Accordingly, he spent œ2500 in securing his seat as a Liberal MP and beat his opponent by 276 votes. Jacob worked feverishly to push his private member's Pharmacy Bill through Parliament and succeeded by the skin of his teeth. On 2 February 1852, the St Albans Bribery Commission published its findings against Jacob, and on 3 May the Borough of St Albans was disenfranchised. He remained in the House of Commons until July when Parliament was dissolved after the fall of the Liberal government.
Medicines from plants and coal
By the mid-19th century, chemists had isolated the active principles from many plants used in medicine. These included codeine (1832) and papaverine (1850) from the opium poppy (Papaver somniferum); aconitine from aconite or common monkshood (Aconitum napellus); atropine from deadly nightshade (Atropa bella-donna); colchicine from the Autumn crocus or meadow saffron (Colchicum Autumnale); hyoscyamine from henbane (Hyoscyamus niger); daturine from thornapple (Datura stramonium); and cocaine from coca (Erythroxylum species). Newly discovered soporifics included ether, chloroform, and nitrous oxide.
Another important raw material was coal. In 1825, the English chemist, Michael *Faraday (1791-1867), isolated benzene from coal tar which was produced commercially as a fuel. Industrial chemists investigated coal tar for medicinal compounds and developed the analgesics, phenacetin and paracetamol. In the 1850s, another English chemist, William Henry *Perkins (1838-1907), attempted to synthesise quinine from coal tar but instead, produced the first synthetic dye, mauvein (mauve). This not only established the synthetic dyestuffs industry but was an important milestone on the road to antimicrobial medicines, antiseptics, and tissue stains for microscope specimens.
Rise of the pharmaceutical industry
In 1858, ER Squibb opened a laboratory to supply medicines to the United States army, and went on to manufacture chloroform and ether. Parke, Davis & Company was founded in 1867, and Eli Lilly in 1876. In 1880, Burroughs Wellcome brought mass-produced, machine-made tablets to England from America, and the German company, Merck, opened an American division in 1891. In 1763, it had been discovered that the bark of the English willow tree (Salix species) reduced fevers in a similar manner to cinchona. After the extraction of quinine from cinchona, chemists looked for the active principle in willow. Salicin (which is converted to salicylic acid in the body) was isolated in 1830, and salicylic acid synthesised in 1852. For many years, it was used as a treatment for rheumatic diseases until the German pharmaceutical company, Bayer, produced acetylsalicylic acid in 1899. It was given the trade name Aspirin and became the world's most popular drug.
Bayer sold Aspirin in a double package with heroin, a morphine-derived substance isolated in 1883. Heroin was so called because of its energetic properties which supposedly calmed all fears, stopped coughs (including those of tuberculosis), and cured morphine addiction. The sleeping potion, chloral hydrate, was introduced in 1869, but soon found to be addictive. It was followed in 1888 by an even more potent drug called sulfonal. In 1903, Bayer produced its first barbiturate, `Veronal', which was followed by `Luminal' in 1912. These were all habit-forming drugs. Once the structure of a drug was identified, the chemistry could be manipulated to produce compounds which had more effective or safer properties. The local anaesthetic, `Novocain' or procaine, synthesised in 1899, was modelled on cocaine but was less hazardous and had a simpler chemical structure.
Bromides
Bromide of potassium was first used during the 1850s to control `hysterical' epilepsy in young women. The English physician, Sir Charles Locock (1799-1875), conceived the idea of its use in this way from a German report which suggested that it caused temporary impotence in men. Since hysteria was believed to be related to sexual disorders (the Greek word hystera means `womb'), the remedy seemed appropriate. It was found to be successful and for some years was confined to use in women who suffered epileptic fits during menstruation. Other physicians preferred to continue with an old remedy, tincture of henbane. The popularity of bromide of potassium rose during the 1860s when physician Samuel Wilks (1824-1911) used it successfully in patients with general paralysis of the insane (syphilis affecting the brain). These patients suffered uncontrollable seizures during the late stage of their disease.
Eventually, by the mid-1870s, it came to be used in all types of epilepsy. It proved so successful that the National Hospital for Paralysis and Epilepsy in London (now the National Hospital for Neurology and Neurosurgery) used 2.5 tons of bromide a year. Unfortunately, its side effects included severe skin rashes and abscesses. Bromide of potassium remained the mainstay of treatment for epilepsy until 1912 when the barbiturate sedative, phenobarbital (Luminal), was introduced. Nevertheless, by 1915, the National Hospital was still using 1.5 tons of bromide a year.
The dried leaves of the coca (Erythroxylum species) bush were chewed by native *American Indians in the Andes from the third century BCE. When the *conquistadors discovered the *Inca Empire of Peru in the 1530s, the use of coca was a court privilege as well as a religious observance. Priests chewed coca during religious ceremonies in order to appease the gods, and the leaves were burned to produce sacred smoke at sacrifices. Coca was an important source of revenue during the period of Spanish colonialism as well as sustaining the miners of Bolivia and Peru who worked in conditions of great hardship. Cocaine, an alkaloid of coca, was isolated by Albert Niemann (1834-1861) in 1860, and recommended as a nerve tonic and an anti-depressant. In 1876, Sir Clifford Allbutt (1836-1925), later Regius Professor of Medicine at Cambridge University, took coca leaves on a walking tour of the Alps.
The Austrian neurologist, Sigmund Freud (1856-1939), began a research project on cocaine which included self-experimentation. Having experienced its numbing sensation in the mouth, he suggested to his friend, Carl Koller (1857-1944), an eye surgeon, that it might be used as a local anaesthetic in the eye. Koller tried this successfully in 1884 and it was thereafter taken up by ophthalmologists throughout the world. In the same year, the American surgeon, William Stewart Halsted (1852-1922), who had spent time in Vienna, began experimenting with cocaine to determine whether it could be used for lumbar anaesthesia. In the course of his experiments he became addicted and was sent off for therapy which involved replacing cocaine with morphine, supposedly a `cure' for drug dependency.
Germ theory and magic bullets
The relationship between basic research in the medical sciences and the development of drugs was symbiotic. The French physiologist, Claude Bernard (1813-1878), showed that drugs did not act uniformly all over the body but at specific sites. For example, the paralysis caused by curare, the arrow poison used by South American Indians, was due to its effect on specialised tissue called the neuromuscular junction. Paul Ehrlich (1854-1914) of Germany, and the British physiologist, John Newport Langley (1852-1925), took this one stage further. Ehrlich investigated the dyes used for staining microscope specimens and noted how particular dyes fixed to specific types of tissue. He proposed that drugs acted on body organs by similar fixation and believed that they would not work unless they were fixed. He called this the `side chain theory'. Langley identified specialised sites of action in organs and nervous tissue.
These concepts developed into the `receptor' theory, which was used to explain the interaction of drugs with cells in all manner of living tissues. Ehrlich conceived the idea of the `magic bullet' whereby drugs might be produced which always found their way to the target. The most important targets discovered in the late 19th century were microorganisms. In France, Louis Pasteur (1822-1895) conceived of the germ theory of disease whereby minute living organisms (microbes) invaded the body. The German bacteriologist, Robert Koch (1843-1910), was the first to implicate bacteria in a disease, anthrax (1876), and went on to discover the organisms responsible for tuberculosis (1882) and cholera (1884). Between 1879-1900, the organisms responsible for major infectious diseases were discovered at the rate of one a year.
Hormones
Drug research was influenced by the increasing understanding of the body's complex nature. In 1883, the Swiss surgeon, Theodor Kocher (1841-1917), noted that patients whose thyroid glands had been removed because of goitre usually died. In animals it was found that death could be prevented by grafting a portion of thyroid gland into the abdomen. Research showed that the thyroid and other glands secreted substances or `chemical messengers' into the bloodstream which acted on distant organs and were essential to the overall function of the body. In 1905, the English physiologists, William Bayliss (1860-1924) and Ernest Starling (1866-1927), named these secretions `hormones' from the Greek word meaning `to excite'. As hormones were synthesised, they became important replacement drugs to treat deficiency of a natural secretion.
Adrenaline, isolated from adrenal glands in 1895, was the first hormone to be chemically isolated (1901). More than 30 corticosteroids were then isolated from the adrenals by researchers such as Tadeus Reichstein (b. 1897) of Switzerland, and the Americans Edward Kendall (1886-1972), and Philip Hench (1890-1965) who pioneered anti-inflammatory treatment with the corticosteroid, cortisone. All 3 won a Nobel Prize in 1950. Kendall also isolated thyroxine from the thyroid gland (1915). Testicular and ovarian hormones, isolated during the 1920s, included testosterone, oestrin, progesterone, oestriol, oestrone, and oestradiol. By 1928, Selmar Ascheim (1878-1979) and Bernhard Zondek (1891-1967) in Berlin, had developed a reliable pregnancy test based on levels of pregnancy hormones in urine.
Neuro-transmitters
The discovery of hormones as `chemical messengers' which relayed information from one part of the body to another prompted research into other kinds of messenger systems. During the 1920s, the Austrian pharmacologist, Otto Loewi (1873-1961), showed that chemical substances were released at nerve endings (hence their alternative name of neurotransmitters) which stimulated or inhibited other nerve cells, muscles, or glands. He and the British physiologist, Sir Henry Hallett Dale (1875-1968), identified one of these chemical or neuro-transmitters as acetylcholine. They shared a Nobel Prize in 1936. Another, noradrenaline, was identified by Ulf von Euler (1905-1983) from Sweden who was awarded a Nobel Prize in 1970.
The discovery of transmitters helped explain the action of certain drugs such as atropine (from Deadly nightshade), curare (the arrow poison from Strychnos toxifera), and eserine (from dried seeds of Physostigma venenosum). These drugs either stimulated or paralysed nerves and muscles. The synthesis of drugs which imitated transmitter activity included those for the treatment of Parkinson's disease, Huntington's chorea, anxiety and depression, eye disorders, gastric disorders, nausea and vomiting. In 1942, the Americans, HR Griffith (1894-1985) and GE Johnson, were the first to use curare as a muscle relaxant during surgery which made it easier for surgeons to operate on the abdomen.
Salvarsan - a treatment for syphilis
In 1905, Fritz Schaudinn (1871-1906) and Erich Hoffmann (1868-1959) in Germany discovered the micro-organism (Treponema pallidum) which caused syphilis. Since the arrival of syphilis in Europe following Christopher *Columbus' (1451-1506) voyage to the Americas, the most important therapy for the disease had been mercury. Patients treated with large doses of mercury often developed mercury poisoning, the symptoms of which included copious salivation (believed to remove the syphilitic poison from the body), loosening of the teeth, and softening of the bones. In 1909, the German immunologist, Paul Ehrlich (1854-1915), and his Japanese colleague, Sahachiro Hata (1873-1938), synthesised a `magic bullet' to seek out and destroy the treponema.
The drug was an arsenic compound which they named `Salvarsan' (salvation through arsenic) although it was also called `606' because it was the 606th arsenical which they had synthesised. Salvarsan was marketed by the German pharmaceutical company, Hoechst, which sent 65,000 free samples to doctors all over the world. Intravenous infusions of salvarsan were used with mercury rubs, but later it was used with bismuth. The minimum duration of treatment was 18 months. In 1908, Ehrlich won a Nobel Prize for salvarsan which became the most important treatment for syphilis until the discovery of penicillin. During the First World War, it was used to treat infected soldiers. A saying amongst them was that `606' was the treatment for syphilis but a bullet from a `303' was the cure!
A red dye kills germs
In 1935, Gerhard Domagk (1895-1964), research director at the German chemical company, IG Farbenindustrie, discovered that a bright red dye called Prontosil was effective in the treatment of streptococcal infection. When Prontosil was analysed by J Tréfouël (1897-1977) at the Pasteur Institute, Paris, it was discovered that the compound split into 2 parts in the body. Only one of the parts, later called sulphanilimide, was effective against the streptococcus bacteria. In fact, sulphanilimide had been synthesised in 1908 by Paul Gelmo at IG Farbenindustrie who found that it enhanced the colour-fastness of synthetic dyes. Seven years later, it was re-discovered by Charles Heidelberger in America who established that it killed bacteria in the test tube but was too toxic to be used on humans. It, therefore, remained as a dye ingredient for the next 20 years.
When sulphanilimide was finally produced as a drug during the mid-1930s, it was used on a group of patients with puerperal fever at Queen Charlotte's Maternity Hospital, London. It reduced the mortality rate from 20% to 4.7% and was hailed as a `miracle drug'. Sulphanilimide was a bacteriostatic compound and worked by preventing bacteria from reproducing. This allowed the body's natural defences to mobilise against the invading organism. Other sulpha drugs were soon synthesised which proved effective against pneumococcal infections. In Britain, the drug company, May & Baker, produced sulphapyridine which cured Winston *Churchill's (1874-1965) pneumonia at a critical stage of the Second World War.
Penicillin - Alexander Fleming
During the First World War, the Scottish bacteriologist, Alexander *Fleming (1881-1955) and his boss, Sir Almroth Wright (1861-1947), spent time in France investigating wounds and resistance to infection. They observed that the strong antiseptics used to clean wounds, which were largely based on Joseph *Lister's (1827-1912) carbolic acid, killed the body's natural defence mechanisms (leucocytes or white blood cells) faster than they killed bacteria. However, it was August 1928 before Fleming, returning from holiday to his laboratory at St Mary's Hospital, London, discovered that a mould had appeared on a culture dish containing staphylococci bacteria, the organisms responsible for boils, abscesses, and pneumonia. The staphylococci had been destroyed by the mould which he identified as a Penicillium species (Penicillium notatum).
Fleming discovered that Penicillium killed bacteria but was non-toxic to leucocytes. Using the simple procedures available at St Mary's, he was unable to concentrate the substance which he called `penicillin' because it was very unstable and easily destroyed. Although he tried it on a few patients with some success, he did not pursue his research because he was, in fact, working in a laboratory which produced vaccines and was not specifically interested in the mode of action of penicillin.
Penicillin - Florey and Chain
In 1938, Ernst Chain (1906-1979), a biochemist who had fled to England from Hitler's purge of German Jewish scientists, began working on penicillin at Oxford University. His boss was Professor Howard Florey (1898-1968). Chain began to purify penicillin out of scientific interest and not because he thought it would have any practical application. However, by May 1940, the Oxford team found that they had isolated a very powerful drug which was effective, not only against staphylococci bacteria but also against streptococci. In order to produce enough penicillin to try it on a patient, they were forced to grow it in milk churns, lemonade bottles, bedpans and a bath tub. Their first patient was a policeman dying of septicaemia following a scratch while pruning his roses. Even his urine was collected to recycle the drug. He improved remarkably after the fourth day but then the penicillin ran out and he died.
Florey and Chain then approached British pharmaceutical companies to take over production but the Second World War had just begun and they were all too busy supplying drugs for the war effort. In July 1941, the Oxford team turned to the United States where, in Peoria, Illinois, the Northern Regional Research Laboratory of the US Department of Agriculture, added a by-product from a corn milling process to the penicillin culture medium and increased the drug yield 10 times. Meanwhile, moulds from all over the world were sent to Peoria in the hope of finding others which would increase the yield even more. A local woman, Mary Hunt, contributed a mouldy cantaloupe bought from a fruit market. This proved so successful that the yield was doubled again. By 1943, British pharmaceutical companies had joined the mass-production of penicillin, and Florey showed that its treatment of war wounds was phenomenally successful.
Penicillin - creation of a legend
In 1945, Florey, Chain and Fleming were awarded a Nobel Prize for their discovery and production of the world's first antibiotic. Florey was created a baronet and the other two received knighthoods. In the aftermath of the war, there was much resentment in Britain regarding the `theft' of penicillin by the United States. The government was accused of `handing over' the manufacture of the antibiotic instead of taking control of a British invention. Even worse was the idea that the British manufacturers of penicillin would be forced to pay royalties to American pharmaceutical companies since they held all the patents for its production. Antagonism also developed between Fleming's team at St Mary's Hospital, London, and Florey and Chain at Oxford who considered that Fleming's glorification as the discoverer of the century's miracle drug was inappropriate.
In 1945, St Mary's Hospital launched an appeal to pay for post-war modernisation. A display entitled, `The Exhibition of Penicillin and Modern Medicine' was prepared for a visit by Queen Elizabeth (b. 1900, now Elizabeth, the Queen Mother) in June 1945. Afterwards, the exhibition toured south and south west England in a train loaned by the Great Western Railway. It stopped at 20 stations and was seen by 70,000 people. In 1944, Imperial Chemical Industries (ICI), one of the manufacturers of penicillin in Britain, launched a film about its discovery which `starred' Fleming, Chain, and Florey, and was shown at a cinema in central London. The film was perceived by its promoters as `a vital piece of national prestige propaganda'. When the National Health Service was formed in 1948, its first annual expenditure for drugs was œ17.5 millions which was œ6 millions higher than expected.
More antibiotics
The development of penicillin by Alexander Fleming (1881-1955), Ernst Chain (1906-1979), and Howard Florey (1898-1968), prompted the search for other antibiotics. In 1945, after penicillin had been introduced into medicine, an Italian professor, Giuseppi Brotzu, isolated a mould of Cephalosporium from a sewage outfall in Sardinia. He sent a specimen to Florey at Oxford University where it was discovered to contain a new penicillin, penicillin N. In 1953, penicillin N was found to contain another substance called cephalosporin C which was useful against staphylococci bacteria that had become resistant to penicillin. In 1964, the pharmaceutical company, Glaxo, introduced the first cephalosporin antibiotic into Britain. Second and third generation cephalosporins followed in 1978 and 1983 respectively.
In 1944, a Russian-American microbiologist, Selman Waksman (1888-1973), discovered a soil-based fungus called Streptomyces griseus from which the antibiotic, streptomycin, was isolated. Streptomycin proved effective against the bacillus causing tuberculosis (Mycobacterium tuberculosis) although the bacillus soon became resistant. The first ever clinical controlled trial was designed to establish the effectiveness of streptomycin in tuberculosis by comparing patients who received the drug with those who did not, and so acted as a `control' group. The trial was organised in 1948 by Austin Bradford Hill (1897-1991) at the Medical Research Council in Britain. In 1950, he and Richard Doll (b.1912) published their report implicating another drug, tobacco, with lung cancer.
Antibiotics to treat cancer
An important group of antibiotics, discovered during the 1950s, were found to stop cell division in cancer cells. These cytotoxic (meaning toxic to cells) antibiotics helped initiate the chemotherapeutic revolution. Mitomycin was discovered in 1956, and others followed. By the 1980s, the most commonly used cytotoxic antibiotics in Britain were doxorubicin (used to treat acute leukaemia, lymphomas, and a variety of solid tumours), actinomycin D (principally used to treat cancers in children), bleomycin (lymphomas and solid tumours), and mitomycin (stomach and breast cancer). By the year 2000, daunorubicin was being used to treat Kaposi's sarcoma, a rare skin cancer associated with Acquired Immune Deficiency Syndrome (AIDS), and mitoxantrone had been introduced for breast cancer.
However, it was well established that prolonged use of cytotoxic antibiotics resulted in cancer cells becoming resistant in the same way that bacteria became resistant to anti-bacterial drugs.
A pill for every ill
After the Second World War, the drugs industry initiated a therapeutic revolution. Important anti-bacterial research was soon joined by research into anti-viral substances, and then a whole range of compounds that regulate or adjust the body's defences. The hunt for drugs to kill viruses was complicated by the fact that these organisms take up residence within infected cells and become encoded into their genetic material. Vaccines for viral infections were being developed during the late 1940s. Polio vaccines were available in 1955 and 1960, measles in 1963, and a triple vaccine for measles, mumps and rubella (MMR) was launched in 1988. The anti-viral drugs, acylovir (herpes virus), ganciclovir (cytomegalovirus), and zidovudine (HIV virus) were also produced during the 1980s.
In 1960, the Australian scientist, Frank Macfarlane Burnet (1899-1985), and Peter Medawar (1915-1987) in Britain, won a Nobel Prize for their work on rejection in organ transplantation. This research led to the development of important immunosuppressant drugs such as azathioprine and cyclosporin without which kidney, heart, and liver transplants would not have progressed. The concept of peptic ulcer disease which many doctors believed was related to stress, resulted in a plethora of therapeutic agents including antacids, reflux suppressants, anti-flatulents, anti-spasmodics, H2 receptor blockers, proton pump inhibitors, cytoprotectants, and prostaglandin analogues. Treatment was often maintained for years until researchers in the 1990s discovered that a bacterium, Helicobacter pylori, caused 80% of stomach ulcers and over 90% of duodenal ulcers.
Cancer treatments
Important new chemotherapeutic agents for cancer were discovered in plant material. The Madagascar periwinkle (Vinca rosea, renamed Catharanthus roseus), first grown in the Chelsea Physic Garden in the 18th century, produced the vinca alkaloids, vincristine, vinblastine, and vindesin. These were used to treat leukaemia, lymphoma, and other cancers such as breast and lung. The bark of the slow-growing Pacific yew tree, a native of the forests of the Northwest Pacific, yielded an anti-cancer drug called Taxol (paclitaxel) which was first used in 1984 to treat women with advanced ovarian cancer. It was later approved for use in breast cancer, and in 1997, for Kaposi's sarcoma, an AIDS-related skin cancer. By 2000, the search for methods of synthesising Taxol became imperative because of its low yield in nature. Treatment for one patient required 60 pounds of bark, or 3, 100-year-old trees.
Tamoxifen, a drug used to treat breast cancer, was developed in Britain during the 1960s, and the first clinical trial was carried out at the Christie Hospital, Manchester, in 1970. In 1998, tamoxifen was also approved in the United States for women at high risk of developing breast cancer although it was also found to increase the risk of these women developing cancer of the womb lining (endometrium). By 2000, scientists in Nottingham were investigating a breast cancer treatment which combined tamoxifen and the plant, borage (Borago officinalis), also called the starflower because of its star-shaped blue flowers. The concentrated amounts of gamma linolenic acid (GLA) in borage were believed to inhibit the spread of tumours by restricting growth of blood vessels.
Medicines to change the mind - lithium
The 1950s brought a range of mind-altering (psychotropic) medicines onto the market. The first was lithium carbonate, first used in 1949 by Australian psychiatrist, John Cade, to treat patients with manic-depressive illness. An alkaline metal, lithium was discovered in 1817 by a student of the Swedish chemist, Johan Jakob Berzelius (1779-1848). It is present in nearly all mineral water. Early 20th century textbooks of psychiatry suggested that the mineral springs of Cornwall, Scotland, and Wales, helped to cure mania. Lithium salts were used in the 19th century to dissolve bladder stones formed by uric acid, and also to treat gout and rheumatism. In 1927, lithium bromide began to replace potassium bromide as a treatment for epilepsy because it had a greater sedative action, but was found to cause heart and kidney damage.
In 1951, French psychiatrists reported some success with lithium in the treatment of manic-depressive (bipolar) illness. However, it was a Danish psychiatrist, Mogens Schou, who persistently used lithium carbonate throughout the 1950s although he could persuade few colleagues to do so. From 1959-1963, there were only 15 publications citing lithium in the treatment of manic-depressive illness. Pharmaceutical companies were reluctant to commit to large-scale production of lithium for clinical use because the salts were readily available (`Dr Gustin's lithium salts' was a popular fizzy drink in France) and could not be patented. Eventually, by 1970, lithium was marketed for both the prevention and treatment of mood swings in manic-depressive illness, and by 1975, there were more than 3000 reports of its efficacy in the medical literature.
Medicines to change the mind - chlorpromazine
Chlorpromazine (Largactil) was synthesised in 1950 by the chemist, Paul Charpentier, working at the French pharmaceutical company, Rhône-Poulenc. It had powerful anti-histamine properties but its potential was not immediately appreciated so it was kept on a reserve shelf. Histamine, a chemical produced naturally in the body (discovered by English physiologist, Sir Henry Dale, 185-1968), had been implicated in a number of conditions such as asthma and allergy. The Swiss physiologist, Daniel Bovet (1907-1992), experimented with anti-histamine compounds to counteract the pathological effects of histamine. Anti-histamines were also shown to have a sedative effect. It was this property which interested the French neurosurgeon, Henri Laborit, who used antihistamine drugs to calm his patients before surgery. He had experienced some success with the antihistamine, promethiazine, but decided to try a more powerful version.
Rhône-Poulenc gave him a sample of chlorpromazine. He found that it induced a sense of `detachment' in his patients, and his colleagues considered its use in psychiatry. The first clinical trials on patients with schizophrenia were performed, in 1953, at the Val-de-Grâce Hospital, Paris. Within a decade, it was claimed that patients who had been confined to mental hospitals were able to leave, the padded cells were shut, and the strait waistcoats confined to cupboards. In reality, high doses of chlorpromazine caused symptoms similar to Parkinson's disease because it blocked production of the neurotransmitter, dopamine (patients with Parkinson's disease have reduced dopamine levels). It also caused other symptoms such as weight gain, hypersensitivity to sunlight, and tardive dyskinesia (TD), characterised by facial grimaces and other head movements.
Medicines to change the mind - benzodiazepines
During the 1960s, the tranquiliser, Librium (chlordiazepoxide), was the most prescribed drug in the world until overtaken in the 1970s by the chemically related Valium (diazepam). Both were discovered in 1958 by Hungarian-born chemist, Leo Sternbach, working at the American laboratory of Swiss pharmaceutical company, Hoffman-La Roche. Librium was an accidental discovery in that Sternbach synthesised 41 compounds during 1955, 40 of which were found to have no tranquilising properties. Sternbach and his team then went on to other work and the 41st compound lay on the laboratory shelf for two years. In 1957, it was `re-discovered' and found to possess quite different molecular properties than the 40 useless compounds.
The director of biological research at Hoffman-La Roche demonstrated its extraordinary tranquilising effect by commissioning a film which showed how wild animals including tigers, panthers, and pumas, could be approached and trained on `Librium'. For humans, the benzodiazepines were an important group of medicines because they had both a tranquilising and an anxiolytic effect. They helped people overcome excessive anxiety, fear, or worry. Nevertheless, by the 1980s, there were concerns that benzodiazepines were being over-prescribed, and were causing problems of dependence in some people. A study in Oxford revealed that, in 1978, benzodiazepines were used in 41% of drug overdose cases. By 1989, this had reduced to 17.2% in line with a reduction in prescribing. The benzodiazepines were, nevertheless, extremely valuable sedatives during minor medical and surgical procedures such as endoscopy and biopsies.
Medicines to change the mind - antidepressants
The first anti-depressant, imipramine (Tofranil), was developed during the mid-1950s by Swiss pharmaceutical company, Geigy. The company was actually looking for new compounds similar to that of chlorpromazine (Largactil) which had been used in the treatment of schizophrenia since 1952. At first, imipramine was thought to be considerably less active than chlorpromazine and was almost abandoned. However, in 1957, Swiss psychiatrist, Roland Kuhn, found that it lifted the mood of patients suffering from melancholia or depression. It was marketed as the first tricyclic antidepressant (so called because of its 3-ring structure). Tricyclics worked by prolonging the effects of the chemical neurotransmitters, noradrenaline and serotonin. A deficit of these transmitters was found to be associated with low mood.
Following the launch of imipramine, other tricyclics were developed which included sedative or stimulating properties. By 1989, there were 11 groups of tricyclic antidepressants available in Britain. Another group of antidepressants, the monoamine oxidase inhibitors (MOAIs) were discovered in 1957 by an American team which included psychiatrist, Nathan Kline. The discovery arose out of the observation that patients with tuberculosis who were treated with the anti-bacterial drug, isoniazid, sometimes showed an elevation of mood mounting to euphoria. It was found that isoniazid prevented the breakdown in the brain of monoamine neurotransmitters, a deficit of which caused lethargy and depression. The Swiss pharmaceutical company, Hoffman-La Roche, developed a MOAI suitable for treating depression which was marketed as Marsilid.
Medicines to change the mind - antidepressants
The first anti-depressant, imipramine (Tofranil), was developed during the mid-1950s by Swiss pharmaceutical company, Geigy. The company was actually looking for new compounds similar to that of chlorpromazine (Largactil) which had been used in the treatment of schizophrenia since 1952. At first, imipramine was thought to be considerably less active than chlorpromazine and was almost abandoned. However, in 1957, Swiss psychiatrist, Roland Kuhn, found that it lifted the mood of patients suffering from melancholia or depression. It was marketed as the first tricyclic antidepressant (so called because of its 3-ring structure). Tricyclics worked by prolonging the effects of the chemical neurotransmitters, noradrenaline and serotonin. A deficit of these transmitters was found to be associated with low mood.
Following the launch of imipramine, other tricyclics were developed which included sedative or stimulating properties. By 1989, there were 11 groups of tricyclic antidepressants available in Britain. Another group of antidepressants, the monoamine oxidase inhibitors (MOAIs) were discovered in 1957 by an American team which included psychiatrist, Nathan Kline. The discovery arose out of the observation that patients with tuberculosis who were treated with the anti-bacterial drug, isoniazid, sometimes showed an elevation of mood mounting to euphoria. It was found that isoniazid prevented the breakdown in the brain of monoamine neurotransmitters, a deficit of which caused lethargy and depression. The Swiss pharmaceutical company, Hoffman-La Roche, developed a MOAI suitable for treating depression which was marketed as Marsilid.
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