Pharmaceuticals in the Environment: Volume 41 - Rilegato

Rilegato

ISBN 10: 178262189X ISBN 13: 9781782621898

Casa editrice: Royal Society of Chemistry, 2015

Riassunto

Medicines play an important role in the treatment and prevention of disease in humans and animals, but residues from these medicines can be released into the environment through a number of routes during their manufacture, use and disposal. It is only recently that the potential environmental impacts of this exposure to pharmaceuticals are being considered.

The book explores where pharmaceutical residues can be found, e.g. in surface waters, drinking water, sediments and the marine environment; the sources of these residues, from manufacture through to disposal of unused medicines; how these residues break down; and how this all impacts on wildlife and human health.

In reviewing the current position and examining further possible impacts, this book is an important reference for researchers working in the pharmaceutical industry, as well as for environmentalists, policy makers and students on pharmacy and environmental science courses wanting to better understand the impacts of pharmaceuticals on the environment.

Su questo libro

Informazioni sull'autore

The series has been edited by Professors Hester and Harrison since it began in 1994.

Roy Harrison OBE is Queen Elizabeth II Birmingham Centenary Professor of Environmental Health at the University of Birmingham. In 2004 he was appointed OBE for services to environmental science. Professor Harrison’s research interests lie in the field of environment and human health. His main specialism is in air pollution, from emissions through atmospheric chemical and physical transformations to exposure and effects on human health. Much of this work is designed to inform the development of policy.

Ron Hester is an emeritus professor of chemistry at the University of York. In addition to his research work on a wide range of applications of vibrational spectroscopy, he has been actively involved in environmental chemistry and was a founder member of the Royal Society of Chemistry’s Environment Group. His current activities are mainly as an editor and as an external examiner and assessor on courses, individual promotions, and departmental/subject area evaluations both in the UK and abroad.

Dalla quarta di copertina

Medicines play an important role in the treatment and prevention of disease in humans and animals, but residues from these medicines can be released into the environment through a number of routes during their manufacture, use and disposal. It is only recently that the potential environmental impacts of this exposure to pharmaceuticals are being considered.

The book explores where pharmaceutical residues can be found, e.g. in surface waters, drinking water, sediments and the marine environment; the sources of these residues, from manufacture through to disposal of unused medicines; how these residues break down; and how this all impacts on wildlife and human health.

In reviewing the current position and examining further possible impacts, this book is an important reference for researchers working in the pharmaceutical industry, as well as for environmentalists, policy makers and students on pharmacy and environmental science courses wanting to better understand the impacts of pharmaceuticals on the environment.

Dal risvolto di copertina interno

Medicines play an important role in the treatment and prevention of disease in humans and animals, but residues from these medicines can be released into the environment through a number of routes during their manufacture, use and disposal. It is only recently that the potential environmental impacts of this exposure to pharmaceuticals are being considered.

The book explores where pharmaceutical residues can be found, e.g. in surface waters, drinking water, sediments and the marine environment; the sources of these residues, from manufacture through to disposal of unused medicines; how these residues break down; and how this all impacts on wildlife and human health.

In reviewing the current position and examining further possible impacts, this book is an important reference for researchers working in the pharmaceutical industry, as well as for environmentalists, policy makers and students on pharmacy and environmental science courses wanting to better understand the impacts of pharmaceuticals on the environment.

Estratto. © Ristampato con autorizzazione. Tutti i diritti riservati.

Pharmaceuticals in the Environment

By The Royal Society of Chemistry, R. E. Hester, R. M. Harrison

The Royal Society of Chemistry

Copyright © 2016 The Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-78262-189-8

Contents

Editors, 
List of Contributors, 
The Pharmaceutical Industry and the Future of Drug Development David Taylor, 1, 
Distribution of Pharmaceutical Residues in the Environment Benoit Roig and Vince D'Aco, 34, 
Pharmaceuticals in the Marine Environment Sally Gaw, Kevin Thomas and Thomas H. Hutchinson, 70, 
Sources of Pharmaceutical Residues in the Environment and their Control Daniel J. Caldwell, 92, 
Pharmaceutical Residues in Sewage Treatment Works and their Fate in the Receiving Environment Nick Voulvoulis, Damia Barceló and Paola Verlicchi, 120, 
Ecotoxicology, Environmental Risk Assessment and Potential Impact on Human Health Mitchell Kostich and Reinhard Länge, 180, 
Impacts of Pharmaceuticals on Terrestrial Wildlife Mark A. Taggart, Ngaio Richards and Chad A. Kinney, 216, 
Veterinary Pharmaceuticals Boris Kolar, Caroline Moermond and Silke Hickmann, 255, 
Subject Index, 286, 

CHAPTER 1

The Pharmaceutical Industry and the Future of Drug Development

DAVID TAYLOR

ABSTRACT

The pharmaceutical industry has a number of unusual characteristics, both in its structure and in the nature of its business operations, which are little known outside the industry but which materially affect the process of bringing new pharmaceuticals to the patient. The development of a new pharmaceutical is very time consuming, extremely costly and high risk, with very little chance of a successful outcome. The process of research and development is described, together with all its challenges, including environmental ones. The commercial realities and constraints of the business, together with its current problems, are discussed, followed by an exploration of some of the likely future commercial and technical developments in the business, including the development of a greener pharmacy.

1 Introduction

The pharmaceutical industry has a number of unusual characteristics that make it very different from what people normally think of as industry. It is also an industry replete with contradictions; for example, despite the undisputed fact that for over a century the industry has made a major contribution to human wellbeing and the reduction of ill health and suffering, it is still regularly identified by the public in opinion surveys as one of the least trusted industries, often being compared unfavourably to the nuclear industry. It is undoubtedly one of the riskiest businesses in which to invest money, yet it is perceived by the general public to be excessively profitable. The major pharma companies rightly promote themselves as being research-based organisations, yet most people believe that they spend more on marketing than on research. Despite the acknowledged risks and costs associated with pharmaceutical development, many citizens still believe that pharmaceuticals should be being developed to meet all human needs and that when developed they should be given away to everyone on the basis of need.

This opening chapter aims to provide a basic understanding of how the industry works and attempts to provide an explanation for some of its contradictions. The objective is to provide a backdrop to the business so that the challenges of the issue of pharmaceuticals in the environment can be better understood.

Note that the words "medicine," "pharmaceutical" and "drug" are often used interchangeably and the word "drug" can also mean both a medicine and an illegal substance, depending on the context. In this chapter the word "pharmaceutical" is arbitrarily assigned to the end-products of the pharmaceutical industry that are used by patients. The word "drug" is mainly used for potential pharmaceuticals whilst under development by the industry.

1.1 Historical Background

Human beings have been using "drugs" to treat illness and disease for more than 3000 years. A few dozen drugs of plant and animal origin were already recorded in China around 1100 BCE and by the end of the 16th century the Chinese were using at least 1900 different remedies. Today Traditional Chinese Medicine recognises more than 13 000 drugs.

Outside China, the first known pharmacopeia, the five volumes of De Material Medica, were written in the first century CE by Dioscorides, a Greek botanist. Herbal practitioners of this early period have been identified in many indigenous populations across the globe, such as North and South America, India and Australia. In the later mediaeval period, herbalism flourished in both the Islamic and Christian parts of the world. This tradition continued up to the 17th century, encompassing the work of Paracelsus in Switzerland and Culpepper in England. Culpepper's work, The English Physician, published in 1652, was one of the first English language pharmacopeias.

Until the 18th century the use of herbal medicines had been entirely based on empiricism: practitioners knew what worked but not why or how. However, in the late 18th century the foundations of pharmacology, the study of the actions of drugs and how they exert their effects, began to emerge. William Withering in the 1780s was one of the first people to study and isolate the active ingredient in a herbal remedy. He isolated digitalis from the foxglove, describing its extraction from various parts of the plant, its subsequent effects and the optimum way of using it to treat patients. The science of pharmacology developed slowly during the next century and Oswald Schmiedeberg (1838–1921) is now generally recognised as the founder of modern pharmacology. In 1872 he became professor of pharmacology at the University of Strassburg in Austria where he studied the pharmacology of chloroform and chloral hydrate and in 1878 published the classic text, Outline of Pharmacology.

Coincidentally, modern organic chemistry also began to emerge at around the same time as pharmacology. Before the 19th century, chemists had generally believed that compounds obtained from living organisms were endowed with a "vital force" that distinguished them from inorganic compounds. However, in 1828 Friedrich Wöhler produced the organic chemical urea, a constituent of urine, from the entirely inorganic compound, ammonium cyanate. Although Wöhler was always cautious about claiming that he had disproved the theory of vital force, this event has often been thought of as the starting point of organic chemistry. These two scientific developments in pharmacology and organic chemistry led, amongst other developments, to the foundation of the pharmaceutical industry in the last decade of the 19th century.

The modern pharmaceutical industry can trace its origin to two main sources: companies such as Merck, Eli Lilly and Roche that had previously supplied natural products such as morphine, quinine and strychnine, moved into large-scale production of drugs in the middle of the 19th century, whilst newly established dyestu? and chemical companies, such as Bayer, ICI, Pfizer & Sandoz, established research labs and discovered medical applications for their products. Nevertheless, growth was relatively modest and at the start of the 1930s most medicines were still sold without a prescription. Almost half of them were compounded locally by pharmacists and in many cases physicians themselves dispensed medicines directly to their patients.

However, a number of major advances were made in the early part of the 20th century. Salicylic acid, a natural constituent of willow bark, had been recorded by Hippocrates as having analgesic properties. In 1897, scientists at Bayer demonstrated that a chemically modified version of salicylic acid had much improved efficacy and the product, aspirin, is still in widespread use today. In the 1920s and 1930s both penicillin and insulin were identified and manufactured, albeit at a modest scale. The Second World War provided a major stimulus to the developing industry, with requirements for the large-scale manufacture of analgesics and antibiotics and increasing demands from governments to undertake research to identify treatments for a wide range of conditions. After the war, the implementation of state healthcare systems in Europe, such as the UK's National Health Service (NHS), created a much more stable market, both for the prescription of drugs and, much more importantly, their reimbursement. This produced a major incentive for further commercial investment in research, development and manufacture. This greater role for the state was paralleled on both sides of the Atlantic, with increasing government regulation of medicine production.

The post-war period from the 1950s to the 1990s saw major advances in drug development with the introduction of new antibiotics, new analgesics, such as acetaminophen and ibuprofen, and complete new classes of pharmaceuticals such as oral contraceptives, β-blockers, ACE inhibitors, benzodiazepines and a wide range of novel anti-cancer medicines.

The thalidomide scandal of 1961 triggered a complete reassessment of state controls on the industry. New regulations now demanded proof of efficacy, purity and safety, with the latter leading to a massive increase in the requirements and costs of research and development, particularly in the clinical testing of new drugs. As the barriers to entry in drug production were raised, a great deal of consolidation occurred in the industry. Likewise, the processes of globalisation, which had begun before the war, increased. This resulted in new drug development being dominated by a small number of very large multi-national companies and the beginning of the era of the "blockbuster" drug.

In 1977, Tagamet, an ulcer medication, became the first ever blockbuster pharmaceutical, earning its manufacturers, GSK, more than US$ 1 billion a year and its creators the Nobel Prize. This was followed by a succession of products, each seemingly more successful than its predecessors. Prozac, the first selective serotonin re-uptake inhibitor (SSRI) was launched by Eli Lilly in 1987 and omeprazole, the first proton pump inhibitor (PPI), was introduced by Astra in 1989. Atorvastatin, marketed as Lipitor in 1996, became the world's best-selling drug of all time, with more than US$ 125 billion in sales over approximately 15 years.

This was probably the golden age for the industry, with research producing an apparently endless stream of increasingly successful and profitable products; since then, the industry has been beset by a series of major problems, many of which have yet to be solved.

1.2 What is a Pharmaceutical?

This may seem an odd question since we all surely know what a pharmaceutical is. However, there is no straightforward scientific answer to this apparently simple question. Pharmaceuticals are not a class of substances like phthalates or PCBs. They have no chemical, physical, structural or biological similarities. There is thus no scientific justification for treating pharmaceuticals collectively as a coherent set of chemical substances.

Pharmaceuticals are often thought of as being complex chemical structures but they can also be simple aromatic molecules like the anaesthetic, propofol (2,6-diisopropylphenol), simple aliphatic molecules like the vasodilator, nitroglycerine (1,2,3-trinitroxypropane), or more complex but still relatively low molecular weight molecules like the statin, atorvastatin (MW 558.6) ((3R, 5R)-7-[2-(4-fluorophenyl) -3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid). Increasingly, new pharmaceuticals are likely to be very high molecular weight biopharmaceuticals such as insulin (MW 5800 Da).

In fact, the only common factor which unites pharmaceuticals is their use; substances that we identify as pharmaceuticals are simply those substances that we use as human (or animal) medicines. This means that, in principle, any substance might be identified, at some point, as a pharmaceutical.

Not surprisingly therefore, many pharmaceuticals are also used for non-pharmaceutical purposes. For example, the vasodilation properties of nitroglycerine were only discovered by William Murrell after its invention by Alfred Nobel as the active constituent of dynamite. Similarly, the discoverers of warfarin ((R,S)-4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one) at the University of Wisconsin in 1948 would be amazed that at the beginning of the 21st century this rat poison is still the most frequently prescribed anticoagulant in the world. This is not just a historical oddity. The most recent example is dimethylfumarate, which has widely been used as a mould inhibitor. It is interesting to note that a year after the European Union applied the new REACH regulation to impose severe restrictions on its use as a mould inhibitor, dimethylfumarate under its trade name, Tecfidera, was granted a pharmaceutical marketing authorisation in 2013 for use against multiple sclerosis. In other words, the global inventory of chemical substances can be divided into two groups: pharmaceuticals and those substances for which no pharmaceutical use has yet been identified, e.g. before 2013 dimethylfumarate was not a pharmaceutical, however, after 2013 it was.

Many commentators seem to believe that pharmaceuticals should be subjected to different regulatory treatment because they are "designed to be biologically active", with the implication that this criterion is sufficient to differentiate pharmaceuticals from other substances. However, this is incorrect, being derived from a misunderstanding about pharmaceutical development and it wrongly implies that pharmaceuticals are uniquely biologically active by design. It would be more appropriate to say that pharmaceuticals are selected from the many substances that produce a specific effect in animals, including humans, based on their overall safety.

The majority of pharmaceuticals are initially discovered using high-throughput screening techniques capable of screening >100 000 compounds day-1, applied to chemical "libraries" containing several million compounds. The vast majority of chemicals are known to exhibit some biological activity, so the screening assay is designed to identify only those substances that exhibit the specific biological activity of interest. It is not unusual for this initial screening step to generate several hundred potential leads which then need to be refined down to 1 or 2 candidates for further investigation. All these initial potential leads exhibit the relevant biological activity but this may be accompanied by other less-welcome toxicological properties which must be ruthlessly screened out of the selected set during the refining period. Thus the final candidate(s) will have the desired biological activity, but few or no undesirable properties; the purpose of the refining process is to eliminate those compounds with worse toxicological profiles, many of which may already exist in the environment.

Thus, from an environmental risk assessment perspective, pharmaceuticals are indistinguishable from any other chemical. They are but one class of the myriad numbers of micro contaminants that emerged at the end of the 20th century due to major improvements in analytical science. However, from a risk-management point of view, pharmaceuticals as a group do need to be treated differently due to their major direct impact on human health and wellbeing. Pharmaceuticals do not pose any more risks to man and the environment than other chemicals, but the risk/benefit calculations may be very different.

Finally, it is worth mentioning the way in which pharmaceuticals are named, as this can be a source of confusion. Pharmaceuticals, as chemical substances, all have systematic IUPAC chemical names to describe their molecular structure. However, although useful to the synthetic chemist, these long and cumbersome names are poorly suited to either the description of experimental work or for use in a marketing context. For example, it is clearly much simpler to describe something as warfarin rather than use its systematic name (R,S)-4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-chromen-2-one. Consequently, during its life cycle the same drug will be described in several different ways. Initially, as it makes its way down the development pathway, the substance will be given a unique reference code, e.g. Sanofi has a series of codes such as SAR391786 and SAR438037 to identify substances in their R&D pipeline. This convention is primarily for simplicity, but it also has the advantage of hiding any structural information about the compound from competitors.

As the drug progresses through clinical trials it will acquire a generic name, which describes the active ingredient. Initially such names were often simple contractions of the systematic name, but in 1953 the World Health Organisation (WHO) created the international non-proprietary name (INN) system to bring some order into the nomenclature. Although there has been a major improvement in generic naming, there are, however, still instances where an active ingredient has acquired more than one generic name from different parts of the world. For example, N-(4-hydroxyphenyl)-ethanamide is known as acetaminophen in the USA and Japan but as paracetamol in the rest of the world. Today, the generic name of a drug will be created from descriptors that classify the drugs into different categories and also separate drugs within categories. The generic name is widely used in the scientific literature and the medical profession since it represents the specific active ingredient whereas the "common" name, by which the drug will usually be known to the public, is the company trade name.

A drug is usually given a trade name during the later stages of its clinical trials as the marketing strategy for the product begins to be developed. The trade name will be protected as a trademark, it relates only to the specific company product and will have been designed with marketing of the drug in mind. For example, Novartis market the β-blocker, metoprolol, as Lopressor since it is effective at lowering blood pressure. Once a drug is out of patent the same active ingredient may acquire a large number of different trade names, which can cause additional confusion, e.g. acetaminophen (paracetamol) is marketed as both panadol and tylenol (and has 4100 other trade names in different parts of the world).

1.33 Environmental Impact

Until the late 1990s the environmental impact of the pharmaceutical industry was universally considered to be insignificant. Any environmental impact was considered to arise solely from manufacturing facilities and, since these were relatively small in size with well-controlled emissions, environmental impacts were not considered to be a problem. It was appreciated that the pharmaceutical products themselves were biologically active, but in view of the small quantities being manufactured and the high cost of production, releases of the active product to the environment from manufacturing were expected to be very small.

(Continues...)

Excerpted from Pharmaceuticals in the Environment by The Royal Society of Chemistry, R. E. Hester, R. M. Harrison. Copyright © 2016 The Royal Society of Chemistry. Excerpted by permission of The Royal Society of Chemistry.
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Dettagli dell'edizione

• Editore: Royal Society of Chemistry
• Data di pubblicazione: 2015
• Lingua: Inglese
• ISBN 10: 178262189X
• ISBN 13: 9781782621898
• Rilegatura: Copertina rigida
• Numero di pagine: 294
• Redattore: Hester R. E., Harrison R. M.
• Contatto del produttore: non disponibile
• Persona responsabile: gpsr@libri.de; gpsr@libri.de; ; Friedensallee 273; Hamburg; 22763; Germania