Key points • Genetic differences contribute substantially to individual (pharmacokinetic and pharmacodynamic) variability (20–50%) in drug response. • Mendelian traits that influence drug metabolism include: (a) deficient thiopurine methyltransferase (TPMT) which inactivates 6-MP (excess haematopoietic suppression); (b) deficient CYP2D6 activity which hydroxylates several drug classes, including opioids, β-blockers, tricyclic antidepressants and SSRIs; (c) deficient CYP2C9 activity which hydroxylates several drugs including sulphonylureas, S-warfarin, losartan; (d) acetylator status (NAT-2), a polymorphism that affects acetylation of drugs, including isoniazid, hydralazine and dapsone; (e) pseudocholinesterase deficiency; this leads to prolonged apnoea after suxamethonium, which is normally inactivated by this enzyme. • Several inherited diseases predispose to drug toxicity: (a) glucose-6-phosphate dehydrogenase deficiency predisposes to haemolysis following many drugs, including primaquine; (b) malignant hyperthermia is a Mendelian dominant affecting the ryanodine receptor in striated muscle, leading to potentially fatal attacks of hyperthermia and muscle spasm after treatment with suxamethonium and/or inhalational anaesthetics; (c) acute porphyrias, attacks of which are particularly triggered by enzyme-inducing agents, as well as drugs, e.g. sulphonamides, rifampicin and antiseizure medications. INHERITED DISEASES THAT PREDISPOSE TO DRUG TOXICITY 85 FURTHER READING Evans DA, McLeod HL, Pritchard S, Tariq M, Mobarek A. Inter-ethnic variability in human drug responses. Drug Metabolism and Disposition 2001; 29: 606–10. Evans WE, McLeod HL. Drug therapy: pharmacogenomics – drug disposition, drug targets, and side effects. New England Journal of Medicine 2003; 348: 538–49. Wang L, Weinshilboum R. Thiopurine S-methyltransferase pharmacogenetics: insights, challenges and future directions. Oncogene 2006; 25: 1629–38. Weinshilboum R. Inheritance and drug response. New England Journal of Medicine 2003; 348: 529–37. Weinshilboum R, Wang L. Pharmacogenomics: bench to bedside. Nature Reviews. Drug Discovery 2004; 3: 739–48. Wilkinson GR. Drug therapy: drug metabolism and variability among patients in drug response. New England Journal of Medicine 2005; 352: 2211–21.
● History 86 ● UK regulatory system 86 ● The process of drug development 86 ● Preclinical studies 87 ● Clinical trials 87 HISTORY Many years before Christ, humans discovered that certain plants influence the course of disease. Primitive tribes used extracts containing active drugs such as opium, ephedrine, cascara, cocaine, ipecacuanha and digitalis. These were probably often combined with strong psychosomatic therapies and the fact that potentially beneficial agents survived the era of magic and superstition says a great deal about the powers of observation of those early ‘researchers’. Many useless and sometimes deleterious treatments also persisted through the centuries, but the desperate situation of the sick and their faith in medicine delayed recognition of the harmful effects of drugs. Any deterioration following drug administration was usually attributed to disease progression, rather than to adverse drug effects. There were notable exceptions to this faith in medicine and some physicians had a short life expectancy as a consequence! Over the last 100 years, there has been an almost exponential growth in the number of drugs introduced into medicine. Properly controlled clinical trials, which are the cornerstone of new drug development and for which the well-organized vaccine trials of the Medical Research Council (MRC) must take much credit, only became widespread after the Second World War. Some conditions did not require clinical trials (e.g. the early use of penicillin in conditions with a predictable natural history and high fatality rate). (Florey is credited with the remark that ‘if you make a real discovery, you don’t need to call in the statisticians’.) Ethical considerations relating to the use of a ‘nontreatment’ group in early trials were sometimes rendered irrelevant by logistic factors such as the lack of availability of drugs. It was not until the 1960s that the appalling potential of drug-induced disease was realized world-wide. Thalidomide was first marketed in West Germany in 1956 as a sedative/ hypnotic, as well as a treatment for morning sickness. The drug was successfully launched in various countries, including the UK in 1958, and was generally accepted as a safe and effective compound, and indeed its advertising slogan was CHAPTER 15 INTRODUCTION OF NEW DRUGS AND CLINICAL TRIALS ● Clinical drug development 89 ● Generic drugs 90 ● Ethics committees 91 ● Globalization 91 ‘the safe hypnotic’. However, in 1961, it became clear that its use in early pregnancy was causally related to rare congenital abnormality, phocomelia, in which the long bones fail to develop. At least 600 such babies were born in Englandand more than 10 000 afflicted babies were born world-wide. The thalidomide tragedy stunned the medical profession, the pharmaceutical industry and the general public. In 1963, the Minister of Health of the UK established a Committee on the Safety of Drugs, since it was clear that some control over the introduction and marketing of drugs was necessary. These attempts at regulation culminated in the Medicines Act (1968). UK REGULATORY SYSTEM The UK comes under European Community (EC) legislation regarding the control of human medicines, which is based upon safety, quality and efficacy. The UK Medicines and Healthcare products Regulation Agency (MHRA) or the European Agency for the Evaluation of Medicinal Products (EMEA) must approve any new medicine before it can be marketed in the UK. All UK clinical trials involving a medicinal product must be approved by the MHRA. The MHRA is assisted by expert advisory groups through the Commission on Human Medicines (CHM) to assess new medicines during their development and licensing. The MHRA is also responsible for the quality and safety monitoring of medicines after licensing. Product labels, patient leaflets, prescribing information and advertising are subject to review by the MHRA. In the UK, there is also extensive ‘self-regulation’ of the pharmaceutical industry through the Association of the British Pharmaceutical Industry (ABPI). The National Institute for Health andClinical Excellence (NICE) is independent of the MHRA. THE PROCESS OF DRUG DEVELOPMENT Drug development is a highly regulated process which should be performed under internationally recognized codes
Soliman s Auricular Therapy Textbook: New Localizations and Evidence Based Therapeutic Approaches was created ( M.D. Nader Soliman )
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Soliman s Auricular Therapy Textbook This textbook is considered the finest ever written in the field of auricular therapy. The auricular acupuncture microsystem is one of the most widely used special acupuncture techniques. This textbook is dedicated to teaching the sound foundations of this unique approach as introduced by its founder Dr. Paul Nogier of France. The scientific bases of the acupuncture microsystem with its three dime... Full description
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