CASE STUDY 1,2

The Global Pharmaceutical Industry: Swallowing a Bitter Pill The case describes the evolution of the pharmaceutical industry and its strategic environment. Attention is drawn to environmental pressures from regulators and payers. Key forces driving the industry are discussed, including addressing unmet medical needs, the importance of innovation and time to market, and globalisation. The case illustrates how an increasingly hostile environment, combined with a decline in R&D productivity, led to waves of job losses, and sparked a fresh round of consolidation. On the global level, the historical supremacy of the US was challenged with the highest market growth rates recorded in the emerging markets. Q1. Identify the main environmental forces currently affecting the global pharmaceutical industry. It is expected that all aspects of the PESTEL analysis will be addressed. Illustrative points are given here, but this is by no means exhaustive. Political Governments focus on the industry as an easy target in the drive to reduce healthcare expenditure; public outcry over safely alerts and international price comparisons; and public pressure to fund cancer medicines. Economic Pharmaceutical sales correlate closely with GDP flattening in established markets and growth in emerging markets; the rise in the power of payers as decisionmakers; in some countries patients are paying a greater proportion of drug costs themselves leading to increased linkage of sales and income levels; availability of venture and depth finance to support biotech innovation. Social Aging population drive not only increases in healthcare costs but also increases in demand for medicines; pressure to act ethically rather than purely following profit; the number of better-informed patients with rising expectations; continued global convergence in medical practice and public acceptance of new technologies such as stem cells and genetic testing

The Global Pharmaceutical Industry In the pharmaceutical industry market segments can be found depending on the criteria used. For example, geographically there are three main market segments (the Triad accounting for 80% and with the strongest growth): The United States of America, Europe and Japan with the main future segment being the least developed countries. Another way of classifying the market segments that the pharmaceutical industries face is by those products directed to primary care (those used by office based practitioners) and specialist products (those used by hospitals). This industry includes quite a few distinguished strategic groups. The ethical drugs are those which are prescribed as opposed to OTC (over the counter) drugs which can be bought without prescriptions. Branded drugs are those which are patented as opposed to generic drugs. Biotech drugs are those that work in the fields of molecular biology and genetic engineering. The macro-environment can be categorised into certain environmental influential areas by

the Pestel framework. The technological and socio-cultural categories are extremely relevant in this industry. Drug companies must face high levels of investment on research and development projects. This causes the transfer of costs from producing the drug to its final consumer price. The USA heavily invests in R&D resulting in higher prices. This is becoming unsustainable for the pharmaceutical industry as prices are higher in the USA than in other countries which should either share part of the R&D burden or rise their own prices. But anyhow these costs are still being sourced in the best place world wide for this kind of investment which is the USA. Moreover costs are rising due to the fact that clinical trials and investigating are becoming more complex and costly and high technology solutions are needed for the cure of any decease. The need of developing cheaper, more effective and tolerable drugs is increasing due...

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The primary focus of this essay is the analysis of the global pharmaceutical industry and the substantially significant factors that shape this industry; the industry is primarily defined by very few yet critically influential factors; these consist of: governing bodies, the role of corporate social responsibility, and the emphasis put on the industry and firms by the Research and Development process. The most consequential factor placing emphasis on the industry is the governing body, with it being the legislative body and largest purchaser of the industry exclusive of the USA creates a strategic dilemma for the corporations in terms of profit maximization. Patent limitation, regulatory controls, price or reimbursement controls and extensive safety legislations are methods adopted by the government to legislate control and limitations over the industry. These legislations construct a paradigm that the main objective behind the intervention is to keep medicinal costs low as the majority of the population i.e. under 18s, over 65s and people primarily on benefits, medical costs are paid for by the government and with the ageing population the expenditure is ever increasing hence the various limitations. Being the legislative body and the largest purchaser gives the government various types of buyer control; the case study implies that the industry is a monopsony, giving the corporations very little bargaining power in terms of profit maximization and can often alter the strategic outlook of a firm, a strategy synthesis states that in some opinions government should set basic rules of conduct and stay out the way, whereas it also suggests they should interfere and stay there (a strategy synthesis, page 360), in this industry they tend to do a mix of these opinions due to the nature of the industry and circumstances created. In the

USA, although the government is not the primary buyer, the insurance companies are, they still play a role in the pricing through.

The Global Pharmaceutical Industry: Conduct an External Analysis

The Global Pharmaceutical Industry: Conduct an external analysis Introduction The pharmaceutical industry is described by high levels of risky and lengthy R&D process, tough competition for intellectual property, tighter government regulations and powerful pressures on buying power. (Johnson, 2006) In 2011, several blockbuster drugs patent like Lipitor will expire, possibly endangering the revenues of the pharmaceutical industry for the next three to five years. On the global level, the historical supremacy of the US was being challenged with the highest market growth rates recorded in emerging markets. The industry more than ever need to get a handle on the slippery business by offering a true step change in strategy. This case study will critically analyse the Global Pharmaceutical Industry with PESTEL, Porters five forces, SWOT analysis and plausible views of industry in the future. PESTLE

PESTLE analysis used to help organisation to understand in depth that what is the current status of the organisation and the external factors which are effecting. It also helps to the Management to make strategy for the future and overcome the weak areas of the organization. PESTLE is comprises of political, Economical, Social, Technological, Legal and Environmental factors. Political The both policies (domestic and foreign) of government have a great effect on the industry innovation as compare to the other factors. To get the attentions of firms due to increase the economic importance, government offer special incentives which encourage to the industry to globalisation. For example GSK increase their operations in Singapore due to low taxes and others government support. Same like, United States purchase more than 45% of drugs, the main reason is to allow foreign industry to compete with local which may help to low prices and reduce health budget. (David Floyd, 2008) From 1980 governments focused on pharmaceutical industry to handle the challenges of price control, monopoly and trade. For example in the European countries like Spain, Portugal, France and Italy the pharmaceutical market is cheap and thus these countries are used to ship their products to UK, Germany and Sweden for high price market. In US the price of pharmaceutical goods are high as compared to neighbour's country Canada due to the lake of price control. Like in US Lipitor (cloistral medicine) were sold with $3.20 per pill in 2003 as that of $1.89 per pill in Canada. (Sarah Holland Jul 2004 ) Environment Environment movements are real threats for Pharmaceutical industry as these movements focus on green environments and reduce chemicals and carbon which comes from pharmaceutical industries. It is not being possible to ignore these issues as they are supposed to be practiced under United Nation charter for clean and better environment. For example Pfizer is a well reputed British Pharmaceutical company which has aims to save the environment as much as possible from chemicals, waste water which includes active pharmaceutical ingredients mixture of different compounds and carbon which comes from their pharmaceutical industries.

Different strategies could be used to reduce carbon and chemical waste from drugs for human environment, like proper consumption ,good way of savages for hospitals waste water like advance waste water treatment technology, private house hold expire drugs, training and education of medical professionals to reduce over prescription, and public education and awareness. These strategies could be help full for save green house environment from drugs. In conclusion if we do focus on three principal strategies to reduce the input of chemicals compounds, carbon, and waste water in to the environment are substitution of complex chemical compounds, advance technical approach, and proper education and training of doctors, retailers and consumers. (Klaus Kmmerer, 2009) Social The social life, physical activities and level of health of a community affects the pharmaceutical industry. Change in social life and trends mention new direction for the local and national pharmaceutical industry. In the same way age of the individuals deeply change the dimensions of the industry like the citizen of a community aged more than 60 yeas consumes more drugs than the young people. Recently, the industry gets attraction and become more popularafter impact of global diseases e.g. SARS, AIDS, because of media and government attention. (Micheal A. Santoro, Date not available) Technology Technology plays a vital role in to pharmaceutical industries according to current state of art methods for development and manufacturing of drugs and open new ways of research and invention. The usage of advance technologies automatically impact on social, economic, and environment. Advance technology in pharmaceutical industries help full to accurate characterize chemical compounds, better control on new enhance scientific methods and their optimization. Which decrease extra time, money and efforts and produce more accurate drugs for specific disease, and decrease all hurdles from research to manufacturing efficiently, reliably, and rapidly. (Troy Shinbrot, Benjamin J. Glasser, 2002) Economy

Currently the pharmaceutical industry is less affected as compare to other manufacturing industries and until 2011 the industry is ideal for foreign direct investment growth. (World investment prospect survey, 2009). Despite this, in 2002 slow economy growth put the pressure on the EU market and restricts it to 8%. The global pharmaceutical industry is effecting due to interest, taxes, inflation and exchange rates which are included in the economic factors of global pharmaceutical industry. Change in the foreign currency rates makes affects on the exports and imports of drugs. High interest rates discourage investment the industry for firms and stake holders. Research and Development is a lengthy procedure which have also economically effect on the industry. Mergers and diversification allows the industry to enter in new market or develop new drugs. In 1996 two big companies, Swiss giants Ciba and Sandoz, merged one company called Novartis and attempted to cut R&D costs (James H. Taggart, 1993) Legal Undoubtedly pharmaceutical industry is a highly regulated and patent law. Pricing policies and product liability laws on pharmaceutical innovation are highly affected. The innovation of pharmaceutical is also affected because of regulation. Which cause delaying the market launch of new products and process through lengthy approval time. In United States the greater restrictions of regulation is evidence to delay in the local market of demanding new drugs. In 1989, 18 of the 23 new drugs introduced and approved for marketing in other countries while in US received their first marketing. (Stevens, Mark, 2009) Furthermore the World Trade Organisation introduced new rules for copyright protection which later overcome the problem of fake production and allowed some relaxation of exporting the Aids drugs to Africa. In 1995, with mutual understanding many countries made different changes in their National Laws Governing IPR which directly impact on pharmaceutical industry. (James, H, 1993) SWOT Swot analysis in pharmaceutical industry provide a crystal clear scenario about on coming threats to this industry , scope of pharmaceutical industry its opportunities , advantages and provide summary analysis of strategic planning model and weakness areas including draw backs ,hurdles related to this industry.

Threats The infrastructure of pharmaceutical industries is very different compare to other major Industries. Pharmaceutical approaching techniques state way comes in to open market environment. The influences of government in shape of pricing and legislation - individual consumers and whole sellers' free choice directly interact with this industry. The most of new drugs approvals and launches has decreased in the past decade, making it hard to make awesome income with these government strategies to decrease health care expenditures gives more threats in pharmaceutical industry. Over the next few years the pharmaceutical industries could be face Series downturn about of patent expiry. Drugs which are contributing 17 to pharmaceutical sales in 2008 lose patent Protection between now and 2012. (K. George Mooney, 2001) Weakness There are multiple examples of weakness associated with pharmaceutical industries. Some are highlights below, for example association of funding and results. Pharmaceutical company funding of clinical trials is strictly linked with published results favouring those companies' interests. This is an important issue which should be solved and is major weakness of Pharmaceutical industry. Another weakness in pharmaceutical industry is shortage of supply and demand of men power in industry and output from universities. There is need to collaboration and partnership between pharmaceutical industries, education institutes, and government to deal with the shortfall the challenge comes from balancing education in basic science with training in the emerging areas of science and technology. (R. Barker, M. Darnbrough, 2007) Strengths The pharmaceutical industry is one of the most productive and profitable industrial sectors. Therefore, effective intellectual property protections play a vital role to maintain innovation and research for products development. Study shows that USA & UK pharmaceutical industry is one of the most power and successful industry sectors in the world. The main reasons behind is commitment in to R&D sector. That's in turn give

sustainable and competitive advantage for more promising growth in industry and its development. Intellectual property protection is a basic strength for the success of the pharmaceutical industry. The pharmaceutical industry is so dependent on the patent protection, because only through strict enforceable patent protection drug companies can generate sufficient revenues. However patent protection is beneficial to inventions in the pharmaceutical industry. (Yu-Shan Chen, Ke-Chiun Chang, 2009) Opportunities Regardless of threats there is vast majority of opportunities with the help of different alliances, pharmaceutical industry can bring amazing resources and capabilities to compete threats and weakness' which is now a day's industry is trying to coping. New partnerships brings industry in to new market , deal with better trading , better economy opportunities , reducing cost ,and help to develop new inventions and research to compete market . One of the most important reasons for making external alliances is state of the art technologies for new products, invention and research which individual companies couldn't handle and develop by their selves from internal resources. (William W. McCutchen Jr., Paul M. Swamidass, 2004). B: Scenario planning for Global pharmaceutical industry Scenario planning methods used for nature and impact of the most certain and important driving forces our world; it is a process that encourages knowledge exchange and mutual understanding of the central issues for the future of the business. The demand is increasing for new drugs as the population rises and their medical support need increases. The process of the pharmaceutical industry can vary but the end result must be an action plan for each scenario with the following: o Environmental scan o Scenario options o Financial projections

o Action plan describing how the scenario would be implemented o Features of Scenario planning and effects. o Advantages. o Multiple scenarios and diverse outcomes. o It includes various input source and helps in discussing with all the participants. Disadvantages o Doesn't quantify the value of possible actions and lack structuring futures. o Non rational procedures for determining the future. Over the next few years, patent expirations will represent lost revenue of between $25 billion and $50 billion which will spur strategic alliances between R&D and generic companies. The industry, experts say, will see a move to specialty products to fill unmet needs and a shift from a treatment and/or cure approach to prevention while pressure to bring product costs down will likely determine which products prevail in the marketplace. (Caribbean Business, MARCH 19. 2009)' Relationship Management and transportation: It is very important to ensure that there is transparency along the entire value chain and especially in the Pharmaceutical industry as it has become a Global industry. It is also very important to maintain the customer trust and also managing the good relations with the entire stakeholder. C. Identification of implication of changing business environment on pharmaceutical firms Drug discovery companies are experiencing many important transformations, which have contributed to the uncertainty of their competitive business environment. The uncertainty is underlined by the abundance of players within the industry.

(Chaudry & Dacin 1997, p. 696). Focus and Cost: Pharmaceutical industry should review all their processes to stay competitive. A strong focus on Business and on core business activities. it is the need to have strong focus of developing processes which can be suitable for using across multiple manufacturing sites. Following are the some of the points which are interlinked and have an impact of decision making process, business practices and behaviour patterns. Slower and more bureaucratic regulatory procedures: Demographic development leads to pressures for medical cost containment: Regional integration: New directions for organizing health care: Rise of patient as consumer: Introduction of new innovative technologies: Shorter effective product patent life: Centralization in drug licensing decisions D: Prevalence of ethical stance' in the pharmaceutical industry and its strategic implications. In 1958 the shortage of polio vaccine and negligence in the law of Cutter pharmaceutical were main ethical challenges. Meanwhile the issues of marketing practices, pricing and clinical study has grown up to till date (Offit, 2005). Physicians' prescription changes the drug sales efforts and marketing of drug companies. (Katz 2003, Blumenthal 2004 As studied has shown that the drug safety and pricing were the two main ethical issues increased during 2004-2005 and observed with 114 times of drug safety which was followed by 89 times of pricing. According to the (USA today, 2005) report, 27.6 % price of 115 brand were increased in four years which raised the question regarding public perception towards waste advertisement and cost of R&D. Even in United State,

pharmaceutical firms were involved in pricing and marketing crimes and had to pay more than one billion dollars fine in 2003 The legalisation of importation and reimportation can be factor of drug price was another issue identified many times in Canada. Through reimportation the prescription cost can be cut for patients and helpful to control the healthcare budgets. (Flaherty and Gilbert, 2003)

Reference: Chaudry, Peggy & Dacin, Peter (1997): Strategic Planning in a Regulated Trade Bloc: The Pharmaceutical Industry in the European Union., European Management Journal, 15:6, 686-697. Blumenthal, D. (2004), "Doctors and drug companies", New England Journal of Medicine, Vol. 351 No.18, pp.1885-90. European Journal of Pharmaceutical Sciences, Challenges faced by thepharmaceutical industry, K. George Mooney Volume 12, Issue 4, February 2001, Pages 353-359 Global pharmaceuticals, Datamonitor publication, 2008, [accessed online] available at: www.datamonitor.com Healy, D. (2003), "In the grip of the python: conflicts at the universityindustry interface", Science and Engineering Ethics, Vol. 9 No.1, pp.5971 James, H. (1993), The world pharmaceutical industry' 4th edition. Chapman and Hall, London, UK Btiz-Lazo, B. and Holland, S (June 2001) Strategy and structure of the pharmaceutical industry, Open University Katz, D., Caplan, A.L., Merz, J.F. (2003), "All gifts large and small: toward an understanding of the ethics of pharmaceutical industry giftoffering", American Journal of Bioethics, Vol. 3 No.3, pp.39-46.

Offit, P.A. (2005), The Cutter Incident: How America's First Polio Vaccine Led to the Growing Vaccine Crisis, Yale University Press, New Haven, CT, The Journal of High Technology Management Research, Volume 15, Issue 2, August 2004, Pages 197-214, William W. McCutchen Jr., Paul M. Swamidass MISG Secretariat (2002), Pharmaceutical Industry Competitiveness Task Force: One Year On Report, Ministerial Industry Strategy Group, London, available at: www.doh.gov.uk /pictf/ pictfonevearon.htm Floyd, D, (2002), Investment Decisions in Eastern Europe, Floyd, D, (2002), Investment Decisions in Eastern Europe, European Business Review, Vol 12, No 2. Yu-Shan Chen, Ke-Chiun Chang .The relationship between a firm's patent quality and its market value The case of US pharmaceutical industry Technological Forecasting and Social Change, In Press, Corrected Proof, Available online 16 July 2009 R. Barker, M. Darnbrough . The Role of the Pharmaceutical Industry Comprehensive Medicinal Chemistry II, 2007, Chapter 1.14, Pages 527552 Micheal A. Santoro, Charting a sustainable path for the Twenty-First Centaury pharmaceutical Industry, Cambridge Univeristy Press, Pages 1 Stevens, Mark , Legal and regulatory updates. Gasson, Tony 2009, Vol. 80 Issue 5, p31-32, 2p, Ebsco publications. End of Paper

Pestel Analysis of Pharmaceutical Industry

ANNUAL REVIEWS Further Quick links to online content Ann. Rev. PharmacoL ToxicoL Copyright 1983 1983. 23:87-101 by Annual Reviews Inc. All rights reserved THE TREATMENT OF ACETAMINOPHEN Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only. POISONING L. F. Prescott and J. A. J. H Critchley Regional Poisoning Treatment Centre, and University Department of Therapeutics and Clinical Pharmacology, The Royal Infirmary, Edinburgh, EH3 9YW, Scotland INTRODUCTION Acetaminophen (paracetamol, N-acetyl-p-aminophenol, 4hydroxyacetani lide) is a non-prescription antipyretic analgesic that was first introduced into clinical medicine towards the end of the last century (1). It attracted little interest until it was found to be the major metabolite of both acetani lide and phenacetin (2, 3) and in recent years it has

become an increasingly popular substitute for aspirin. Acetaminophen seemed to be remarkably safe when taken in recommended doses and formal toxicity studies were never carried out. In 1964 Eder (4) first reported liver damage in cats given 25-50 mglKg of acetaminophen daily for 26 weeks, and two years later Boyd & Bereczky described extensive hepatic necrosis in acute toxicity studies in rats (5). At the same time liver damage was first reported in man following acetaminophen overdosage (6, 7). The use of acetaminophen for self-poisoning has since increased dramatically in many countries and acute hepatic necrosis, sometimes fatal, has attracted much attention as the major complication (8-16). CLINICAL MANIFESTATIONS ACETAMINOPHEN POISONING AND COMPLICATIONS OF

Apart from nausea and vomiting there are no specific early signs of severe intoxication and consciousness is not impaired. However, 12 to 36 hours after ingestion biochemical evidence of acute hepatic injury may become apparent with maximum abnormalities of liver function usually occurring 87

88 PRESCOIT & CRITCHLEY on the third day. The pattern is characteristic of extensive acute necrosis with gross elevation of plasma aspartate and alanine aminotransferase (AST or SOOT, ALT or SGPT) activity, mild hyperbilirubinemia, and prolonga tion of the prothrombin time (9-11). Associated abnormalities include im pairment of bromsulphthalein clearance (17). abnormal glucose tolerance (7. 18), and increased serum concentrations of bile acids and ferritin (19. 20). In survivors hepatic regeneration is normally rapid and complete with return of liver function tests to normal within one to three weeks. Fulminant hepatic failure (which is usually fatal) develops on the third to the sixth day in a small minority of severely poisoned patients. and renal failure due to acute tubular necrosis is another uncommon complication (10. 21. 22). Liver biopsies and postmortem studies reveal extensive cen trilobular hepatic necrosis without inflammatory reaction (6, 11, 23, 24). The acute hepatotoxicity of acetaminophen has been confirmed repeatedly in animals but there are marked species differences in susceptibility (25-27). Contrary to popular belief, severe liver damage (arbitrarily defined as elevation of the plasma AST or ALT activity above 1000 u/l) and fatal hepatic failure are not inevitable complications of acetaminophen overdos age. Indeed. without specific therapy fewer than 10% of unselected patients referred to hospital develop severe liver damage, about 1 % suffer acute renal failure. and 1 to 2% die in hepatic failure (26). Until the development of rational therapy based on the biochemical mechanisms of acetaminophen hepatotoxicity (28), there was no effective treatment for overdosage and the increasing incidence of poisoning was a cause for concern. Allegedly successful treatment with antihistamines and corticosteroids (8) was uncontrolled and had no scientific or statistical basis. Indeed. subsequent studies in animals showed that such treatment actually increased the lethality of acetaminophen without protecting against liver damage (29). A controlled trial of heparin therapy showed no benefit (30). Forced diuresis has been tried but is likewise of no value. The renal clear ance of acetaminophen is not pH-dependent, and even after overdosage an insignificant fraction of the dose is excreted unchanged in the urine (31). Hemodialysis was also advocated, but it did not prevent liver damage, and insignificant amounts of drug were removed. In one study, 11 of 15 patients subjected to this procedure had not absorbed enough drug to be at risk of liver damage in

the first place (32). MECHANISMS OF ACETAMINOPHEN HEPATOTOXICITY The effective treatment of acetaminophen poisoning only became possible with the discovery by Mitchell and his colleagues of the metabolic activa tion of acetaminophen and the vital protective role played by reduced Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only.

ACETAMINOPHEN POISONING 89 Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only. glutathione (33-36). These workers showed that a small fraction of a dose of the drug is converted by cytochrome P-450-dependent mixed function oxidase to an e1ectrophilic arylating metabolite that binds covalently to hepatic macromolecules, causing cell damage and necrosis. The reactive metabolite is thought to be N-acetylbenzoquinoneimine formed by N hydroxylation (28, 37). It is normally rapidly inactivated by preferential conjugation with reduced glutathione and eventually excreted in the urine as cysteine and mercapturic acid conjugates of acetaminophen. After a toxic dose, hepatic glutathione is depleted; when concentrations fall below 20 to 30% of normal, the excess metabolite binds covalently to essential hepatic proteins and enzymes. Hepatic necrosis is directly related to the extent of glutathione depletion and covalent binding (27, 33-36, 38). The extent of conversion of acetaminophen to its toxic metabolite is reflected in the fraction of the dose recovered in the urine as cysteine and mercapturic acid conjugates. Highly susceptible species such as the hamster excrete much more than resistant species such as the rat (25); liver damage following overdosage of acetaminophen in man is associated with increased urinary excretion of these conjugates (26, 39). PROTECTION AGAINST HEPATOTOXICITY EXPERIMENTAL ACETAMINOPHEN

Factors that modify hepatic microsomal enzyme activity and glutathione status greatly influence the toxicity of acetaminophen. Thus Mitchell et al showed that liver damage is increased by stimulation of hepatic microsomal enzymes with inducing agents such as phenobarbital, and decreased by inhibition with cobaltous chloride or piperonyl butoxide (28,33). Similarly, covalent binding and hepatic necrosis are increased if glutathione stores are depleted by prior administration of diethyl maleate, and decreased by glu tathione precursors such as cysteine (28, 36). Glutathione depletion pro duced by fasting and low protein or yeast diets also potentiates experimental acetaminophen hepatotoxicity (40,41). These general principles have been amply confirmed by other

workers and provide a sound basis for the treat ment of acetaminophen poisoning in man. Inhibition of Metabolic Activation Selective inhibition of the minor route of metabolism that generates the toxic metabolite of acetaminophen is an attractive possibility. However, safe effective inhibition of the metabolic activation of acetaminophen has not yet been investigated adequately in man and this approach has not been ex ploited clinically. Recent studies have shown that the acute toxicity of acetaminophen in animals is significantly reduced by cimetidine (42-44) and by acute administration of ethanol (45, 46). Protection was attributed

90 PRESCOIT & CRITCHLEY to inhibition of the metabolic activation of acetaminophen but other mecha nisms have not been excluded. In the case of ethanol, this hypothesis is supported by the observation that it significantly reduces the excretion of the mercapturic acid conjugate of acetaminophen in rats (46). In man, an acute ethanol load (1.72 g/Kg over 8 hours) markedly decreases the frac tion of an oral dose of 20 mglKg of acetaminophen excreted as the cysteine and mercapturic acid conjugates,but oral cimetidine in divided doses total ling 2 g over 16 hours has no such effect (J. A. J. H. Critchley and L. F. Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only. Prescott, unpublished). The protective effect of acute ethanol is of particular interest since chronic pretreatment enhances experimental acetaminophen-induced hepatotoxicity (47-50) and increases the urinary excretion of the mercaptu ric acid conjugate (51), presumably as a result of microsomal enzyme induction. Similarly, chronic alcoholics and patients who have previously been taking agents that induce drug metabolizing enzymes seem to be at increased risk of liver damage following acetaminophen overdosage (26, 52, 53), whereas acute ingestion of ethanol at the same time appears to offer some protection (16). However, in contrast to the findings in experimental animals, chronic heavy ethanol intake in man is not associated with in creased metabolic activation of acetaminophen (54). In addition, the uri nary excretion of the cysteine and mercapturic acid conjugates of acetaminophen is not increased in patients induced by chronic treatment with anticonvulsants or rifampicin (55). The results of animal studies in volving the selective induction and inhibition of acetaminophen metabolism thus cannot be extrapolated directly to man. Sulphydryl Compounds Glutathione itself might be considered the ideal antidote for acetaminophen poisoning. However, it is normally synthesized in situ,

and because it enters cells with difficulty, glutathione is relatively ineffective even when given in very large doses (56-58). On the other hand, glutathione precursors such as cysteine, N-acetylcysteine, and methionine and other sulphur-containing compounds including cysteamine, S-adenosylmethionine, a,-mercaptopro pionyl-glycine, dithiocarb, propylthiouracil, and even dimethyl-sulphoxide are very effective in preventing experimental acetaminophen-induced hepatotoxicity (28,38,41,56,59-66). Most of these agents have been shown to reduce the extent of acetaminophen-induced glutathione depletion. Over the last decade cysteamine, methionine and Nacetylcysteine have been studied extensively in man and the clinical management of severe acetaminophen poisoning has been transformed. Even when administration is delayed for as long as 8 to 10 hours after ingestion they have proved remarkably effective in preventing liver damage, renal failure, and death from acetaminophen overdosage.

ACETAMINOPHEN POISONING 91 Stimulation of Sulphate Conjugation Acetaminophen is extensively metabolized, with sulphate and glucuronide conjugation accounting for about 30% and 60% respectively of a therapeu tic dose in man (67). However, the availability of inorganic sulphate is limited and sulphate conjugation is saturated after overdosage. Slattery & Levy (68) proposed a pharmacokinetic model based on dose-dependent saturation of both sulphate and glucuronide conjugation with increasing conversion of the drug to the toxic metabolite. Unfortunately, their model was based on the results of metabolic studies reported by Davis et al (39), which differ markedly from those observed by other workers using different analytical methods. Sulphate conjugation is undoubtedly saturated with overdosage of acetaminophen but there is no evidence of similar saturation of glucuronide conjugation in man (26). According to the above hypothesis, it was suggested that restoration of sulphate conjugation by provision of inorganic sulphate would significantly enhance the elimination of acetaminophen after overdosage and hence reduce its toxicity. In rats sodium sulphate enhanced the sulphate conjugation of acetaminophen and marginally increased its rate of elimination (69, 70) and it slightly increased the acute LD50 in mice (71). However, the protective effect was minor compared to that produced by glutathione precursors and is unlikely to be of clinical significance. Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only. TREATMENT OF ACETAMINOPHEN POISONING Clinical assessment of the efficacy of treatment for acetaminophen poison ing is beset with difficulties. There are few specialist units with an interest in drug overdosage and poisoning; placebo-controlled trials cannot now be carried out because of ethical constraints, and the great majority of patients do not absorb enough drug to be at risk of severe liver damage anyway. Toxicity depends primarily on the balance between the rates of formation of the reactive metabolite and synthesis of glutathione and is influenced by many factors including age, diet, nutritional state, fasting, and previous and concurrent intake of other drugs including ethanol (26).

Not surprisingly, there is marked individual variation in susceptibility (72) with a variable threshold dose for toxicity that presumably corresponds to the point of critical depletion of hepatic glutathione (36). In man, significant liver dam age is very uncommon following absorption of less than 125 mglKg of acetaminophen, whereas severe liver damage occurs in some 50% of indi viduals absorbing 250 mg/Kg, and in virtually all absorbing 350 mglKg (26). Unfortunately, self-poisoners are notoriously unreliable historians and unknown amounts of drug may be lost by vomiting and gastric lavage. The

92 PRESCOTI & CRITCHLEY dose absorbed can therefore only be determined by measurement of the plasma concentrations of acetaminophen. Assessment of Risk To assess the effects of any treatment it is necessary to define the risk of liver damage according to the plasma concentrations of acetaminophen in rela tion to the time since ingestion (10, 73-75). Severe liver damage with plasma AST or ALT activity exceeding 1000 ull occurs in about 60% of patients with plasma acetaminophen concentrations above a "treatment" line join ing semilog plots of 200 ILg/ml at 4 hours and 30 ILg/ml at 15 hours after ingestion. The incidence is 90% above a similar parallel line joining 300 ILglml at 4 hours and 45 ILglml at 15 hours, and such patients are at high risk. Plasma concentrations cannot be interpreted less than 4 hours after ingestion, and difficulties also arise when absorption is delayed by combined overdosage with drugs such as narcotic analgesics. The plasma acetamino phen half-life is directly related to the extent of liver damage (10, 31, 74) but its measurement takes time and is not practicable because treatment must be started as soon as possible. The marked individual variation in response to acetaminophen makes it virtually impossible to determine the effects of treatment unless compari sons are made in substantial numbers of patients, preferably those at high risk. One patient may develop liver damage with relatively low initial plasma acetaminophen concentrations while another with concentrations several times higher may escape completely. Nevertheless, there are many anecdotal accounts of "successful" treatment. The historical control data with which comparisons must be made is very limited and the much-quoted "nomogram" published by Rumack & Matthew (76) as a guide to prognosis was actually taken from the original data obtained in Edinburgh (10, 73). Further difficulties have arisen through the use of nonspecific analytical methods for the estimation of plasma acetaminophen. Those that depend on direct acid hydrolysis to paminopheno1 without prior extraction also include acetaminophen conjugates present in high concentrations, and may overestimate the true result by as much as 700% (77). Fortunately, cystea mine, methionine, and N-acetylcysteine have been dramatically effective in

preventing liver damage after acetaminophen overdosage, and despite all these difficulties their value is not in doubt. Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only. General Measures Gastric aspiration and lavage are normally carried out in patients admitted within 4 hours of overdosage. Activated charcoal and cholestyramine may reduce the absorption of acetaminophen if given within one hour of inges-

ACETAMINOPHEN POISONING 93 tion (78, 79) but are unlikely to be useful in practice because the great majority of patients do not arrive in hospital in time for such treatment to be effective. Fluid balance should be maintained and complications such as hepatic and renal failure are managed conventionally. Cysteamine Mitchell et al (28) showed that cysteamine protected mice against the acute toxicity of acetaminophen even when treatment was delayed for 2 hours. Shortly thereafter we reported the first successful treatment of severe acetaminophen poisoning in man using intravenous cysteamine. Seven adults with a mean plasma acetaminophen concentration of 373 p.g/ml at 4 hours were given 3.2 g over 20 hours and treatment was started 4.5 to 10 hours after ingestion of the acetaminophen. None of the patients developed the expected severe liver damage (73). Subsequent reports confirmed the protective action of cysteamine when treatment was started within 10 to 12 hours (80-83). Thus severe liver damage was completely prevented in one series of 27 severely poisoned patients treated within 10 hours (80) and occurred in only one of 14 similar patients in another (83). Douglas et al (84) failed to appreciate the importance of early treatment and claimed that cysteamine therapy was of no advantage despite evidence to the contrary in their patients admitted within 9 hours. With the exception of one report in which plasma acetaminophen was estimated by an inappropriate method (82), treatment after 12 hours was found to be of no benefit. Although effective, cysteamine produced very unpleasant gastrointestinal and central nervous system toxicity and it was not available commercially as a phar maceutical formulation. Other agents were therefore investigated. Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only. Methionine Methionine protects rats against acetaminophen-induced liver damage and its incorporation into analgesic tablets was proposed as a simple answer to the problems of acetaminophen overdosage (41). Intravenous

and oral methionine usually prevents severe liver damage following overdosage of acetaminophen if given within 10 to 12 hours (80, 83, 85, 86). However, it seems to be less reliable than intravenous cysteamine and N-acetylcysteine (26). Thus severe liver damage occurred in 3 of 15 severely poisoned pa tients given 20 g of methionine intravenously within 10 hours (80) and in 7 of 96 similar patients given 10 g orally (86). In addition, 3 patients treated with oral methionine within 12 hours developed fulminant hepatic failure (12). There is some doubt concerning the safety of late treatment with methio nine. It may aggravate or precipitate hepatic encephalopathy and late treat ment or delayed absorption may therefore be hazardous in patients with

94 PRESCOTI & CRITCHLEY impending severe liver damage methionine with acute acetaminophen poisoning is increased by late treatment with (12, 85, 89). Indeed, the mortality in mice (61). Most patients develop nausea and vomiting within a few hours of ingestion of a toxic dose of acetaminophen and delayed or incom plete absorption may contribute to the failure of oral methionine in some patients (87). Treatment with oral methionine is simple and cheap. N-Acetylcysteine Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only. Following the demonstration of its protective effects in animals sive clinical studies have confirmed the efficacy and safety of N-acetylcys teine in the treatment of acetaminophen poisoning (16,88-91) and it is now considered the treatment of choice. Intravenous N-acetylcysteine given within 10 hours in a dose of 300 mglKg over 20 hours prevented liver damage, renal failure, and death in patients with severe acetaminophen . poisoning liver damage in severely poisoned patients at high risk when given within (60), exten (88, 89), and was completely effective in preventing even triyial 8 hours (89). An extensive nationwide multicenter study of oral N-acetyl cysteine is currently in progress in the USA. (16, 90). Of 662 patients referred to the coordinating center in Denver, 57 were considered to be at less effective orally than intravenously. Thus, severe liver damage

"probable risk" and received oral N-acetylcysteine within 10 hours. Despite the very large total dose of 1330 mg/Kg, N-acetylcysteine appeared to be patients given a much smaller dose of intravenous N-acetylcysteine within 7 of the 57 patients developed (16) compared with only 1 of 62 severely poisoned 10 hours (91). Like all other agents studied in man, the protective effect of 8 to 10 hours, and it is completely ineffective after 15 to 16 hours (16, 91). Unlike N-acetylcysteine falls off rapidly if treatment is delayed beyond methionine, late treatment with N-acetylcysteine does not increase m6rtal ity in experimental acetaminophen poisoning is not recommended. (61). There is no clear evi dence that it aggravates hepatic failure in man, but treatment after 24 hours N-acetylcysteine has lorig been available as a mucolytic and an intrave nous formulation was recently introduced in the U.K. specifically for the treatment of acetaminophen poisoning. There have been two reports of transient mild allergic reactions verse effects have been noted. (92, 93), but otherwise no significant ad Other Agents Dimercaprol and D-penicillamine appear to offer little or no protection against acetaminophen toxicity in man (80, 81, 94).

ACETAMINOPHEN POISONING 95 Oral Versus Intravenous Therapy There has been controversy over the relative merits of oral and intravenous therapy. The oral route is convenient and has the great advantage that a substantial fraction of the dose should he delivered directly to the liver. However, nausea and vomiting are consistent features of severe acetamino phen intoxication (89, 91) and efficacy must inevitably be compromised by incomplete or delayed absorption. Vomiting occurred in 77% of 52 severely poisoned patients in one report (9 1), and in all of 4 16 patients given oral N-acetylcysteine in another (90). It was recently claimed that vomiting occurred in only 12% of 433 patients with acetaminophen overdosage (95). However, the patients were unselected and it is probably no coincidence that only 12% were shown to be severely poisoned. Acetaminophen poison ing is a potentially fatal condition and the ingestion-treatment interval is critical. Severe liver damage has been attributed to failure of absorption of oral methionine (87) and this route cannot be recommended because of the very high incidence of nausea and vomiting in the very patients who need treatment most. Oral therapy is clearly contraindicated in patients who have been given emetics or activated charcoal. MECHANISMS OF PROTECTION Precursors such as cysteine, N-acetylcysteine, and methionine probably act primarily by stimulating glutathione synthesis and hence facilitating the glutathione conjugation of acetaminophen (38). Other agents such as cys teamine and dimethylsulphoxide also antagonise the glutathione depletion induced by acetaminophen (59, 64) and indirect stimulation of glutathione synthesis could contribute to their protective action (97). Cysteamine may also act by inhibiting the metabolic activation of acetaminophen (38, 98, 99). Oxothiazolidine carboxylic acid is converted to cysteine by 5-oxo-L prolinase and stimulates glutathione synthesis. It reverses acetaminophen induced depletion of hepatic glutathione in animals and has been proposed as an effective intracellular delivery system for cysteine in the treatment of acetaminophen overdosage (100). Cysteamine, cysteine, Nacetylcysteine, and d.-mercaptopropionylglycine have all been shown to react directly with the toxic metabolite ofacetamino phen to form the corresponding conjugates (99). However, this is probably not important since conjugation with glutathione is catalysed by glutath ione-S-

transferase and takes place much more readily (38, 96). Propylthi ouracil is unusual in that it can substitute for glutathione as a substrate for glutathione-S-transferase, and its protective action may involve direct con jugation with the reactive metabolite of acetaminophen (66). Methionine, Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only.

96 PRESCOTI & CRITCHLEY which does not contain an SH group, does not form an adduct directly with the acetaminophen metabolite (99) and does not prevent its covalent bind ing in vitro (101). It presumably acts indirectly after conversion to homo cysteine and cysteine and the delay may account for its relative lack of efficacy. Other mechanisms may contribute to protection. Thus acetaminophen may be regenerated from N-acetyl-benzoquinoneimine by reducing agents such as cysteine and ascorbic acid under certain conditions (102). [Ascorbic Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only. acid can inhibit the covalent binding of acetaminophen to hepatic mi crosomes in vitro (103), and it has been reported to reduce the lethality of acetaminophen in mice (104)]. In addition, the metabolism of sulphydryl compounds to inorganic sulphate can undoubtedly promote sulphate conju gation as an alternative route of elimination of acetaminophen. The plasma concentrations of acetaminophen sulphate in poisoned patients are in creased by treatment with cysteamine and Nacetylcysteine (67) and subse quently there may be a delayed minor decrease in the plasma half-life of the drug (73). However, enhancement of sulphate conjugation is unlikely to be relevant to the protective effects of SUlphydryl compounds in man. OTHER METHODS OF TREATMENT The only other recent approach to the treatment of acetaminophen poison ing has been the use of charcoal hemoperfusion. The drug can be removed effectively by this technique and clearances of 70 to 200 ml/min have been reported ( l 05 . 106). However. it is inconceivable that this treatment could

be instituted early enough to remove sufficient drug to prevent the critical glutathione depletion and irreversible covalent binding that seems to occur 8 to 10 hours after ingestion of a toxic dose. The first controlled trial of early hemoperfusion showed no benefit and the average amount of acetamino phen removed was less than 1.5 g (107). In one anecdotal report claiming success, cysteamine had also been given and treatment was probably not necessary in the first place because plasma acetaminophen concentrations would have been greatly overestimated by the unsuitable analytical method used (108). It is even more difficult to accept recent claims for the benefit of late charcoal hemoperfusion. In one report, treatment was started in 7 severely poisoned patients an average of 23 hours after the acetaminophen was taken and a mean of 2.4 g was removed. According to the elevation of plasma bilirubin and prothrombin time ration, 5 patients developed severe liver damage and one died in hepatic failure. Only 0.38 and 0.36 g of acetaminophen were removed from the two patients who did not develop severe liver damage (106). There seems to be no justification for the use of hemoperfusion in the late treatment of acetaminophen poisoning.

ACETAMINOPHEN POISONING 97 SUMMARY Acetaminophen has become a very popular over-the-counter analgesic in some countries and as a result it is used increasingly as an agent for self poisoning. Without treatment only a minority of patients develop severe liver damage and colleagues discovered the biochemical mechanisms of toxicity in 1 to 2% die in hepatic failure. Until Mitchell and his 1973 there was no effective treatment. They showed that the metabolic activation of Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only. acetaminophen resulted in the formation of a reactive arylating intermedi ate, and that hepatic reduced glutathione played an essential protective role by preferential conjugation and inactivation of the metabolite. Early treat ment with sulphydryl compounds and glutathione precursors has been dramatically effective in preventing liver damage, renal failure, and death following acetaminophen overdosage. It seems likely that these agents act primarily by stimulating glutathione synthesis. Inhibition of the metabolic activation of acetaminophen is another potential therapeutic approach that has not yet been put to the test clinically. The clinical management of acetaminophen poisoning has been transformed and it is particularly grati fying to have effective treatment based on a well established biochemical mechanism of toxicity. It is likely that effective treatment will be developed for toxicity caused through similar mechanisms by other agents. Literature Cited 1. Smith, P. K. 1958. Acetophenetidin. A Critical Bibliographic Review, p. 3. Lon don: Wiley. 18Opp. 2. Brodie, B. B., Axelrod, J. 1948. The es timation of acetanilide and its metabolic products, aniline, N-acetyl-pamino phenol and p-aminol'henol (free and to tal conjugated) in biological fluids and tissues. 1. PharmacoL Exp. Ther. 94: 22-28 3. Brodie, B. B., Axelrod, 1. 1949. The fate of acetophenetidin (phenacetin)

in man and methods for the estimation of acetophenetidin and its metabolites in biological material 1. PharmacoL Exp. Ther. 97:58-67 4. Eder, H. 1964. Chronic toxicity studies on phenacetin, N-acetyl-paminophenol (NAPA) and acetylsalicylic acid on cats. Acta PharmacoL ToxicoL 21:197204 5. Boyd, E. M., Bereczky, G. M. 1966. Liver necrosis from paracetamol. Brit. 1. PharmacoL 26:606-14 6. Davidson, D. G. D., Eastham, W. N. 1966. Acute liver necrosis following overdose of paracetamol. Brit. Med 1. 2:497-99 7. Thomson, 1. S., Prescott, L. F. 1966. Liver damage and impaired glucose tol erance after paracetamol overdosage. Brit. Med J. 2:506-7 8. MacLean, D., Peters, T. J., Brown, R. A. G., McCathie, M., Baines, G. F., Robertson, P. G. C. 1968. Treatment of acute paracetamol poisoning. Lancet 2:849-52 9. Proudfoot, A. T., Wright, N. 1970. Acute paracetamol poisoning. Brit. Med. J. 3:557-58 10. Prescott, L. F., Wright, N., Roscoe, P., Brown, S. S. 1971. Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1:519-22 11. Clark, R., Thompson, R. P. H., Bori rakchanyavat, V., Widdop, B., David son, A. R., et aI. 1973. Hepatic damage and death from overdose of paraceta mol. Lancet 1:6669 12. Canalese, J., Gimson, A. E. S., Davis, M., Williams, R. 1981. Factors con tributing to mortality in paracetamol induced hepatic failure. Brit. Med. J. 282:199-201

98 PRESCOIT & CRITCHLEY chows Arch. A Pathol AnaL Histol 370:333-44 Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only. 236:18775 16. Rumack, B. H., Peterson, R. C., Koch, G. G., Amara, I. A. 1981. Acetamino phen overdose. 662 cases with evalu 17. S. B., Burk, R. F. 1978. Acetaminophen overdoses at a County Hospital: a year's experience. South. Med. /. 71:1359--63 14. Hamlyn, A. N., Douglas, A. P., lames, O. 1978. The spectrum of paracetamol (acetaminophen) overdose: clinical and epidemiological studies. Postgrad. Med. /. 54:400-4 15. McJunkin, B., Barwick, K. W., Little, W. C., Winfield, 1. B. 1976. Fatal mas sive hepatic necrosis following aceta minophen overdose. /. Am. Med. Assoc. 13. Cohen, 25. Jollow, D. J., Thorgeirsson, S. S., Pot 251-71 26. Prescott, L. F. 1982. Paracetamol over ter, W. Z., Hashimoto, M., Mitchell, 1. R. 1974. Acetaminophen-induced hepatic necrosis. VI. Metabolic disposi tion of toxic and nontoxic doses of acetaminophen. Pharmacology 12: 18. 19. 20. 21. 22. 23. 24.

ation of oral acetylcysteine treatment. Arch. Intern. Med. 141:380-85 Davis, M., Ideo, G., Harrison, N. G., Williams, R. 1975. Hepatic glutathione depletion and impaired bromosulph thalein clearance early after paraceta mol overdose in man and the rat. Clin. Sci Mol Med. 49:495-502 Record, C. 0., Chase, R. A., Alberti, K. G. M. M., Williams, R. 1975. Distur bances in glucose metabolism in pa tients with liver damage due to paracetamol overdose. Clin. Sci Molec. Med. 49:473-79 lames, 0., Lesna, M., Roberts, S. H., Pulman, L., Douglas, A. P., et al' 1975. Liver damage after paracetamol over dose: comparison of liver function tests, fasting serum bile acids, and liver his tology. Lancet 2:579-81 Eastham, E. 1., Bell, 1. I., Douglas, A. P. 1976. Serum ferritin levels in acute hepatocellular damage from paraceta mol overdosage. Brit. Med. /. 1:750-51 Kleinman, J. G., Breitenfteld, R. V., Roth, D. A. 1980. Acute renal failure associated with acetaminophen inges tion: report of a case and review of the literature. Clin. Nephrol. 14:201-5 Cobden, I., Record, C. 0., Ward, M. K., Kerr, D. N. S. 1982. Paracetamol induced acute renal failure in the ab sence of fulminant liver damage. Brit Med. /. 284:21-22 Portmann, B., Talbot, I. C., Day, D. W., Davidson, A. R., Murray-Lyon, I. M., Williams, R. 1975. Histopathologi cal changes in the liver following a paracetamol overdose: correlation with clinical and biochemical parameters. /. Patho/. 117:169-81 Lesna, M., Watson, A. J., Douglas, A. P., HarnIyn, A. N., James, O. F. W. 1976. Evaluation of paracetamol induced damage in liver biopsies. Virdosage: pharmacological considerations and clinical management. Drugs. In press 27. Davis, D. C., Potter, W. Z., 10llow, D. 1., Mitchell, 1. R. 1974. Species differ ences in hepatic glutathione depletion, covalent binding and hepatic necrosis after acetaminophen. Life Sci. 14:2099injury: protective role of glutathione in man and rationale for therapy. Clin. Pharmacol Ther. 16:676--84 29. Nimmo, 1., Dixon, M. F., Prescott, L. F. 1973. Effects of mepyramine, prome thazine, and hydrocortisone on para cetamol-induced hepatic necrosis in the rat. Clin. Toxicol 6:7581 30. Gazzard, B. G., Clark, R., Borirak chanyavat, V., Williams, R. 1974. A controlled trial of heparin therapy in the coagulation defect of paracetamol induced hepatic necrosis. Gut 15:89-93 31. Prescott, L. F., Wright, N. 1973. The effects of hepatic and renal damage on paracetamo1 metabolism and excretion following overdosage. A pharmacoki netic study. Brit. /. Pharmacol 49:

2109 28. Mitchell, 1. R., Thorgeirsson, S. S., Pot ter, W. Z., Jollow, D. J., Keiser, H. 1974. Acetaminophen-induced hepatic 602-13 32. Farid, N. R., Glynn, J. P., Kerr, D. N. S. 1972. Haemodialysis in paracetamol self-poisoning. Lancet 2:396--98 33. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Davis, D. C., Gillette, J. R., Brodie, B. B. 1973. Acetaminophen-induced 185-94 34. Jollow, D.l., Mitchell, 1. R., Potter, W. Z., Davis, D. C., Gillette, J. R., Brodie, B. B. 1973. Acetaminophen-induced hepatic necrosis. I. Role of drug metab olism. /. Pharmacol Exp. Ther. 187: hepatic necrosis. II. Role of covalent binding in vivo. /. PharmacoL Exp. Ther. 187:195-202 35. Potter, W. Z., Davis, D. C., Mitchell, J. R., Jollow, D. I., Gillette, 1. R., Brodie, B. B. 1973. Acetaminophen-induced hepatic necrosis. III. Cytochrome P4SO-mediated covalent binding in vitro. /. Pharmacol Exp. Ther. 187:203-10

ACETAMINOPHEN POISONING 36. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Gillette, J. R., Brodie, B. B. 1973. Acetaminophen-induced hepatic necro sis. IV. Protective role of glutathione. J. PharmacaL Exp. Ther. 187:211-17 37. Miner, D. J., Kissinger, P. T. 1979. Evi dence for the involvement of N-acetyl pquinoneimine in acetaminophen me tabolism. Biochem. Pharmacal 28: 3285-90 38. Moldeus, P. 1981. Use of isolated cells in the study of paracetamol metabolism and toxicity: capacity of conjugative pathways and glutathione homeostasis. In Drug Reactions and the Liver, ed. M. Davis, J. M. Tredger, R. Williams, pp. 144--56. London: Pitman. 364pp. 39. Davis, M., Simmons, C. J., Harrison, N. G., Williams, R. 1976. Paracetamol overdose in man: relationship between pattern of urinary metabolites and se verity of liver damage. Q. J. Med. 4S: 181-91 40. Pessayre, D., Wandscheer, J. -C., Cob ert, B., Level, R., Degott, C., Batt, A. M., Martin, N., Benhamou, J. P. 1980. Additive effects of inducers and fasting on acetaminophen hepatotoxicity. Bio chem. Pharmacol 29:2219-23 41. McLean, A. E. M., Day, P. A. 1975. The efFect of diet on the toxicity of paracetamol and the safety of paraceta mol-methionine mixtures. Biochem. Pharmacal 24:37-42 42. Abernethy, D. R., Greenblatt, D. J., Di voll, M. 1982. Differential effects of cimetidine on drug oxidation vs conju gation: potential mode of therapy for acetaminophen hepatotoxicity. Clin. Pharmacol Ther. 31:198 (Abstr.) 43. Donn, K. H., Rudd, G. D., Grisham, J. W., Koch, G. G. 1982. Prevention of acetaminophen-induced hepatic injury by cimetidine. Clin. Pharmacal Ther. 31:218-19 (Abstr.) 44. Mitchell, M. C., Schenker, S., Avant, G. R., Speeg, K. V. 1981. Cimetidine protects against acetaminophen hepato toxicity in rats. Gastroenterology 81 : 1052-60 45. Sato, C., Nakano, M. Lieber, C. S. 1981. Prevention of acetaminophen-induced hepatotoxicity by acute ethanol admin istration in the rat: comparison with carbon tetrachloride-induced hepato toxicity. J. Pharmacal Exp. Ther. 218: 80510 46. Sato, C., Lieber, C. S. 1981. Mechanism of the preventive effect of ethanol on acetaminophen-induced hepatotoxicity. J. Pharmacol Exp. Ther. 218:811-15 99 47. Moldeus, P., Andersson, B., Norling, A., Ormstad, K. 1980. Effect of chronic ethanol administration on drug metabo lism in isolated hepatocytes with em phasis on paracetamol activation. Bio chern. PharmacoL 29:1741-45 48. Peterson, F. J., Holloway, D. E., Erick son,

R. R., Duquette, P. H., McClain, C. J., Holtzman, J. L. 1980. Ethanol induction of acetaminophen toxicity and metabolism. Life Sci. 27:170511 49. Teschke, R., Stutz, G., Strohmeyer, G. 1979. Increased paracetamol-induced hepatotoxicity after chronic alcohol consumption. Biochem. Biophys. Res. Commun. 91:368-74 50. Strubelt, 0., Obermeier, F., Siegen, C. P. 1978. The inlluence of ethanol pre treatment on the effects of nine hepato toxic agents. Acta Pharmacol Toxicol 43:211-18 51. Sato, C., Matsuda, Y., Lieber, C. S. 1981. Increased hepatotoxicity of acetaminophen after chronic ethanol consumption in the rat. Gastroen terology 80:140-48 52. Wright, N., Prescott, L. F. 1973. Poten tiation by previous drug therapy of hepatotoxicity following paracetamol overdosage. Scott. Med J. 18:56-58 53. McClain, C. J., Kromhout, J. P., Peter son, F. J., Holtzman, J. L. 1980. Poten tiation of acetaminophen hepatotoxicity by alcohol. J. Am. Med Assoc. 244: 251-53 54. Critchley, J. A. J. H., Cregeen, R. J., BalaliMood, M., Pentland, B., Pre scott, L. F. 1982. Paracetamol metabo lism in heavy drinkers. Brit. J. Clin. Pharmacol 13:276--77P 55. Prescott, L. F., Critchley, J. A. J. H., Balali-Mood, M., Pentland, B. 1981. Effects of microsomal enzyme induction on paracetamol metabolism in man. Brit. J. Clin. Pharmacol 12:149-53 56. Gazzard, B. G., Hughes, R. D., Port mann, B., Dordoni, B., Williams, R. 1974. Protection of rats against the hepatotoxic effect of paracetamol. Brit. J. Exp. Pathol 55:601-5 57. Benedetti, M. S., Louis, A., Malnoe, A., Schneider, M., Lam, R., et al. 1975. Prevention of paracetamol-induced liver damage in nuce with glutathione. J. Pharm. Pharmacol 27:629-32 58. Malnoe, A., Louis, A., Benedetti, M. S., Schneider, M., Smith, R. L., et al. 1975. Effect of liposomal entrapment on the protective action of glutathione against paracetamol-induced liver necrosis. Biochem. Soc. Trans. 3:730-32 Annu. Rev. Pharmacol. Toxicol. 1983.23:87-101. Downloaded from www.annualreviews.org by Queen Mary & Westfield on 03/14/11. For personal use only.

100 PRESCOTI' & CRITCHLEY sodium sulfate in mice. Res. Commun. 59. Strubelt, 0., Siegers, C. P., Schiitt, A. 1974. The curative effects of cystea mine, cysteine, and dithiocarb in experi mental paracetamol poisoning. Arch. Toxicol 33:55-64 60. Piperno, E., Berssenbruegge, D. A. 1976. Reversal of experimental para cetamol toxicosis with Nacetylcys teine. Lancet 2:738-39 61. Piperno, E., Mosher, A. H., Berssen bruegge, D. A., Winkler, I. D., Smith, R.. B. 1978. Pathophysiology of acetaminophen overdosage toxicity: im plications for management. Pediatrics 1)2:880--89 (Suppl.) 62. Labadarios, D., Davis, M., Portmann, B., Williams, R. 1977. Paracetamol induced hepatic necrosis in the mouse relationship between covalent binding, hepatic glutathione depletion, and the protective effect of 4-mercaptopropio nyl-g1ycine. Biochem. Pharmacol 26: . 31- J5 63. Chiu, S., Bhakthan, N. M. G. 1978. Ex perimental acetaminophen-induced hepatic necrosis: biochemical and elec tron microscopic study of cysteamine protection. Lab. Invest. 39:193-203 64. Siegers, C. -Po 1978. Antidotal effects of dimethyl sulphoxide against paraceta mol-, bromobenzene-, and thioaceta mideinduced hepatotoxicity. J. Pharm. Pharmacol 30:375-77 65. Stramentinoli, G., Pezzoli, C., GaIli Kienle, M. 1979. Protective role of S adenosyl-L-methionine against aceta minophen-induced mortality and hepatotoxicity in mice. Biochem. Phar macol 28:3567-71 66. Yamada, T., Ludwig, S., Kuhlenkamp, I., Kaplowitz, N. 1981. Direct protec tion against acetaminoJ;?hen hepatotox icity by propylthiouracil. J. C/in. Invest 67:688-95 67. Prescott, L. F. 1980. Kinetics and me tabolism of paracetamol and phenace tin. Brit J. Clin. Pharmacol 100Suppl. 2):291985 68. Slattery, I. T., Levy, G. 1979. Acetaminophen kinetics in acutely poi soned patients. Clin. Pharmacol Ther. 25:184-95 69. Galinsky, R. E., Slattery, I. T., Levy, G. 1979. Effect of sodium sulfate on acetaminophen elimination by rats. J. Pharm. Sci. 68:803-5 70. Galinsky, R. E., Levy, G. 1979. Effect of N-acetylcysteine on the pharmacoki netics of acetaminophen m rats. Life Sci. 25:693-700 71. Slattery, J. T., Levy, G. 1977. Reduc tion of acetaminophen toxicity by Chem. Pathol Pharmacol 18:167-70 72. Mitchell, I. R. 1977. Host snsceptibility and acetaminophen liver injury. Ann. Intern. Med. 87:37778 73. Prescott, L. F., Newton, R. W., Swain son, C. P., Wright, N.,

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