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Furthermore purchase levitra extra dosage 40mg with visa, repeated doses of actvated charcoal enhance the faecal eliminaton of some drugs (that undergo enterohepatc or enteroenteric recycling) several hours afer ingeston and afer they have been absorbed 60mg levitra extra dosage with mastercard, for example phenobarbital, theophylline. Contraindicatons Poisoning by hydrocarbons with high potental for harm if aspirated; poisoning by corrosive substances-may prevent visualizaton of lesions caused by poison. Adverse Efects Black stools; vomitng, constpaton or diarrhoea; pneumonits-due to aspiraton. Calcium Disodium Edetate Pregnancy Category-B Indicatons Lead poisoning (acute and chronic) and lead encephalopathy. Dose Intravenous injecton Lead poisoning without encephalopathy: 1000 mg/m2/day as contnous infusion for 5 days. Lead encephalopathy: 1500 mg/m2/day by contnous intravenous infusion in 5% dextrose or 0. Lignocaine or procaine should be added to the injecton to minimize pain at the injecton site. Precautons Ensure adequate urine output, pre-existng mild renal disease; patents with lead encephalopathy and cerebral edema may experience a lethal increase in intracranial pressure following intravenous infusion, the intramuscular route is preferred for these patents. Adverse Efects Renal tubular toxicity which may lead to acute renal failure, fever, chills, lacrimaton, increased prothrombin tme, pain at intramuscular injecton site; hypotension; cardiac rhythm irregularites; thirst; headache; fatgue; malaise; urinary frequency; glycosuria; proteinuria; microscopic hematuria; histamine-like reactons. The only early features of poisoning, nausea and vomitng, usually setle within 24 h. Persistence beyond this tme, ofen with the onset of right subcostal pain and tenderness, usually indicates the development of liver damage which is maximal 3-4 days afer ingeston. In spite of a lack of signifcant early symptoms, patents who have taken an overdose of paracetamol should be transferred to hospital urgently. Administraton of actvated charcoal should be considered if paracetamol in excess of 150 mg/kg or 12g, whichever is smaller, is thought to have been ingested within the previous hour. N-Acetylcysteine or N-methionine protect the liver if given within 10-12 h of ingestng paracetamol. Acetylcysteine, given intravenously is most efectve within 8 h of overdosage, but is efectve for up to and possibly beyond 24 h. Alternatvely, methionine may be given by mouth provided the overdose was ingested within 10-12 h and the patent is not vomitng. Concur- rent use of actvated charcoal and specifc oral antdotes should be avoided. In remote areas methionine should be given, since adminis- traton of acetylcysteine outside hospital is not generally prac- tcable. Once the patent is in hospital the need to contnue antdote treatment can be assessed from plasma-paracetamol concentratons. Opioid Analgesic Overdosage: Opioids cause varying degrees of coma, respiratory depression and pinpoint pupils. Naloxone has a shorter duraton of acton than many opioids so close monitoring and repeated injectons are required depending on respiratory rate and depth of coma; naloxone may alternatvely be given by intravenous infusion. The efects of some opioids such as buprenorphine are only partally reversed by naloxone. Acute withdrawal syndromes may be precipitated by the use of naloxone in patents with a physical dependence on opioids or in overdosage with large doses; a withdrawal syndrome may occur in neonates of opioid-dependent mothers. Inital treatment of organophosphate or carbamate poisoning includes preventon of further absorpton by emptying the stomach by gastric lavage, moving patent to fresh air supply, removing contaminated clothing and washing contaminated skin. Organophosphates inhibit cholinesterases and thus prolong the efects of acetylcholine. Toxicity depends on the partcular compound involved and onset afer ingeston, skin exposure may be delayed. Atropine will reverse the muscarinic efects of acetylcholine and is used (in conjuncton with oximes such as pralidoxime) with additonal symptomatc treatment. Additonal treatment for carbamate poisoning is generally symp- tomatc and supportve. Atropine may be given but may not be required because of the rapidly reversible type of cholineste- rase inhibiton produced (oximes should not be given). Iron Poisoning and Iron and Aluminium Overload: Mortality from iron poisoning is reduced by specifc therapy with desferrioxamine which chelates iron. Before administra- ton of desferrioxamine the stomach should be empted by gastric lavage (with a wide-bore tube) within 1 h of ingestng a signifcant quantty of iron or if radiography reveals tablets in the stomach. It is used in the diagnosis of aluminium overload and to treat aluminium overload in patents with end- stage renal failure undergoing maintenance haemodialysis. Heavy Metal Poisoning: Heavy metal poisoning may be treated with a range of ant- dotes including dimercaprol, penicillamine, potassium ferric hexacyanoferrate and Sodium calcium edetate. Methaemoglobinaemia: Methylthioninium chloride can lower the levels of methae- moglobin in red blood cells and is used in the treatment of methaemoglobinaemia. In large doses, it may cause methae- moglobinaemia and therefore methaemoglobin levels should be monitored during treatment. Cyanide Poisoning: Cyanide poisoning may be treated with Sodium nitrite followed by Sodium thiosulphate. Following that infusion of atropine at 10-20 % of total inital dose required/hour; may require boluses during infusion. Contraindicatons In myasthenia gravis (but may be used to decrease muscarinic side-efects of antcholinesterases), paralytc ileus, pyloric stenosis and prostatc enlargement; refux oesophagits; unstable cardiac rhythm. Precautons Elderly, Down syndrome; angle-closure glaucoma; myasthenia gravis; prostatc enlargement; pyrexia; lactaton (Appendix 7b); interactons (Appendix 6a); pregnancy (Appendix 7c). Adverse Efects Constpaton, transient bradycardia (followed by tachycardia, palpitaton and arrhythmias), reduced bronchial secretons, urinary urgency and retenton, dilataton of the pupils with loss of accommodaton, photophobia, dry mouth, fushing and dryness of the skin. Occasionally, confusion (partcularly in the elderly), nausea, vomitng and giddiness; very rarely, angle-closure glaucoma may occur. Desferrioxamine Mesylate* Pregnancy Category-C Indicatons Acute iron poisoning; chronic iron overload; aluminium overload; primary hemochromatosis. Afer 1 to 2 h reduce to 3-4 mg/kg/h for the next 22-23 hrs (max dose is 100 mg/kg over 24 hrs). Precautons Renal impairment; eye and ear examinatons before and at 3-month intervals during treatment; aluminium encephalopathy (may exacerbate neurological dysfuncton); children under 3 years (may retard growth); lactaton; interactons (Appendix 6c). Adverse Efects Anaphylaxis; fushing, urtcaria, hypotension, shock (especially if given by too rapid intravenous infusion); gastrointestnal disturbances; fever, headache, arthralgia, myalgia; arrhythmias; renal impairment; blood disorders; neurological disturbances including neuropathy, paraesthesia and dizziness; convulsions; Yersinia and mucormycosis infectons; visual disturbances (including lens opacity and retnopathy) and hearing loss; rash; rarely, growth retardaton (in young children); rarely, acute respiratory distress syndrome; pain on intramuscular or subcutaneous injecton; local irritaton on prolonged subcutaneous infusion; reddish- brown discolouraton of urine. Precautons Hypertension; renal impairment (discontnue or use with extreme cauton if renal failure occurs during treatment); any abnormal reacton such as hyperpyrexia should be assessed; elderly; pregnancy (Appendix 7c); lactaton, alkalinize urine to pH of 7. Adverse Efects Hypertension, tachycardia; malaise, nausea, vomitng, abdominal pain, salivaton, lacrimaton, sweatng, burning sensaton in the mouth, throat and eyes; feeling of constricton in throat and chest; headache, muscle spasms, tngling of the extremites; fever in children; local pain and abscess at injecton site, iron toxicity potentaton. Child- 20 mg/kg/day administered in 3-4 divided doses, initatng treatment at 25% of this dose and gradually increasing to full dose over 2-3 weeks to minimize adverse reactons. Precautons Monitor throughout treatment including blood counts and urine tests; renal impairment; immunosuppressive treatment; avoid oral iron within 2 h of a dose; hepatc impairment; pregnancy (Appendix 7c). In Wilson’s disease, consider withdrawal if platelet count falls below 120 000/mm3 or white blood cells below 2500/mm3 or if 3 successive falls within reference range (can restart at reduced dose when counts return to reference range but permanent withdrawal necessary if neutropenia or thrombocytopenia recur). In Wilson’s disease warn patent to tell doctor immediately if sore throat, fever, infecton, non-specifc illness, unexplained bleeding and bruising, purpura, mouth ulcers or rashes develop. Adverse Efects Initally nausea (less of a problem if taken with food and on retring), anorexia, fever; taste loss (mineral supplements not recommended); blood disorders including thrombocytopenia, neutropenia, agranulocytosis and aplastc anaemia; proteinuria, rarely, haematuria (withdraw immediately); haemolytc anaemia, nephrotc syndrome, lupus erythematosus- like syndrome, myasthenia gravis-like syndrome, polymyosits (rarely, with cardiac involvement), dermatomyosits, mouth ulcers, stomatts, alopecia, bronchiolits and pneumonits, pemphigus, Goodpasture syndrome and Stevens-Johnson syndrome also reported; male and female breast enlargement reported; rash early in treatment (usually allergic-may need temporary withdrawal), late rashes (reduce dose or withdraw treatment). Flumazenil* Pregnancy Category-C Indicatons Antdote for benzodiazepine overdose, reversal of sedatve efects produced by benzodiazepenes administered during general anaesthesia or diagnostc or therapeutc procedures. Contraindicatons Epilepsy, neuromuscular blockade, hypersensitvity to benzodiazepines, patents of suspected tricyclic antdepressant overdose, raised intracranial pressure. Precautons History of seizures, panic atack, alcohol drug dependence, bleeding disorder, liver disease, head injury, respiratory depression, pregnancy (Appendix 7c). Adverse efects Convulsions, fatgue, injecton site pains, increased sweatng, facial erythema, raised intracranial pressure, agitaton, dizziness, abnormal vision, may cause complete heart block, fushing, transient increase in blood pressure and heart-rate. Methylene Blue (Methylthioninium Chloride)* Pregnancy Category-C Indicatons Acute methaemoglobinaemia. Dose Intravenous injecton Methaemoglobinaemia caused by high dosage of prilocaine infusion: 1-2 mg/kg intravenously over 5 minutes, followed immediately by a fuid fush of 15-30 ml to minimize local pain. Contraindicatons Severe renal impairment; methaemoglo- binaemia due to chlorate or induced by sodium nitrite in treatment of cyanide poisoning; afects ability to drive machinery. Naloxone* Pregnancy Category-B Schedule X Indicatons Opioid overdosage; postoperatve respiratory depression.

Miotto K order levitra extra dosage 40 mg on-line, Darakjian J generic 60mg levitra extra dosage overnight delivery, Basch J et al (2001) Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal. Hickman M, Carnwath Z, Madden P et al (2003) Drug-related mortality and fatal overdose risk: pilot cohort study of heroin users recruited from specialist drug treatment sites in London. Smyth B, Hoffman V, Fan J et al (2007) Years of potential life lost among heroin addicts 33 years after treatment. Shahani R, Streutker C, Dickson B et al (2007) Ketamine-associated ulcerative cystitis: a new clinical entity. European Monitoring Centre for Drugs and Drug Addiction (2009) Polydrug use: patterns and responses. Cruts G, Buster M, Vicente J et al (2008) Estimating the total mortality among problem drug users. British Medical Association (2007) Fetal alcohol spectrum disorders – a guide for healthcare professionals. British Medical Association (2004) Smoking and reproductive life – the impact of smoking on sexual, reproductive and child health. Cole C, Jones L, McVeigh J et al (2011) Adulterants in illicit drugs: a review of empirical evidence. Department of Health (2002) Getting ahead of the curve: a strategy for combating infectious diseases (including other aspects of health protection). Aldington S, Williams M, Nowitz M et al (2007) Effects of cannabis on pulmonary structure, function and symptoms. Bancroft A, Wilson S, Cunningham-Burley S et al (2004) Parental drug and alcohol misuse. Kübler D & Wälti S (2001) Metropolitan governance and democracy: how to evaluate new tendencies? In: Mclaverty P (ed) Public participation and developments in community governance. Officer J (2009) Trends in drug use of Scottish drivers arrested under Section 4 of the Road Traffic Act – a 10 year review. 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Kuepper R, Van Os J, Lieb R et al (2011) Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. Advisory Council on the Misuse of Drugs (2008) Cannabis: classification and public health. Arseneault L, Cannon M, Witton J et al (2004) Causal association between cannabis and psychosis: examination of the evidence. Zuckerman M (1994) Behavioural expressions and biosocial bases of sensation seeking. Schulteis G & Koob G (1996) Reinforcement processes in opiate addiction: a homeostatic model. Rende R & Slomkowski C (2009) Incorporating the family as a critical context in genetic studies of children: implications for understanding pathways to risky behavior and substance use. McArdle P, Wiegersma A, Gilvarry E et al (2002) European adolescent substance use: the roles of family structure, function and gender. A 4-year prospective examination of risk factors in a community sample of adolescents and young adults. Kokkevi A, Richardson C, Florescu S et al (2007) Psychosocial correlates of substance use in adolescence: a cross-national study in six European countries. Ledoux S, Miller P, Choquet M et al (2002) Family structure, parent–child relationships, and alcohol and other drug use among teenagers in France and the United Kingdom. Best D, Gross S, Manning V et al (2005) Cannabis use in adolescents: the impact of risk and protective factors and social functioning. McKeganey N, McIntosh J, MacDonald F et al (2004) Preteen children and illegal drugs. McVie S & Holmes L (2005) Adolescent smoking, drinking and drug use at ages 12 to 17. McIntosh J, MacDonald F & McKeganey N (2006) Why do children experiment with illegal drugs? Turner K, West P, Gordon J et al (2006) Could the peer group explain school differences in pupil smoking rates? North West Public Health Observatory (2010) Indications of public health in the English regions. The influence of personal, social and environmental factors on substance use among adolescents in Scotland. European Monitoring Centre for Drugs and Drug Addicition (2008) Drugs and vulnerable groups of young people. National Collaborating Centre for Drug Addiction (2005) Drug prevention among vulnerable young people. One problem among many: drug use among care leavers in transition to independent living. Newburn T & Person G (2002) The place and meaning of drug use in the lives of young people in care. Rugg J (2000) Making connections: tackling youth homelessness through a multi-agency approach. Fountain J, Howes S, Marsden J et al (2003) Drug and alcohol use and the link with homelessness: results from a survey of homeless people in London. Youth homelessness and substance use: report to the drugs and alcohol research unit. In: Kimler B & Hoorens S (eds) Understanding illicit drug markets, supply-reduction efforts, and drug-related crime in the European Union. 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The determination of the truth or falsity of information obtained in hypnosis would have to be based on outside criteria generic levitra extra dosage 40 mg with mastercard. Defensive Uses of Hypnosis Simulation of Hypnosis An interrogator who employs hypnosis may find that his subject apparently enters trance and gives the desired information generic levitra extra dosage 40mg with amex. The classical view holds that subjects are unable to deceive experienced hypnotists because hypnotic behavior "looks different" in a number of ways. Furthermore, claims have been made that in order to detect fraud the hypnotist need only suggest anesthesia to the subject and test for it with a painful stimulus. However, there are some indications in the literature that the detection of simulation is not a simple task. For example, Pattie (55), a thoroughly experienced investigator, felt that it was necessary to request his subjects sign forms reading as follows: I, realizing that the experiment performed on me will probably be published in a scientific journal, solemnly declare that I was not faking or imitating the hypnotic trance but that I was genuinely hypnotized and do not remember the events of the experimental periods. He has been unable to discover any physiological indices which differentiate simulators from deeply hypnotized subjects. In addition he also found that the overwhelming majority of apparently naive subjects are capable of simulating well enough to deceive even experienced hypnotists. Regarding pain, Orne (2) found and Shor (68) has confirmed that the simulating subjects generally tolerated higher levels of electric shock than did subjects in deep hypnosis. Using a fairly wide spectrum of behavioral tasks, they found it was not possible to differentiate unequivocally between real and simulating subjects. However, certain kinds of behavior were observed only in the true hypnotic subjects, although not in all of them. Typically, this mixture controverts the rules of logic normally operating in the waking state. For example, a subject might describe an hallucination of an individual sitting in a chair as "I can see Mr. However, trance logic helps discriminate neither those real subjects who do not manifest this behavior nor those simulators who have been taught to demonstrate it. Considerable research remains to be done on the recognition of simulating behavior. At our present state of knowledge it is vital to bear in mind that the deep hypnosis is essentially a clinical diagnosis. Although under some circumstances this diagnosis can be made with a high degree of reliability, definitive signs of deep trance have not yet been identified. Until such pathognomic signs are developed, a subject trained to employ trance logic may not find it too difficult to deceive an interrogator. Training in Hypnosis in Anticipation of Future Interrogation Three related suggestions have been made for what may be called the defensive use of hypnosis. Thus, Estabrooks (22) proposed that hypnosis might be useful in (a) preventing subsequent trance induction in captured personnel, (b) causing personnel possessing sensitive information to develop amnesia for this material in case of capture, and (c) enabling captured personnel to resist stressful and painful -197- interrogations by training them to develop anesthesia and analgesia when required. Any objective evaluation of these proposals is made difficult by the paucity of relevant studies, and we are forced to extrapolate from the meager evidence available. In judging the practicality of these suggestions it is necessary first of all to take into account that only approximately 20%, of the military population can be expected to go into a sufficiently deep somnambulistic state conducive to such training. Furthermore, both the full cooperation of the military personnel involved and the availability of competent hypnotists would have to be taken for granted. The proposal to train individuals not to do something they are able to avoid anyway appears to be of doubtful utility. It may be sufficient to warn them of possible techniques of trance induction and inform them that they are able to resist, if they so desire. In fact, the question ought to be raised whether training in hypnosis may not precondition an individual for subsequent trance induction, regardless of suggestions that they ought to resist hypnosis. There is no evidence that training in hypnosis predisposes subjects toward trance induction with or without their cooperation. However, there is considerable evidence that training in hypnosis makes subsequent trance induction easier with only token cooperation by the subject. Effectiveness of Posthypnotic Suggestions Designed to Prevent Subsequent Trance Induction. As a matter of routine, subjects are given the suggestion that they will enter hypnosis only with a competent psychologist or physician, and only if they desire to do so. Nevertheless, in several instances these experimental subjects have permitted themselves to enter hypnosis with individuals whom they -198- knew to be inexperienced. At times they have reported compulsive laughing jags just before falling asleep, in line with the posthypnotic suggestion, which did not, however, prevent their entering hypnosis. Two subjects trained in this manner entered hypnosis while watching a stage demonstration from the audience, again despite suggestions to the contrary. This observation has been confirmed by Sutcliffe (71), who has had similar experiences. Furthermore, the writer has himself hypnotized three subjects who had received specific suggestions from other hypnotists that they would be unable to enter trance with anyone else. It has been noted during psychotherapy that patients who have had considerable hypnotic experience will sometimes use the trance state as a defense mechanism in order to avoid awareness of painful material. Such material will emerge during spontaneous trance and will subsequently be repressed when the patient emerges from the hypnotic state. The writer has observed this several times in clinical situations and it has been reported in personal communications by several other therapists. Since hypnosis may occur spontaneously in therapeutic situations as a means for avoidance of stressful situations, it may well occur equally spontaneously in other stress situations, and could be utilized by an alert interrogator. We have been able to terminate hypnosis in several instances when trance had been induced by inexperienced hypnotists who were unable to terminate it. In these instances it was necessary to establish a hypnotic relationship with an uncommunicative subject in deep hypnosis. Contrary to popular belief, this can be accomplished readily and rapidly usually in less than half an hour. These findings are relevant to the dangers of spontaneously occurring trance during interrogation. Thus, although the interrogator may not have induced the trance, he could assume the role of hypnotist and communicate with the subject. If the hypnotist has sufficient skill and experience, he might well be able to utilize the very suggestions given against entering hypnosis as the necessary wedge to induce hypnosis. Thus, if the suggestion has been given that the subject will not enter trance but -199- will laugh, and the hypnotist observes the subject beginning to laugh, he might suggest that the subject will begin to laugh more and more and will laugh so hard that he will become exhausted and go to sleep. In the same manner a posthypnotic suggestion of a headache or any other subjective experience which aught to prevent hypnosis can be utilized as a means of inducing it. Another danger of the hypnotically trained soldier is the greater likelihood of spontaneous appearance of trance in a stressful situation such as interrogation. Hence, the use of trance as a means of preventing subsequent trance induction by a potential captor has inherent dangers. A blanket suggestion to forget all sensitive material will frequently fail to take effect. It is well known that the effectiveness and permanency of a hypnotic suggestion are directly related to the concrete definition of a specific task. As a rule, general suggestions such as blanket amnesia have unpredictable effects even in very good subjects. It may be possible to suggest that a soldier only remember his name, rank, and serial number in the event of capture. However, this raises not only the serious question of whether this could be accomplished but also of whether it might deprive the soldier of information which may be vital to him during captivity. A state of severe psychopathology would be artificially induced, which may be adaptive in some respects but extremely disturbing in others. The decision of what to say during interrogation would be made for the soldier beforehand. The inevitable impoverishment of knowledge and loss of ego control would furnish the interrogator a very effective way of controlling his captive. The captive would be seriously distressed by the feeling of loss of self-evident and necessary information, and the interrogator would be a able to assume the role of a helpful individual ready to assist the recall of memory. Such a quasi-therapeutic relationship would inevitably produce an alliance between captive and interrogator with concomitant formation of a strong positive relationship. Recall would eventually take place, as in the treatment of amnesia under normal circumstances. In other words, the induced psychopathology may be sufficiently -200- disturbing to the captive to make him the easy victim of any technique aimed at relieving his discomfort.

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In some instances cheap levitra extra dosage 40 mg without prescription, an agent buy levitra extra dosage 60 mg on-line, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group. Group 3—The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circums- tances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is ina- dequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category. This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents or mixtures for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity in experimental animals, consistently and strongly supported by a broad range of other relevant data, may be classified in this group. For several compounds evaluated in this volume, no data were available on carcino- genicity in experimental animals, and this limited the possibility of a comprehensive evaluation of their carcinogenic risks to humans. Although they may not have been tested for carcinogenicity, the Working Group suspected that studies might have been conducted by pharmaceutical companies but never published. The Working Group encourages pharmaceutical companies and cognizant governmental agencies to make available all studies of carcinogenesis that have been, or will be, carried out on pharma- ceutical agents in the form of publications or technical reports. Two chemicals were tested for carcinogenicity in genetically engineered mice which are particularly susceptible to induction of tumours at certain sites through specific mechanisms. The use of such animals for evaluation of the carcinogenicity of chemicals has been reviewed (McGregor et al. Some, but not all, of these transgenic (‘knockout’) models can be considered the laboratory counterparts of certain rare human genetic syndromes, and the models may be particularly useful for testing drugs to be administered to individuals with such syndromes. Also, genetically engineered mice that lack one copy of an essential tumour suppressor gene, such as p53, model the situation in which a functioning copy of the suppressor gene has been lost in the somatic cells of a normal individual through a stochastic process. The transgenic models may therefore also be useful for studying the mechanism or mode of action of chemicals and, in parti- cular, to test genetic targets of carcinogenicity. Because of the limited database on the responses of particular genetically engineered mice to chemical carcinogens, however, the results of bioassays with these animals must be interpreted with caution. In two large, well-conducted trials, initial therapy with multiple drugs followed by simplification of the regimen in a maintenance phase has been shown to be less effective than continued multi-agent therapy (Havlir et al. Centers for Disease Control and Prevention, 1998; Gazzard & Moyle, 1998) on the goals of combination therapy, monitoring and recommended combinations. These beneficial results may, however, mask potential carcinogenic effects of the antiviral agents. Much of the evidence on the possible carcinogenic effects of antiretroviral agents in humans is derived from trials designed to evaluate the efficacy of these agents in the treatment of patients with immunosuppression of varying severity. In consequence, the survival of infected patients was relatively poor and the opportunity for long-term follow-up to assess cancer risk was limited. In addition, the occurrence of cancer may have been underascertained, and in many of the studies, no formal, appropriate analyses of cancer rates were presented. While the situation is similar in other developed countries, most developing countries are currently unable to offer these therapies because of their cost. The topological changes mediated by these enzymes are important for chromosomal replication and conden- sation, and disruption of their function may prevent accurate chromosomal segregation and increase recombination. Such combinations may confound analysis of the association of specific agents with leukaemia. Furthermore, in some studies in which patients were treated with etoposide and/or teniposide, the authors used various empi- rical conversion factors to derive an ‘equivalent dose’ of etoposide from that of teni- poside. The conversions were based, however, on the therapeutic effects rather than on metabolic considerations or on possible leukaemogenic potency at a given dose. Such studies do not allow evaluation of the carcinogenicity of either compound as a single agent. Additional chromosomal and genetic changes may occur in secondary leukaemias (Corral et al. The suspension may also contain carboxymethylcellulose sodium, flavours (banana, orange), glycerol, methyl 4-hydroxybenzoate, microcrystalline cellulose, propyl 4-hydroxybenzoate, sorbitol and vanillin. The cream may also contain cetostearyl alcohol, glycerol monostearate, liquid paraffin, macrogol stearate, petroleum jelly, poloxamer 407, poly- oxyethylene fatty acid, propylene glycol, sodium lauryl sulfate and soft white paraffin. Aciclovir sodium is available as a powder for injection or intravenous infusion in dosages of 25 and 50 mg/mL. After reconstitution with sterile water for injection, aci- clovir sodium solutions containing 50 mg/mL aciclovir, have a pH of approximately 11 (10. The following impurities are limited by the requirements of the British and Euro- pean pharmacopoeias: 2-amino-9-{[2-(acetyloxy)ethoxy]methyl]}-1,9-dihydro-6H- purin-6-one; 2-amino-1,7-dihydro-6H-purin-6-one; 2-amino-7-{[2-hydroxyethoxy]- methyl}-1,7-dihydro-6H-purin-6-one; 2-amino-9-{[2-(benzoyloxy)ethoxy]methyl}- 1,9-dihydro-6H-purin-6-one; 6-amino-9-{[2-hydroxyethoxy]methyl}-1,3-dihydro-2H- purin-2-one; 2-acetamido-9-{[2-hydroxyethoxy]methyl}-1,9-dihydro-6H-purin-6-one; 2-acetamido-9-{[2-(acetyloxy)ethoxy]methyl}-1,9-dihydro-6H-purin-6-one; and 2-ace- tamido-9-{[2-(benzoyloxy)ethoxy]methyl}-1,9-dihydro-6H-purin-6-one (British Phar- macopoeial Commission, 1996; Council of Europe, 1998). Those that have been dis- continued include Acicloftal, Aciviran, Clovix, Viclocir, Vipral and Zovir. Trade names for aciclovir sodium include Acic, Aciclovir Alonga, Aciclovir- Austropharm, Aciclovir Biochemie, Aciclovir Brahms i. By 1988, aciclovir had been licensed in more than 40 countries, and it was estimated that intravenous and oral preparations had already been used in over 10 million courses of treatment (Tilson, 1988). It is also the drug of choice for treatment of herpes simplex encephalitis (American Hospital Formulary Service, 1997; Medical Economics Data Production, 1999). Aciclovir is frequently given orally in the management of first and recurrent epi- sodes of mucocutaneous herpes in selected patients, for the acute treatment of herpes zoster (shingles) and for the treatment of chickenpox in adults and children. The oral doses of aciclovir for adults range from 200 mg every 4 h (while awake) to 800 mg three times a day for 5–10 days. The oral dose for treatment of chickenpox and herpes zoster is 800 mg aciclovir every 4 h for 5–10 days. Topical treatment of the affected skin or mucous membrane (not conjunctival) with 5% ointment or cream is given up to every 3 h. For ocular herpes simplex keratitis, a 3% ointment may be applied five times daily up to every 4 h until 3 days after healing (Gennaro, 1995; American Hospital Formulary Service, 1999; Royal Pharmaceutical Society of Great Britain, 1999). In young children, aciclovir is given intravenously at 250–500 mg/m2 of body- surface area every 8 h. In older children and adults, intravenous injections are given at 5–10 mg/kg bw every 8 h (Thomas, 1998; Royal Pharmaceutical Society of Great Britain, 1999). Doses of aciclovir should be reduced in patients with renal impairment (American Hospital Formulary Service, 1999; Royal Pharmaceutical Society of Great Britain, 1999). The patients were treated with aci- clovir at various doses, continously and/or for five-day periods for treatment of epi- sodes of infection. In 389 patients who were still under treatment and active surveillance five years after the beginning of the first study, one cancer each of the thyroid, pancreas (resulting in death) and ovary and one malignant melanoma were observed (Goldberg et al. Thus, the numbers of cancers that were expected were not given, and the relative risk could not be calculated. Furthermore, the low age of the patients, indicating a small expected number of cancers, resulted in poor statistical power to identify an effect. Tissues from control animals and those at the high dose were evaluated histologically. The mean body weights of females at the intermediate and high doses were 2 g higher than those of the control group (p < 0. Treatment did not affect survival in males, and females at the two higher doses had significantly (p < 0. Tissues from control animals and those at the high dose were evaluated by microscopy. Treatment did not affect survival rates, except that of females at the inter- mediate dose, which was significantly shorter than that of control females (p < 0. No increase in the incidence of benign or malignant tumours was observed (Tucker et al. This series of events occurs readily in herpesvirus-infected tissues but poorly in normal tissues, since the initial phosphorylation is accomplished mainly by a herpesvirus-specific deoxynucleoside (thymidine) kinase (Elion, 1983; Laskin, 1984; King, 1988). The aci- clovir triphosphate is formed readily and is more persistent than the parent compound, remaining for several hours in cultured cells. When taken orally, the drug is poorly absorbed from the gastrointestinal tract, with a reported bioavailability of 15–30%, owing to its limited solubility in an aqueous environment; therefore, intravenous dosing is considered more effective (O’Brien & Campoli-Richards, 1989). The drug is widely distributed throughout the body and has been found in plasma, kidney, lung, liver, heart, vagina, brain, cerebrospinal fluid, aqueous humor, saliva and skin (Laskin, 1983; de Miranda & Blum, 1983; Rogers & Fowle, 1983; Brigden & Whiteman, 1985; O’Brien & Campoli-Richards, 1989; Vergin et al. After oral doses of 200 mg taken four to five times daily or 400 mg taken two to three times daily, the peak plasma concentration is about 2 μmol/L (0. After oral administration, the amount of aciclovir in the kidney and lung was actually higher than that in plasma, while the concentration in cerebrospinal fluid was half of that in plasma (Blum et al.

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