Levitra with Dapoxetine

By N. Domenik. West Virginia State University.

Acidic compounds tend to have better bioavailability characteristics discount levitra with dapoxetine 40/60 mg, because in the acidic pH 6 purchase levitra with dapoxetine 40/60mg on-line. In other words buy levitra with dapoxetine 40/60mg with mastercard, acidic compounds have a lower risk than basic compounds of entering the liver and being degraded buy 40/60 mg levitra with dapoxetine amex. As another beneft for slightly acidic drugs, highly ionized drugs, either acidic or basic, may also cause patient discomfort due to direct irritation of the gastrointesti- nal lining. Taken together what we have discussed, slightly acidic drugs are favored for improved gastrointestinal absorption, less frst-pass metabolism, and less mucosal irritation. In general, hydrophobic compounds are often favored for pharmacological activity over hydrophilic compounds due to desolvation entropy [14]. Simply put, a hydropho- bic compound is more entropically favored to release water molecules before binding to the often hydrophobic active site of the target biological substance. Hydrophobic compounds need to spend less energy to part with water because they have fewer interactions with water. Interestingly, compounds with high hydrogen bond poten- tials can interact with water and would thus exhibit unfavored desolvation entropy. Hence, lipophilicity is pre- ferred in both pharmacodynamics and pharmacokinetics. One of the goals of rational drug design is to optimize lipid solubility for membrane permeation while retaining a signifcant pharmacological activity. However, simply increasing the lipid solubility of a drug may have undesired effects such as decreasing water solubility and bioavail- ability, increasing plasma protein binding with a high affnity, and increasing uptake by the liver and spleen macrophages. Such inad- vertent binding delays and prevents the drug from reaching its target site of action. Hence, the less bound a drug is, the more effciently it can traverse cell membranes. Acidic and neutral drugs will primarily bind to albumin, which is basic, or to lipopro- tein when albumin becomes saturated. Only the unbound drug exhibits pharmacologic effects, is metabolized and is excreted. Generally speaking, protein binding should be minimized to reduce unpre- dictable pharmacokinetic factors. The activity of a thrombin inhibitor is lower if it has high plasma protein bind- ing [15]. Dabigatran is a univalent direct thrombin inhibitor that was derived from a peptide drug. In the design of dabigatran, a carboxylate function was purposely imple- mented to increase hydrophilicity, which would decrease plasma protein binding and increase inhibitory activity (Figure 8. The carboxylate function was attached such that it would not greatly affect the interactions between the drug and the target enzyme, thrombin. Indeed, for certain cases, a fne tuning of a drug design could potentially reduce plasma protein binding. This high protein binding decrease drug effcacy, and a larger quantity of the drug would need to be given to compensate. This increase in pill burden subsequently introduces risks of adverse drug reactions, compliance, and cost issues. Hence, despite its lower plasma protein binding profle, hepatic metabolism of indinavir greatly reduces its biological half-life to an impractical 2 h. The fne balance between plasma protein binding and hepatic metabolism has yet to be resolved. However, one should recall that a hydrophilic drug also tends to have higher clearance than a lipophilic drug, which has higher membrane permeability (Section 8. Of course, the choice of salt form for ionized compounds would affect the extent of solubilization. It should be noted that the water solubility factor has already been taken into account by the distribution coeffcient, because water solubility correlates well with log D6. Moreover, one should not forget that from a very simplistic viewpoint, the word “hydrophilic” suggests that the compound would “love to be in water. A way of improving water solubility in a peptide drug is to introduce a water solubilization moiety. Phospholipids are a major component of cell membranes by forming a lipid bilayer within the membrane. Generally speaking, phospholipids have an amphipathic character where the “head” of the molecule is a hydrophilic phos- phate group, while the “tail” is lipophilic. Much like a phospholipid, the structure of amprenavir can be considered as the lipophilic “tail” and the phosphate group as the hydrophilic “head. Consequently, fosamprenavir is a slow-release version of amprenavir that reduces the “pill burden” of the standard regimen of amprenavir. It is noteworthy that plasma protein binding for fosampre- navir is still theoretically 90% because conversion to the parent drug, amprenavir, is needed before reaching the bloodstream. The depicted spacer demonstrated an improvement in water solubility from less than 0. Different spacers would produce different prodrugs with different water solubility and conversion time values. This means that the water solubility and conversion time of the prodrug can be controlled by the structural features of the spacer. In the exemplifed cleaner strategy that does not require a spacer, water solubility was 13 mg/mL with a conversion half-life of less than 1 min. Thus, we have shown that prodrugs of drugs with little water solubility could exhibit much improved water solubility profles and modifable conversion time. Lipinski’s rule attempts to associate the drug’s susceptibility to metabolic reactions with its ability to form hydrogen bonds. A hydrogen atom attached to a relatively electronegative atom is a hydrogen bond donor. An electronegative atom is a hydrogen bond acceptor, regard- less of whether it is bonded to a hydrogen atom or not. Drugs with a high hydrogen-bond potential have a higher risk of undergoing acid–base reactions or reactions that are catalyzed by enzymes. These reactions often change the chemical structure of the drug, thereby deactivating the drug and increase the hydrophilicity of the drug thus facilitating clearance of the drug from the body. In contrast to Lipinski’s oversimplifed rule on hydrogen bond acceptors and donors, several structural characteristics, that is, chemical functional groups have been strongly correlated with oral bioavailability. Certain functional groups are more susceptible to transformations in the gut wall, liver, or conjugated in several ways. For a functional group, the signifcance in reducing bioavailability is related to the metabolic reactivity of the function. Structural functions that can undergo metabolic reactions have been parameterized into quantitative structure–activity relationship equations to predict oral bioavailability [13]. One should note that functionally reactive groups and hydrogen bond potential contribute to hydrophilicity. Readily oxidized entities, thiols and dihydropyridines, have the most pronounced effect on oral bioavailability. The reactions are rapid and produce hydrophilic metabo- lites that are readily cleared from the body. Peptide drugs containing thiol containing amino acid cysteine are often promptly deactivated. The formation of a glucuronide metabolite is an example of a sugar-conjugated phenol group. Functional groups that are known to easily undergo hydrolysis include esters, lactones, β-lactams, and alkyl carbamates. Metabolic carbon oxidative processes play a signifcant role in reducing bioavail- ability, where para-hydroxylation of an activated aromatic ring has the largest effect, followed by aryl methyl and allylic groups contributing to a lesser extent. Reduc- tion of ketones may contribute to the same extent as aromatic para-hydroxylation on decreasing bioavailability. As examples, amino acids serine and threonine each possesses an alcoholic hydroxy group. However, certain compounds, such as lidocaine and ketamine, may undergo rapid dealkylation. The reactivity of aromatic and heterocyclic amines, hydrazines, hydrazones, and amidines to metabolic acetylation and oxidation seems to be proportional to their pKa values. In other words, their signifcance in metabolic deactivation is related to their pKa values. Issues with metabolic transformations and conjugations can be addressed by further improving on the structure of the peptide drug.

Evidence is continuing to emerge on the adverse effects of a number of specific drugs: • babies born to opioid-dependent mothers may suffer neonatal abstinence syndrome generic levitra with dapoxetine 40/60mg with mastercard. They are commonly added to enhance or mimic the effects of an illicit drug (eg procaine in cocaine) discount levitra with dapoxetine 40/60mg amex, or to facilitate its administration (eg caffeine in heroin) buy levitra with dapoxetine 40/60mg overnight delivery. A more detailed overview of the evidence of drug adulterants levitra with dapoxetine 40/60 mg cheap, including information on the potential reasons for their inclusion and the health effects, is provided in Appendix 5. Dependence per se is not necessarily significantly harmful but the risk of harm is intrinsically raised because of the chronic drug use. In the case of heroin, for example, as noted previously, its chronic use is characterised by profound psychological and physical dependence. Different drugs vary in their propensity to give rise to dependence (dependence potential, see Glossary). Illicit drugs such as heroin, crack cocaine and methamphetamine – as well as the licit drugs, tobacco and alcohol – rank highly in their tendency to encourage repeated use. Some of these social harms result from the illegality of the drugs, while others are caused by factors such as the psychopharmacological effects of the drug. Drug law offences include possession, dealing or trafficking of drugs covered under the Misuse of Drugs Act 1971. Illicit drug use is also associated with a number of other criminal behaviours, which in turn are linked to underlying socioeconomic factors. Dependent use of drugs is associated with increased levels of acquisitive crime – such as theft, street robbery, car break-ins and burglary – as a means to fund habits. The link between illicit drug use and crime is complex and multifaceted, as not all drug types are associated with all forms of crime, and some drugs are not associated with crime at all. In England and Wales, according to the Home Office Arrestee survey 2003-2006, 81 per cent of regular (at least weekly) users of heroin or crack reported having committed acquisitive crime in the 12 months prior to arrest, compared to 30 per cent of respondents who did not use heroin or crack regularly (ie did not use them weekly). A high level of drug use in the community is also linked to unsafe communities, through increases in violent incidents, antisocial behaviour, prostitution, begging, unusable public spaces, and people sleeping rough. While drug use cannot be causally linkedd to road crashes, a number of small-scale studies provide some information on its prevalence: • in 1989, random samples from a number of road traffic accident fatalities showed that only 3 per cent of the drivers involved in accidents had been driving with drugs in their systems, compared to 35 per cent for alcohol (25% over the legal limit)113 • a 2001 study of fatal road accident casualties found that at least one impairing prescription or illegal drug was detected in 24. There was a substantial increase in the incidence of cannabis in fatal road casualties, from 2. The authors found that those who had consumed drugs were no more likely to have also consumed alcohol than drivers who had not used drugs – when considering drivers over the legal limit for blood alcohol, there was no significant difference (at the 5% significance level) between those with no drugs, single drug use and multiple drug use: 20. These include costs to the individual, such as the costs related to premature death, drug-related illness and the loss of earnings through criminality/imprisonment, sickness, temporary or permanent unemployment and reduced educational attainment. The costs to society can be divided into four broad categories: • healthcare service costs: including costs to primary care services and hospital services (A&E, medical and surgical inpatient services, paediatric services, psychiatric services, and outpatient departments) • costs of drug-related crime, disorder and antisocial behaviour: including costs to the criminal justice system, costs to services (eg social work services), costs of drug-driving, and the human cost of drug-related harm (eg domestic abuse, assault) • loss of productivity and profitability in the workplace: including costs to the economy from drug-related deaths and drug-related lost working days • impact on family and social networks: including human and emotional costs such as breakdown of marital and family relationships, poverty, loss of employment, domestic and child abuse, and homelessness. The most recent data available indicate that there are around 6,400 admissions for drug-related mental health and behavioural disorders each year in England, and over 12,500 admissions for drug poisoning. The criminal justice costs associated with illicit drug use, including prison costs, are discussed in more detail in Section 6. Summary • The use of illicit drugs is associated with a range of physical, psychological and social harms. These are affected by the dosage of drug, the pattern of drug use and the mode of administration. The vast majority of these deaths are in men and many are associated with polydrug or polysubstance use. Ecstasy-related deaths are very rare and deaths from cannabis overdose do not occur. These can result from the illegality of the drugs, or from factors such as the psychopharmacological effects of the drug. They have associated costs for the individual related to loss of earnings, reduced educational attainment and damage to personal relationships. High levels of drug use in a community are linked to unsafe communities because of the associated social problems. The relative levels of harm for the different drugs correlate poorly with the legal classification of drugs. The economic and social costs of Class A drug use in 2003-2004 in England and Wales were estimated to be £15. There is general consensus that drug use is a multifaceted ‘biopsychosocial’ phenomenon. This term is used to encapsulate that drug use is influenced by biological, psychological and social factors. Although distinct theories have been developed for each of these factors, which are discussed in this chapter, there is often a degree of overlap between these explanations. Using only one model to explain why people use drugs may not be appropriate to describe all types of behaviour. In addition to biopsychosocial influences, the extent to which drugs are obtainable and aspirational is thought to influence their use. It should be noted that there are similarities between what influences illicit drug use and what influences alcohol and tobacco use. The following case study illustrates the multifactorial aetiology of drug dependence. He has not used any heroin or other opioid drugs for the past four years and has not injected at all for the past eight years. His main problem is his alcohol use, which has been increasing ever since he came into treatment and became much worse when he stopped using heroin. He is now drinking about two cans of strong lager (10 units) several days a week, although he is sometimes able to stay off alcohol for two or three days per week. He was offered treatment then, but as he did not want to have a liver biopsy did not want to be referred. Two years ago he was admitted to hospital with jaundice and ascites and diagnosed with advanced hepatic cirrhosis. He did well during that admission, and following medical treatment improved substantially and was able to return to work. This was not started though, as he continued to drink alcohol after a short (3-month) period of abstinence. His mother was depressed and he was taken into care when his behaviour became unmanageable as a teenager. As an older adolescent, he was caught by the police a few times for minor acquisitive offending and served one short sentence in a young offenders’ unit. He spent some time in South America in his 20s but returned to England and started working as a computer technician. He still works freelance and is able to get work from a friend who runs his own business. He has a keyworker (see Glossary) but does not use the sessions well and generally just wants to collect a prescription. Again he did well and was booked in to see the hepatitis clinical nurse specialist to talk about interferon and ribavarin treatment. The hepatologist explained to him in detail the prognostic implications of his liver damage and the nature of the treatment. He was also advised to stay on methadone (for a discussion of methadone therapy, see Chapter 8), as further withdrawal symptoms may have jeopardised his ability to stay free of illicit drugs and alcohol. Case study details provided by Dr Emily Finch, a consultant addiction psychiatrist. This means that not every person will themselves carry the gene or become drug dependent. Evidence for the heritability of drug use is derived from a range of research designs. The most robust evidence for the genetic influence of drug use comes from twin studies; research using family- and adoption-based designs has also shown an effect. Given the breadth of high-quality research using twin studies, this section will only briefly examine family- and adoption-based designs, before focusing on twin studies. While there is evidence that substance use disorders cluster in families, it is not clear from family-based designs whether these can be wholly attributable to heritable factors. This is because the family design cannot distinguish between whether the cause of familial similarity is genetic or environmental in nature. Adoption studies are based on a comparison of the concordanceb between offspring behaviour and the characteristics of both the adoptive and biological parents.

When calculating the elimination rate constant from two different plasma concentrations best levitra with dapoxetine 40/60 mg, the concentrations should be at least one half-life apart to determine a reasonably accurate slope of the line generic levitra with dapoxetine 40/60mg. Drug concentrations less than one half-life apart can incur great errors in the estimate of the elimination rate constant (K) buy 40/60mg levitra with dapoxetine. With the information just determined discount 40/60 mg levitra with dapoxetine with amex, calculate when the next vancomycin dose should be given and what it should be. Assume that the plasma vancomycin concentration should decline to 10 mg/L before another dose is given and that the plasma concentration desired 2 hours after the infusion is complete is 20 mg/L. First, we must know the time needed for the plasma concentration to decline to 10 mg/L. It can easily be calculated from the known plasma concentrations, the elimination rate constant, and the desired trough plasma concentration: -Kt Ctrough = Cpeak(steady state)e where: Cpeak(steady state) = observed concentration of 29 mg/L, -1 K = elimination rate constant (0. Next, we determine dosing interval and maintenance dose as follows: (See Equation 13-4. Rearranging to solve for K0: Because 350 mg is used instead of 366 mg, the peak will be 19. Finally, we must check to see what our trough concentration will be after rounding both dose and dosing interval. Plasma concentrations after loading dose of vancomycin in patient with renal impairment (29 mg/L at 2 hours and 17. She was given a 1000-mg vancomycin loading dose and is now receiving 500 mg (infused over 1 hour) every 12 hours. Predict the steady-state Cpeak and Ctrough from this dose, using population average values for K and V. How do they compare to the recommended Cpeak of 18-26 mg/L and Ctrough of 5-10 mg/L? The equation for a one-compartment, intermittent-infusion drug can be used to solve for Cpeak(steady state) and Ctrough(steady state): (See Equation 13-3. By application of the general equation for a one-compartment, first-order, intermittently infused drug, we get: (See Equation 13-3. Therefore: This value is within the desired Cpeak range of 18-26 mg/L for this patient. Then: Using this new dosing interval of 48 hours, we can solve for the maintenance dose that gives our desired Cpeak and Ctrough of 25 and 5-10 mg/L, respectively: (See Equation 13-3. Then: Note that this answer can range from 1245 to 1345 mg, depending on the amount of rounding used in this complex calculation. Try to develop a step-by-step model to walk you through the calculations, such as: 1. While she was on this dose, plasma concentrations from the laboratory were out of the desired range, confirming that this dose was wrong. Cpeak (drawn 2 hours after the end of a 1-hour infusion) was 23 mg/L, and Ctrough was 14 mg/L (Figure 13-6). By substituting the above values, we obtain: -1 Note the differences between the previously estimated K and V of 0. Now, to calculate the best dosing interval to get a Cpeak of 25 mg/L and a Ctrough(steady state) of approximately 7 mg/L, we would use: (See Equation 13-4. Then: Being conservative, we would round this dose to 800 mg, which would slightly lower the actual peak value from 25 to approximately 24 mg/L. We can use the following equation, where t′′ is now the number of hours between the peak and trough (t′′ = τ - t - t′). How long will you hold this dose before beginning the new regimen of 800 mg every 24 hours? The formula for calculating the number of hours to hold the dose is: -Kt Ctrough(desired) = Ctrough(actual)e (See Equation 3-2. This formula is an application of the general formula (see Lesson 3) that the concentration at any time equals a previous concentration multiplied by the fraction remaining: -Kt C = C0e where: C = drug concentration at time t, C0 = drug concentration at some earlier time or time zero, and -Kt e = fraction of original or previous concentration remaining. The same equation can be used to determine the amount of time to hold the dose from the last Cpeak of 23 mg/L. Note that you can calculate time to hold using either Cpeak or Ctrough; both methods give the correct answer. We can estimate how many drug half-lives to wait for her concentration to approach our desired amount of 7 mg/L as follows. Because a concentration of 7 mg/L is acceptable, we only need to hold the next scheduled dose for an additional 13 hours before beginning the new dose of 800 mg every 24 hours. He has been treated with 750 mg of vancomycin every 16 hours for the last 10 days. His most recent Cpeak was 26 mg/L (drawn 2 hours after a 1-hour vancomycin infusion), and his most recent Ctrough was 9 mg/L. You are asked to determine if it is possible to obtain a Cpeak of approximately 25 mg/L and a Ctrough of around 5 mg/L with a once-a-day dose. Before answering this question, we must be sure we know what the question is asking. By substituting the above values, we obtain: Next, we use our general equation to solve for K0 (maintenance dose) with our predetermined 24- hour dosing interval: where: Cpeak(steady state) = desired peak concentration at steady state (25 mg/L), K0 = drug infusion rate (also maintenance dose you are trying to calculate, in milligrams per hour), V = calculated volume of distribution (33. By substituting the above values, we obtain: This dose could be rounded up or down to 800 or 900 mg given every 24 hours. Remember that the desired peak concentration of 25 mg/L will be slightly higher or lower if the dose is rounded up or down, and the adjusted desired peak can be calculated as shown in previous cases. Finally, we must check to see that our Ctrough concentration with this dose is acceptable (assume a dose of 900 mg was given for a desired peak of 26. Even though once-daily dosing is convenient for this patient, we need to consider whether the trough concentration will be adequate for this patient with endocarditis. Examples of such recommendations can be found in Morbidity and Mortality Weekly Report (e. Individualization of theophylline dosage maximizes therapeutic benefit while minimizing adverse effects. Theophylline is used less frequently in the treatment of asthma as beta-2 agonists and anti-inflammatory agents (corticosteroids) have become the first-line therapies. However, theophylline is still occasionally used for treatment of nocturnal or mild persistent asthma, and dosage individualization is 1 2 necessary. Although theophylline was once thought to have primarily a bronchodilator effect, it is now recognized to have anti-inflammatory effects as well. The therapeutic range is now generally accepted to be 5-15 mg/L, a decrease from the previously accepted range of 10-20 mg/L. This newer range is probably more relevant to bronchodilator effects; anti-inflammatory effects may be achieved at lower concentrations. Theophylline is eliminated from circulation through hepatic oxidative metabolism (cytochrome P450) and has a low intrinsic clearance (see Lesson 9). Therefore, total hepatic clearance of theophylline is determined by the intrinsic clearance of the liver and is not dependent on liver blood flow. Theophylline may undergo nonlinear, or Michaelis-Menten, pharmacokinetics (see Lesson 10) even within the therapeutic range, but this is more likely to occur at concentrations above the 4 therapeutic range. Diseases that affect liver blood flow, such as cirrhosis and heart failure, may reduce theophylline clearance. Drugs that alter hepatic oxidative metabolism can also dramatically 5 6 affect theophylline clearance. Some drugs, such as cimetidine and erythromycin, will decrease theophylline clearance and cause increased plasma theophylline concentrations (Table 14-1). Suppository and rectal solution forms of the drug are available but are not commonly used. Intravenous infusion involves administration of theophylline itself or in a salt form (such as aminophylline). When theophylline derivatives are used, the theophylline dose equivalent should be calculated. Therefore, to obtain the theophylline dose equivalent, the aminophylline dose should be multiplied by 0. Others are designed to slowly release drug in the gastrointestinal tract for up to 24 hours after administration. Determine an appropriate loading dose of aminophylline to produce a theophylline concentration of 15 mcg/mL. In this case, the desired plasma theophylline concentration is 15 mcg/mL, the aminophylline salt equivalent (S) is 0. In patients more than 7 50% above ideal body weight, volume of distribution should be calculated using ideal body weight.

Thirty-five patients cheap 40/60mg levitra with dapoxetine with amex, treated between 1979 and 1983 generic levitra with dapoxetine 40/60mg overnight delivery, received cisplatin buy levitra with dapoxetine 40/60 mg with mastercard, vinblastine and bleomycin and levitra with dapoxetine 40/60 mg for sale, at relapse, bleomycin (15 mg/m2 weekly), etoposide (120 mg/m2 for five days) and cisplatin (20 mg/m2 for five days). In the subgroup of 20 patients who had received a cumulative etoposide dose of > 2000 mg/m2, two cases of acute myelomonocytic leukaemia occurred. For the 177 patients treated after 1983 to 1989 with first-line bleomycin, etoposide and cisplatin, the doses were adjusted according to risk category: 115 patients received standard doses (100 mg/m2 etopside for five days (cumulative dose, 2000 mg/m2), 20 mg/m2 cisplatin for five days, 15 mg/m2 bleomycin weekly). In 62 patients who received high- dose treatment consisting of etoposide (200 mg/m2 for five days; cumulative dose, 3000 mg/m2), cisplatin (40 mg/m2 for five days) and bleomycin (15 mg/m2 weekly), two cases of acute myeloblastic leukaemia (one in a patient with extragonal germ-cell tumour) and one case of myelodysplastic syndrome developed. The latencies after eto- poside treatment were 15 and 29 months for acute myeloblastic leukaemia and 68 months for the case of myelodysplastic syndrome. The expected number of de-novo cases of acute myeloid leukaemia was estimated from the leukaemia incidence reported in the Danish Cancer Registry for 1973–77. No leukaemias or dysplastic syndromes were observed among the 130 patients who had received ≤ 2000 mg/m2 etoposide, whereas five cases were seen among the 82 patients who had received > 2000 mg/m2 (p = 0. Although five cases of leukaemia and dysplastic syndrome were found in the 212 etoposide-treated patients, none was found in a previous cohort of 127 patients with germ-cell tumour treated with vinblastine and similar doses of cisplatin and bleomycin (p = 0. Bokemeyer and Schmoll (1993) assessed the risk for secondary neoplasms after therapy for germ-cell tumours in 1025 patients treated between 1970 and 1990 in Germany. Patients followed-up for longer than 12 months were eligible (1018 patients; 394 had seminomatous germ-cell tumours). The median follow-up was 61 months, and the median age of the patients at diagnosis was 28. The chemotherapy regimens consisted mainly of cisplatin, bleomycin and either vinblastine or etoposide. A total of 293 patients received etoposide during their treatment: 221 patients received cumu- lative doses of ≤ 2000 mg/m2; 72 patients received > 2000 mg/m2. The cumulative incidence of second tumours after etoposide-containing therapy was 1. Among the 221 patients who received ≤ 2000 mg/m2 etoposide, three developed a secondary tumour: one carcinoid tumour, one rhabdomyosarcoma and one lymphoblastic leukaemia; the last patient had received four cycles of bleomycin, etoposide and cisplatin (cumulative dose of etoposide, 2000 mg/m2), and the interval to second leukaemia was 16 months. The study was limited to those who had achieved complete remission or a stable partial response with no tumour markers after chemotherapy, with a minimum follow-up of 12 months. The first cohort consisted of 22 patients who were treated between 1983 and 1989 with three or four cycles of bleomycin, etoposide and cisplatin as induction chemotherapy followed by cisplatin, etoposide and ifosfamide as salvage chemotherapy at relapse. The second cohort was composed of 50 patients with metastatic testi- cular cancer who had been treated during 1984–88 with first-line chemotherapy consisting of a ‘double-dose’ of cisplatin, a ‘double-dose’ of etoposide and bleomycin (175 mg/m2 cisplatin and 1000 mg/m2 etoposide per cycle; four cycles). The third cohort consisted of 41 patients who had been treated in a stepwise dose–escalation protocol with the cisplatin, etoposide and ifosfamide regimen as first-line therapy for ‘advanced’ germ- cell tumours. The patients were treated during 1989–92 with 150 mg/m2 cisplatin and 8000 mg/m2 ifosfamide plus either 750 mg/m2 or 1000 g/m2 etoposide per cycle for four consecutive cycles. The fourth cohort consisted of 15 patients treated between 1990 and 1993 for relapsed testicular cancer with high doses of carboplatin, etoposide and ifos- famide followed by autologous stem-cell rescue. These patients had received primary chemotherapy that included etoposide and at least one regimen of salvage therapy with etoposide before the high-dose treatment, which resulted in a median cumulative dose of etoposide of 5300 mg/m2. The cumulative incidence of secondary leukaemia in the group of 128 patients after 4. When compared with the annual incidence of five cases of myeloid leukaemia per 100 000 persons in the general population, the relative risk for secondary leukaemia was increased approxi- mately 30- to 35-fold, which is not statistically significant. The Working Group also noted that there may have been overlap with the previous study. The records of 302 patients (median age, 29 years) with germ-cell tumours (241 testicular, 33 retroperitoneal and 28 mediastinal) who were treated with high-dose chemotherapy in clinical trials in Germany and France between 1986 and 1996 were reviewed. Of the three German trials, the first included first- line therapy with one cycle of standard-dose cisplatin 20 mg/m2, etoposide 100 mg/m2 and ifosfamide 1200 mg/m2 daily for five days followed by three to four cycles of of the same treatment escalated over seven doses: the highest consisted of 20 mg/m2 cisplatin, 300 mg/m2 etoposide and 2400 mg/m2 ifosfamide daily for five consecutive days every three weeks. In the second German trial, patients who relapsed after receiving cisplatin and etoposide-based chemotherapy received two cycles of a standard-dose cisplatin, etoposide and ifosfamide regimen followed by two cycles of 500 mg/m2 carboplatin, 400 mg/m2 etoposide and 2500 mg/m2 cyclophosphamide. In the third German trial, patients who relapsed after initial therapy with cisplatin and etoposide received two cycles of standard-dose cisplatin, etoposide and ifosfamide followed by carboplatin, 300–400 mg/m2 etoposide and ifosfamide. All the patients in France were treated with high-dose etoposide-containing chemotherapy including cisplatin, carboplatin and cyclophosphamide or ifosfamide, either as first-line consoli- dation therapy (patients with poor prognostic criteria) or as treatment for relapsed germ-cell tumour. All patients received either autologous bone marrow or autologous peripheral blood stem-cell support, and most patients also received granulocyte- or granulocyte–macrophage colony-stimulating factor after high-dose chemotherapy. The median cumulative dose of etoposide was 5000 mg/m2 (range, 2400–14 000 mg/m2). Six patients developed a secondary haematological malignancy (four acute myeloid leukaemias and two myelodysplastic syndromes). The two cases of myelodysplastic syndrome occurred in patients with a primary mediastinal germ-cell tumour and were excluded from the analysis. For the total group of 302 patients, the cumulative incidence of acute myeloid leukaemia was 1. Two of the malignancies were acute monoblastic leukaemia and two were acute myelomonocytic leukaemia; three were found in patients with testicular cancer as the primary tumour. Patients who did not achieve complete remission or who died of germ-cell cancer were not excluded from the analysis. A total of 541 patients were followed-up for more than two years and 331 for more than five years. None of them had a primary mediastinal germ-cell tumour, and only one patient had received radio- therapy. The median interval between the onset of treatment and the development of leukaemia was 27 months. Four of six cases were acute myelomonocytic leukaemia, one was acute myeloid and the other acute myeloblastic leukaemia. The cumulative dose of etoposide in the cases of leukaemia ranged from 720 to 5000 mg/m2. Two of 25 patients who received total doses > 2000 mg/m2 developed acute myeloid leukaemia, whereas four of 636 who received < 2000 mg/m2 developed acute myeloid leukaemia (p = 0. Four patients developed solid tumours (excluding cancer of the contra- lateral testis). Six patients with acute myeloid leukaemia were identified; however, four of them had a mediastinal germ-cell tumour. One patient aged 31 with testicular cancer had received cisplatin, etoposide (cumulative dose, 2000 mg/m2), vinblastine, bleomycin, dactinomycin and cyclophosphamide as induction plus salvage therapy. The second patient with testicular cancer, a man aged 35, had received induction therapy consisting of cisplatin, carboplatin and etoposide (cumulative dose, 1300 mg/m2). Thus, one of the 310 patients (291 treated with bleomycin, carboplastin and cisplatin) who had received only one etoposide- containing induction chemotherapy regimen subsequently developed acute myeloid leukaemia, giving a definite incidence [an approximate actuarial risk] of less than 1. Three of the five developed acute leukaemia associated with a primary mediastinal germ-cell tumour and were excluded from the study. Twelve cases of leukaemia or myelodysplastic syndrome (10 cases of acute myeloid leukaemia, one case of acute lymphoblastic leukaemia and one of myelodysplastic syndrome, were observed among 1720 patients with germ-cell tumours. On the basis of 8699 patient–years of follow-up and an annual incidence rate of 3–4 cases of acute myeloid leukaemia per 100 000 population (Parkin et al. According to Bokemeyer and Schmoll (1995), the cumulative risk for acute myeloid leukaemia was only 0. Cohort studies of other types of cancer are summarized in Table 4 and are described below. The expected number of cases of acute myeloid leukaemia in the general population can be approximated from a world standardized incidence rate of 4–5 per 100 000 persons (see text). After having achieved complete remission, the patients received maintenance treatment with epipodophyllotoxins according to seven schedules (Table 5): 580 patients received teniposide (see monograph, this volume), and a substantial proportion of these (301) also received etoposide. In addition, most patients received methotrexate, mercaptopurine, prednisone, vincristine, asparaginase and cytarabine, and some patients received cyclophosphamide, doxorubicin and cranial irradiation. Acute myeloid leukaemia developed in 21 children (as a first adverse event in 17), with an overall cumulative risk of 3. The median interval between the diagnoses of acute lymphoblastic leukaemia and acute myeloid leukaemia was 40 months.