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By K. Osko. Montana State University-Billings. 2018.

There is substantial evidence that good-quality staff interactions are of benefit for recovery discount cialis 2.5mg without prescription. Some people who use drugs report experiencing disapproval and frustration in their interaction with healthcare services buy cheap cialis 10mg on line,1 and this can be a significant barrier to accessing healthcare generic cialis 20mg on line. As discussed in Chapter 8, health professionals who adopt a non- judgemental, non-stigmatising empathic stance are most likely to be effective in delivering healthcare for these patients. There is consistent evidence that in primary care settings, in hospitals, and in mental health settings, doctors frequently do not address alcohol and drug use. The medical frame of reference is a useful one in which to approach drug use – non-judgemental, factual, professional, accurate diagnosis and provision of information and referral, monitoring the response. Contrary to pessimism and reluctance to address drug use as a health issue, there is evidence that, in relation to the legal drugs alcohol and tobacco, medical management can have significant impact,6-9 but it is unclear how far this can be extrapolated to illicit drugs. Opportunistic identification of drug use, and provision of brief health advice, may be useful in triggering individuals to reflect on, and sometimes to modify, their use of drugs. The appropriate response may involve provision of information about health risks and harms, or referral for management. Screening and brief advice from physicians can affect the motivation for change among patients, including those with substance dependence. The doctor must also consider the impact the drug use may be having on children and young people. Relevant information will include family risk factors, such as drug and alcohol misuse, or previous instances of abuse or neglect, but you should not usually share complete records. This section looks at strategies to reduce use in those who are already using drugs. McCambridge and Strang tested brief interventions in young people,16 and found that a single session of motivational interviewing (including discussing illicit drug use) led successfully to reduction in use of these drugs among young people. The intervention took place across 10 further education colleges across inner London, with 200 young people aged 16-20 years who were currently using illegal drugs. Those randomised to motivational interviewing reduced their use of cannabis (and cigarettes and alcohol). Those most at risk benefited the most: for cannabis, the effect was greater among heavier users. The effect of reduction in cannabis use was also greater among youth usually considered vulnerable or high risk according to other criteria – for example young male individuals who smoked cannabis the most frequently, were in receipt of benefits, and had a prior history of selling drugs. In the group that received additional counselling, there was half the rate of drug injection at 6-month follow-up, four times the likelihood of abstinence (confirmed by urinalysis), and significantly lower arrest rates. It requires medical management of the drug use and its sequelae, but also includes referring to other disciplines, such as social services, that can help with the wider aspects of improving quality of life. Medical management of dependent drug use focuses directly on treating physical and mental health issues and may involve prescribing. This section presents some of the safety issues that are important in this context. It considers the appropriate and safe prescribing of drugs of dependence and ways to minimise the risks of diversion, misuse and iatrogenic dependence. Misuse of, and dependence on, prescribed drugs (in particular opioids and benzodiazepines) is a rapidly growing public health problem in many jurisdictions internationally. In addition to minimising misuse, diversion and iatrogenic dependence, the medical professional must consider the physical safety of the prescribed drugs, as is the case in all prescribing. The impact of injudicious prescribing is illustrated in a study from Melbourne, Australia, where researchers investigated the medical attendances of young people who had died of opioid overdoses. Such withdrawal is characterised by autonomic overactivity (tachycardia, hypertension, tremor and sweating), cognitive changes (confusion, agitation, sometimes psychosis) and perceptual disturbances (formication – a tactile hallucination of insects crawling on or in the skin, illusions, visual hallucinations). One role of therapeutic detoxification from illicit drugs is management of a clinical emergency, stabilising the individual and slowing the rate of change to allow their physiology to adapt. A second role is to decrease the distressing or uncomfortable symptoms of withdrawal, and, through this, a third role is to enhance engagement and increase the likelihood of continued abstinence. It is also essential that the medical professional promotes continued engagement and continues to provide support after the detoxification process is complete. This is relevant in considering illicit drug use, as it is usual for people who become dependent on illicit drugs to misuse a range of drugs, including alcohol and benzodiazepines. Where withdrawal from most illicit drugs is not associated with severe morbidity, withdrawal from benzodiazepines often poses a greater risk. Withdrawal symptoms come on within two to three half-lives of the particular benzodiazepine (eg 2-3 days after short- and medium-acting compounds and 7-10 days after long- acting compounds) and usually subside within a few weeks. Others can be managed by specialists, with high-dose diazepam and baclofen, titrated against withdrawal severity in ambulatory settings, but this needs to be backed up with access to inpatient treatment if required, because of the possible severity of the withdrawal symptoms. Methadone or buprenorphine are offered as the first-line treatment in opioid detoxification. Following successful opioid detoxification, patients should be offered and engaged in continued support and monitoring designed to maintain abstinence. The medical professional must also educate the patient regarding the loss of opioid tolerance following detoxification, and the ensuing increased risk of overdose and death if opioids are used again during this period. While the two syndromes are distinct, they share symptoms, including dysphoric mood, fatigue, vivid or unpleasant dreams, insomnia or hypersomnia, increased appetite and psychomotor agitation or retardation. The medical professional should also be aware of the possible responses of patients aiming to reduce their withdrawal symptoms, including relapsing42 and self-medication with other substances. There was a strong, significant correlation between distress experienced during withdrawals and the use of other substances to relieve the distress. The medical professional must also address relapse prevention strategies with those undergoing detoxification. Its use requires significant motivation for compliance and thus its use as an effective therapeutic strategy is limited. A Cochrane review addressing the use of psychostimulants to maintain abstinence from cocaine use found studies in this area to be currently inconclusive. Individuals with cocaine and/or opioid dependence and who are in close contact with a non-drug-using partner benefit from behavioural couples therapy, both during treatment and at follow-up. The earlier members of this population are able to access treatment services, the better the outcome will be for their general physical health, the pregnancy and the neonate. A sensitive, non-judgemental approach is essential in engaging this population and optimising treatment effectiveness. Medical professionals have a role to play not only in portraying this through their own clinical care and manner, but in leading their clinical teams to be approachable, non-judgemental and patient centred in this situation. This will include attention not only to physical healthcare and management of drug use, but sensitive attention to the coexistent psychological difficulties and social concerns that the patient may be experiencing. The medical professional and the full multidisciplinary team will need to address the woman’s fears about the involvement of children’s services; anxiety and guilt about the potential impact of their drug use on their baby;62 and concerns the patient may have about finances, support networks, and coping strategies during pregnancy and their forthcoming parenthood. They also recommend that a variety of methods (eg text messaging) should be used to maintain contact and engagement, and to remind women of upcoming and missed appointments. Multiagency team work is also essential, working with social care professionals and ensuring seamless communication between general practice and the specialist services involved in the patient’s antenatal care, including obstetrics, specialist drug services and any other specialist healthcare services. Multiagency case conferences, with prospective parents invited as participating attendees, will facilitate good inter-team communication and optimise clinical care.

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Close supervision is then needed to ensure that treatment regimens are tolerated and that appropriate changes are made to the regimen as the disease progresses buy 2.5 mg cialis fast delivery. The most efectve form of therapy is a combinaton of levodopa and a peripheral dopa-decarboxylase inhibitor purchase cialis 20mg without a prescription, such as carbi- dopa discount 2.5 mg cialis otc. The response to levodopa with carbidopa is a compromise between increased mobility and adverse efects. Dyskinesias may be dose limitng and increasingly frequent with increased duraton of treatment. Many factors including tolerance and progression of the disease may result in complicatons afer 2-5 years of treatment. The ‘on-of’ phenomenon is character- ized by sudden swings from mobility to episodes of akinesia, tremor and rigidity lastng from a few minutes to several hours. Amelioraton of these efects can sometmes be achieved by administering levodopa in a sustained-release preparaton or in a greater number of fractonated doses throughout the day. Psychiatric symptoms inducing disrupton of sleep, vivid dreams and hallucinatons are characteristc adverse efects that may occur at any tme, especially in the elderly and may require dose reducton or withdrawal of levodopa. Treatment for idiopathic parkinsonism is ofen initated with a dopamine receptor agonist such as bromocriptne. Supple- mentary use of amantadine, bromocriptne or the monoam- ine-oxidase-B inhibitor, selegiline can be of value either to enhance the efect of levodopa or to reduce ‘end-of-dose’ fuctuatons and ‘on-of’ efects. Antcholinergic (more correctly termed antmuscarinic) drugs such as biperiden are usually sufcient in drug-induced parkinsonism. Drugs Used in Essental Tremor and Related Disorders: Essental Tremor: It can be treated with β-blockers such as propranolol (120 mg daily) (chapter 13. If there is no response within three months, the drug should be withdrawn and small doses of an antcholinergic drug such as biperiden should be given. In patents who fail to respond to either levo- dopa or an antcholinergic, other drugs including diazepam, baclofen, carbamazepine or phenothiazines may be of value. Psychological treatments have also been used successfully in the management of dyskinesias. Chorea: Choreiform movements can be induced by certain drugs including levodopa, phenytoin and antpsychotc drugs. The aim of therapy is to reduce dopamin- ergic transmission which results from excessive or enhanced cholinergic actvity. Tetrabenazine, the dopamine-depletng drug, is used to control movement disor- ders in Huntngton’s chorea and related disorders. Tics: Tics which resemble choreiform movements are commonly associated with anxiety. However, in the more complex multple tc disorder, Tourete syndrome, treatment with antpsychotc drugs may be required. Tardive Dyskinesia: It is associated with chronic administraton of antpsychotc drugs. It is characterized by involuntary, repettve, choreiform movement of the cheek, mouth and fngers. The frst step of treatment should always be discontnuaton of the antpsy- chotc drug or dosage reducton if the underlying psychotc disorder permits. Dose Oral Adult- Medicine-induced extra-pyramidal symptoms, parkinsonism: initally 1 mg twice daily, increased gradually to 2 mg thrice daily; usual maintenance dose 3 to 12 mg daily in divided doses. Intramuscular injecton or Slow intravenous injecton Adult- Medicine-induced extra-pyramidal symptoms, parkinsonism: 2. Contraindicatons Angle-closure glaucoma; bowel obstructon; megacolon; untreated urinary retenton; prostatc hypertrophy; myasthenia gravis; gastrointestnal obstructon. Precautons Elderly; cardiovascular disease, hepatc or renal impairment; avoid abrupt withdrawal; paediatric use; pregnancy (Appendix 7c); lactaton. May impair ability to perform skilled tasks, for example operatng machinery, driving. Adverse Efects Drowsiness, dry mouth, constpaton, blurred vision; hesitancy of micturiton, dizziness, tachycardia, arrhythmias; confusion, euphoria, excitement, agitaton, hallucinatons and psychiatric disturbances with high dosage, especially in the elderly and other susceptble patents, may require withdrawal of treatment; impaired memory, mild postural hypotension; urinary retenton. Contraindicatons Hypersensitvity to bromocriptne or other ergot alkaloids; ischaemic heart disease; toxaemia of pregnancy and hypertension in postpartum women or in puerperium. Should not be used postpartum or in puerperium in women with high blood pressure, coronary artery disease or symptoms (or history) of serious mental disorder; monitor blood pressure carefully (especially during frst few days) in postpartum women. Very rarely, hypertension, myocardial infarcton, seizures or stroke (both sometmes preceded by severe headache or visual disturbances) and mental disorders have been reported in postpartum women given bromocriptne for lactaton suppression-cauton with anthypertensive therapy and avoid other ergot alkaloids. Levodopa + Carbidopa* Pregnancy Category-C Schedule H Indicatons All forms of parkinsonism other than medicine-induced. Dose Oral Adult- Parkinsonism: expressed in terms of levodopa, initally 100 mg (with carbidopa 10 mg) twice daily, increased by 100 mg (with carbidopa 10 mg) every few days as necessary, to a max. Optmum daily dose must be determined for each patent by careful monitoring and be taken afer meals. Contraindicatons Concurrent use of monoamine oxidase inhibitors; undiagnosed chin lesion; lactaton; psychosis; decompensated endocrine; angle- closure glaucoma; confrmed or suspected malignant melanoma. Adverse Efects Nausea, anorexia and vomitng, partcularly at the start of treatment; postural hypotension at the start of treatment, partcularly in elderly and those receiving anthypertensives; excessive drowsiness and sudden onset of sleep (warn patent of these efects); confusion, vivid dreams, dizziness, tachycardia, arrhythmias; reddish discolouraton of body fuids; insomnia, headache, fushing, gastrointestnal bleeding, peripheral neuropathy; taste disturbances, pruritus, rash, liver enzyme changes; psychiatric symptoms including psychosis, depression, hallucinatons, delusions and neurological disturbances including dyskinesias may be dose-limitng; painful dystonic spasms (‘end-of-dose’ efects) and (‘on-of’ efects) afer prolonged treatment (see notes above); neuroleptc malignant syndrome, on sudden withdrawal; rarely, hypersensitvity, dyspnoea; upper respiratory infecton. Dose 1 mg daily, increased gradually; usual maintenance dose 5 to 15 mg daily in 3 to 4 divided doses (max. Precautons Use with cauton in cardiovascular disease, hypertension, psychotc disorders, prostatc hypertrophy, pyrexia, in those susceptble to angle-closure glaucoma and in the elderly. Elderly males with possible prostate hypertrophy; tardive dyskinesia; neuroleptc malignant syndrome. Use with cauton in renal impairment and hepatc impairment, lactaton and interactons (Appendix 6a). Adverse Efects Constpaton, dry mouth, nausea, vomitng, tachycardia, dizziness, confusion, euphoria, hallucinatons, impaired memory, anxiety, restlessness, urinary retenton, blurred vision and rash. The drug of choice will depend on the primary diagnosis, seizure type, efcacy of the drug and the patent’s tolerance of treatment. If a drug fails to control the seizures afer it has been used in full thera- peutc dosage for an adequate period, or if it is not tolerated, it should be gradually substtuted with another drug, with the frst drug being withdrawn only when the new regimen is established. If monotherpy is inefectve, next alternatve drug should be started, and try to withdraw frst drug if there was no response for that drug or contnue with that if there was partal response for inital drug. Inital dose of the drug of choice should be determined on the basis of the degree of urgency, the size and age of the patent. All antepileptcs commonly produce neurological adverse efects at higher dose ranges and patents should be monitored closely for adverse efects to help in accurate dose ttraton. Except for phenytoin, it is rarely, useful to measure plasma-drug concentratons as an aid to dose adjust- ment.

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Dose Oral Adult- Parkinsonism: expressed in terms of levodopa purchase cialis 2.5 mg without prescription, initally 100 mg (with carbidopa 10 mg) twice daily order cialis 20mg line, increased by 100 mg (with carbidopa 10 mg) every few days as necessary order cialis 5mg with mastercard, to a max. Optmum daily dose must be determined for each patent by careful monitoring and be taken afer meals. Contraindicatons Concurrent use of monoamine oxidase inhibitors; undiagnosed chin lesion; lactaton; psychosis; decompensated endocrine; angle- closure glaucoma; confrmed or suspected malignant melanoma. Adverse Efects Nausea, anorexia and vomitng, partcularly at the start of treatment; postural hypotension at the start of treatment, partcularly in elderly and those receiving anthypertensives; excessive drowsiness and sudden onset of sleep (warn patent of these efects); confusion, vivid dreams, dizziness, tachycardia, arrhythmias; reddish discolouraton of body fuids; insomnia, headache, fushing, gastrointestnal bleeding, peripheral neuropathy; taste disturbances, pruritus, rash, liver enzyme changes; psychiatric symptoms including psychosis, depression, hallucinatons, delusions and neurological disturbances including dyskinesias may be dose-limitng; painful dystonic spasms (‘end-of-dose’ efects) and (‘on-of’ efects) afer prolonged treatment (see notes above); neuroleptc malignant syndrome, on sudden withdrawal; rarely, hypersensitvity, dyspnoea; upper respiratory infecton. Dose 1 mg daily, increased gradually; usual maintenance dose 5 to 15 mg daily in 3 to 4 divided doses (max. Precautons Use with cauton in cardiovascular disease, hypertension, psychotc disorders, prostatc hypertrophy, pyrexia, in those susceptble to angle-closure glaucoma and in the elderly. Elderly males with possible prostate hypertrophy; tardive dyskinesia; neuroleptc malignant syndrome. Use with cauton in renal impairment and hepatc impairment, lactaton and interactons (Appendix 6a). Adverse Efects Constpaton, dry mouth, nausea, vomitng, tachycardia, dizziness, confusion, euphoria, hallucinatons, impaired memory, anxiety, restlessness, urinary retenton, blurred vision and rash. The drug of choice will depend on the primary diagnosis, seizure type, efcacy of the drug and the patent’s tolerance of treatment. If a drug fails to control the seizures afer it has been used in full thera- peutc dosage for an adequate period, or if it is not tolerated, it should be gradually substtuted with another drug, with the frst drug being withdrawn only when the new regimen is established. If monotherpy is inefectve, next alternatve drug should be started, and try to withdraw frst drug if there was no response for that drug or contnue with that if there was partal response for inital drug. Inital dose of the drug of choice should be determined on the basis of the degree of urgency, the size and age of the patent. All antepileptcs commonly produce neurological adverse efects at higher dose ranges and patents should be monitored closely for adverse efects to help in accurate dose ttraton. Except for phenytoin, it is rarely, useful to measure plasma-drug concentratons as an aid to dose adjust- ment. Non-compliance, inappropriate dosing and overdosing is a major impediment to efectve antepileptc treatment. Withdrawal: Treatment is normally contnued for a minimum of two years of seizure free period. Withdrawal should be extended over a period of several months because abrupt withdrawal can lead to recurrence of seizure and or/status epileptcus. A general rule for duraton of tapering is how many years patent had taken that partcular drug, over a period of so many months it should be tapered. In patents receiving several antepileptc drugs, only one drug should be withdrawn at a tme. Pregnancy and Lactaton: Untreated epilepsy during pregnancy may cause harm to the fetus; there is therefore no justfcaton for abrupt with- drawal of treatment although withdrawal of therapy may be an opton if the patent has been seizure-free for at least 2 years; resumpton of treatment may be considered afer the frst trimester. If antepileptcs are contnued in pregnancy, monotherapy with the lowest efectve dose is preferred, with adjustment made to take account of changes in plasma levels associated with pregnancy. There is an increased risk of birth defects with the use of antconvulsants, partcularly carbamazepine, valproate and phenytoin. However, if there is good seizure control, there is probably no advantage in changing pregnant patents’ antepileptc drugs. In view of the risks of neural tube and other defects, patents who may become pregnant should be informed of the risks and referred for advice and pregnant patents should be ofered counselling and antenatal screening. To counteract the risk of neural tube defects, adequate folate supplements are advised for women before and during pregnancy. In view of the risk of neonatal bleeding associated with carbamazepine, phenobar- bital and phenytoin, prophylactc phytomenadione (vitamin K1 ) is recommended for the neonate and the mother before delivery. Driving: Regulatons are in place in many countries which may, for example, restrict driving by patents with epilepsy to those whose seizures are controlled. Choice of Antepileptc in Management of Convulsive Disorders Generalized Tonic-Clonic Seizures: Phenobarbital, phenytoin and valproate are widely used in the treatment of these conditons. However, each of these drugs is associated with dose-related and idiosyncratc adverse efects and monitoring of haematological and hepatc func- ton is routnely not advised. Absence Seizures: Both ethosuximide and valproate are recommended in the treatment of absence seizures (pett mal) and are usually well tolerated. However, ethosuximide can, rarely, cause lupus erythematosus and psychoses which call for immediate, but cautous, discontnuaton. Absence seizures are commonly associated with tonic-clonic seizures and valproate is preferred since it has a broad spectrum of actvity. Tonic Seizures, Atonic Seizures and Atypical Absence Seizures: Phenobarbital or phenytoin is widely used for tonic seizures, valproate or clonazepam for atonic seizures and clonazepam for atypical absence seizures. Myoclonic Seizures: Valproate is widely used and most efectve for juvenile myoclonic seizures. As juvenile myoclonic epilepsy is associ- ated with a high relapse rate, it is ofen necessary to contnue therapy indefnitely. Other myoclonic seizures are ofen resistant to treatment and some do not have an epileptc basis. Valproate or clonazepam can be of value in this case and other antepileptc drugs may be useful in intractable cases. Both drugs are generally well accepted, although tolerance to clonazepam has been reported. Infantle Spasm (Infantle Myoclonic Epilepsy): Infantle spasms, which are ofen associated with severe brain damage, can be resistant to antepileptc drugs. Febrile Convulsions: Sponging with tepid water and antpyretc such as para- cetamol is efectve in controlling the temperature. Intermitent prophylaxis, with diazepam (or clobazam) admin- istered at the onset of fever, may prevent recurrence of febrile convulsions. Use of antepileptcs for contnuous prophylaxis is controversial; it is probably indicated in only a small proporton of children including those who already have evident neuro- logical abnormalites, or who have had previous prolonged or focal convulsions. Phenobarbital may be used for this purpose but careful clinical monitoring and dosage adjustment are necessary in order to minimize the risk of adverse efects. Status Epileptcus: Status epileptcus is a medical emergency which carries a high mortality rate. Inital management includes positoning the patent to avoid injury, supportng respiraton including provi- sion of oxygen, maintaining blood pressure and the correc- ton of any hypoglycaemia; hypocalcemia or any other elec- trolyte disturbance; maintenance of the airway and assisted ventlaton are crucial even when the seizures are controlled, because the drugs used in its management may cause respira- tory depression. Lorazepam, which acts rapidly, should be administered frst and should be followed immediately by a loading dose of phenytoin which has a longer-actng efect. When cannulaton is difcult or impossible, diazepam may be administered rectally as a soluton (absorpton from supposi- tories is too slow for treatment of status epileptcus). Intrave- nous phenobarbital is also efectve but is more likely to cause respiratory depression; it is used in refractory cases but should be avoided in patents who have recently received oral pheno- barbital.

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Peri- pheral neuropathy has been observed mainly at high doses and in individuals treated for at least four months generic 2.5 mg cialis. The effect has been demonstrated in 12–34% of didanosine- treated patients discount cialis 5 mg with visa, and is reversible upon withdrawal of the drug (Rozencweig et al buy cialis 10 mg on line. Among 7806 zidovudine-resistant patients participating in the Didanosine Expanded Access Program, 5% reported pancreatitis (Pike & Nicaise, 1993). In all of the studies, the symptoms correlated with cumulative treatment and typically subsided after disconti- nuation of therapy. Like zidovudine and zalcitabine, didanosine occasionally caused a rare (1 in 105 to 1 in 106 patients) idiosyncratic syndrome consisting of increased liver enzyme acti- vity, hepatic steatosis, fulminant hepatitis and severe lactic acidosis after long-term (more than three months) treatment; this syndrome can be fatal (Lai et al. Other miscellaneous and rare human toxic effects include acute, reversible thrombocytopenia (Lor & Liu, 1993), retinal toxicity (Cobo et al. Cell-mediated (T cell) immunity was moderately suppressed at 250 mg/kg bw for > 14 days, and suppression of humoral (B cell) immune response was observed at 100 mg/kg bw given for > 28 days. In order to investigate the mechanism of didanosine-induced neuropathy, rats were dosed orally twice daily with 41. Myelin splitting and intramyelin oedema were observed in the sciatic nerves of treated animals in a dose-related fashion (Schmued et al. In rabbits given 750 or 1500 mg/kg bw didanosine per day for 6 or 16 weeks, no evidence of peripheral neuropathy was found (Warner et al. Attempts to model the effects of didanosine in the human pancreas have been unsuccessful. No changes in the numbers of resorptions or pups per litter or in external embryo morphology were reported in animals examined on gestational day 11. The pups of treated dams were born live, developed at a normal rate and had a normal lifespan (Sieh et al. No selective cytotoxicity was seen in neuronal, cardiac or skeletal muscle or cartilage cells (Sieh et al. References such as The Physician’s Desk Reference (Medical Economics Data Production, 1999) provide results but few or no details of the experimental conditions used in the assays. The manufacturer of the drug has yet to publish a detailed report equivalent to those available in the literature on aciclovir and zidovudine. Mutagenicity was seen in vitro and in vivo only with high doses of didanosine (Table 1). Didanosine did not induce reverse mutation in Salmonella typhimurium with or without exogenous metabolic activation [no information on doses or strains] and did not induce differential toxicity in Escherichia coli or Bacillus subtilis. Didanosine caused clastogenic effects in Chinese hamster ovary cells and human lymphocytes. Studies of the mutagenicity of didanosine in animals in vivo are limited to assays for micronucleus formation in rodents. As didanosine can be inacti- vated by the low pH of the stomach, it was subsequently administered by intra- peritoneal injection for three consecutive days. A significant clastogenic response was found in peripheral blood at the low and high doses. Over a range of concentrations, the induced mutant frequencies at the two loci were three to four times greater than the values obtained after exposure to didanosine or zidovudine alone. The few available studies on the mutagenicity of didanosine show that it produces primarily clastogenic effects at high doses. It is in widespread use in combination regimens with other antiretroviral agents, and potentiation of the anti- viral effect of didanosine by hydroxyurea is being investigated. About half of the human urinary metabolites are represented by hypoxanthine, and 40% is unchanged drug. Phosphorylation is a minor pathway but is essential for the antiviral activity of the drug. The toxic effects of didanosine in humans include peripheral neuropathy, pancrea- titis, hepatitis and leukopenia. No relevant studies of the reproductive and prenatal effects of didanosine in humans were available. Didanosine crosses the placenta of women and monkeys by bidirectional, passive diffusion. Didanosine but not didanosine triphosphate was observed in placental and fetal tissues. Little information was available on the genetic and related effects of didanosine. Treatment of human cells in culture significantly increased the mutant frequencies after short-term expo- sure to concentrations 10–20-fold greater than the peak plasma concentrations found in some patients. In the same studies, didanosine was more cytotoxic and less muta- genic than zidovudine. There is inadequate evidence in experimental animals for the carcinogenicity of didanosine. Overall evaluation Didanosine is not classifiable as to its carcinogenicity to humans (Group 3). A review of its antiviral activity, pharmaco- kinetic properties and therapeutic potential in human immunodeficiency virus infection. The gelatin capsules may also contain citric acid, gelatin, glycerol, iron oxide, parabens (ethyl and propyl), polyethylene glycol 400, sorbitol and titanium dioxide. Etoposide concentrate for injection is a sterile, non-aqueous solution of the drug in a vehicle, which may be benzyl alcohol, citric acid, ethanol, polyethylene glycol 300 or polysorbate 80. Etoposide phosphate for injection is a sterile, non-pyrogenic, lyophilized powder containing sodium citrate and dextran 40; after reconstitution of the drug with water for injection to a concentration of 1 mg/mL, the solution has a pH of 2. The following impurities are limited by the requirements of The British Pharma- copoeia: 4′-carbenzoxy ethylidene lignan P, picroethylidene lignan P, α-ethylidene lignan P, lignan P and 4′-demethylepipodophyllotoxin (British Pharmacopoeia Commission, 1994). Trade names for etoposide phosphate include Etopofos and Etopophos (Swiss Pharmaceutical Society, 1999). Methods for the analysis of etoposide and its metabolites in plasma, serum and urine have included reversed-phase high-performance liquid chromatography with oxidative electrochemical detection, fluorescence detection and ultraviolet detection. Podophyllotoxin is isolated from the dried roots and rhizomes of species of the genus Podophyllin, such as the may apple or American mandrake (Podophyllin peltatum L. Etoposide can be synthesized from naturally occurring podophyllotoxin by first treating the podophyllotoxin with hydrogen bromide to produce 1-bromo-1-deoxyepi- podophyllotoxin, which is demethylated to 1-bromo-4′-demethylepipodophyllotoxin. The bromine is replaced by a hydroxy group, resulting in 4′-demethylepipodo- phyllotoxin. After protection of the phenolic hydroxyl, the 4-hydroxy group is coupled with 2,3,4,6-tetra-O-acetyl-β-D-glucopyranose. The protecting group at the 4′- hydroxy is removed by hydrogenolysis and the acyl groups by hydrolysis, and the cyclic O-4,6 acetal is formed by reaction with acetaldehyde dimethyl acetal (Holthuis et al. During early clinical trials for cancer chemotherapeutic use, podophyllotoxin proved to be too toxic and, in the 1960s, two epipodophyllotoxins were described, teniposide (see monograph, this volume) and etoposide (Keller-Juslén et al.