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PubMed1996

Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis.

Riluzole, a benzothiazole, affects neurons by 3 mechanisms: by inhibiting excitatory amino acid release, inhibiting events following stimulation of excitatory amino acid receptors and stabilising the inactivated state of voltage-dependent sodium channels. It has demonstrated neuroprotective activity in vivo and in vitro. Results from 2 randomised double-blind placebo-controlled trials in patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) have demonstrated that riluzole can extend survival and/or time to tracheostomy. After 18 months, the relative risk of death or tracheostomy with riluzole 100 mg/day was reduced by 21%. Although riluzole slowed the rate of deterioration in muscle strength in the first trial, this was not confirmed in the second, larger trial. Riluzole had no effect on any other functional or secondary variable. Gastrointestinal effects, anorexia, asthenia, circumoral paraesthesia and dizziness were reported more frequently with riluzole than placebo. Elevated alanine aminotransferase levels were observed in 10.6 versus 3.8% of patients treated with riluzole 100 mg/day versus placebo, leading to treatment withdrawal in 3.8 versus 2.1% of patients. In conclusion, riluzole is the first drug that has been shown to have an effect on survival in patients with ALS. Although the effect of riluzole was modest, it has allowed some insight into the pathogenesis of ALS from which future gains may be made.

Administration, Oral↗
PubMed1997

Carvedilol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders.

Carvedilol competitively blocks beta 1, beta 2 and alpha 1 receptors. The drug lacks sympathomimetic activity and has vasodilating properties that are exerted primarily through alpha 1-blockade. Animal models indicate that carvedilol confers protection against myocardial necrosis, arrhythmia and cell damage caused by oxidising free radicals, and the drug has no adverse effects on plasma lipid profiles. Recent data have confirmed the antihypertensive efficacy of carvedilol in patients with mild to moderate essential hypertension. Carvedilol has similar efficacy to other beta-blocking agents, calcium antagonists, ACE inhibitors and hydrochlorothiazide. Carvedilol also improves exercise tolerance and ischaemic symptoms in patients with stable angina pectoris. Significant reductions in serious cardiac events after acute myocardial infarction and in frequency and severity of ischaemic events in patients with unstable angina have also been demonstrated. Interest in the use of carvedilol in patients with congestive heart failure (CHF) has culminated in the publication of a cumulative analysis of data from 1094 patients with mild to severe CHF who participated in the US Carvedilol Heart Failure Study Program (4 trials). After a median follow-up of 6.5 months, a significant overall reduction in mortality relative to placebo (3.2 vs 7.8%) was revealed in patients who had received carvedilol 6.25 to 50 mg twice daily (plus diuretics and ACE inhibitors). All-cause mortality, risk of hospitalisation for cardiovascular reasons and hospitalisation costs were also reduced significantly (by 65, 28% and 62%, respectively) in these trials. In addition, the Australia and New Zealand Heart Failure Research Collaborative Group showed a 26% reduction in the combined risk of death or hospitalisation with carvedilol 12.5 to 50 mg/day relative to placebo after a mean 19-month follow-up period in 415 patients with CHF (relative risk 0.74). Adverse events with carvedilol appear to be less frequent than with other beta-blocking agents, are dosage-related and are usually seen early in therapy. Events most commonly reported are related to the vasodilating (postural hypotension, dizziness and headaches) and the beta-blocking (dyspnoea, bronchospasm, bradycardia, malaise and asthenia) properties of the drug. Carvedilol appears to date to have little effect on the incidence of worsening heart failure. Concomitant administration of carvedilol with some medications requires monitoring. Carvedilol is therefore likely to have a beneficial role in the management of controlled CHF, but further clinical studies are required to show the place of beta-adrenoceptor blocking therapy in general in this indication, and the position of carvedilol relative to other similar agents. Carvedilol is also confirmed as effective in the management of mild to moderate hypertension and ischaemic heart disease.

Adrenergic beta-Antagonists↗
PubMed1998

Raltitrexed. A review of its pharmacological properties and clinical efficacy in the management of advanced colorectal cancer.

Raltitrexed (ZD-1694) is a quinazoline-based folate analogue that exerts its cytotoxic activity by the specific inhibition of thymidylate synthase. In vitro studies show that raltitrexed is actively transported into cells and is then rapidly and extensively metabolised to a series of polyglutamates. These metabolites are significantly more potent inhibitors of thymidylate synthase than the parent drug and are retained intracellularly, producing prolonged cytotoxic effects without the need for continuous drug exposure. Phase III clinical trials in patients with advanced colorectal cancer evaluated raltitrexed 3 mg/m2 administered as a 15-minute intravenous infusion once every 3 weeks. This schedule produced objective response rates of 14.3 to 19.3%, which were similar to those in patients treated with fluorouracil plus leucovorin (15.2 to 18.1%). Median survival durations ranged from 9.7 to 10.9 months with raltitrexed treatment and from 10.2 to 12.7 months with fluorouracil plus leucovorin. The major toxicities associated with raltitrexed involve the haematological and gastrointestinal systems, although severe asthenia also occurred in 6 to 18% of patients receiving the drug. Grade 3 or 4 nausea or vomiting occurred in up to 13% of raltitrexed recipients and grade 3 or 4 diarrhoea in up to 14%. Similar incidences of grade 3 or 4 nausea or vomiting and diarrhoea were seen with fluorouracil plus leucovorin treatment. Raltitrexed generally showed significant advantages over fluorouracil plus leucovorin with respect to the incidence of leucopenia and mucositis. A greater proportion of raltitrexed than fluorouracil plus leucovorin recipients were able to receive the scheduled dosage. Thus, with its similar efficacy to fluorouracil-based regimens, convenient administration schedule and favourable tolerability profile, raltitrexed provides clinicians with a worthwhile alternative to fluorouracil-based treatment for patients with advanced colorectal cancer.

Antimetabolites, Antineoplastic↗
PubMed1998

Tiagabine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in the management of epilepsy.

Tiagabine is a gamma-aminobutyric acid (GABA) uptake inhibitor which is structurally related to nipecotic acid but has an improved ability to cross the blood-brain barrier. Clinical trials have shown that tiagabine is effective as add-on therapy in the management of patients with refractory partial epilepsy. In short term studies of this indication, tiagabine < or = 64 mg/day for 7 to 12 weeks reduced the complex partial and simple partial seizure frequency by > or = 50% in 8 to 31 and 28.2 to 37% of patients, respectively. Tiagabine appeared to produce a sustained reduction in seizure frequency in studies of up to 12 months' duration. Data from preliminary studies are currently insufficient to confirm the usefulness of tiagabine when used as monotherapy or in the treatment of children with epilepsy. Further studies are, therefore, necessary to more fully elucidate the efficacy of the drug in these settings. Adverse events associated with tiagabine are primarily CNS-related and include dizziness, asthenia, nonspecific nervousness and tremor. Skin rash or psychosis occurred with similar frequencies among tiagabine- and placebo-treated patients. With long term administration (> or = 1 year for many patients), the profile and incidence of adverse events was similar to that for short term therapy. Tiagabine does not appear to affect the hepatic metabolism of other drugs such as carbamazepine and phenytoin. Possible disadvantages of tiagabine include its short plasma elimination half-life, necessitating 2 to 4 times daily administration, and its inducible hepatic metabolism. Thus, tiagabine is a new antiepileptic agent with a novel mechanism of action, which has demonstrated efficacy in the adjunctive treatment of patients with refractory partial epilepsy. Further investigation of the efficacy of tiagabine is expected to provide a clearer definition of its place in the treatment of epilepsy and its relative merits in relation to other antiepileptic drugs.

Animals↗
PubMed1998

A review of the drug treatment of cachexia associated with cancer.

In the past 20 years, cachexia in cancer patients has attracted increasing interest from both clinicians and basic researchers. It is now clear that the cachexia is secondary to major metabolic abnormalities due to tumour by-products and cytokine release. These metabolic abnormalities produce numerous symptoms such as cachexia, anorexia and asthenia. There are now effective drugs such as corticosteroids and progestational drugs that have been shown to improve appetite, food intake and sensation of well-being, and which elicit bodyweight gain. While hydrazine (hydrazine sulfate) has received much attention, unfortunately it has been shown to be ineffective in improving the symptoms of the patient with cancer cachexia. A new group of drugs, such as thalidomide and melatonin because of their effects on tumour necrosis factor-alpha, and beta 2-adrenoceptor agonists because of their effects on muscle metabolism, and other agents, is presently reaching the clinical trial stage. There is now the possibility of addressing this fascinating syndrome at a different level and an opportunity for combined therapy to try to improve the quality of life of these patients.

Cachexia↗
PubMed1998

Abacavir.

Abacavir is a nucleoside analogue reverse transcriptase inhibitor that inhibits clinical isolates of HIV in vitro with a potency similar to that of zidovudine. Resistance to abacavir develops relatively slowly. Cross-resistance between abacavir and didanosine, zalcitabine or lamivudine, but not zidovudine or stavudine, has been reported in vitro. Abacavir has good oral bioavailability, as demonstrated in animals, and penetrates the CNS. Treatment with abacavir, alone or in combination with other anti-HIV agents (zidovudine, lamivudine, nevirapine, amprenavir and/or other protease inhibitors), decreased viral load and increased CD4+ cell count in patients with HIV infection. Effectiveness was maintained for at least 48 weeks. In early phase I/II trials, headache, gastrointestinal disturbances, rash, malaise, fatigue and/or asthenia were the most common adverse events reported with abacavir alone or in combination with other anti-HIV agents. Hypersensitivity reactions lead to discontinuation of therapy in 2 to 3% of patients.

Anti-HIV Agents↗
PubMed1998

Nelfinavir. A review of its therapeutic efficacy in HIV infection.

UNLABELLED: Nelfinavir is a selective inhibitor of HIV protease, the enzyme responsible for post-translational processing of HIV propeptides. In the presence of the drug, immature, noninfectious virus particles are produced. Nelfinavir in combination with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors and/or other protease inhibitors profoundly suppresses viral replication. Plasma HIV RNA levels (viral loan) rapidly fall below the limit of detection (LOD; usually 400 or 500 copies/ml in the majority of patients. When used in combination with NRTIs, nelfinavir 1250mg twice daily produced similar results to 3-times-daily nelfinavir at a range of total daily dosages. In an ongoing study > 70% of adults receiving a nelfinavir based combination regimen had plasma HIV RNA levels below the LOD (< 400 copies/ml) after 84 weeks. In addition, 73% of paediatric patients receiving nelfinavir plus at least 1 new NRTI had viral loads below the LOD (< 400 copies/ml) after 34 weeks. Furthermore, CD4+ cell counts generally increased in conjunction with reductions in viral load. Combination therapy with nelfinavir and saquinavir results in higher saquinavir plasma concentrations, make twice-daily administration of saquinavir feasible and may delay the emergence of resistant viral strains. A unique mutation at codon 30 (D30N) of the protease gene confers resistance to nelfinavir, but HIV with D30N mutation remains fully susceptible to indinavir, ritonavir and saquinavir in vitro. Nonetheless, in clinical use, significant cross-resistance is seen with all currently available protease inhibitors. Diarrhoea is the most frequently reported adverse event in patients receiving nelfinavir-based combination therapy and has been reported in up to 32% of nelfinavir recipients in randomised trials. Diarrhoea is generally of mild to moderate severity and does not result in weight loss. Rash, nausea, headache and asthenia were each reported in < or = 5% of patients. Approximately 5% of patients enrolled in an expanded access programme in the US discontinued nelfinavir because of adverse events. Nelfinavir is metabolised by the cytochrome P450 system. Several clinically significant pharmacokinetic drug interactions between nelfinavir and other drugs (i.e. ketoconazole, rifabutin, rifabutin, rifampicin), including other protease inhibitors (i.e. indinavir, ritonavir, saquinavir) have been documented. As with other available protease inhibitors, hyperglycaemia, hyperlipidaemia and abnormal fat distribution have been reported, albeit infrequently, in association with nelfinavir. CONCLUSION: Nelfinavir-based combination regimens are well tolerated and produce profound and prolonged suppression of HIV replication in adult and paediatric patients. Hence, nelfinavir is suitable for inclusion in antiretroviral regimens for initial therapy for HIV infection and, alternatively, in regimens for patients unable to tolerate other protease inhibitors.

Adult↗
PubMed1998

Trandolapril. An update of its pharmacology and therapeutic use in cardiovascular disorders.

UNLABELLED: Trandolapril is an orally administered angiotensin converting enzyme (ACE) inhibitor that has been used in the treatment of patients with hypertension and congestive heart failure (CHF), and after myocardial infarction (MI). Trandolapril is a nonsulfhydryl prodrug that is hydrolysed to the active diacid trandolaprilat. Trandolapril 2 mg once daily provides effective control of blood pressure (BP) over 24 hours in patients with mild to moderate hypertension, with a trough/peak ratio of BP reduction (as determined by 24-hour ambulatory monitoring) consistently > or = 50%. Trandolapril has similar antihypertensive efficacy to enalapril as indicated by several clinical trials. Combined therapy with trandolapril and sustained-release verapamil has a significantly greater antihypertensive effect than either agent alone. Only limited data are available on the use of trandolapril in patients with CHF, although ACE inhibitors as a class are recommended as first line therapy in such patients. In the Trandolapril Cardiac Evaluation (TRACE) study, trandolapril 1 to 4 mg once daily resulted in an early and long term reduction in all-cause mortality, including cardiovascular mortality, in patients with left ventricular (LV) dysfunction after an MI. Trandolapril therapy was commenced a mean 4.5 days after acute MI and continued for 24 to 50 months. At study end, the relative risk of death from any cause with trandolapril versus placebo was 0.78 (p = 0.001). The tolerability profile of trandolapril is similar to that of other ACE inhibitors. Most adverse events are mild and transient in nature, and include cough, asthenia, dizziness, headache and nausea. Trandolapril has no adverse effect on lipid or carbohydrate metabolism. CONCLUSIONS: trandolapril has a favourable pharmacological profile and an antihypertensive efficacy at least comparable to that of other ACE inhibitors. The pharmacological characteristics of trandolapril allow it to provide good 24-hour control of BP with once-daily administration. Trandolapril has also demonstrated some efficacy in a small number of patients with CHF. In addition, trandolapril provides long term protection against all-cause mortality in patients with LV dysfunction after MI. The results of the Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) study will determine its potential as a cardioprotective agent in patients with coronary artery disease and preserved LV function. Thus, trandolapril represents an effective, well-tolerated and convenient treatment option for patients with mild to moderate hypertension or LV systolic dysfunction after MI.

Aged↗
PubMed1999

Zolmitriptan: a review of its use in migraine.

UNLABELLED: Zolmitriptan is a selective serotonin 5-HT1B/1D receptor agonist ('triptan'). Its efficacy and tolerability have been assessed in a number of randomised, placebo-controlled, double-blind trials in large numbers of adults with moderate to severe migraine attacks. Oral zolmitriptan 2.5 and 5mg has a rapid onset of action (significant headache relief is observed at 45 minutes) and efficacy is sustained in most patients who respond at 2 hours. The drug is significantly more effective than placebo as measured by a number of parameters including 2-hour headache response rates and pain-free response rates. Other symptoms of migraine, including nausea, photophobia and phonophobia are also alleviated with zolmitriptan. Zolmitriptan is effective in the treatment of migraine associated with menses and migraine with aura. There is some evidence to support the use of zolmitriptan in patients with migraine who have had a poor response to previous therapy. The efficacy of zolmitriptan appears to be maintained, with no tachyphylaxis, following repeated administration for multiple attacks of migraine over a prolonged period of time, with high headache response rates reported over all attacks. In comparison with placebo, the incidence of persistent migraine headache is reduced by zolmitriptan and recurrent migraine headache occurs less frequently with the active treatment. Zolmitriptan has also demonstrated efficacy in the treatment of persistent and/or recurrent migraine headache. For relief of migraine headache, zolmitriptan 5mg had similar efficacy to sumatriptan 100mg for a single attack, but generally was more effective than sumatriptan 25 and 50mg for multiple attacks, in single trials. The incidence of recurrent headache with zolmitriptan was similar to that with sumatriptan. Zolmitriptan is generally well tolerated with most adverse events being mild to moderate, transient and resolving without intervention or the need for treatment withdrawal. The most common adverse events with zolmitriptan therapy are asthenia, heaviness other than that of the chest or neck, dry mouth, nausea, dizziness, somnolence, paraesthesia, warm sensation, tightness, vasodilation and chest pain. CONCLUSION: Zolmitriptan is effective across a wide range of migraine subtypes, maintains efficacy when used in the long term and is generally well tolerated. Further clinical experience is necessary to define the position of zolmitriptan among other currently or soon to be available selective 5-HT1B/1D receptor agonists. However, on the basis of available data, zolmitriptan should emerge as a useful treatment option in the management of patients with moderate to severe migraine.

Age Factors↗
PubMed2000

Ganirelix.

Ganirelix is a synthetic third generation gonadotropin-releasing hormone (GnRH) antagonist that is administered via the subcutaneous route. The drug competitively blocks GnRH receptors in the anterior pituitary gland, preventing endogenous GnRH from inducing luteinising hormone (LH) and follicle stimulating hormone release. Ganirelix effectively inhibited LH surges during controlled ovarian stimulation in a large, multicentre clinical trial in women undergoing in vitro fertilisation. A vital pregnancy rate per embryo transfer of 40.3% was achieved at weeks 5 to 6 after treatment with the 0.25 mg/day dosage. Subcutaneous ganirelix has been generally well tolerated in clinical trials. The most common adverse events were local injection site events, asthenia, nausea, malaise, headache and fatigue.

Animals↗
PubMed2000

Levetiracetam. A review of its adjunctive use in the management of partial onset seizures.

UNLABELLED: Levetiracetam, the S-enantiomer of alpha-ethyl-2-oxo-1-pyrollidine acetamide, is approved for use as adjunctive therapy in adult patients with partial onset seizures. Oral levetiracetam 1000, 2000 and 3000 mg/day administered as adjunctive therapy for up to 18 weeks significantly increased responder rates and reduced seizure frequency compared with placebo in 3 well designed pivotal trials in adults with treatment-refractory partial seizures with or without secondary generalisation. Levetiracetam 3000 mg/day also significantly increased the number of seizure-free patients, but the effects of levetiracetam 1000 and 2000 mg/day on this end-point were unclear. Effects on seizure severity were not assessed in these trials. Although not yet approved as monotherapy or for use in paediatric patients, efficacy was observed with levetiracetam 3000 mg/day as monotherapy in adult patients with refractory partial seizures with or without secondary generalisation and with the 10 to 40 mg/kg/day dosage as adjunctive therapy in children with refractory partial seizures. However, these data are limited. Oral levetiracetam 1000, 2000 and 3000 mg/day as adjunctive therapy is generally well tolerated with an overall incidence of adverse events similar to that observed with placebo. The most commonly reported events in individual clinical trials were CNS-related and included somnolence, asthenia, headache and dizziness. Levetiracetam administered as adjunctive therapy does not appear to interact with other anticonvulsant drugs, and no clinically relevant interactions were observed between levetiracetam and digoxin, warfarin or probenecid; oral contraceptive protective efficacy was also not affected by levetiracetam. CONCLUSIONS: Levetiracetam is a new anticonvulsant agent with a favourable tolerability profile and a low potential for drug interactions. It has shown efficacy as adjunctive therapy in patients with treatment-refractory partial onset seizures with or without secondary generalisation in clinical trials. Direct comparative trials with other anticonvulsant agents are not yet available, but placebo-controlled clinical evidence to date suggests that levetiracetam (1000, 2000 and 3000 mg/day) is a useful option as adjunctive therapy in patients with this subtype of epilepsy.

Administration, Oral↗
PubMed2000

Fluvoxamine. An updated review of its use in the management of adults with anxiety disorders.

UNLABELLED: Fluvoxamine is a potent and selective serotonin reuptake inhibitor (SSRI) that has little or no effect on other monoamine reuptake mechanisms. Relative to other SSRIs, fluvoxamine is a weak inhibitor of cytochrome P450 (CYP) 2D6, a moderate inhibitor of CYP2C19 and CYP3A4 and a potent inhibitor of CYP1A2. In randomised, double-blind trials. fluvoxamine 100 to 300 mg/day for 6 to 10 weeks significantly reduced symptoms of obsessive-compulsive disorder (OCD) compared with placebo. Response rates of 38 to 52% have been reported with fluvoxamine, compared with response rates of 0 to 18% with placebo. In patients with OCD, fluvoxamine had similar efficacy to that of clomipramine and, in smaller trials, the SSRIs paroxetine and citalopram and was significantly more effective than desipramine. Maintenance therapy with fluvoxamine may reduce the likelihood of relapses in up to 67% of patients with OCD. Fluvoxamine < or = 300 mg/day for 6 to 8 weeks was as effective as imipramine in patients with panic disorder, and significantly more effective than placebo. In addition, treatment with fluvoxamine < or = 300 mg/day for > or = 8 weeks improved symptoms of social phobia (social anxiety disorder), post-traumatic stress disorder (PTSD), pathological gambling, compulsive buying, trichotillomania, kleptomania, body dysmorphic disorder, eating disorders and autistic disorder. Large trials comparing the efficacy of fluvoxamine and other SSRIs in patients with anxiety disorders are warranted. Fluvoxamine is generally well tolerated; in postmarketing studies, nausea was the only adverse event occurring in >10% of patients with less commonly reported events including somnolence, asthenia, headache, dry mouth and insomnia. Fluvoxamine is associated with a low risk of suicidal behaviour, sexual dysfunction and withdrawal syndrome. Fewer anticholinergic or cardiovascular events are associated with fluvoxamine than tricyclic antidepressants. Although comparative data are lacking, the tolerability profile of fluvoxamine appears to be broadly similar to those of other SSRIs. CONCLUSION: Fluvoxamine has demonstrated short term efficacy in the treatment of OCD, panic disorder, social phobia, PTSD and in a range of obsessive-compulsive spectrum disorders. The drug is as effective as clomipramine in patients with OCD but appears to have a better tolerability profile. On the basis of current treatment guidelines, fluvoxamine, like other SSRIs, is recommended as first-line treatment for a number of anxiety disorders. It appears to offer some pharmacokinetic advantages and a different drug interaction profile to the other SSRIs with a broadly similar spectrum of adverse events. However, direct comparisons are required to assess the relative efficacy and tolerability of the different agents of this drug class.

Adult↗
PubMed2000

Cerivastatin: a review of its pharmacological properties and therapeutic efficacy in the management of hypercholesterolaemia.

UNLABELLED: Cerivastatin is an HMG-CoA reductase inhibitor used for the treatment of patients with hypercholesterolaemia. The lipid-lowering efficacy of cerivastatin has been demonstrated in a number of large multicentre, randomised clinical trials. Earlier studies used cerivastatin at relatively low dosages of < or =0.3mg orally once daily, but more recent studies have focused on dosages of 0.4 or 0.8 mg/day currently recommended by the US Food and Drug Administration (FDA). Along with modest improvements in serum levels of triglycerides and high density lipoprotein (HDL)-cholesterol, cerivastatin 0.4 to 0.8 mg/day achieved marked reductions in serum levels of low density lipoprotein (LDL)-cholesterol (33.4 to 44.0%) and total cholesterol (23.0 to 30.8%). These ranges included results of a pivotal North American trial in almost 1000 patients with hypercholesterolaemia. In this 8-week study, US National Cholesterol Education Program (Adult Treatment Panel II) [NCEP] target levels for LDL-cholesterol were achieved in 84% of patients randomised to receive cerivastatin 0.8 mg/day, 73% of those treated with cerivastatin 0.4 mg/day and <10% of placebo recipients. Among patients with baseline serum LDL-cholesterol levels meeting NCEP guidelines for starting pharmacotherapy, 75% achieved target LDL-cholesterol levels with cerivastatin 0.8 mg/day. In 90% of all patients receiving cerivastatin 0.8 mg/day, LDL-cholesterol levels were reduced by 23.9 to 58.4% (6th to 95th percentile). Various subanalyses of clinical trials with cerivastatin indicate that the greatest lipid-lowering response can be expected in women and elderly patients. Cerivastatin is generally well tolerated and adverse events have usually been mild and transient. The overall incidence and nature of adverse events reported with cerivastatin in clinical trials was similar to that of placebo. The most frequent adverse events associated with cerivastatin were headache, GI disturbances, asthenia, pharyngitis and rhinitis. In the large pivotal trial, significant elevations in serum levels of creatine kinase and transaminases were reported in a small proportion of patients receiving cerivastatin but not in placebo recipients. As with other HMG-CoA reductase inhibitors, rare reports of myopathy and rhabdomyolysis have occurred with cerivastatin, although gemfibrozil or cyclosporin were administered concomitantly in most cases. Postmarketing surveillance studies in the US have been performed. In 3 mandated formulary switch conversion studies, cerivastatin was either equivalent or superior to other HMG-CoA reductase inhibitors, including atorvastatin, in reducing serum LDL-cholesterol levels or achieving NCEP target levels. Pharmacoeconomic data with cerivastatin are limited, but analyses conducted to date in the US and Italy suggest that cerivastatin compares favourably with other available HMG-CoA reductase inhibitors in terms of its cost per life-year gained. CONCLUSION: Cerivastatin is a well tolerated and effective lipid-lowering agent for patients with hypercholesterolaemia. When given at dosages currently recommended by the FDA in the US, cerivastatin achieves marked reductions in serum levels of LDL-cholesterol, reaching NCEP target levels in the vast majority of patients. Thus, cerivastatin provides a useful (and potentially cost effective) alternative to other currently available HMG-CoA reductase inhibitors as a first-line agent for hypercholesterolaemia.

Administration, Oral↗
PubMed2000

Lopinavir.

Lopinavir is a protease inhibitor with high specificity for HIV-1 protease. Ritonavir strongly inhibits lopinavir metabolism; coadministration of lopinavir and ritonavir in healthy volunteers increased the area under the lopinavir plasma concentration-time curve >100-fold. Trough plasma concentration: antiviral 50% effective concentration ratio for lopinavir was >75 for wild-type HIV at the dose used in clinical trials, compared to values of < or = 4 for other commonly used protease inhibitors. Coformulated lopinavir and ritonavir (lopinavir/ ritonavir) 400/100mg twice daily for 48 weeks suppressed HIV replication in significantly more antiretroviral-naive patients than nelfinavir 750mg 3 times daily (all patients also received stavudine and lamivudine). Suppression of viral replication was observed in most protease inhibitor-experienced patients with lopinavir/ ritonavir (400/100, 400/200 or 533/133mg twice daily for 48 or 96 weeks) in combination with > or = 2 nucleoside reverse transcriptase inhibitors (NRTIs) and either efavirenz or nevirapine. 48 weeks of treatment with twice daily lopinavir/ ritonavir (230/57.5 or 300/75 mg/m2 for the first 12 weeks and then 300/75 mg/m2) in combination with 1 or2 NRTIs, with or without nevirapine, suppressed viral replication in the majority of antiretroviral-naive and -experienced paediatric patients (aged 6 months to 12 years). Diarrhoea, nausea and asthenia were the most frequently reported adverse effects in patients receiving lopinavir/ritonavir-based regimens. Elevated total cholesterol, triglyceride and hepatic enzyme levels were also reported.

Adult↗
PubMed2002

Paroxetine: an update of its use in psychiatric disorders in adults.

Paroxetine is a selective serotonin reuptake inhibitor (SSRI), with antidepressant and anxiolytic activity. In 6- to 24-week well designed trials, oral paroxetine 10 to 50 mg/day was significantly more effective than placebo, at least as effective as tricyclic antidepressants (TCAs) and as effective as other SSRIs and other antidepressants in the treatment of major depressive disorder. Relapse or recurrence over 1 year after the initial response was significantly lower with paroxetine 10 to 50 mg/day than with placebo and similar to that with imipramine 50 to 275 mg/day. The efficacy of paroxetine 10 to 40 mg/day was similar to that of TCAs and fluoxetine 20 to 60 mg/day in 6- to 12-week trials in patients aged > or =60 years with major depression. Paroxetine 10 to 40 mg/day improved depressive symptoms to an extent similar to that of TCAs in patients with comorbid illness, and was more effective than placebo in the treatment of dysthymia and minor depression. Paroxetine 20 to 60 mg/day was more effective than placebo after 8 to 12 weeks' treatment of obsessive-compulsive disorder (OCD), panic disorder, social anxiety disorder (social phobia), generalised anxiety disorder (GAD) and post-traumatic stress disorder (PTSD). Improvement was maintained or relapse was prevented for 24 weeks to 1 year in patients with OCD, panic disorder, social anxiety disorder or GAD. The efficacy of paroxetine was similar to that of other SSRIs in patients with OCD and panic disorder and similar to that of imipramine but greater than that of 2'chlordesmethyldiazepam in patients with GAD. Paroxetine is generally well tolerated in adults, elderly individuals and patients with comorbid illness, with a tolerability profile similar to that of other SSRIs. The most common adverse events with paroxetine were nausea, sexual dysfunction, somnolence, asthenia, headache, constipation, dizziness, sweating, tremor and decreased appetite. In conclusion, paroxetine, in common with other SSRIs, is generally better tolerated than TCAs and is a first-line treatment option for major depressive disorder, dysthymia or minor depression. Like other SSRIs, paroxetine is also an appropriate first-line therapy for OCD, panic disorder, social anxiety disorder, GAD and PTSD. Notably, paroxetine is the only SSRI currently approved for the treatment of social anxiety disorder and GAD, which makes it the only drug of its class indicated for all five anxiety disorders in addition to major depressive disorder. Thus, given the high degree of psychiatric comorbidity of depression and anxiety, paroxetine is an important first-line option for the treatment of major depressive disorder, OCD, panic disorder, social anxiety disorder, GAD and PTSD.

Administration, Oral↗
PubMed2002

ET-743.

ET-743 is a novel antineoplastic DNA-binding agent derived from the marine tunicate Ecteinascidia turbinata. It has significant cytotoxic activity against soft tissue sarcomas (STS). It also has in vitro activity against melanoma, breast, ovarian, colon, renal, non-small cell lung and prostate carcinomas. The drug has unique mechanism of action which includes in vitro inhibition of transcription-dependent nucleotide excision repair pathways and inhibition of cell cycle progression leading to p53-independent apoptosis. It also selectively inhibits transcriptional activation of multidrug-resistance (MDR1) gene in human sarcoma cells in vivo. The efficacy of ET-743 has been investigated in patients with advanced STS in three multicentre phase II clinical trials. Patients receiving ET-743 as second- or third-line treatment had partial tumour response rates of 6 to 8%. Patients receiving ET-743 as first-line chemotherapy had a partial response rate of 18%. Forty-two to 50% of all patients in these trials achieved stable disease. All responses were durable up to 14 months. A pooled analysis of the three multicentre phase II trials showed the following: median overall survival time of 10.2 months, 1-year survival rate of 40% and 6-month progression-free rate of 27.2%. ET-743 is generally well tolerated. The most common adverse events in clinical trials were non-cumulative haematological and hepatic toxicities. Transient and reversible elevation of hepatic transaminases, nausea, vomiting and asthenia were common but seldom severe and never treatment-limiting. Mucositis, alopecia and cardiac or neurotoxicities were not observed.

Antineoplastic Agents, Alkylating↗
PubMed2003

Capecitabine: a review of its pharmacology and therapeutic efficacy in the management of advanced breast cancer.

Capecitabine is an orally administered prodrug of fluorouracil which is indicated in the US and Europe, in combination with docetaxel, for the treatment of patients with metastatic breast cancer failing anthracycline therapy, and as monotherapy for metastatic breast cancer resistant to paclitaxel and anthracycline therapy (US) or failing intensive chemotherapy (Europe). Capecitabine is also approved for use in metastatic colorectal cancer. Capecitabine is metabolically activated preferentially at the tumour site, and shows antineoplastic activity and synergy with other cytotoxic agents including cyclophosphamide or docetaxel in animal models. Bioavailability after oral administration is close to 100%. In patients with pretreated advanced breast cancer, capecitabine is effective as monotherapy and also in combination with other agents. Combination therapy with capecitabine 1,250 mg/m(2) twice daily for 2 weeks of every 3-week cycle plus intravenous docetaxel 75 mg/m(2) on day one of each cycle was superior to intravenous monotherapy with docetaxel 100 mg/m(2) on day one of each cycle. Capecitabine plus docetaxel significantly reduced the risks of disease progression and death by 35% (p = 0.0001) and 23% (p < 0.05), respectively, and significantly increased median survival (p < 0.05) and objective response rates (p < 0.01). Efficacy has also been demonstrated with capecitabine monotherapy and combination therapy in previously untreated patients in preliminary trials. The most common adverse effects occurring in patients receiving capecitabine monotherapy include lymphopenia, anaemia, diarrhoea, hand-and-foot syndrome, nausea, fatigue, hyperbilirubinaemia, dermatitis and vomiting (all >25% incidence). While gastrointestinal events and hand-and-foot syndrome occurred more often with capecitabine than with paclitaxel or a regimen of cyclophosphamide, methotrexate and fluorouracil (CMF), neutropenic fever, arthralgia, pyrexia and myalgia were more common with paclitaxel, and nausea, stomatitis, alopecia and asthenia were more common with CMF. The incidence of adverse effects and hospitalisation was similar in patients receiving capecitabine plus docetaxel and those receiving docetaxel monotherapy. In conclusion, capecitabine, an oral prodrug of fluorouracil which is activated preferentially at the tumour site, is an effective and convenient addition to the intravenous polychemotherapeutic treatment of advanced breast cancer in pretreated patients, and also has potential as a component of first-line combination regimens. Combined capecitabine plus docetaxel therapy resulted in similar rates of treatment-related adverse effects and hospitalisation to those seen with docetaxel monotherapy. Capecitabine is also effective as monotherapy in pretreated patients and phase II data for capecitabine as first-line monotherapy are also promising. While gastrointestinal effects and hand-and-foot syndrome occur often with capecitabine, the tolerability profile was comparatively favourable for other adverse effects (notably, neutropenia and alopecia).

Administration, Oral↗
PubMed2003

Lopinavir/ritonavir: a review of its use in the management of HIV infection.

Lopinavir is a novel protease inhibitor (PI) developed from ritonavir. Coadministration with low-dose ritonavir significantly improves the pharmacokinetic properties and hence the activity of lopinavir against HIV-1 protease. Coformulated lopinavir/ritonavir was developed for ease of administration and to ensure both drugs are taken together, as part of combination therapy with other antiretroviral agents. Coformulated lopinavir/ritonavir-based regimens provide adequate and durable suppression of viral load and sustained improvements in CD4+ cell counts, as demonstrated in randomised trials in antiretroviral therapy-naive and -experienced adults and children. To date, development of primary resistance to lopinavir/ritonavir has not been observed in 470 antiretroviral therapy-naive patients treated for >48 weeks. The lopinavir/ritonavir-based regimen was more effective than nelfinavir in antiretroviral therapy-naive HIV-1-infected patients in a phase III trial. The coformulation is also effective as 'salvage' therapy, as shown by low cross-resistance rates in patients who failed to respond to treatment with other PIs in phase II trials. Coformulated lopinavir/ritonavir was well tolerated in both antiretroviral therapy-naive and -experienced HIV-1-infected adults and children with low rates of study drug-related treatment discontinuations. The most common adverse event in adults associated with lopinavir/ritonavir was diarrhoea, followed by other gastrointestinal disturbances, asthenia, headache and skin rash. The incidence of moderate-to-severe adverse events in children was low, skin rash being the most common. Changes in body fat composition occurred with equal frequency in lopinavir/ritonavir- and nelfinavir-treated naive patients, through week 60 in a phase III study. Although laboratory abnormalities occurred with similar frequency in both treatment groups, triglycerides grade 3/4 elevations were significantly more frequent with lopinavir/ritonavir. Total cholesterol and triglycerides grade 3/4 elevations appear to occur more frequently in PI-experienced than in PI-naive lopinavir/ritonavir-treated patients. A number of clinically important drug interactions have been reported with lopinavir/ritonavir necessitating dosage adjustments of lopinavir/ritonavir and/or the interacting drugs, and several other drugs are contraindicated in patients receiving the coformulation. CONCLUSION: Coformulated lopinavir/ritonavir is a novel PI that, in combination with other antiretroviral agents, suppresses plasma viral load and enhances immunological status in therapy-naive and -experienced patients with HIV-1 infection. Lopinavir/ritonavir appears more effective than nelfinavir in 'naive' patients and is also suitable for 'salvage' therapy, because of its high barrier to development of resistance. Given its clinical efficacy, a tolerability profile in keeping with this class of drugs, favourable resistance profile and easy-to-adhere-to administration regimen, coformulated lopinavir/ritonavir should be regarded as a first-line option when including a PI in the management of HIV-1 infection. OVERVIEW OF PHARMACODYNAMIC PROPERTIES: Lopinavir/ritonavir is a coformulation of two structurally related protease inhibitor (PI) antiretroviral agents. Lopinavir is a highly potent and selective inhibitor of the HIV type 1 (HIV-1) protease, an essential enzyme for production of mature, infective virus. It acts by arresting maturation of HIV-1 thereby blocking its infectivity. Thus, the main antiviral action of lopinavir is to prevent subsequent infections of susceptible cells; it has no effect on cells with already integrated viral DNA. Lopinavir has an approximate, equals 10-fold higher in vitro activity against both wild-type and mutant HIV-1 proteases than ritonavir; however, its in vivo activity is greatly attenuated by a high first-pass hepatic metabolism. The low-dose ritonavir coadministered with lopinavir inhibits metabolic inactivation of lopinavir and acts only as its pharmacokinetic enhancer. Therefore, the antiretroviral activity of roviral activity of coformulated lopinavir/ritonavir 400/100mg twice daily is derived solely from lopinavir plasma concentrations. Combining lopinavir with low-dose ritonavir produces lopinavir concentrations far exceeding those needed to suppress 50% of in vitro and in vivo viral replication in CD4+ cells and monocyte/macrophages (main human reservoirs of HIV-1 infection). Thus far, no resistance to lopinavir has been detected in clinical trials in antiretroviral therapy-naive patients treated for up to 204 weeks and only 12% of HIV-1 strains from patients in whom prior treatment with multiple PIs have failed, have been observed to develop resistance to coformulated lopinavir/ritonavir. A strong negative correlation was found between the number of PI mutations at baseline and the viral response rates achieved with lopinavir/ritonavir-based regimens in PI-experienced patients, indicating that resistance to lopinavir increases with increasing number of PI mutations and that five PI mutations represent the clinically relevant genotypic breakpoint for lopinavir. OVERVIEW OF PHARMACOKINETIC PROPERTIES: The absolute bioavailability of lopinavir coformulated with ritonavir in humans has not yet been established. Multiple-dosage absorption pharmacokinetics of lopinavir/ritonavir 400/100mg twice daily (the mean peak [C(max)] and trough [C(trough)] plasma concentrations at steady-state and the 12-hour area under the plasma concentration-time curve [AUC(12)] of either drug) were stable in antiretroviral therapy-naive and single PI-experienced adult patients receiving therapy over a 24-week evaluation period. The C(trough) values of lopinavir, achieved with lopinavir/ritonavir 400/100mg twice daily, were median 84-fold higher than the protein binding-adjusted 50% effective concentration (EC(50)) of lopinavir against wild-type HIV-1 in antiretroviral therapy-naive HIV-1-infected patients in a phase II study. Bioavailability of lopinavir administered in either the capsule or the liquid lopinavir/ritonavir formulation can be increased substantially with concurrent ingestion of food with moderate-to-high fat content. At steady state, lopinavir is approximately 98-99% plasma protein bound and the percentage of its unbound (i.e. pharmacologically active) fraction is dependent on total drug plasma concentration. Both lopinavir and ritonavir penetrate poorly into the human genital tracts and the cerebrospinal fluid. Both agents undergo extensive and rapid first-pass metabolism by hepatic cytochrome P450 (CYP) 3A4 isoenzyme. However, ritonavir also potently inhibits this enzyme and acts as a pharmacokinetic enhancer of lopinavir. The elimination half-life and apparent oral clearance of lopinavir average approximately 4-6 hours and approximately 6-7 L/h, respectively, with lopinavir/ritonavir 400/100mg twice daily administration. Less than 3% and 20% of the lopinavir dose is excreted unchanged in the urine and faeces, respectively. Limited data show similar pharmacokinetics of lopinavir in children as in adults. DRUG INTERACTIONS: Coformulated lopinavir/ritonavir has the potential to interact with wide variety of drugs via several mechanisms, mostly involving the CYP enzymes. Coadministration of lopinavir/ritonavir is contraindicated with certain drugs (i.e. flecainide, propafenone, astemizole, terfenadine, ergot derivatives, cisapride, pimozide, midazolam and triazolam) that are highly dependent on CYP3A or CYP2D6 for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. Coadministration with lopinavir/ritonavir is also not recommended for drugs or herbal products (i.e. rifampicin [rifampin] and St. John's wort [Hypericum perforatum]) that may substantially reduce lopinavir plasma concentrations, or drugs whose plasma concentrations elevated by the coformulation may lead to serious adverse reactions (i.e. simvastatin and lovastatin). However, a recent study in healthy volunteers suggests that adequate lopinavir concentrations may be achieved during rifampicin coadministration by increasing the twice-daily dosage of lopinavir/ritonavir in conjunction with therapeutic drug monitoring. The liquid (but not the capsule) formulation of lopinavir/ritonavir contains 42.4% ethanol (v/v) and should not be coadministered with drugs capable of producing disulfiram-like reactions (e.g. disulfiram, metronidazole). Coadministration with saquinavir or indinavir requires no dosage adjustment, whereas coadministration with amprenavir, nevirapine or efavirenz requires a dosage increase of the coformulation typically by 33%. As the oral bioavailability of both didanosine and lopinavir/ritonavir is significantly affected by concurrent food ingestion, didanosine should be administered 1 hour before or 2 hours after lopinavir/ritonavir has been taken with food. Interactions between lopinavir/ritonavir and other nucleoside reverse transcriptase inhibitors (NRTIs) are not expected. The coformulation is also likely to increase plasma concentrations of non-antiretroviral drugs metabolised through the CYP3A pathway. To reduce the risk of their toxicity when coadministered with lopinavir/ritonavir, the recommended actions include: (i) monitoring of the drug plasma concentration (antiarrhythmics and immunosuppressants) or the international normalised ratio (warfarin); (ii) the use of alternative treatment (atorvastatin) or birth control methods (ethinylestradiol); and (iii) dosage adjustment (clarithromycin [only in patients with renal failure], rifabutin, dihydropyridine calcium-channel blockers, atorvastatin, ketoconazole and itraconazole). (ABSTRACT TRUNCATED)

Clinical Trials as Topic↗