Amisulpride: a review of its use in the management of schizophrenia.

UNLABELLED: Amisulpride, a substituted benzamide derivative, is a second-generation (atypical) antipsychotic. At low doses, it enhances dopaminergic neurotransmission by preferentially blocking presynaptic dopamine D2/D3 autoreceptors. At higher doses, amisupride antagonises postsynaptic dopamine D2 and D3 receptors, preferentially in the limbic system rather than the striatum, thereby reducing dopaminergic transmission. In patients with acute exacerbations of schizophrenia, the recommended dosage of amisulpride is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. In comparative trials, amisulpride administered within this range (400 to 1200 mg/day) was as effective as haloperidol 5 to 40 mg/day, flupenthixol 25 mg/day and risperidone 8 mg/day in patients with acute exacerbations of schizophrenia with predominantly positive symptoms. Amisulpride was more effective than haloperidol but equally effective as risperidone in controlling negative symptoms. Amisulpride 400 to 800 mg/day was more effective than haloperidol, risperidone and flupenthixol in controlling affective symptoms in these patients. In randomised, double-blind trials involving patients with predominantly negative symptoms of schizophrenia, amisulpride 50 to 300 mg/day was more effective than placebo. Amisulpride is effective as maintenance therapy in patients with chronic schizophrenia. Long-term treatment with amisulpride was associated with improvements in quality of life and social functioning. Amisulpride is generally well tolerated. In well-controlled trials, the neurological tolerability profile (including ratings on extrapyramidal symptom scales) of amisulpride 400 to 1200 mg/day was superior to that of the conventional antipsychotics (haloperidol or flupenthixol), but was similar to that of the atypical antipsychotic risperidone. At low dosages of amisulpride (< or =300 mg/day), the incidence of adverse events (including extrapyramidal symptoms) reported with amisulpride was similar to that with placebo. CONCLUSION: In comparative trials, amisulpride 400 to 1200 mg/day showed efficacy in reducing overall symptomatology and positive symptoms similar to that of conventional antipsychotics and newer atypical antipsychotics in patients with acute exacerbations of schizophrenia. Moreover, its effective alleviation of negative and affective symptoms, its lower association with extrapyramidal symptoms and loss of cognitive function than conventional antipsychotics and its long-term efficacy justifies consideration of the use of higher dosages of amisulpride in this group of patients. Consequently, the dosage of amisulpride that is recommended in patients with acute exacerbations of schizophrenia is 400 to 800 mg/day, although dosages < or =1200 mg/day may be administered. Lower dosages of amisulpride (50 to 300 mg/day) should be considered for the management of patients with negative symptoms of schizophrenia. Amisulpride is a first-line treatment option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.

Olanzapine: a review of its use in the treatment of bipolar I disorder.

UNLABELLED: Olanzapine, a thienobenzodiazepine derivative, is a psychotropic agent that has shown efficacy in the treatment of patients with bipolar I disorder. Olanzapine has a multireceptorial binding profile including a greater affinity for serotonin 5-HT(2A) than for dopamine D(2) receptors. Olanzapine 5 to 20 mg/day demonstrated significantly greater antimanic efficacy than placebo in two double-blind, randomised 3- or 4-week trials of patients with bipolar I disorder of either manic or mixed episodes, with or without psychotic features. Additionally, in one of these trials, improvements in cognitive function and hostility were superior with olanzapine. In cohorts of severely depressed and rapid cycling patients, improvements in manic and depressive symptoms and in manic symptoms only, were superior with olanzapine compared with placebo. Significant improvements from baseline in symptoms of mania, depression, cognitive functioning and hostility were seen with olanzapine in a 49-week extension phase study. In double-blind trials, olanzapine 10 mg/day appeared to have similar antimanic efficacy to oral lithium 400mg twice daily in the treatment of patients with pure mania (4-week small study). In patients with acute manic or mixed episodes olanzapine 5 to 20 mg/day appeared to be more effective than oral valproate semisodium (divalproex sodium) 500 to 2500 mg/day (3-week study) and at least as effective as oral haloperidol 3 to 15 mg/day (12-week study). Preliminary results from a large 6-week placebo-controlled study suggest that olanzapine 5 to 20 mg/day in combination with mood stabilisers (lithium or valproate semisodium) provides effective augmentation of antimanic treatment of patients with bipolar I disorder, with benefits seen in the first week. Adverse events reported significantly more often with olanzapine than with placebo were somnolence, dry mouth, dizziness and bodyweight gain, and in comparison with valproate semisodium were somnolence, dry mouth, increased appetite and bodyweight gain. Olanzapine was generally well tolerated with no clinically relevant abnormalities in laboratory tests, vital signs or electrocardiogram results. CONCLUSION: Olanzapine demonstrated superior efficacy compared with placebo in the short-term treatment of patients with bipolar I disorder with manic or mixed episodes, with or without psychotic features, and was generally well tolerated. According to preliminary data the antimanic efficacy of olanzapine appears similar to that of haloperidol and better than that of valproate semisodium in patients with bipolar I disorder experiencing a manic or mixed episode; among nonpsychotic patients with manic or mixed episodes olanzapine appears to be superior to haloperidol. Available data support the choice of olanzapine as an option in the short-term management of mania in patients with bipolar I disorder with manic or mixed episodes, with or without psychotic features.

Cyclosporin: an updated review of the pharmacokinetic properties, clinical efficacy and tolerability of a microemulsion-based formulation (neoral)1 in organ transplantation.

UNLABELLED: Cyclosporin is a lipophilic cyclic polypeptide immunosuppressant that interferes with the activity of T cells chiefly via calcineurin inhibition. The original oil-based oral formulation of this drug (Sandimmun)l was characterised by high intra- and interpatient pharmacokinetic variability, with poor bioavailability in many patients; a novel microemulsion formulation (Neoral)1 was therefore developed to circumvent these problems. Studies show increases, attributable chiefly to improved absorption in patients who absorb the drug only poorly from the original formulation, in mean systemic exposure to cyclosporin with the microemulsion, with no clinically significant differences in tolerability or drug interaction profiles. Cyclosporin microemulsion is at least as effective as the oil-based formulation in renal, liver and heart transplant recipients, with trends towards decreased incidence of acute rejection with the microemulsion formulation in some (statistically significant in a few) trials. Cyclosporin microemulsion and tacrolimus appear to have similar efficacy in preventing acute rejection episodes in most renal, pancreas-kidney, liver and heart transplant recipients. However, there are indications of superior efficacy for tacrolimus in some trials, particularly in the prevention of severe acute rejection and in Black transplant recipients. Current 12-month data also indicate equivalent efficacy of sirolimus in renal transplantation. Conversion from the oil-based to microemulsion formulation in stable renal, liver and heart transplant recipients is achievable with no change in acute rejection rates. The addition of an anti-interleukin-2 receptor monoclonal antibody and/or mycophenolate mofetil to cyclosporin microemulsion plus corticosteroids decreases rates of acute rejection; corticosteroid withdrawal without increased acute rejection rates was also achieved on the addition of these agents in some trials. Pharmacoeconomic analyses have shown savings in direct healthcare costs in kidney or liver transplantation when cyclosporin microemulsion is used in preference to the oil-based formulation, although studies incorporating indirect costs or expressing costs in terms of therapeutic outcomes are currently unavailable. CONCLUSIONS: The introduction of cyclosporin microemulsion has consolidated the place of the drug as a mainstay of therapy in all types of solid organ transplantation; research into optimisation of outcomes through more effective therapeutic monitoring in patients receiving this formulation is ongoing. Several novel immunosuppressants have been introduced in recent years: further clinical and pharmacoeconomic research will be needed to clarify the relative positioning of these agents, particularly with respect to specific patient groups. Other new drugs (basiliximab/daclizumab and mycophenolate mofetil) offer particular advantages when used in combination with cyclosporin.

Venlafaxine extended-release: a review of its use in the management of major depression.

UNLABELLED: Venlafaxine inhibits presynaptic reuptake of serotonin (5-hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine). Venlafaxine extended-release (XR) has been investigated in patients with major depression and in patients with major depression with associated anxiety in randomised, double-blind, multicentre trials. A therapeutic response in patients with major depression was evident at week 2 of treatment with venlafaxine XR 75 to 225 mg/day in a placebo-controlled trial. By week 4, the drug was significantly more effective than placebo at reducing both the Hamilton Rating Scale for Depression (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores. Furthermore, cumulative relapse rates were lower among recipients of venlafaxine XR 75 to 225 mg/day than placebo recipients after 3 and 6 months in another trial. Venlafaxine XR 75 to 150 mg/day was significantly more effective than venlafaxine immediate-release (IR) 75 to 150 mg/day or placebo during a 12-week study. Reductions from baseline in all 4 efficacy parameters (HAM-D, MADRS, HAM-D depressed mood item and the Clinical Global Impression Severity of Illness scale) were significantly higher among patients treated with venlafaxine XR than venlafaxine IR or placebo at week 12 (using an intent-to-treat, last observation carried forward analysis). Venlafaxine XR 75 to 225 mg/day was compared with fluoxetine 20 to 60 mg/day in patients with major depression in 2 randomised, double-blind, placebo-controlled, multicentre studies. Remission rates were significantly in favour of venlafaxine XR recipients in one study: 37, 22 and 18% of patients treated with venlafaxine XR, fluoxetine or placebo, respectively, achieved full remission (HAM-D total score < or = 7 at end-point). In the other trial, venlafaxine XR and fluoxetine had comparable efficacy in reducing HAM-D and Hamilton Rating Scale for Anxiety (HAM-A) total scores compared with placebo. However, the HAM-A response rate was significantly higher with venlafaxine XR than with fluoxetine at week 12. In a comparative study involving paroxetine, reductions from baseline in HAM-D and MADRS total scores in patients given venlafaxine XR 75 mg/day or paroxetine 20 mg/day for 12 weeks were significant, but no significant differences between treatment groups were evident. Discontinuation rates because of unsatisfactory clinical response were similar among patients treated with venlafaxine XR, fluoxetine or paroxetine. Adverse events pertaining to the digestive (nausea, dry mouth), nervous (dizziness, somnolence, insomnia) and urogenital (abnormal ejaculation) systems as well as sweating were the most frequently reported adverse events during 8 to 12 weeks of treatment in 3 randomised, double-blind, multicentre trials. Comparative studies with fluoxetine and paroxetine demonstrated a similar adverse event profile to venlafaxine XR. CONCLUSION: Venlafaxine XR has shown efficacy in the treatment of major depression and was at least as effective as fluoxetine or paroxetine and more effective than venlafaxine IR. Furthermore, it is effective at reducing symptoms of anxiety in depressed patients. The incidence of adverse events in recipients of venlafaxine XR is similar to that in patients receiving treatment with well established selective serotonin reuptake inhibitors. As an effective and well tolerated antidepressant, venlafaxine XR should be considered as a first-line pharmacological treatment in patients with major depression.

Efavirenz: a pharmacoeconomic review of its use in HIV infection.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of patients with HIV infection. Both US and British treatment guidelines for HIV infection recommend NNRTI- or protease inhibitor-based combinations [i.e. with nucleoside reverse transcriptase inhibitors (NRTIs)] as first-line treatmentoptions in the management of HIV disease. Results of a pivotal randomised study (DMP 266-006) comparing efavirenz- versus indinavir-based triple combination therapy in patients with HIV infection (the majority of whom were antiretroviral therapy-naive) showed the efavirenz-based regimen was better tolerated and had greater success in achieving reductions in viral load below the limit of detection. These and other clinical data were incorporated into economic models in 2 analyses, one conducted in the US and the other in Canada. The US analysis examined long term clinical and economic outcomes predicted on the basis of response (viral load and CD4+ cell counts), tolerability and willingness to adhere to therapy. The efavirenz-based regimen was the dominant treatment strategy as it was predicted to improve survival and reduce direct medical costs in the US healthcare system. Compared with the indinavir-containing regimen, survival was increased by 11% (absolute difference) and cumulative costs were reduced by $US10,326 per patient (1998 discounted costs) at 5 years after starting treatment with efavirenz-based therapy. The Canadian analysis was conducted from the perspective of the Ontario healthcare system. This study did not consider differences in clinical efficacy between treatment groups, costs of study medication or outcomes beyond 1 year--all factors that would have favoured the efavirenz-based regimen. Of the 2 treatment options, the efavirenz-based regimen was associated with 7.4% lower average annual medical care costs, primarily because of greater costs associated with adverse clinical events with the indinavir-based regimen. In conclusion, current treatment guidelines for HIV infection recognise efavirenz-based combination regimens as a first-line treatment option. A pivotal comparative clinical trial (DMP 266-006) showed a significantly greater virological response to efavirenz- than indinavir-based triple combination therapy, and the efavirenz-based regimen was better tolerated. These clinical data are supported by pharmacoeconomic analyses conducted in the US and Canada, both of which showed lower medical care costs with the efavirenz-based regimen. The US analysis also predicted long term health benefits, such as improved survival, with efavirenz- versus indinavir-based triple combination therapy. These results must be weighed against the inherent difficulties of predicting long term treatment failure rates from short term data, and the limited number of pharmacoeconomic analyses conducted with efavirenz to date.

Linezolid: a review of its use in the management of serious gram-positive infections.

UNLABELLED: Linezolid is the first of a new class of antibacterial drugs, the oxazolidinones. It has inhibitory activity against a broad range of gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), glycopeptide-intermediate S. aureus (GISA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae. The drug also shows activity against certain anaerobes, including Clostridium perfringens, C. difficile, Peptostreptococcus spp. and Bacteroidesfragilis. In controlled phase III studies, linezolid was as effective as vancomycin in the treatment of patients with infections caused by methicillin-resistant staphylococci and also demonstrated efficacy against infections caused by VRE. Further phase III studies have demonstrated that linezolid is an effective treatment for patients with nosocomial pneumonia, for hospitalised patients with community-acquired pneumonia, and for patients with complicated skin or soft tissue infections (SSTIs). In these studies, linezolid was as effective as established treatments, including third-generation cephalosporins in patients with pneumonia, and oxacillin in patients with complicated SSTIs. Oral linezolid 400 or 600mg twice daily was as effective as clarithromycin 250mg twice daily or cefpodoxime proxetil 200mg twice daily in the treatment of patients with uncomplicated SSTIs or community-acquired pneumonia. Linezolid is a generally well tolerated drug. The most frequently reported adverse events in linezolid recipients were diarrhoea, headache, nausea and vomiting. Thrombocytopenia was also documented in a small proportion (about 2%) of patients treated with the drug. CONCLUSIONS: Linezolid has good activity against gram-positive bacteria, particularly multidrug resistant strains of S. aureus (including GISA), Enterococcus faecium and E. faecalis (including VRE). In controlled clinical trials, linezolid was as effective as vancomycin in eradicating infections caused by methicillin-resistant Staphylococcus spp. and has demonstrated efficacy against infections caused by VRE. As the level of resistance to vancomycin increases among S. aureus and enterococci, linezolid is poised to play an important role in the management of serious gram-positive infections.

Cefpodoxime proxetil: a review of its use in the management of bacterial infections in paediatric patients.

UNLABELLED: Cefpodoxime proxetil is an oral third generation cephalosporin with a broad spectrum of antibacterial activity. The drug has in vitro activity against many common Gram-positive and Gram-negative pathogens associated with common paediatric infections, making the drug a useful option for empirical therapy. In randomised controlled trials conducted in children with acute otitis media, oral cefpodoxime proxetil 8 to 10 mg/kg/day (usually administered in 2 divided doses) for 5 to 10 days was at least as effective as standard regimens of amoxicillin/ clavulanic acid, cefixime, cefuroxime axetil or cefaclor as assessed by either clinical or bacteriological criteria. Cefpodoxime 8 to 10 mg/kg/day (administered in 2 divided doses) for 5 to 10 days was at least as effective as standard 10-day regimens of penicillin V in the treatment of children with pharyngitis and/or tonsillitis. Significant differences in favour of cefpodoxime proxetil were demonstrated in terms of clinical (1 study) and bacteriological (2 studies) criteria. The clinical efficacy of 5 days of treatment with cefpodoxime proxetil is similar to that of 10 days of treatment with penicillin V. In children with lower respiratory tract infections (primarily pneumonia), clinical and bacteriological efficacy rates achieved with cefpodoxime proxetil treatment were similar to those produced by cefuroxime axetil or amoxicillin/clavulanic acid in randomised controlled trials. Cefpodoxime proxetil also demonstrated clinical efficacy in paediatric patients with skin and soft tissue infections. In randomised studies that included both adults and children with a variety of infections (e.g. abscess, atheroma, furuncle and carbuncle, infected wounds, cellulitis), cefpodoxime proxetil showed efficacy similar to that of cefuroxime axetil or cefaclor. Cefpodoxime proxetil is well tolerated by paediatric patients, with adverse events (primarily gastrointestinal tract disturbances and skin rashes) that are consistent with those reported for other oral cephalosporins. CONCLUSION: Cefpodoxime proxetil is a third generation cephalosporin with a broad spectrum of antibacterial activity and a favourable pharmacokinetic profile which allows twice-daily administration. It is generally well tolerated and demonstrates good bacteriological and clinical efficacy in paediatric patients with various infectious diseases, including acute otitis media, tonsillitis and/or pharyngitis. Based on these characteristics, cefpodoxime proxetil is a suitable option for the treatment of paediatric patients with various common bacterial infections.

Oseltamivir: a review of its use in influenza.

UNLABELLED: Oseltamivir is a prodrug of oseltamivir carboxylate (Ro 64-0802, GS4071), a potent and selective inhibitor of the neuraminidase glycoprotein essential for replication of influenza A and B viruses. Studies in volunteers with experimental human influenza A or B showed that administration of oral oseltamivir 20 to 200 mg twice daily for 5 days reduced both the quantity and duration of viral shedding compared with placebo. Subsequent assessment of the drug at a dosage of 75 mg twice daily for 5 days in otherwise healthy adults with naturally acquired febrile influenza showed that oseltamivir reduced the duration of the disease by up to 1.5 days and the severity of illness by up to 38% compared with placebo when initiated within 36 hours of symptom onset (earlier initiation of therapy was associated with faster resolution). The incidence of secondary complications and the use of antibacterials were also reduced significantly in oseltamivir recipients. A liquid formulation of oseltamivir (2 mg/kg twice daily for 5 days) has been shown to be effective in the treatment of children with influenza, and data presented in abstracts suggest that the drug may also be of use in high-risk populations such as the elderly or those with chronic cardiac or respiratory disease. In addition to treatment efficacy, the drug has demonstrated efficacy when used for seasonal or household prophylaxis. Oral oseltamivir (75 mg once or twice daily for 6 weeks) during a period of local influenza activity significantly prevented the development of naturally acquired influenza by >70% compared with placebo in unvaccinated otherwise healthy adults. The drug also demonstrated efficacy when used adjunctively in previously vaccinated high-risk elderly patients (92% protective efficacy). Short term administration of oseltamivir (75 mg once daily for 7 days) may significantly reduce the risk of illness in household contacts of infected persons when administered within 48 hours of symptom onset in the infected person. Oseltamivir 75 mg twice daily for 5 days was well tolerated in clinical trials in healthy adults and high-risk patients, with nausea and vomiting being the most commonly reported events. Gastrointestinal events were mild and transient and both nausea and vomiting were less likely when oseltamivir was taken with food. CONCLUSIONS: Oseltamivir is a well tolerated orally active neuraminidase inhibitor which significantly reduces the duration of symptomatic illness and hastens the return to normal levels of activity when initiated promptly in patients with naturally acquired influenza. It therefore represents a useful therapeutic alternative to zanamivir (especially in patients who prefer oral administration or who have an underlying respiratory disorder) and the M2 inhibitors amantadine and rimantadine (because of its broader spectrum of anti-influenza activity and lower likelihood of resistance) in patients with influenza. In addition, although annual vaccination remains the best means of influenza prevention, there may be a place for oseltamivir in providing household prophylaxis or adjunctive prophylaxis in high-risk vaccinated patients during an outbreak of the disease or for use in patients in whom vaccination is unsuitable or ineffective.

Caffeine citrate: a review of its use in apnoea of prematurity.

UNLABELLED: Apnoea of prematurity is a common condition in neonates born at less than 37 weeks' gestational age; it affects approximately 90% of premature neonates weighing under 1000 g at birth, and 25% of infants with a birthweight of less than 2500 g. Caffeine, a methylxanthine which occurs naturally in many plants, has been used for over 20 years to treat apnoea of prematurity. In a recent double-blind, placebo-controlled trial, apnoea was eliminated or reduced by at least 50% in significantly more neonates receiving caffeine citrate as first-line treatment than those receiving placebo. In a nonblind trial, caffeine citrate was more effective at reducing apnoeic episodes when compared with neonates receiving no treatment. Caffeine as first-line treatment demonstrated similar efficacy to theophylline or aminophylline (theophylline ethylenediamine) in 4 small randomised studies. Caffeine citrate was generally well tolerated in short term clinical trials, with very few adverse events reported. Caffeine was associated with fewer adverse events than theophylline in randomised trials. No differences in the incidence of individual adverse events were reported between caffeine citrate and placebo in a double-blind, randomised trial. Long term tolerability data are not yet available. CONCLUSIONS: Caffeine citrate was generally well tolerated by neonates in clinical trials and it decreased the incidence of apnoea of prematurity compared with placebo. It has demonstrated similar efficacy to theophylline, but is generally better tolerated and has a wider therapeutic index. Caffeine citrate should, therefore, be considered the drug of choice when pharmacological treatment of apnoea of prematurity is required.

Enoxaparin: in the prevention of venous thromboembolism in medical patients.

Enoxaparin (enoxaparin sodium) is a low-molecular-weight heparin that binds to and increases the activity of antithrombin III. The resulting complex inhibits prothrombinase-mediated thrombin generation and direct thrombin generation by binding to factor Xa and thrombin factor IIa. Enoxaparin, used as prophylaxis in medically ill patients at increased risk for thromboembolism, has shown significantly increased efficacy compared with placebo in reducing the incidence of deep vein thrombosis and pulmonary embolism. Indeed, 291 patients receiving subcutaneous enoxaparin 40 mg/day had a frequency of venous thromboembolism of 5.5% during 14 days of treatment, whereas 14.9% of the 288 placebo recipients experienced thromboemboli (p < 0.001). There was no reduction in the incidence of thromboembolism in the 287 recipients of enoxaparin 20 mg/day (15%). In other studies, prophylactic treatment for 7 days with subcutaneous enoxaparin 40 mg/day was at least as effective as unfractionated heparin in reducing the frequency of venous thromboembolism in 959 nonsurgical patients at increased risk for deep vein thrombosis and pulmonary embolism (total incidence = 0.2 and 1.4%, respectively). Moreover, enoxaparin recipients experienced fewer adverse events than did heparin recipients. The most frequent adverse events reported in medically ill and surgical patients receiving enoxaparin 40 mg/day were hemorrhage (17.4 vs 14.3% for placebo), hematoma at injection site, anemia, fever, peripheral edema, nausea, ecchymosis and edema (unspecified site).

Peginterferon-alpha-2a (40 kD): a review of its use in the management of chronic hepatitis C.

UNLABELLED: Peginterferon-alpha-2a (40 kD) is a new 'pegylated' subcutaneous formulation of interferon-alpha-2a that has been developed to improve on the pharmacokinetic profile and therapeutic efficacy of interferon-alpha-2a. Peginterferon-alpha-2a (40 kD) is produced by the covalent attachment of recombinant interferon-alpha-2a to a branched mobile 40 kD polyethylene glycol moiety, which shields the interferon-alpha-2a molecule from enzymatic degradation, reduces systemic clearance and enables once-weekly administration. Peginterferon-alpha-2a (40 kD) was significantly more effective than interferon-alpha-2a in interferon-alpha therapy-naive adults with chronic hepatitis C in three nonblind, randomised, multicentre trials. Virological responses (intention-to-treat results) were achieved in 44 to 69% of patients with or without cirrhosis after 48 weeks of treatment with peginterferon-alpha-2a (40kD) 180 microg/week; sustained virological responses 24 weeks after the end of treatment occurred in 30 to 39% of patients. Virological responses at the end of treatment and at long-term follow-up were significantly higher than those achieved with interferon-alpha-2a. Peginterferon-alpha-2a (40 kD) was significantly more effective than interferon-alpha in patients with or without cirrhosis infected with HCV genotype 1. Sustained biochemical responses achieved with peginterferon-alpha-2a (40 kD) 180 microg/week ranged from 34 to 45% and were significantly higher than with interferon-alpha-2a. Recipients of peginterferon-alpha-2a (40 kD) also experienced histological improvements; 24 weeks after discontinuation of treatment with peginterferon-alpha-2a (40 kD) 180 microg/week, 54 to 63% of patients had a > or =2-point improvement in histological activity index score. Peginterferon-alpha-2a (40 kD) produced histological responses in patients (with or without cirrhosis) with or without a sustained virological response. Peginterferon-alpha-2a (40 kD) produced better results than interferon-alpha-2a alone or interferon-alpha-2b plus oral ribavirin on various measures of quality of life in patients with chronic hepatitis C. The tolerability profile of peginterferon-alpha-2a (40 kD) is broadly similar to that of interferon-alpha-2a in patients with chronic hepatitis C with or without cirrhosis. Headache, fatigue and myalgia are among the most common adverse events. CONCLUSION: Peginterferon-alpha-2a (40 kD) administered once weekly produces significantly higher sustained responses, without compromising tolerability, than interferon-alpha-2a administered thrice weekly in noncirrhotic or cirrhotic patients with chronic hepatitis C, including those infected with HCV genotype 1 - a group in whom interferon-alpha treatment has usually been unsuccessful. Peginterferon-alpha-2a (40 kD) is a valuable new treatment option and appears poised to play an important role in the first-line treatment of patients with chronic hepatitis C, including difficult-to-treat patients such as those with compensated cirrhosis and/or those infected with HCV genotype 1.

Nevirapine: a review of its use in the prevention and treatment of paediatric HIV infection.

UNLABELLED: Nevirapine is a highly specific inhibitor of HIV-1 reverse transcriptase (RT), an important therapeutic target for the treatment of HIV infection. It was the first non-nucleoside RT inhibitor (NNRTI) to be approved for use in HIV-infected individuals, including children. Nevirapine inhibits replication of multiple HIV-1 strains and clinical isolates in cultured human T cells, but has no activity against other retroviral RTs (including HIV-2 RT) or endogenous human DNA polymerases. Monotherapy with nevirapine rapidly selects for high level drug resistance conferred by a single amino acid substitution in the HIV RT gene. The pattern of resistance mutations selected by nevirapine overlaps with those of other NNRTIs, but is distinct from those of nucleoside analogue RT inhibitors and protease inhibitors. The pharmacokinetics of nevirapine are characterised by rapid and nearly complete oral absorption, an apparently even distribution throughout all organs and tissues in the body, and a long elimination half-life. Nevirapine is both metabolised by and induces the activity of cytochrome P450 isoenzymes. Caution is required when coadministering nevirapine with other drugs metabolised by this system, including HIV protease inhibitors. As a single dose therapy given to pregnant women in labour and to neonates shortly after birth, nevirapine reduced the rate of perinatal HIV transmission by 47% compared with a short course of intrapartum and neonatal zidovudine in a randomised trial in breastfeeding women in Uganda. Nevirapine was more cost effective than zidovudine-based regimens for the prevention of perinatal HIV transmission in a cost-effectiveness model in sub-Saharan Africa. Nevirapine has shown antiretroviral efficacy as part of combination therapy with zidovudine and either didanosine or lamivudine in small numbers of paediatric patients in phase I/II trials. Triple therapy of nevirapine, zidovudine and didanosine was moderately effective in a randomised, nonblind trial in patients with advanced disease. The most frequent adverse event associated with nevirapine is rash, which occasionally develops into severe rash or Stevens-Johnson syndrome. Elevations in liver enzyme levels can occasionally lead to severe complications in patients receiving multiple dose nevirapine. CONCLUSION: Single dose nevirapine appears to be the most cost-effective of available options for the prevention of perinatal HIV transmission suitable for use in developing countries. In addition, preliminary clinical trial data suggest that nevirapine adds to the efficacy of combination therapy for the treatment of HIV infection in infants and children, and is reasonably well tolerated.

Abacavir: a review of its clinical potential in patients with HIV infection.

UNLABELLED: Abacavir is a carbocyclic 2'-deoxyguanosine nucleoside analogue. It is metabolised intracellularly to a 2'-deoxyguanosine nucleoside analogue which competitively inhibits HIV reverse transcriptase and terminates proviral DNA chain extension. In double-blind trials in antiretroviral therapy-experienced or -naive patients, reductions in HIV RNA levels were greater and more prolonged in patients receiving abacavir in combination with other antiretroviral drugs than in those receiving placebo in combination with the same agents. Furthermore, abacavir in combination with lamivudine and zidovudine reduced viral load to below detectable levels in a proportion of patients, and to a similar extent to the protease inhibitor indinavir in combination with lamivudine and zidovudine. Greatest viral load reductions were seen in antiretroviral therapy-naive patients. Preliminary results suggest that the viral suppression achieved with a protease inhibitor plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) can be maintained as effectively with abacavir in combination with 2 NRTIs as it can be by continuing the protease inhibitor-containing treatment regimen. Initial virological data from studies of combination regimens including abacavir and protease inhibitors appear promising but larger controlled trials are required to confirm these observations. Nausea is the most frequently reported adverse event in patients receiving abacavir-containing combination therapy. Adverse events tend to be reported most frequently soon after starting treatment; the majority of events are mild or moderate in intensity and transient. Other adverse events reported in >5% of patients include vomiting, malaise and fatigue, headache, diarrhoea, sleep disorders, cough, anorexia and rash. A major cause of abacavir treatment discontinuation is the development of a hypersensitivity reaction which has been reported in 3 to 5% of patients. The reaction usually occurs within 6 weeks of commencing treatment, shows evidence of multiorgan system involvement and typically includes fever and/or rash. Symptoms resolve rapidly after discontinuation of treatment. Continuing treatment or rechallenge can result in more severe symptoms, life-threatening hypotension and even death. CONCLUSION: Abacavir used in combination with other antiretroviral drugs effectively reduces viral load in both adults and children with HIV infection. Although these responses are greatest in individuals with little or no previous antiretroviral treatment, useful responses are still sometimes achieved in heavily pretreated individuals. Abacavir in combination with lamivudine and zidovudine provides a simple and convenient dosage regimen which is generally well tolerated, able to produce sustained suppression of viral replication and has the advantage of sparing other classes of antiretroviral drugs for subsequent use. This triple combination represents an alternative antiretroviral regimen for patients intolerant to protease inhibitors or those wishing to retain the option of protease inhibitors for later use. Further clinical studies are needed to define the activity of abacavir in combination with protease inhibitors and non-nucleoside reverse transcriptase inhibitors.

Tramadol: a review of its use in perioperative pain.

UNLABELLED: Tramadol is a synthetic, centrally acting analgesic agent with 2 distinct, synergistic mechanisms of action, acting as both a weak opioid agonist and an inhibitor of monoamine neurotransmitter reuptake. The 2 enantiomers of racemic tramadol function in a complementary manner to enhance the analgesic efficacy and improve the tolerability profile of tramadol. In several comparative, well designed studies, oral and parenteral tramadol effectively relieved moderate to severe postoperative pain associated with surgery. Its overall analgesic efficacy was similar to that of morphine or alfentanil and superior to that of pentazocine. Tramadol provided effective analgesia in children and in adults for both inpatient and day surgery. Tramadol was generally well tolerated in clinical trials. The most common adverse events (incidence of 1.6 to 6.1%) were nausea, dizziness, drowsiness, sweating, vomiting and dry mouth. Importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters at recommended doses in adults or children. Tramadol also has a low potential for abuse or dependence. CONCLUSIONS: The efficacy of tramadol for the management of moderate to severe postoperative pain has been demonstrated in both inpatients and day surgery patients. Most importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters. Tramadol may prove particularly useful in patients with poor cardiopulmonary function, including the elderly, the obese and smokers, in patients with impaired hepatic or renal function, and in patients in whom nonsteroidal anti-inflammatory drugs are not recommended or need to be used with caution. Parenteral or oral tramadol has proved to be an effective and well tolerated analgesic agent in the perioperative setting.

Coxsackievirus infection of the pancreas: evaluation of receptor expression, pathogenesis, and immunopathology.

Coxsackievirus type B (CVB) infection of the pancreas induces a massive cellular infiltrate composed of natural killer cells, T cells, and macrophages and leads to the destruction of exocrine tissue. The physiological manifestations of pancreatic CVB infection are correlated with viral tropism; the virus infects acinar cells but spares the islets of Langerhans. Here we evaluate the mechanisms underlying pancreatic inflammation and destruction and identify the determinants of viral tropism. T-cell-mediated immunopathology has been invoked, along with direct virus-mediated cytopathicity, to explain certain aspects of CVB-induced pancreatic disease. However, we show here that in the pancreas, the extent of inflammation and tissue destruction appears unaltered in the absence of the cytolytic protein perforin; these findings exclude any requirement for perforin-mediated lysis by natural killer cells or cytotoxic T cells in CVB3-induced pancreatic damage. Furthermore, perforin-mediated cytotoxic T-cell activity does not contribute to the control of CVB infection in this organ. In addition, we demonstrate that the recently identified coxsackie-adenovirus receptor is expressed at high levels in acinar cells but is barely detectable in islets, which is consistent with its being a major determinant of virus tropism and, therefore, of disease. However, further studies using various cell lines of pancreatic origin reveal secondary determinants of virus tropism.

Valaciclovir: a review of its long term utility in the management of genital herpes simplex virus and cytomegalovirus infections.

UNLABELLED: Valaciclovir is an aciclovir prodrug used to treat infections caused by herpes simplex virus (HSV) and varicella zoster virus, and for prophylaxis against cytomegalovirus (CMV). Oral valaciclovir provides significantly better oral bioavailability than oral aciclovir itself, contributing to the need for less frequent administration. Several studies have demonstrated the efficacy of long term (> 90 days) therapy with valaciclovir for the suppression of genital HSV disease in otherwise healthy individuals with HSV infection. In 1 randomised, double-blind trial, once daily valaciclovir (1000 mg, 500 mg and 250 mg) produced statistically significant suppression of disease recurrence, as did twice daily valaciclovir 250 mg and aciclovir 400 mg. Valaciclovir dosages of > or = 500 mg daily are recommended for suppression of genital herpes recurrences in immunocompetent individuals. This disease occurs frequently in patients with human immunodeficiency virus (HIV) infection and, in a single randomised double-blind trial, prophylactic valaciclovir (1000 mg once daily or 500 mg twice daily) and aciclovir (400 mg twice daily) were found to be of similar efficacy in the suppression of genital herpes. However, a higher than expected dropout rate indicated that more studies of valaciclovir in patients with HIV are required. In a randomised trial of patients undergoing renal transplant, valaciclovir 2 g 4 times daily for 90 days significantly reduced the incidence and delayed the onset of CMV disease: the incidence in valaciclovir-treated patients who were CMV-seronegative at baseline, and recieived a kidney from a CMV-seropositive donor, was 3% versus 45% for placebo after 90 days of treatment. Acute graft rejection was also reduced in the valaciclovir-treated group. A small study in heart transplant patients compared valaciclovir (2 g 4 times daily) with aciclovir (200 mg 4 times daily) and found a significant reduction in CMV antigenaemia favouring valacilovir at the end of the treatment period. Additional reductions in other indices of CMV in those given valaciclovir compared with aciclovir were also noted. In a preliminary study of prophylaxis for CMV disease in bone marrow transplant recipients valaciclovir (2 g 4 times daily) was superior to aciclovir (800 mg 4 times daily) in terms of time to CMV viraemia or viruria. Although valaciclovir (8 g/day for approximately 30 weeks) reduced the incidence and time to CMV disease compared with aciclovir (3.2 g/day) in patients with advanced HIV disease, valaciclovir was associated with more gastrointestinal complaints and an increased risk of death, leading to premature termination of the study. As yet, no trials comparing the efficacy of valaciclovir with famciclovir (the oral prodrug for penciclovir) in the suppression of recurrent episodes of genital herpes have been published, nor have direct comparisons been made, between valaciclovir with ganciclovir in patients with CMV disease. Valaciclovir is well tolerated at dosages used to suppress recurrent episodes of genital herpes (500 to 1000 mg/day) in immunocompetent and HIV seropositive individuals, with headache being reported most often. However, a potentially fatal thrombotic microangiopathy (TMA)-like syndrome has been reported in some immunocompromised patients receiving high-dose prophylactic valaciclovir therapy (8 g/day) for CMV disease for prolonged periods, and the risk of this syndrome appears to be higher in patients with advanced HIV disease. While the clinical benefits of valaciclovir in some immunocompromised patients may outweigh the risk of TMA, close monitoring for symptoms of TMA is indicated in all immunocompromised patients receiving high-dose valaciclovir. CONCLUSION: Oral valaciclovir is an effective drug for the suppression of recurrent episodes of genital herpes in immunocompetent and immunocompromised individuals. (ABSTRACT TRUNCATED)

Alosetron.

Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist which has been evaluated for the management of irritable bowel syndrome (IBS). It blocked the fast 5HT3-mediated depolarisation of guinea-pig myenteric and submucosal neurons in vitro, with half-maximal inhibition at approximately 55 nmol/L. Alosetron attenuated the visceral nociceptive effect of rectal distension in conscious or anaesthetised dogs. It increased the compliance of the colon to distension in patients with IBS and delayed colonic transit in patients with IBS or carcinoid diarrhoea and in healthy volunteers. A single dose of alosetron 4 mg increased in vivo fluid absorption in normal human small intestine. In clinical trials in patients with IBS, alosetron 1 mg twice daily was effective in relieving abdominal pain and discomfort. Alosetron was most effective in female patients and particularly in those with diarrhoea-predominant IBS. In patients with IBS and healthy volunteers who received alosetron, the most common adverse event was constipation.

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.

Delavirdine: a review of its use in HIV infection.

UNLABELLED: Delavirdine, a bisheteroarylpiperazine derivative, is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that allosterically binds to HIV-1 reverse transcriptase, inhibiting both the RNA- and DNA-directed DNA polymerase functions of the enzyme. Delavirdine in combination with nucleoside reverse transcriptase inhibitors (NRTIs) produced sustained reductions in plasma viral loads and improvements in immunological responses in large randomised, double-blind, placebo-controlled studies of 48 to 54 weeks' duration. In patients with advanced HIV infection, triple therapy with delavirdine, zidovudine and lamivudine, didanosine or zalcitabine for 1 year significantly prolonged the time to virological failure compared with dual therapy (delavirdine plus zidovudine or 2 NRTIs; p < 0.0001). After 50 weeks' treatment, plasma HIV RNA levels were below the limit of detection (LOD; <50 copies/ml) for 40% of patients receiving triple therapy but for only 6% of those receiving dual NRTI therapy. Preliminary results suggest that delavirdine also has beneficial effects on surrogate markers as a component of protease inhibitor-containing triple or quadruple regimens. At 16 to 48 weeks, the minimum mean reduction in plasma viral load from baseline was 2.5 log10 copies/ml and mean CD4+ counts increased by 100 to 313 cells/microl. The proportion of patients with plasma HIV RNAlevels below the LOD (usually 200 to 500 copies/ml) ranged from 48 to 100% after > or = 16 weeks. Delavirdine was also effective as a component of saquinavir soft gel capsule-containing salvage regimens. Since delavirdine shares a common metabolic pathway (cytochrome P450 3A pathway) with other NNRTIs, HIV protease inhibitors and several drugs used to treat opportunistic infections in patients infected with HIV, the drug is associated with a number of pharmacokinetic interactions. Some of these drug interactions are clinically significant, necessitating dosage adjustments or avoidance of co-administration. Delavirdine is not recommended for use with lovastatin, simvastatin, rifabutin, rifampicin, sildenafil, ergot derivatives, quinidine, midazolam, carbamazepine, phenobarbital or phenytoin. Importantly, the drug favourably increases the plasma concentration of several protease inhibitors. Delavirdine is generally well tolerated. Skin rash is the most frequently reported adverse effect, occurring in 18 to 50% of patients receiving delavirdine-containing combination therapy in clinical trials. Although a high proportion of patients developed a rash, it was typically mild to moderate in intensity, did not result in discontinuation or adjustment of treatment in most patients and resolved quickly. The occurrence of Stevens-Johnson syndrome was rare (1 case in 1,000 patients). A retrospective analysis of pooled clinical trial data indicated that there was no significant difference in the incidence of liver toxicity, liver failure or noninfectious hepatitis between delavirdine-containing and non-delavirdine-containing antiretroviral treatment groups. In addition, the incidence of lipodystrophy, metabolic lipid disorders, hyperglycaemia and hypertriglyceridaemia was not significantly different between these 2 treatment groups. CONCLUSIONS: In combination with NRTIs. delavirdine produces sustained improvements in surrogate markers of HIV disease and prolongs the time to virological failure in adult patients with HIV infection. Preliminary data of delavirdine as a component of protease inhibitor-containing triple or quadruple highly active antiretroviral therapy regimens indicate that patients achieve marked improvements in virological and immunological markers. The drug is generally well tolerated, with a transient skin rash, typically of mild to moderate intensity, being the most common adverse effect. Delavirdine is an effective component of recommended antiretroviral treatment strategies for adult patients with HIV infection and, in combination with 2 NRTIs as a first-line therapy, the drug has the advantage of sparing protease inhibitors for subsequent use. Since delavirdine favourably increases plasma concentrations of several protease inhibitors, the drug may also be beneficial as a component of salvage therapy in combination with protease inhibitors.

Gatifloxacin.

Gatifloxacin is a novel extended-spectrum fluoroquinolone with improved gram-positive and anaerobe coverage compared with older agents such as ciprofloxacin. It has good activity (but is slightly less active than ciprofloxacin) against Enterobacteriaceae. Gatifloxacin is generally 2- to 4-fold more active than ciprofloxacin against staphylococci, streptococci and enterococci and 4- to 16-fold more active than ciprofloxacin against anaerobes, including Clostridium and Bacteroides spp. In comparative clinical trials that included patients with lower respiratory tract, urinary tract, skin and soft tissue or gonococcal infections, clinical cure rates of > or = 89% were achieved with oral gatifloxacin 400 mg/day for 7 to 14 days. Data from a subset of North American patients included in a multinational trial showed that oral gatifloxacin 400 mg/day produced a significantly higher clinical cure rate than cefuroxime axetil 250 mg twice daily (89 vs 77%; p = 0.01) in patients with acute exacerbations of chronic bronchitis. The clinical efficacy of gatifloxacin was similar to that of clarithromycin or levofloxacin or ceftriaxone (with or without erythromycin) in the treatment of patients with community-acquired pneumonia. Oral gatifloxacin 400 mg/day showed clinical and bacteriological efficacy similar to that of levofloxacin in patients with skin and soft tissue infections. In patients with urinary tract infections, clinical cure and bacterial eradication rates achieved with a single 400 g oral dose of gatifloxacin were similar to those produced with ciprofloxacin. In a pooled analysis of tolerability data from trials that included 3021 patients treated with oral gatifloxacin 400 mg/day, the most commonly reported adverse events were nausea (8%), diarrhoea (4%), headache (4%) and dizziness (3%). The drug was reported to be well tolerated. Gatifloxacin does not appear to cause phototoxic effects.