Indobufen: an updated review of its use in the management of atherothrombosis

Indobufen inhibits platelet aggregation by reversibly inhibiting the platelet cyclooxygenase enzyme thereby suppressing thromboxane synthesis. Clinical trials have evaluated the efficacy of oral indobufen in the secondary prevention of thromboembolic complications in patients with or without atrial fibrillation, in the prevention of graft occlusion after coronary artery bypass graft (CABG) surgery and in the treatment of intermittent claudication. In the secondary prevention of thromboembolic events indobufen 200 mg once or twice daily was significantly more effective than no treatment although not as effective as ticlopidine 250 mg once or twice daily, during 1-year nonblind clinical trials. Compared with placebo, indobufen 100 mg twice daily significantly reduced the risk of stroke in a small 28-month trial of patients at increased risk of systemic embolism (50% had atrial fibrillation). Furthermore, in patients with nonrheumatic atrial fibrillation and a recent cerebrovascular event enrolled in the 1-year Studio Italiano Fibrillazione Atriale (SIFA) trial, indobufen 100 or 200 mg twice daily was as effective as warfarin (titrated to produce an international normalised ratio of 2.0 to 3.5) in the secondary prevention of thromboembolic events; the incidences of the composite end-point of major vascular events (10.6 vs 9.0%) and recurrent stroke (5 vs 4%) were similar between treatments. In 2 large 12-month trials, the Studio Indobufene nel Bypass Aortocoronarico (SINBA) and the UK study, indobufen 200 mg twice daily was as effective as aspirin (acetylsalicylic acid) 300 or 325 mg plus dipyridamole 75 mg 3 times daily in the prevention of early and late occlusion of saphenous grafts in patients after CABG surgery. Indobufen 200 mg twice daily for 6 months significantly improved walking capacity compared with placebo, and caused a more pronounced improvement in both pain-free and total walking distance than either pentoxifylline 300 mg or aspirin 500 mg twice daily in separate 6- and 12-month studies of patients with intermittent claudication. Oral indobufen up to 200 mg twice daily was generally well tolerated in >5000 patients with atherosclerotic disease. Adverse events (predominantly gastrointestinal), reported by 3.9% of patients, rarely required withdrawal from treatment. In the SINBA and UK studies, fewer adverse events and less gastrointestinal bleeding were seen with indobufen than with aspirin plus dipyridamole treatment, while in the SIFA trial, noncerebral bleeding events occurred significantly less frequently in indobufen than warfarin recipients (0.6 vs 5.1%) and major bleeding events occurred only in the warfarin group. Conclusion: Indobufen is as effective as warfarin in the prophylaxis of thromboembolic events in at risk patients with nonrheumatic atrial fibrillation, as aspirin plus dipyridamole in the prevention of CABG occlusion and may be more effective than aspirin or pentoxifylline in improving walking capacity in patients with intermittent claudication. The improved tolerability profile of indobufen (favourable gastric tolerance and reduced haemorrhagic complications) compared with aspirin 300 to 325 mg 3 times daily or warfarin, in addition to a similar antiplatelet effect, suggests indobufen can be considered a drug with a definite role in the management of atherothrombotic events. In particular, indobufen may be an effective alternative for at risk patients with nonrheumatic atrial fibrillation in whom anticoagulant therapy is contraindicated or who are at higher risk of bleeding.     

Olanzapine: an updated review of its use in the management of schizophrenia

Olanzapine, a thienobenzodiazepine derivative, is a second generation (atypical) antipsychotic agent which has proven efficacy against the positive and negative symptoms of schizophrenia. Compared with conventional antipsychotics, it has greater affinity for serotonin 5-HT2A than for dopamine D2 receptors. In large, well controlled trials in patients with schizophrenia or related psychoses, olanzapine 5 to 20 mg/day was significantly superior to haloperidol 5 to 20 mg/day in overall improvements in psychopathology rating scales and in the treatment of depressive and negative symptoms, and was comparable in effects on positive psychotic symptoms. The 1-year risk of relapse (rehospitalisation) was significantly lower with olanzapine than with haloperidol treatment. In the first double-blind comparative study (28-week) of olanzapine and risperidone, olanzapine 10 to 20 mg/day proved to be significantly more effective than risperidone 4 to 12 mg/day in the treatment of negative and depressive symptoms but not on overall psychopathology symptoms. In contrast, preliminary results from an 8-week controlled study suggested risperidone 2 to 6 mg/day was superior to olanzapine 5 to 20 mg/day against positive and anxiety/depressive symptoms (p < 0.05), although consistent with the first study, both agents demonstrated similar efficacy on measures of overall psychopathology. Improvements in general cognitive function seen with olanzapine treatment in a 1-year controlled study of patients with early-phase schizophrenia, were significantly greater than changes seen with either risperidone or haloperidol. However, preliminary results from an 8-week trial showed comparable cognitive enhancing effects of olanzapine and risperidone treatment in patients with schizophrenia or schizoaffective disorder. Several studies indicate that olanzapine has benefits against symptoms of aggression and agitation, while other studies strongly support the effectiveness of olanzapine in the treatment of depressive symptomatology. Olanzapine is associated with significantly fewer extrapyramidal symptoms than haloperidol and risperidone. In addition, olanzapine is not associated with a risk of agranulocytosis as seen with clozapine or clinically significant hyperprolactinaemia as seen with risperidone or prolongation of the QT interval. The most common adverse effects reported with olanzapine are bodyweight gain, somnolence, dizziness, anticholinergic effects (constipation and dry mouth) and transient asymptomatic liver enzyme elevations. In comparison with haloperidol, the adverse events reported significantly more frequently with olanzapine in > or = 3.5% of patients were dry mouth, bodyweight gain and increased appetite and compared with risperidone, only bodyweight gain occurred significantly more frequently with olanzapine. The high acquisition cost of olanzapine is offset by reductions in other treatment costs (inpatient and/or outpatient services) of schizophrenia. Pharmacoeconomic analyses indicate that olanzapine does not significantly increase, and may even decrease, the overall direct treatment costs of schizophrenia, compared with haloperidol. Compared with risperidone, olanzapine has also been reported to decrease overall treatment costs, despite the several-fold higher daily acquisition cost of the drug. Olanzapine treatment improves quality of life in patients with schizophrenia and related psychoses to a greater extent than haloperidol, and to broadly the same extent as risperidone. CONCLUSIONS: Olanzapine demonstrated superior antipsychotic efficacy compared with haloperidol in the treatment of acute phase schizophrenia, and in the treatment of some patients with first-episode or treatment-resistant schizophrenia. The reduced risk of adverse events and therapeutic superiority compared with haloperidol and risperidone in the treatment of negative and depressive symptoms support the choice of olanzapine as a first-line option in the management of schizophrenia in the acute phase and for the maintenance of treatment response.     

Meropenem: an updated review of its use in the management of intra-abdominal infections

Meropenem is a carbapenem antibacterial agent with a broad spectrum of activity which encompasses gram-negative, gram-positive and anaerobic bacteria. Like other carbapenems, meropenem is stable against chromosomal and extended-spectrum beta-lactamases. In patients with moderate to severe intra-abdominal infections, empirical monotherapy with meropenem achieved clinical response rates ranging from 91 to 100% in 7 randomised comparative trials. Efficacy rates were similar to those of imipenem/cilastatin (94 to 97%), clindamycin plus tobramycin (93%) and, overall, to cefotaxime plus metronidazole (75 to 100%), although there were differences between trials versus this combination regimen. According to limited data, meropenem also achieved clinical response rates of over 80% in patients with severe intra-abdominal infections. Meropenem is well tolerated, the most common adverse events being diarrhoea, rash, nausea/vomiting and inflammation at the injection site which are reported in <2.5% of patients each. Meropenem also has an improved CNS tolerability profile compared with imipenem/cilastatin. Conclusions: Extensive comparative clinical data demonstrate that meropenem can be used effectively as empirical monotherapy in moderate to severe intra-abdominal infections. It also shows potential in the most severe forms of infection, although experience in this infection type remains limited. Compared with standard combination regimens, meropenem offers the benefits of ease of administration without the need for monitoring. It also offers improved CNS tolerability compared with imipenem/cilastatin with the option of a higher maximum dosage, which may be a particular advantage in patients with severe intra-abdominal infections.     

Enfuvirtide: a review of its use in the management of HIV infection

Enfuvirtide (Fuzeon), a fusion inhibitor, is indicated in combination with other antiretroviral agents in the treatment of HIV infection in treatment-experienced adults and children aged >6 years.The addition of subcutaneous enfuvirtide to an optimised antiretroviral background regimen improved the virological and immunological response in treatment-experienced HIV-infected patients in the two large, well designed TORO (T-20 vs Optimised Regimen Only) trials. Although injection-site reactions occurred almost universally in enfuvirtide recipients, they were rarely treatment-limiting. Enfuvirtide was otherwise generally well tolerated. The challenge for clinicians is in determining the appropriate timing for enfuvirtide initiation, which requires consideration of the likelihood of a better virological response with the construction of an active background regimen versus the potential for a low rate of adherence to therapy in patients in the early stages of treatment and/or disease development. Enfuvirtide is a novel antiretroviral that is effective in HIV-infected patients whose treatment options are limited by multi-class antiretroviral resistance.     

Atazanavir: a review of its use in the management of HIV infection

Atazanavir (Reyataz) is a novel protease inhibitor (PI) approved for use in combination with other antiretroviral drugs for the treatment of HIV infection. In antiretroviral therapy (ART)-experienced patients the drug is administered with low-dose ritonavir (i.e. boosted). In the US, unboosted atazanavir is also approved for use in ART-naive patients. In adult patients with HIV infection, atazanavir-containing highly active antiretroviral therapy (HAART) regimens provided marked improvements in virological and immunological markers and was generally well tolerated. Furthermore, recommended atazanavir regimens were no less effective than, and generally as well tolerated as, other HAART regimens in these patients, including regimens containing co-formulated lopinavir/ritonavir. Atazanavir may have an advantage over other PIs because of its favourable effect on lipid profiles, once-daily dosing, low capsule burden and, in patients with low prior PI exposure, a favourable resistance profile. Given these advantages and taking into consideration between-country differences in the approved indications, atazanavir is a valuable option as the PI component of HAART for the management of HIV infection in adult ART-naive patients, particularly where metabolic complications are a concern, and as a first- or second-line PI in combination with low-dose ritonavir in adult ART-experienced patients.     

Tipranavir: a review of its use in the management of HIV infection

Tipranavir (Aptivus) is a selective nonpeptidic HIV-1 protease inhibitor (PI) that is used in the treatment of treatment-experienced adults with HIV-1 infection. Tipranavir is administered orally twice daily and must be given in combination with low-dose ritonavir, which is used to boost its bioavailability.The durable efficacy of tipranavir, in combination with low-dose ritonavir (tipranavir/ritonavir 500 mg/200 mg twice daily), has been demonstrated in well designed trials in treatment-experienced adults infected with multidrug-resistant strains of HIV-1. In treatment-experienced adults with HIV-1 infection receiving an optimized background regimen, viral suppression was greater and immunological responses were better with regimens containing tipranavir/ritonavir than with comparator ritonavir-boosted PI-containing regimens. The efficacy benefit appeared to be more marked in patients receiving two fully active drugs in the regimen, with the combination of tipranavir/ritonavir and enfuvirtide (for the first time) appearing to be the most successful. Although tipranavir is generally well tolerated, clinical hepatitis and hepatic decompensation, and intracranial haemorrhage have been associated with the drug. Tipranavir also has a complex drug-interaction profile. Thus, tipranavir, administered with ritonavir, is an effective treatment option for use in the combination therapy of adults with HIV-1 infection who have been previously treated with other antiretroviral drugs.     

Insulin glargine: an updated review of its use in the management of diabetes mellitus

Insulin glargine is a human insulin analogue prepared by recombinant DNA technology. Modification of the human insulin molecule at position A21 and at the C-terminus of the B-chain results in the formation of a stable compound that is soluble at pH 4.0, but forms amorphous microprecipitates in subcutaneous tissue from which small amounts of insulin glargine are gradually released. The plasma concentration versus time profile of insulin glargine is therefore relatively constant in relation to conventional human insulins, with no pronounced peak over 24 hours. This allows once-daily administration as basal therapy. Early randomised trials with insulin glargine generally showed greater reductions in fasting blood or plasma glucose levels and a reduced frequency of nocturnal hypoglycaemia relative to neutral protamine Hagedorn (NPH) insulin in patients with type 1 diabetes mellitus. In addition to this basal therapy, patients continued to use the regular mealtime insulin regimen to which they were accustomed. More recent data with insulin glargine have included evidence of improved glycaemic control, with improvements in satisfaction with treatment over NPH insulin. Furthermore, the time of day at which insulin glargine is injected has no clinically relevant effect on glycaemic control in these patients. There are also data from small, nonblind studies to suggest comparable glycaemic control with insulin glargine and continuous subcutaneous insulin infusion. Results from comparative studies and meta-analyses in individuals with type 2 diabetes show lower incidences of nocturnal hypoglycaemia with insulin glargine than with NPH insulin, with two studies showing a significantly greater improvement in glycosylated haemoglobin levels with insulin glargine than with NPH. Insulin glargine is well tolerated, and is not associated with greater immunogenicity or increases in bodyweight than NPH insulin. Long-term data show maintenance of glycaemic control with insulin glargine for up to 39 months in adults and children with type 1 and adults with type 2 diabetes. In conclusion, insulin glargine is an effective and well tolerated basal insulin therapy when given as a single daily subcutaneous injection to patients with diabetes, with benefits in terms of glycaemic control and reduced frequency of hypoglycaemia over regimens based on conventional basal insulins. Accumulating data and official recommendations show the suitability of insulin glargine for first-line use in selected patients with type 2 diabetes who require insulin treatment, as well as in patients with type 1 disease, and confirm its use in children and adolescents.     

Cefuroxime axetil: an updated review of its use in the management of bacterial infections

Cefuroxime axetil, a prodrug of the cephalosporin cefuroxime, has proven in vitro antibacterial activity against several gram-positive and gram-negative organisms, including those most frequently associated with various common community-acquired infections. In numerous randomised, controlled trials, 5 to 10 days' treatment with oral cefuroxime axetil (250 or 500 mg twice daily) was an effective treatment in patients with upper (URTI) and lower respiratory tract infections (LRTI) as assessed by clinical and bacteriological criteria. The drug was as effective as several other cephalosporins, quinolones, macrolides and amoxicillin/clavulanic acid. Shorter courses (5 to 10 days') of cefuroxime axetil were at least as effective as a 10 day course. Furthermore, sequential therapy with intravenous cefuroxime (750 mg 2 or 3 times daily for 2 to 5 days) followed by oral cefuroxime axetil (500 mg twice daily for 3 to 8 days) proved an effective treatment in adult patients with community-acquired pneumonia (CAP). This approach provided similar efficacy to intravenous ampicillin/sulbactam followed by oral amoxicillin/clavulanic acid, a full parenteral course of cefuroxime, or intravenous then oral azithromycin or clarithromycin. Additionally, cefuroxime axetil was an effective treatment in patients with genitourinary, skin and soft-tissue infections, and erythema migrans associated with early stage Lyme disease. The drug is well tolerated by adult and paediatric patients, with adverse effects that are consistent with those of other cephalosporins. The majority of adverse events (primarily gastrointestinal disturbances) were mild to moderate in intensity and reversible upon discontinuation of treatment, with very few serious adverse events reported. Conclusions: Cefuroxime axetil is a broad spectrum antibacterial agent with a pharmacokinetic profile that permits convenient twice-daily administration. The drug is an effective and well tolerated treatment in patients with various infections, including otitis media, pharyngitis, sinusitis, CAP and acute exacerbations of chronic bronchitis. Cefuroxime axetil proved effective as a component of intravenous/oral sequential therapy in the treatment of CAP, although there are currently no dosage recommendations available for this regimen in some countries. Cefuroxime axetil may be considered as an empirical therapy for a range of community-acquired infections, including those in which beta-lactamase-producing strains of common respiratory pathogens are identified as the causative organisms. In an era of rapidly emerging bacterial resistance, empirical treatment with bacterial agents, potentially preventing the emergence of bacterial resistance to agents such as cefuroxime axetil may ensure the appropriate use of newer antibacterial agents, potentially preventing the emergence of bacterial resistance to these newer drugs.     

Perindopril: an updated review of its use in hypertension

Perindopril erbumine (perindopril) is a prodrug ester of perindoprilat, an angiotensin converting enzyme (ACE) inhibitor. Perindopril 4 to 8 mg once daily significantly reduces supine systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline values in hypertensive patients. These reductions are maintained for at least 24 hours, as evidenced by trough/peak ratios of >50%. Vascular abnormalities associated with hypertension were improved or normalised during perindopril treatment. Perindopril 4 to 8 mg once daily significantly decreased carotid-femoral aortic pulse wave velocity (PWV), improved arterial compliance, reduced left ventricular mass index and, in patients with recent cerebral ischaemia and/or stroke, preserved cerebral blood flow despite significantly reducing SBP and DBP. Further research is needed to establish the significance of promising results showing that reductions in aortic PWV were associated with reduced mortality in patients with end-stage renal failure, a third of whom received perindopril. Response rates (numbers of patients with supine DBP < or = 90 mm Hg) were significantly higher with perindopril 4 to 8 mg once daily (67 to 80%) than with captopril 25 to 50 mg twice daily (44 to 57%) in 3 randomised double-blind trials. In other clinical trials, the antihypertensive effects of perindopril were similar to those of other ACE inhibitors (including enalapril) and calcium-channel antagonists. Combination treatment with perindopril and an antihypertensive agent from another treatment class provided additional benefits, either as first-line treatment or in patients failing to respond to monotherapy. Perindopril monotherapy was also effective in the elderly and in patients with hypertension and concomitant disease. Perindopril has a similar adverse event profile to that of other ACE inhibitors; cough is the most common event reported during treatment, and is also the most common adverse event responsible for treatment withdrawal. Conclusions: Perindopril is a well tolerated ACE inhibitor that is significantly better than captopril (in terms of response rates) in the treatment of hypertension, and as effective as other ACE inhibitors. Perindopril appears to reverse some of the vascular abnormalities associated with hypertension, including arterial stiffness and left ventricular hypertrophy, although further research is needed to confirm promising results regarding its ability to decrease associated cardiovascular morbidity and mortality. Results from ongoing studies will help confirm the place of perindopril in the treatment of hypertension; currently, it is an effective and well tolerated treatment for patients with mild to moderate essential hypertension.     

Irbesartan: an updated review of its use in cardiovascular disorders

Irbesartan interrupts the renin-angiotensin system via selective blockade of the angiotensin II subtype 1 receptor; the latter being responsible for the pressor related effects of angiotensin II. As treatment for mild to moderate hypertension, irbesartan 150 mg/day controlled diastolic BP in 56% of patients according to pooled data from several phase III studies and 77% of patients in a large phase IV study. in comparative trials, irbesartan was significantly more effective than losartan and valsartan as treatment for mild to moderate essential hypertension and as effective as enalapril or atenolol. Results from many studies show an additive antihypertensive effect when hydrochlorothiazide is added to irbesartan monotherapy. The drug also induces statistically significant regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy, and preliminary evidence suggests it has beneficial haemodynamic effects in patients with heart failure. Irbesartan is very well tolerated, exhibiting an adverse event profile similar to that seen with placebo in comparative trials. In conclusion, although the role of irbesartan as a treatment for heart failure is little clearer than it was 2 years ago, the place of the drug in the management of hypertension is now better established. There is evidence to suggest the drug may have a role as initial therapy for hypertension, although formal recommendation in management guidelines will almost certainly not occur until long term morbidity and mortality benefits are established.