Mirtazapine: a review of its use in major depression and other psychiatric disorders.

Mirtazapine (Remeron, Zispin) is a noradrenergic and specific serotonergic antidepressant (NaSSA) that is approved in many counties for use in the treatment of major depression. Monotherapy with mirtazapine 15-45 mg/day leads to rapid and sustained improvements in depressive symptoms in patients with major depression, including the elderly. It is as effective as other antidepressants and may have a more rapid onset of action than selective serotonin reuptake inhibitors (SSRIs). Furthermore, it may also have a higher sustained remission rate than amitriptyline. Preliminary data suggest that mirtazapine may also be effective in the treatment of anxiety disorders (including post-traumatic stress disorder, panic disorder and social anxiety disorder), obsessive-compulsive disorder, undifferentiated somatoform disorder and, as add-on therapy, in schizophrenia, although large, well designed trials are needed to confirm these findings. Mirtazapine is generally well tolerated in patients with depression. In conclusion, mirtazapine is an effective antidepressant for the treatment of major depression and also has the potential to be of use in other psychiatric indications.

Adalimumab: in plaque psoriasis.

Adalimumab is a recombinant, human, IgG1 monoclonal antibody specific for tumor necrosis factor. The clinical efficacy and safety of adalimumab (40 mg administered subcutaneously every other week) in patients with moderate-to-severe chronic plaque psoriasis have been demonstrated in several randomized, double-blind clinical trials, including the pivotal trials REVEAL (n = 1212) and CHAMPION (n = 271). Based on these trials, adalimumab was significantly more effective than placebo and methotrexate at relieving the signs and symptoms of psoriasis after 16 weeks of treatment, as assessed by the percentage of patients achieving a 75% improvement from baseline in Psoriasis Area and Severity Index. Based on open-label extension studies of up to 2 years' duration, the efficacy of adalimumab was sustained over the long term. Of patients who had responded to 33 weeks of treatment with adalimumab in REVEAL, patients randomized to remain on adalimumab for an additional 19 weeks of treatment were significantly less likely to experience loss of an adequate response than patients who were transferred to placebo. Compared with placebo or methotrexate, adalimumab was associated with significantly greater improvements in dermatology-specific and general measures of health-related quality of life in patients with plaque psoriasis. Adalimumab was generally well tolerated in trials in patients with plaque psoriasis, and the adverse-event profile was similar to that associated with its use in rheumatoid arthritis.

Irbesartan: a review of its use in hypertension and diabetic nephropathy.

Irbesartan (Aprovel, Avapro, Irbetan, Karvea), an angiotensin II receptor type 1 antagonist, is approved in many countries worldwide for the treatment of hypertension. It is also approved in some regions for the treatment of nephropathy in patients with hypertension and type 2 diabetes mellitus. In adults with essential hypertension, irbesartan is effective at reducing blood pressure (BP) over a 24-hour period with once-daily administration. Irbesartan also slows the progression of renal disease in hypertensive patients with type 2 diabetes, with this effect partly independent of its BP-lowering effect. In addition, irbesartan was generally well tolerated in clinical trials. Thus, irbesartan is a useful treatment option for patients with hypertension, including those with type 2 diabetes and nephropathy.

Sildenafil: a review of its use in pulmonary arterial hypertension.

Sildenafil citrate (Revatio), an inhibitor of phosphodiesterase type 5 (PDE5), is approved for use in the US, Europe and other countries for the treatment of pulmonary arterial hypertension (PAH). Oral sildenafil 20 mg three times daily added to conventional background therapy was significantly more effective than placebo at increasing exercise capacity in patients with idiopathic PAH or PAH associated with connective tissue diseases or repaired congenital systemic-to-pulmonary shunts. Sildenafil was also associated with improvements in WHO functional class and haemodynamic parameters, and was generally well tolerated. Sildenafil provides benefits in terms of exercise capacity when added to epoprostenol; however, these findings come from a trial that did not use the approved dosage of sildenafil. In conclusion, sildenafil is an effective oral treatment option for patients with PAH.

Recombinant factor VIIa (eptacog alfa): a review of its use in congenital hemophilia with inhibitors, acquired hemophilia, and other congenital bleeding disorders.

Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is structurally similar to human plasma-derived coagulation factor VIIa, but is manufactured using DNA biotechnology. Recombinant factor VIIa interacts with thrombin-activated platelets to produce a thrombin burst leading to accelerated fibrin clot formation localized to the site of vascular injury. It is approved in many countries for use as an intravenous hemostatic agent in patients with congenital hemophilia with inhibitors, and also for acquired hemophilia, factor VII deficiency, and Glanzmann thrombasthenia in some countries. Studies have shown it to be effective and generally well tolerated when used intravenously to treat bleeding episodes or provide hemostatic cover during surgery in patients with congenital hemophilia with inhibitors, acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia. Based on available data, its efficacy in terms of patient-assessed response may be similar to that of activated prothrombin complex concentrate (aPCC), but treatment with a single 270 microg/kg dose of recombinant factor VIIa might reduce the need for rescue therapy compared with aPCC. Recombinant factor VIIa is not immunogenic in patients with hemophilia, does not produce an anamnestic response in hemophilia patients with inhibitors, and has very low thrombogenicity. It is recommended in guidelines as the treatment of choice for bleeds in patients with hemophilia B with high-responding inhibitors and for patients with factor VII deficiency, and is also a first-line therapeutic option for high-responder hemophilia A patients with inhibitors and those with acquired hemophilia. Cost data from pharmacoeconomic analyses support its use in hemophilia patients with inhibitors. Thus, recombinant factor VIIa is a valuable treatment option for patients with these rare, but potentially serious, bleeding disorders.

Fenofibrate: a review of its use in primary dyslipidaemia, the metabolic syndrome and type 2 diabetes mellitus.

Fenofibrate is a fibric acid derivative indicated for use in the treatment of primary hypercholesterolaemia, mixed dyslipidaemia and hypertriglyceridaemia in adults who have not responded to nonpharmacological measures. Its lipid-modifying effects are mediated by activation of peroxisome proliferator-activated receptor-alpha. Fenofibrate also has nonlipid (i.e. pleiotropic) effects (e.g. it reduces fibrinogen, C-reactive protein and uric acid levels and improves flow-mediated dilatation). Fenofibrate improves lipid levels (in particular triglyceride [TG] and high-density lipoprotein-cholesterol [HDL-C] levels) in patients with primary dyslipidaemia. Its lipid-lowering profile means that fenofibrate is particularly well suited for use in atherogenic dyslipidaemia (characterised by high TG levels, low HDL-C levels and small, dense low-density lipoprotein [LDL] particles), which is commonly seen in patients with the metabolic syndrome and type 2 diabetes mellitus. Indeed, fenofibrate improves the components of atherogenic dyslipidaemia in patients with these conditions, including a shift from small, dense LDL particles to larger, more buoyant LDL particles. Greater improvements in lipid levels are seen when fenofibrate is administered in combination with an HMG-CoA reductase inhibitor (statin) or in combination with ezetimibe, compared with monotherapy with these agents. In the DAIS study, fenofibrate significantly slowed the angiographic progression of focal coronary atherosclerosis in patients with type 2 diabetes. In terms of clinical outcomes, although no significant reduction in the risk of coronary events was seen with fenofibrate in the FIELD trial in patients with type 2 diabetes, treatment was associated with a significantly reduced risk of total cardiovascular disease (CVD) events, primarily through the prevention of non-fatal myocardial infarction and coronary revascularisation. Subgroup analyses revealed significant reductions in total CVD events and coronary heart disease events in patients with no previous CVD, suggesting a potential role for primary prevention with fenofibrate in patients with early type 2 diabetes. Improvements were also seen in microvascular outcomes with fenofibrate in the FIELD trial. Fenofibrate is generally well tolerated, both as monotherapy and when administered in combination with a statin. Combination therapy with fenofibrate plus a statin appears to be associated with a low risk of rhabdomyolysis; no cases of rhabdomyolysis were reported in patients receiving such therapy in the FIELD trial. Thus, fenofibrate is a valuable lipid-lowering agent, particularly in patients with atherogenic dyslipidaemia.

Efavirenz/emtricitabine/tenofovir disoproxil fumarate: triple combination tablet.

A new formulation combining fixed doses of the nucleoside reverse transcriptase inhibitors emtricitabine (200mg) and tenofovir disoproxil fumarate (tenofovir DF; 300 mg) with the non-nucleoside reverse transcriptase inhibitor efavirenz (600 mg) represents the first once-daily, one-tablet antiretroviral regimen. Co-formulated efavirenz/emtricitabine/tenofovir DF demonstrated bioequivalence to concomitant administration of the individual agents in a pharmacokinetic trial in healthy volunteers (n = 48). Co-formulated efavirenz/emtricitabine/tenofovir DF has not been evaluated in clinical trials. However, a once-daily regimen of efavirenz, emtricitabine and tenofovir DF (administered as individual agents) was superior to once-daily efavirenz plus twice-daily co-formulated lamivudine/zidovudine in terms of virological suppression, immunological recovery and adverse events resulting in discontinuation of the study medications in a randomised, multicentre, noninferiority study in treatment-naive patients with HIV infection (n = 517). Both regimens are currently recommended as initial antiretroviral therapy. Preliminary data suggest that co-formulated efavirenz/emtricitabine/tenofovir DF, like the individual agents in combination with other antiretroviral drugs, is generally well tolerated. CNS adverse events, primarily headache and dizziness, were the most common treatment-emergent, drug-related adverse events in the pharmacokinetic study involving the co-formulation.

Intravenous ibandronate: in the treatment of osteoporosis.

Ibandronate (ibandronic acid) is a potent nitrogen-containing bisphosphonate that inhibits osteoclast-mediated bone resorption in women with postmenopausal osteoporosis. Recently, an intravenous (IV) formulation of ibandronate for intermittent injection, which circumvents the fasting and posture requirements associated with administration of oral bisphosphonates, was approved for use in this patient population. In initial placebo-controlled studies of 1 year's duration, IV ibandronate (< or =2mg once every 3 months) increased lumbar spine bone mineral density (BMD) and reduced levels of biochemical markers of bone turnover in a dose-dependent manner. Dosages < or =1mg every 3 months were found to be suboptimal in terms of fracture prevention in a 3-year trial. Subsequently, the large randomised, double-blind, noninferiority DIVA trial showed that, in terms of increasing lumbar spine BMD (primary endpoint), IV ibandronate 3mg once every 3 months and 2mg once every 2 months for 1 year were noninferior and also superior to oral ibandronate 2.5mg once daily, a regimen with proven antifracture efficacy. Median reductions from baseline in biochemical markers of bone turnover were similar for the IV and oral regimens. IV ibandronate was generally well tolerated in clinical trials. Treatment-related adverse events included musculoskeletal events and transient influenza-like symptoms, the latter mainly associated with the first dose.

Decitabine: in myelodysplastic syndromes.

Decitabine is a hypomethylating agent. Its action in DNA leads to the reactivation of tumour suppressor genes and the subsequent differentiation of cancer cells. In a randomised, phase III trial in patients (n = 170) with myelodysplastic syndromes (MDS), intravenous decitabine (45 mg/m(2)/day for 3 consecutive days every 6 weeks) combined with supportive care achieved a higher response rate (including eight complete and seven partial responses) than supportive care alone, which achieved no responses (17% vs 0%; p < 0.001). The median times to response and duration of response were 3.3 and 10.3 months in the phase III trial. In three phase II studies in patients (n = 29-87) with MDS treated with decitabine (40 or 50 mg/m(2)/day for 3 days every 5-6 weeks), the percentage of patients achieving a complete or partial response or an improvement ranged from 26% to 49%, and the median duration of response or improvement ranged from 4.9 to 8.3 months. The main adverse event associated with decitabine is myelosuppression.

Modified-release nifedipine: a review of the use of modified-release formulations in the treatment of hypertension and angina pectoris.

Nifedipine is a dihydropyridine calcium channel antagonist with predominantly vasodilatory activity. Modified-release formulations of nifedipine are effective antihypertensive and antianginal therapies and are generally well tolerated. Among the available formulations, those that produce a gradual increase in plasma nifedipine concentration, which is then sustained over a 24-hour period, are preferred, as they cause a gradual onset of vasodilatation and avoid baroreflex sympathetic activation (for example, nifedipine gastrointestinal therapeutic system [GITS] and a Japanese controlled-release formulation). Modified-release nifedipine had beneficial effects on a number of markers of vascular function, and nifedipine GITS reduced the need for coronary procedures in patients with coronary artery disease. In patients with hypertension, nifedipine GITS and nifedipine retard had beneficial effects on the overall incidence of major cardiovascular events, as did nifedipine retard in patients with concurrent hypertension and coronary artery disease.

Everolimus: a review of its use in renal and cardiac transplantation.

Everolimus (Certican) is an orally administered mammalian target of rapamycin inhibitor (proliferation signal inhibitor) derived from sirolimus (rapamycin), which is used as part of immunosuppressant therapy in kidney and heart transplantation. When evaluated as part of triple therapy with ciclosporin and corticosteroids, everolimus showed equivalent efficacy to mycophenolate mofetil after renal transplantation, and superiority to azathioprine in cardiac transplant recipients, in terms of reducing efficacy failure after transplantation. Everolimus potentiates ciclosporin-associated nephrotoxicity, and it is recommended that concentration-controlled everolimus is used with reduced-dosage ciclosporin in order to limit renal toxicity while retaining immunosuppressive efficacy. Ongoing trials with everolimus, such as the evaluation of ciclosporin-withdrawal strategies, should help clarify its optimal usage. The use of everolimus may be associated with reduced rates of cytomegalovirus (CMV) infection and of cardiac allograft vasculopathy. Available data suggest that everolimus may be cost-neutral for healthcare providers.

Tipranavir: a ritonavir-boosted protease inhibitor.

Tipranavir is a non-peptidic HIV-1 protease inhibitor. It binds strongly and selectively, has a favourable resistance profile, and is administered orally twice daily with a subtherapeutic dosage of ritonavir in a 'boosted' regimen (TPV/r) in order to increase its bioavailability. Analysis of clinical isolates from treatment-experienced patients identified the following tipranavir resistance-associated HIV protease mutations: L10V, I13V, K20M/R/V, L33F, E35G, M36I, K43T, M46L, I47V, I54A/M/V, Q58E, H69K, T74P, V82L/T, N83D, I84V. In two large, well designed phase III trials in protease inhibitor-experienced, HIV-infected patients, the RESIST (Randomised Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir)-1 and -2 studies, oral TPV/r 500mg/200mg twice daily achieved a significantly better virological response after 24 weeks than standard ritonavir-boosted protease inhibitors. This held true for the proportion of patients achieving a >or=1 log(10) decrease in plasma HIV-RNA levels (viral load) [42% and 41% vs 22% and 15%; both p < 0.0001; primary endpoint] and other virological parameters (the proportion of patients with undetectable viral load and total viral load reduction). In addition, a significantly larger increase in CD4+ cell count was achieved with TPV/r than comparator regimens in these trials. The most common adverse events in clinical trials of tipranavir were gastrointestinal. The incidence of treatment discontinuation because of adverse events in the RESIST trials was 8% (pooled data).

Atorvastatin: a review of its use in the primary prevention of cardiovascular events in patients with type 2 diabetes mellitus.

Atorvastatin (Lipitor) is an HMG-CoA reductase inhibitor with well documented lipid-lowering effects. It has recently been evaluated for the primary prevention of major cardiovascular events in patients with type 2 diabetes mellitus without elevated serum low-density lipoprotein (LDL)-cholesterol levels. Atorvastatin 10mg daily for 4 years was effective at reducing the risk of a first major cardiovascular event, including stroke, in a large, placebo-controlled, multicentre trial in patients with type 2 diabetes and at least one other coronary heart disease (CHD) risk factor, but without markedly elevated LDL-cholesterol levels. In this trial, known as CARDS (the Collaborative AtoRvastatin Diabetes Study), atorvastatin had a similar tolerability profile to that of placebo. Thus, atorvastatin has a potential role in the primary prevention of cardiovascular events in diabetic patients at risk of CHD, irrespective of pre-treatment LDL-cholesterol levels.

Sulfasalazine: a review of its use in the management of rheumatoid arthritis.

Sulfasalazine (salazosulfapyridine) [Azulfidine, Salazopyrin] is a well established disease-modifying antirheumatic drug (DMARD) used in the treatment of patients with rheumatoid arthritis. Clinical trials with sulfasalazine have used an array of measures of disease activity, such as the number of tender and swollen joints, Ritchie articular index (RAI) and erythrocyte sedimentation rate (ESR). In randomised, double-blind, placebo-controlled trials, sulfasalazine was associated with statistically significant benefits for various measures of disease activity, according to results of individual trials and/or meta-analysis. Sulfasalazine was associated with broadly similar efficacy to that of various other DMARDs in several randomised, double-blind, comparative trials. Promising results have also been demonstrated with sulfasalazine in combination with other DMARDs (e.g. methotrexate and hydroxychloroquine) in patients with early rheumatoid arthritis and in those with more established disease. Sulfasalazine was generally well tolerated in clinical trials, the most frequently reported adverse effects being adverse gastrointestinal effects, headache, dizziness and rash; myelosuppression can also occur. Sulfasalazine has a relatively short lag time until its onset of action and is often considered to be among the more efficacious traditional DMARDs. Based on considerations of safety, convenience and cost, many rheumatologists (particularly outside of the US) select sulfasalazine as initial therapy, although preferred first-line treatment options vary between countries.

Lansoprazole: in the treatment of gastro-oesophageal reflux disease in children and adolescents.

Lansoprazole is a proton pump inhibitor that inactivates the H(+)/K(+)-ATPase pump in parietal cells, thus inhibiting gastric acid secretion and increasing intragastric pH. In an open-label, uncontrolled trial in children aged 1-11 years with gastro-oesophageal reflux disease (GORD), treatment with lansoprazole 15 or 30 mg (depending on weight) once daily for 8-12 weeks improved symptoms compared with baseline in 76% of patients (47 of 62) based on patient diaries and healed erosive oesophagitis (confirmed endoscopically) in all 27 children who had it at baseline. In adolescents aged 12-17 years with GORD, 8 weeks' treatment with lansoprazole 15 mg (in 64 patients with non-erosive disease) or 30 mg (in 23 patients with erosive oesophagitis) once daily reduced the frequency and severity of symptoms by 63% and 69% compared with baseline, based on patient diaries. In this open-label, uncontrolled trial, 96% of evaluable patients with erosive disease (21 of 22) had mucosal healing by week 8, as confirmed by endoscopy; mucosal healing did not occur after an additional 4 weeks' treatment in one patient. Lansoprazole was generally well tolerated in children and adolescents, with the most common treatment-related adverse events being gastrointestinal events and headache.

Gatifloxacin: a review of its use in the treatment of bacterial infections in the US.

Gatifloxacin (Tequin) is an 8-methoxy fluoroquinolone approved in the US for use in the treatment of community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), acute sinusitis, uncomplicated and complicated urinary tract infections (UTIs), pyelonephritis, gonorrhoea and uncomplicated skin and skin structure infections. Gatifloxacin has a broad spectrum of antibacterial activity in vitro and good clinical and bacteriological efficacy in patients with indicated infections following once-daily administration by the intravenous or oral routes. It is generally well tolerated; the most common adverse events are associated with the gastrointestinal tract and CNS. Recent approvals for the use of gatifloxacin in the treatment of CAP due to multidrug-resistant Streptococcus pneumoniae (MDRSP) and in uncomplicated skin and skin structure infections extend the role of this drug in the treatment of bacterial infections in the US.

Eplerenone: a review of its use in essential hypertension.

Eplerenone is a selective aldosterone blocker (SAB) approved for the treatment of essential hypertension. Oral eplerenone reduced BP effectively in patients with essential hypertension, both as monotherapy and in combination with other agents. The drug is generally well tolerated; the risk of hyperkalemia can be managed through careful selection and monitoring of patients. Preliminary data suggest that treatment of hypertension with eplerenone may provide protective effects against end-organ disease; further work is needed to elucidate the clinical significance of these findings, and to evaluate the outcome of treatment of hypertension in terms of cardiovascular morbidity and mortality and quality of life. In the meantime, as the first SAB to become available, eplerenone is an interesting addition to the drugs currently available for the treatment of hypertension.

Eplerenone : a pharmacoeconomic review of its use in patients with post-myocardial infarction heart failure.

Eplerenone (Inspra) is a selective aldosterone blocker. When added to standard medical therapy, eplerenone significantly improved morbidity and mortality in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI), in a well designed, placebo-controlled trial known as EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study). Although eplerenone was generally well tolerated, it was associated with a higher incidence of hyperkalaemia than placebo.Cost-effectiveness analyses based on this trial have been performed in the US, The Netherlands, Germany, France and Spain. Direct medical costs were analysed based on prospectively collected resource-use data with local costs applied; modelling was conducted to calculate incremental costs per life-year or QALY gained, with survival curves assumed to remain parallel after treatment ended. Eplerenone was associated with a gain of 0.0304 life-years (approximately 11 days) compared with placebo during the study period. Based on these analyses, eplerenone was cost effective compared with placebo in patients with LV systolic dysfunction and heart failure after an MI when added to standard therapy for 16 months. The incremental cost per life-year gained for eplerenone versus placebo (for a range of three different life-expectancy projections) was 10,402-21,876 US dollars in the US (year 2001 costs, except for eplerenone [2004]) [equivalent to 12,274-25,814 euro; mid-2001 exchange rate], 5,365-12,795 euro for The Netherlands (year 2003 costs), 6,956-14,628 euro for Germany, 5,432-11,423 euro for France and 8,626-18,141 euro for Spain (year of costing not reported). The US, Dutch, French and Spanish analyses estimated that >90% of observations for incremental cost per life-year gained were below a threshold of 50,000 US dollars or 50,000 euro. Incremental costs per QALY gained for eplerenone versus placebo in the US, Dutch, French and Spanish analyses were 15,330-32,405 US dollars (18,089-38,238 euro), 12,148, 8,005-16,922 euro and 12,713-26, 873 euro, respectively. Clinical and pharmacoeconomic data comparing eplerenone with another active drug, such as spironolactone, in this patient population are not available. In conclusion, when added to standard therapy in patients with LV systolic dysfunction and heart failure after an acute MI, eplerenone was associated with significant reductions in mortality and morbidity compared with placebo. Despite some inherent limitations, available pharmacoeconomic data from Europe and the US indicate that eplerenone is a cost-effective treatment compared with placebo in terms of incremental cost per life-year gained in this patient population.

Imatinib mesylate: in the treatment of gastrointestinal stromal tumours.

Imatinib mesylate (imatinib) is an orally administered competitive inhibitor of the tyrosine kinases associated with the KIT protein (stem cell factor receptor), ABL protein and platelet-derived growth factor receptors. The KIT tyrosine kinase is abnormally expressed in gastrointestinal stromal tumour (GIST), a rare neoplasm for which there has been no effective systemic therapy. In a randomised, nonblind, multicentre study that evaluated imatinib 400 or 600mg once daily in 147 patients with advanced GIST, confirmed partial responses were achieved in 54% of patients overall (median duration of follow-up was 288 days). Stable disease was experienced by 28% of patients and the estimated 1-year survival rate was 88%. Similar response rates were reported in a smaller, dose-escalation study, in which objective tumour response was a secondary endpoint. Although nearly all patients with GIST treated with imatinib experienced adverse events, most events were mild or moderate in nature. Severe or serious adverse events occurred in 21% of patients in the larger study, and included gastrointestinal or tumour haemorrhage. The control of cellular processes, such as cell growth, division and death, involves signal transduction, which commonly involves the transfer of phosphate from adenosine triphosphate (ATP) to tyrosine residues on substrate proteins, by tyrosine kinase enzymes. Activation of oncogenes coding for kinase proteins can lead to the production of kinases that are continually active in the absence of a normal stimulus,leading to increased cell proliferation and/or decreased apoptosis. A major focus of cancer research in recent years has been to identify oncogenic molecules and the signal transduction pathways in which they are involved, in order to develop specifically targeted drugs. One such drug is imatinib mesylate (imatinib, Glivic/Gleevec), an orally administered 2-phenylaminopyrimidine derivative that is a competitive inhibitor of the tyrosine kinases associated with platelet-derived growth factor (PDGF) receptors, the Abelson (ABL) protein and the KIT protein (also known as stem cell factor [SCF] receptor). Imatinib was initially evaluated for the treatment of chronic myeloid leukaemia (CML) [reviewed previously in Drugs]. More recently, imatinib has been approved for the treatment of patients with advanced gastrointestinal stromal tumour (GIST), in which KIT, a tyrosine kinase receptor, is abnormally expressed. GISTs are soft tissue gastrointestinal sarcomas probably arising from mesenchymal cells. They are rare neoplasms, with between 5000 and 10 000 new cases being diagnosed each year in the US. GISTs occur throughout the gastrointestinal tract but the stomach and small intestine are the most common sites. Symptoms depend on the site and size of the tumour, and may include abdominal pain, gastrointestinal bleeding or signs of obstruction; small tumours may be asymptomatic. The diagnosis of GIST is made by immunohistochemical staining for CD117, a cell surface antigen on the extracellular domain of KIT, in conjunction with pathological examination of tissue with light microscopy. All GISTs may have some degree of malignant potential. They are unresponsive to standard chemotherapy and to radiotherapy, and the mainstay of treatment in the past has been surgery. However, recurrence rates are high, and there has been no effective systemic treatment for unresectable GIST or metastatic disease. For patients in whom complete resection is not possible, or in patients with metastatic or recurrent disease, the median duration of survival is 9-12 months, and 10-19 months, respectively. Gain-of-function mutations of the KIT proto-oncogene occur in up to 90% of GISTs, allowing constitutive activation of tyrosine kinase (i.e. auto-phosphorylation of tyrosine residues independent of ligand-receptor binding), leading to aberrant cell division and tumour growth. Imatinib selectively inhibits the tyrosine kinase activity associated with KIT, which forms the rationale for evaluating its effects in GIST. Subsequent to initial evidence of the clinical efficacy of imatinib in a single patient with progressive, metastatic, CD117-positive GIST, formal studies of imatinib in this new indication were initiated. This article summarises the pharmacology, efficacy and tolerability profile of imatinib in the treatment of patients with advanced GIST.

Levofloxacin: a review of its use in the treatment of bacterial infections in the United States.

UNLABELLED: Levofloxacin (Levaquin) is a fluoroquinolone antibacterial agent with a broad spectrum of activity against Gram-positive and Gram-negative bacteria and atypical respiratory pathogens. It is active against both penicillin-susceptible and penicillin-resistant Streptococcus pneumoniae. The prevalence of S. pneumoniae resistance to levofloxacin is <1% overall in the US.A number of randomised comparative trials in the US have demonstrated the efficacy of levofloxacin in the treatment of infections of the respiratory tract, genitourinary tract, skin and skin structures. Sequential intravenous to oral levofloxacin 750mg once daily for 7-14 days was as effective in the treatment of nosocomial pneumonia as intravenous imipenem/cilastatin 500-1000mg every 6-8 hours followed by oral ciprofloxacin 750mg twice daily in one study. In patients with mild to severe community-acquired pneumonia (CAP), intravenous and/or oral levofloxacin 500mg once daily for 7-14 days achieved clinical and bacteriological response rates similar to those with comparator agents, including amoxicillin/clavulanic acid, clarithromycin, azithromycin, ceftriaxone and/or cefuroxime axetil and gatifloxacin. A recent study indicates that intravenous or oral levofloxacin 750mg once daily for 5 days is as effective as 500mg once daily for 10 days, in the treatment of mild to severe CAP. Exacerbations of chronic bronchitis and acute maxillary sinusitis respond well to treatment with oral levofloxacin 500mg once daily for 7 and 10-14 days, respectively. Oral levofloxacin was as effective as ofloxacin in uncomplicated urinary tract infections and ciprofloxacin or lomefloxacin in complicated urinary tract infections. In men with chronic bacterial prostatitis treated for 28 days, oral levofloxacin 500mg once daily achieved similar clinical and bacteriological response rates to oral ciprofloxacin 500mg twice daily. Uncomplicated skin infections responded well to oral levofloxacin 500mg once daily for 7-10 days, while in complicated skin infections intravenous and/or oral levofloxacin 750mg for 7-14 days was at least as effective as intravenous ticarcillin/clavulanic acid (+/- switch to oral amoxicillin/clavulanic acid) administered for the same duration. Levofloxacin is generally well tolerated, with the most frequently reported adverse events being nausea and diarrhoea; in comparison with some other quinolones it has a low photosensitising potential and clinically significant cardiac and hepatic adverse events are rare. CONCLUSION: Levofloxacin is a broad-spectrum antibacterial agent with activity against a range of Gram-positive and Gram-negative bacteria and atypical organisms. It provides clinical and bacteriological efficacy in a range of infections, including those caused by both penicillin-susceptible and -resistant strains of S. pneumoniae. Levofloxacin is well tolerated, and is associated with few of the phototoxic, cardiac or hepatic adverse events seen with some other quinolones. It also has a pharmacokinetic profile that is compatible with once-daily administration and allows for sequential intravenous to oral therapy. The recent approvals in the US for use in the treatment of nosocomial pneumonia and chronic bacterial prostatitis, and the introduction of a short-course, high-dose regimen for use in CAP, further extend the role of levofloxacin in treating bacterial infections.