Lanthanum carbonate: a review of its use in lowering serum phosphate in patients with end-stage renal disease.

Orally administered lanthanum carbonate (Fosrenol) dissociates in the acid environment of the upper gastrointestinal tract to release the cation lanthanum, which then binds dietary phosphate. Lanthanum carbonate was effective in reducing levels of serum phosphate and serum calcium x phosphate product and then maintaining these levels within target ranges for up to 6 years in adult patients with end-stage renal disease (ESRD) on haemodialysis or peritoneal dialysis. The reduction in serum phosphate levels with lanthanum carbonate was generally similar to that with calcium carbonate or sevelamer hydrochloride. This agent was generally well tolerated, with the most frequently reported adverse events being gastrointestinal in nature and occurring at a similar rate to that with calcium carbonate. However, lanthanum carbonate was associated with fewer episodes of hypercalcaemia than calcium carbonate. Overall, lanthanum carbonate is a valuable option for the reduction of serum phosphate levels in patients with ESRD on haemodialysis or peritoneal dialysis.

Aprepitant: a review of its use in the prevention of nausea and vomiting.

Aprepitant (Emend) is a neurokinin-1 (NK(1)) receptor antagonist that is able to alleviate the emetic effects of substance P. When combined with a standard regimen of a corticosteroid (dexamethasone) and a serotonin 5-HT(3) receptor antagonist (ondansetron), oral aprepitant (125 mg on day 1 then 80 mg once daily on days 2 and 3) was effective in the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with single or multiple cycles of highly emetogenic chemotherapy (HEC). This aprepitant regimen was also effective in the prevention of CINV in patients treated with single or multiple cycles of moderately emetogenic chemotherapy (MEC). A single oral dose of aprepitant 40 mg administered prior to patients undergoing abdominal surgery was also effective in the prevention of postoperative nausea and vomiting (PONV). Aprepitant was generally well tolerated. Aprepitant is a recommended option for the treatment of PONV, and when combined with a corticosteroid and 5-HT(3) receptor antagonist is a recommended regimen for the treatment of CINV.

Eslicarbazepine acetate.

Eslicarbazepine acetate, a prodrug of eslicarbazepine (S-licarbazepine), is a novel, voltage-gated sodium channel antagonist under development for the adjunctive treatment of adult patients experiencing treatment-refractory partial-onset seizures. * In phase III trials, eslicarbazepine acetate 800 and 1200 mg once daily significantly reduced seizure frequency compared with placebo over 12 weeks of maintenance treatment in adults experiencing partial-onset seizures who were taking 1-3 concomitant antiepileptic drugs. * During long-term, open-label treatment for up to 1 year, eslicarbazepine acetate at a median dosage of 800 mg once daily produced sustained reductions from baseline in seizure frequency. * Long-term treatment with eslicarbazepine acetate significantly improved from baseline health-related quality of life as assessed by the Quality-of-Life in Epilepsy Inventory-31 instrument. Similarly, eslicarbazepine acetate significantly reduced depressive symptoms assessed by the Montgomery-Asberg Depression Rating Scale. * Eslicarbazepine acetate was generally well tolerated in clinical trials. The majority of treatment-emergent adverse events were of mild to moderate severity and most occurred early in treatment.

Mosapride in gastrointestinal disorders.

Mosapride was effective in improving overall symptoms in patients with gastrointestinal disorders, including chronic gastritis, gastro-oesophageal reflux disease and functional dyspepsia. Mosapride was more effective than teprenone in improving gastric stasis symptoms and gastric pain after 2 weeks of therapy (p < 0.001) in an open-label trial in 1042 patients with functional dyspepsia. Mosapride was as effective as famotidine and itopride, but more effective than tandospirone, in improving overall or individual symptoms of functional dyspepsia in randomized trials. However, in one randomized, double-blind trial in patients with mild to severe disease, the improvement in overall symptoms of functional dyspepsia did not differ significantly between mosapride or placebo treatment. Mosapride was well tolerated, with diarrhoea/loose stools, dry mouth, malaise and headache being reported in <5% of patients.

Rosuvastatin: a review of its effect on atherosclerosis.

The HMG-CoA reductase inhibitor (statin) rosuvastatin (Crestor) is widely available for use in the management of dyslipidemia, and was recently approved in the US to slow the progression of atherosclerosis as part of a strategy to lower low-density lipoprotein-cholesterol (LDL-C) and total cholesterol (TC) to target levels. Rosuvastatin has greater lipid-lowering efficacy than any of the other currently available statins, and significantly more patients receiving rosuvastatin than other statins achieve LDL-C goals. Rosuvastatin delayed the progression of carotid atherosclerosis in patients with subclinical carotid atherosclerosis, moderately elevated cholesterol levels, and a low risk of cardiovascular disease in a primary prevention trial (METEOR). The results of METEOR suggest a possible role for the earlier use of rosuvastatin in primary prevention, although more data are needed from trials examining the effects of the drug on cardiovascular endpoints. Significant regression of atherosclerosis was seen with rosuvastatin 40 mg/day in patients with established coronary heart disease (CHD) in the ASTEROID trial, supporting the use of intensive lipid lowering in secondary prevention patients (although it should be noted that it has not yet been established that atherosclerotic regression translates into improved cardiovascular outcomes). Rosuvastatin is generally well tolerated, with a similar tolerability profile to that of other currently available statins. Thus, rosuvastatin is an important lipid-lowering treatment option that has been shown to cause regression of atherosclerosis in secondary prevention patients, and has a potential future role in delaying atherosclerosis in primary prevention patients.

Nilotinib.

Nilotinib is an orally administered BCR-ABL tyrosine kinase inhibitor that has shown good clinical efficacy in imatinib-resistant or -intolerant, Philadelphia chromosome-positive, chronic myeloid leukaemia (CML) in a phase I/II trial. The phase I component of the trial established the dosage regimen used in the phase II part of the trial, which included several arms. Three of these arms, or phase II trials, evaluated nilotinib in each of the three phases of CML (chronic, accelerated or blast crisis).I n the phase II trial in patients with chronic-phase CML, major cytogenetic response (primary endpoint) was achieved in 48% of the 280 patients who received nilotinib and had a follow-up period of > or = 6 months. Major cytogenetic response rates did not differ between imatinib-resistant and -intolerant patients, and nilotinib was effective in patients with BCR-ABL mutations (except T315I). Haematologic response rate (primary endpoint) was 47% in the phase II trial with nilotinib in patients with accelerated-phase CML (n = 119). Complete haematologic response was achieved in 26% of patients and 21% had no evidence of leukaemia or returned to chronic-phase CML. Major cytogenetic response, an important secondary endpoint in the trial, occurred in 29% of patients. Data from the phase II trial in patients with CML in blast crisis (n = 135) also showed promising results, with 39% of patients achieving haematologic response with nilotinib. Adverse events reported with nilotinib have generally been of mild to moderate severity. Grade 3 or 4 neutropenia and thrombocytopenia were reported in 29% of patients each.

Amlodipine/Valsartan: fixed-dose combination in hypertension.

Amlodipine, a dihydropyridine calcium channel blocker, and valsartan, an angiotensin II receptor blocker, are established antihypertensive agents. Fixed-dose combinations of amlodipine/valsartan are available in several European countries and in the US. Individual dose titration with amlodipine and valsartan is generally recommended before changing to the fixed-dose combination. Amlodipine/valsartan, at approved dosage regimens, achieved significantly greater reductions in mean sitting diastolic and systolic blood pressure (BP) than amlodipine or valsartan monotherapy, or placebo in two randomized, double-blind, factorial trials in patients with mild to moderate hypertension. Approximately 80-90% of patients receiving approved dosages of amlodipine/valsartan achieved a response, defined as a mean sitting diastolic BP <90 mmHg or a >or= 10 mmHg reduction from baseline. Subgroup analyses of data from the two trials showed that the antihypertensive efficacy of amlodipine/valsartan in the elderly, Black patients and those with stage 2 hypertension was consistent with that observed in the overall study population. Marked reductions in BP were also observed in patients whose BP was previously uncontrolled on monotherapy (with various antihypertensives) who were switched (without washout) to amlodipine/valsartan in a phase IIIb-IV study. Amlodipine/valsartan was generally well tolerated in clinical trials. In particular, the incidence of peripheral oedema was significantly lower in patients receiving amlodipine/valsartan than in those treated with amlodipine monotherapy.

Colesevelam: a review of its use in hypercholesterolemia.

Colesevelam hydrochloride (Cholestagel, WelChol is an orally administered, non-absorbable, polymeric, bile-acid-binding agent with a higher affinity for glycocholic acid in vitro and greater capacity for binding bile acids in vivo than other bile-acid-binding agents. In randomized controlled trials in patients with primary hypercholesterolemia, colesevelam monotherapy reduced mean serum low-density lipoprotein-cholesterol (LDL-C) levels by 9-19%. In combination with an HMG-CoA reductase inhibitor (statin) or fenofibrate, colesevelam induced additive reductions in LDL-C 10-16% greater than those achieved by monotherapy with a statin (in patients with primary hypercholesterolemia) or fenofibrate (in patients with mixed hyperlipidemia). Colesevelam was generally well tolerated, with a relatively low incidence of gastrointestinal adverse events and a high compliance rate. Thus, colesevelam provides a useful addition to primary therapy with statins in the treatment of primary hypercholesterolemia, or fenofibrate in the treatment of mixed hyperlipidemia.

Delayed-release Multi Matrix System (MMX) mesalazine: in ulcerative colitis.

* Mesalazine appears to act locally on the mucosa of the colon and reduces the inflammation associated with ulcerative colitis. * Following oral administration, the majority (*78%) of a dose of delayed-release Multi Matrix System (MMX) mesalazine passes unabsorbed through the upper gastrointestinal tract to reach and traverse the entire length of the colon. * In a well designed phase III trial in patients with active, mild to moderate ulcerative colitis (n = 262), significantly (p < 0.01) more MMX mesalazine 2.4 (34%) or 4.8 g/day (29%) recipients than placebo recipients (13%) achieved clinical and endoscopic remission after 8 weeks of treatment.* In a second phase III trial (n = 341), clinical and endoscopic remission rates with MMX mesalazine 2.4 (40.5%) and 4.8 g/day (41.2%) were significantly (p < 0.01) greater than with placebo (22.1%) after 8 weeks, while the remission rate with non-MMX delayed-release mesalazine (Asacol) [32.6%] did not differ from placebo.* Overall, MMX mesalazine was generally well tolerated in controlled clinical trials, with a similar incidence of treatment-emergent adverse events in placebo (66%) and MMX mesalazine (56%) recipients in a pooled analysis; most adverse events were of mild or moderate severity. Two of 434 MMX mesalazine recipients experienced serious adverse events that were considered treatment related (pancreatitis caused by mesalazine sensitivity).

Drospirenone/ethinylestradiol 3mg/20microg (24/4 day regimen): a review of its use in contraception, premenstrual dysphoric disorder and moderate acne vulgaris.

Drospirenone 3mg with ethinylestradiol 20microg (Yaz) is a low-dose combined oral contraceptive (COC) administered in a regimen of 24 days of active tablets followed by a short hormone-free interval (4 days; 24/4 regimen). Drospirenone, unlike other synthetic progestogens used in COCs, is a 17alpha-spirolactone derivative and a 17alpha-spironolactone analogue with antimineralocorticoid and antiandrogenic properties. Drospirenone/ethinylestradiol 3mg/20microg (24/4) is approved in the US for the prevention of pregnancy in women, for the treatment of the symptoms of premenstrual dysphoric disorder (PMDD) and for the treatment of moderate acne vulgaris in women who wish to use an oral contraceptive for contraception.Drospirenone/ethinylestradiol 3mg/20microg (24/4) provided 99% contraceptive protection over 1 year of treatment in two large studies. The same treatment regimen over three treatment cycles also significantly improved the emotional and physical symptoms associated with PMDD, and improved moderate acne vulgaris over six treatment cycles in double-blind trials. It was generally well tolerated, with adverse events generally typical of those experienced with other COCs and which were most likely to occur in the first few cycles. Clinical trials indicate that drospirenone/ethinylestradiol 3mg/20microg (24/4) is a good long-term contraceptive option, and additionally offers relief of symptoms that characterise PMDD and has a favourable effect on moderate acne vulgaris.

Spotlight on quetiapine in bipolar depression.

Quetiapine (Seroquel) is the only atypical antipsychotic approved in the US for use as monotherapy in both bipolar mania and depression, offering potential compliance advantages. Monotherapy with oral quetiapine 300 mg/day is effective in the treatment of patients with bipolar I or II depression. Rapid and sustained improvements in depressive and anxiety symptoms are seen with quetiapine, as well as improvements in health-related quality of life. Quetiapine is generally well tolerated in bipolar depression and is not associated with an increased risk of treatment-emergent mania. Thus, despite the current lack of data from active comparator trials, quetiapine monotherapy should be considered a first-line option for the acute treatment of bipolar depression.

Imidapril: a review of its use in essential hypertension, Type 1 diabetic nephropathy and chronic heart failure.

Imidapril (Tanatril), through its active metabolite imidaprilat, acts as an ACE inhibitor to suppress the conversion of angiotensin I to angiotensin II and thereby reduce total peripheral resistance and systemic blood pressure (BP). In clinical trials, oral imidapril was an effective antihypertensive agent in the treatment of mild to moderate essential hypertension. Some evidence suggests that imidapril also improves exercise capacity in patients with chronic heart failure (CHF) and reduces urinary albumin excretion rate in patients with type 1 diabetes mellitus. Imidapril was well tolerated, with a lower incidence of dry cough than enalapril or benazepril, and is a first choice ACE inhibitor for the treatment of mild to moderate essential hypertension.

Quetiapine: a review of its use in the treatment of bipolar depression.

Quetiapine (Seroquel) is the only atypical antipsychotic approved in the US for use as monotherapy in both bipolar mania and depression, offering potential compliance advantages. Monotherapy with oral quetiapine 300 mg/day is effective in the treatment of patients with bipolar I or II depression. Rapid and sustained improvements in depressive and anxiety symptoms are seen with quetiapine, as well as improvements in health-related quality of life (HR-QOL). Quetiapine is generally well tolerated in bipolar depression and is not associated with an increased risk of treatment-emergent mania. Thus, despite the current lack of data from active comparator trials, quetiapine monotherapy should be considered a first-line option for the acute treatment of bipolar depression.

Sodium oxybate: a review of its use in the management of narcolepsy.

Sodium oxybate (Xyrem) is the sodium salt of the CNS depressant gamma-hydroxybutyric acid (GHB) and is therefore subject to prescription restrictions. It is approved in the US for the treatment of cataplexy and excessive daytime sleepiness (EDS) in patients with narcolepsy, and in the EU for the treatment of narcolepsy with cataplexy. Sodium oxybate is generally well tolerated and effective in the treatment of symptoms of narcolepsy with cataplexy. While its short half-life necessitates twice-nightly administration, it is highly effective in reducing the frequency of cataplexy, improving sleep architecture and reducing EDS in patients with narcolepsy. Sodium oxybate therefore offers a valuable alternative or addition to the use of TCAs, SSRIs and stimulants in the treatment of the symptoms of narcolepsy including cataplexy and EDS.

P2Y1 receptor modulation of the pre-Bötzinger complex inspiratory rhythm generating network in vitro.

ATP is released during hypoxia from the ventrolateral medulla (VLM) and activates purinergic P2 receptors (P2Rs) at unknown loci to offset the secondary hypoxic depression of breathing. In this study, we used rhythmically active medullary slices from neonatal rat to map, in relation to anatomical and molecular markers of the pre-Bötzinger complex (preBötC) (a proposed site of rhythm generation), the effects of ATP on respiratory rhythm and identify the P2R subtypes responsible for these actions. Unilateral microinjections of ATP in a three-dimensional grid within the VLM revealed a "hotspot" where ATP (0.1 mM) evoked a rapid 2.2 +/- 0.1-fold increase in inspiratory frequency followed by a brief reduction to 0.83 +/- 0.02 of baseline. The hotspot was identified as the preBötC based on histology, overlap of injection sites with NK1R immunolabeling, and potentiation or inhibition of respiratory frequency by SP ([Sar9-Met(O2)11]-substance P) or DAMGO ([D-Ala2,N-MePhe4,Gly-ol5]-enkephalin), respectively. The relative potency of P2R agonists [2MeSADP (2-methylthioadenosine 5'-diphosphate) approximately = 2MeSATP (2-methylthioadenosine 5'-triphosphate) approximately = ATPgammas (adenosine 5'-[gamma-thio]triphosphate tetralithium salt) approximately = ATP >> UTP approximately = alphabeta meATP (alpha,beta-methylene-adenosine 5'-triphosphate)] and attenuation of the ATP response by MRS2179 (2'-deoxy-N6-methyladenosine-3',5'-bisphosphate) (P2Y1 antagonist) indicate that the excitation is mediated by P2Y1Rs. The post-ATP inhibition, which was never observed in response to ATPgammas, is dependent on ATP hydrolysis. These data establish in neonatal rats that respiratory rhythm generating networks in the preBötC are exquisitely sensitive to P2Y1R activation, and suggest a role for P2Y1Rs in respiratory motor control, particularly in the P2R excitation of rhythm that occurs during hypoxia.

Ramipril: a review of its use in preventing cardiovascular outcomes in high-risk patients.

Ramipril is an oral, non-sulfhydryl ACE inhibitor thought to act in the renin-angiotensin-aldosterone system to decrease vasopressor activity, aldosterone secretion, and bradykinin degradation. Ramipril is generally well tolerated and effective in the treatment of patients aged > or =55 years at high risk for the development of cardiovascular (CV) events, in whom the risk of myocardial infarction (MI), stroke, and CV death can be significantly reduced. The risk of these CV outcomes may also be reduced with ramipril therapy in various subgroups; these include patients with diabetes mellitus, peripheral arterial disease (PAD) or renal insufficiency, and women. Thus, ramipril, in addition to lifestyle interventions, should be considered an important therapy in the prevention of CV outcomes in high-risk patients.

Rimonabant.

Rimonabant is the first of a new class of selective cannabinoid receptor-1 blockers. It reduces the overactivity of the endocannabinoid system, improving lipid and glucose metabolism and regulating food intake and energy balance. In four randomised, double-blind clinical trials in overweight or obese adults with or without type 2 diabetes and/or dyslipidaemia, oral rimonabant 20mg once daily reduced weight and waist circumference to a significantly greater extent than placebo. A significantly greater proportion of rimonabant than placebo recipients achieved the clinically significant weight-loss target of > or =5% or > or =10% of initial weight. Rimonabant was associated with significant improvements in glycaemic control relative to placebo, with approximately equal to 57% of the reduction in glycosylated haemoglobin being independent of the effects of weight loss in one trial. Improvements in other cardiometabolic risk factors (i.e. increases in high-density lipoprotein-cholesterol [HDL-C] and decreases in triglyceride [TG] levels) were significantly greater with rimonabant than with placebo. The improvement in lipid profile also demonstrated a weight-independent effect, with approximately equal to 47-58% of the improvement in HDL-C and TG being beyond that expected through weight loss alone. Rimonabant was generally well tolerated, with most adverse events considered mild to moderate in severity.

Intravenous nicardipine: its use in the short-term treatment of hypertension and various other indications.

Nicardipine is a water soluble calcium channel antagonist, with predominantly vasodilatory actions. Intravenous (IV) nicardipine (Cardene IV), which demonstrates a relatively rapid onset/offset of action, is used in situations requiring the rapid control of blood pressure (BP). IV nicardipine was as effective as IV nitroprusside in the short-term reduction of BP in patients with severe or postoperative hypertension. A potential role for IV nicardipine in the intraoperative acute control of BP in patients undergoing various surgical procedures (including cardiovascular, neurovascular and abdominal surgery), and in the deliberate induction of reduced BP in surgical procedures in which haemostasis may be difficult (e.g. surgery involving the hip or spine) was demonstrated in preliminary studies. Preliminary studies also indicated the ability of a bolus dose of IV nicardipine to attenuate the hypertensive response, but not the increase in tachycardia, after laryngoscopy and tracheal intubation in anaesthetised patients. In large, well designed studies, IV nicardipine prevented cerebral vasospasm in patients with recent aneurysmal subarachnoid haemorrhage; however, overall clinical outcomes at 3 months were similar to those in patients who received standard management. Small preliminary studies have investigated the use of IV nicardipine in a variety of other settings, including acute intracerebral haemorrhage, acute ischaemic stroke, pre-eclampsia, acute aortic dissection, premature labour and electroconvulsive therapy.In conclusion, the efficacy of IV nicardipine in the short-term treatment of hypertension in settings for which oral therapy is not feasible or not desirable is well established. The ability to titrate IV nicardipine to the tolerance levels of individual patients makes this agent an attractive option, especially in critically ill patients or those undergoing surgery. Potential exists for further investigation of the use of this agent in clinical settings where a vasodilatory agent with minimal inotropic effects is appropriate.

Entecavir: a review of its use in chronic hepatitis B.

Entecavir (Baraclude) is a novel nucleoside analogue of 2'-deoxyguanosine whose intracellular triphosphate form inhibits replication of the hepatitis B virus (HBV). In large, randomised, double-blind, phase III clinical trials in patients with chronic HBV infection, oral entecavir 0.5 or 1.0mg once daily for up to 96 weeks was superior to lamivudine 100 mg/day in improving hepatic histology, normalising aminotransferase levels and suppressing viraemia to levels undetectable by polymerase chain reaction (PCR) assay in nucleoside-naive hepatitis B e antigen (HBeAg)-negative (precore or core promoter mutants) and/or HBeAg-positive patients, and in lamivudine-refractory (persistent viraemia during lamivudine therapy) HBeAg-positive patients. In addition, the tolerability profile of entecavir was generally similar to that of lamivudine. Thus, entecavir is a primary option in the treatment of chronic HBV infection in both nucleoside-naive and lamivudine-refractory patients.