Altered anxiety-related and social behaviors in the Fmr1 knockout mouse model of fragile X syndrome.

The loss of fragile X mental retardation (FMR1) gene function causes fragile X syndrome (FXS), a common mental retardation syndrome. Anxiety and abnormal social behaviors are prominent features of FXS in humans. To better understand the role of FMR1 in these behaviors, we analyzed anxiety-related and social behaviors in Fmr1 knockout (KO) mice. In the mirrored chamber test, Fmr1 KO mice showed greater aversion to the central mirrored chamber than wild-type (WT) littermates, suggesting increased anxiety-like responses to reflected images of mice. Fmr1 KO mice exhibited abnormal social interactions in a tube test of social dominance, winning fewer matches than WT littermates. In a partition test, Fmr1 KO mice had normal levels of social interest and social recognition. However, during direct interaction tests, Fmr1 KO mice showed significant increases in sniffing behaviors. We further tested the influence of environmental familiarity on the social responses of Fmr1 KO mice to unfamiliar partners. In unfamiliar partitioned cages, Fmr1 KO mice did not differ from WT mice in investigation of unfamiliar partners. However, in familiar partitioned cages, Fmr1 KO mice showed less investigation of a newly introduced partner during the first 5 min and more investigation during the last 5 min of a 20-min partition test, behaviors consistent with initial social anxiety followed by enhanced social investigation. Our findings indicate that the loss of Fmr1 gene function results in altered anxiety and social behavior in mice and demonstrate that the Fmr1 KO mouse is a relevant animal model for the abnormal social responses seen in FXS.

Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells.

The immune mechanisms regulating epithelial cell repair after injury remain poorly defined. We demonstrate here that lymphotoxin beta receptor (LTßR) signaling in intestinal epithelial cells promotes self-repair after mucosal damage. Using a conditional gene-targeted approach, we demonstrate that LTßR signaling in intestinal epithelial cells is essential for epithelial interleukin-23 (IL-23) production and protection against epithelial injury. We further show that epithelial-derived IL-23 promotes mucosal wound healing by inducing the IL-22-mediated proliferation and survival of epithelial cells and mucus production. Additionally, we identified CD4(-)CCR6(+)T-bet(-) RAR-related orphan receptor gamma t (RORγt)(+) lymphoid tissue inducer cells as the main producers of protective IL-22 after epithelial damage. Thus, our results reveal a novel role for LTßR signaling in epithelial cells in the regulation of intestinal epithelial cell homeostasis to limit mucosal damage.

Polyethylene glycol-liposomal doxorubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in the management of AIDS-related Kaposi's sarcoma.

Doxorubicin is an antineoplastic drug which has in vitro and in vivo activity against a number of malignancies including Kaposi's sarcoma. Incorporation of doxorubicin into polyethylene glycol-coated (pegylated) liposomes alters the pharmacokinetics of the drug. Liposomal doxorubicin has a smaller volume of distribution and slower plasma clearance than standard free doxorubicin. The liposomal formulation achieves higher concentrations in the highly vascularised lesions of Kaposi's sarcoma than in normal tissue. Liposomal doxorubicin monotherapy in patients with AIDS-related Kaposi's sarcoma produced overall response rates (complete plus partial) of 43 and 59% in large comparative studies and 67 to 100% in noncomparative studies which included > or = 20 patients. In comparative studies, liposomal doxorubicin was significantly more effective than the combination of standard doxorubicin, bleomycin and vincristine (overall response rates of 43 and 25%, respectively) and bleomycin and vincristine (BV) [overall response rates of 59 and 23%, respectively]. In addition, overall response rates to the liposomal drug were higher in both treatment arms of 2 smaller comparative studies which compared liposomal doxorubicin with BV, but significant between-treatment differences were not detected. Patient numbers in these 2 studies, however, may have been too small to detect significant differences. Liposomal doxorubicin is generally well tolerated. Myelosuppression is the most common dose-limiting adverse effect in patients with AIDS and Kaposi's sarcoma. Neutropenia occurs most often; anaemia and thrombocytopenia occur less frequently, as do nausea and vomiting and stomatitis. Palmar-plantar erythrodysaesthesia occurs in some patients, most commonly after 6 to 8 weeks of chemotherapy. Although symptoms may occasionally be severe, the syndrome usually does not require dosage reduction or treatment delay. Limited data suggest that the incidence of cardiotoxicity may be lower after liposomal doxorubicin than after equivalent doses of standard doxorubicin. Overall, liposomal doxorubicin appears to be one of the most active single agents available for treating patients with AIDS-related Kaposi's sarcoma. The therapeutic potential of liposomal doxorubicin administered in combination with other active agents to patients with Kaposi's sarcoma is, as yet, unknown. However, administered alone, the drug seems to be more effective than the best available combination chemotherapy regimens.

Cefotaxime. A reappraisal of its antibacterial activity and pharmacokinetic properties, and a review of its therapeutic efficacy when administered twice daily for the treatment of mild to moderate infections.

Cefotaxime is well established as an effective and well tolerated antibacterial drug for 3 times daily parenteral treatment of a variety of moderate to severe infections in hospitalised patients. Its frequency of administration has recently been reassessed with a 12-hourly regimen. Comparative studies in hospitalised patients with nosocomial or community-acquired lower respiratory tract infections, demonstrate the similar clinical and bacteriological efficacy of twice daily cefotaxime 1 or 2 g and the same daily dose of ceftriaxone, usually administered once daily. Cefotaxime 2 g twice daily was also similar in efficacy to ceftriaxone 2 g once daily. Retrospective and post-marketing studies also reveal the similar efficacy of cefotaxime administered twice and 3 times daily, and pharmacoeconomic studies suggest that total direct costs of treatment with cefotaxime compared is similar to that with other third generation cephalosporins in currently used dosage regimens. When administered twice daily, cefotaxime is, thus, an effective antibacterial agent for the treatment of hospitalised patients outside the intensive care unit with a variety of mild to moderate non-CNS infections caused by susceptible organisms. When appropriately administered twice daily there is potential to lower the cost of antibacterial treatment without compromising efficacy.

Troglitazone.

Troglitazone decreases insulin resistance (improves insulin sensitivity), which results in reduced plasma glucose and insulin levels in patients with non-insulin-dependent diabetes mellitus (NIDDM). Risk factors for cardiovascular disease such as elevated proinsulin and triglyceride levels are also reduced by troglitazone. In clinical trials, troglitazone 200 to 800 mg daily (alone or in combination with other oral antidiabetic agents or insulin) reduced plasma or serum glucose levels and glycosylated haemoglobin compared with both baseline and placebo in patients with NIDDM refractory to other oral antidiabetic agents (usually sulphonylureas). Troglitazone was generally well tolerated in clinical trials. In patients in the US, the incidence of adverse events in troglitazone recipients was similar to that in placebo recipients.

Butenafine.

Butenafine is a new antifungal agent with primary fungicidal activity against dermatophytes such as Trichophyton mentagrophytes, Microsporum canis and Trichophyton rubrum which cause tinea infections. 14C-labelled butenafine (approximately 30 micrograms/g tissue) was found within guinea-pig dorsal skin 24 hours after topical application. Most of the drug was distributed into the epidermis including the horny layer. Small amounts were found in the dermis, probably transported via sebaceous glands and hair follicles. In vitro, the minimum concentration that completely inhibited growth of dermatophytes (MIC) and the minimum fungicidal concentrations (MFC) for butenafine against T. mentagrophytes and M. canis were similar (0.012 to 0.05 mg/L) and were 4 to 130 times lower than those for naftifine, tolnaftate, clotrimazole and bifonazole. It also has greater activity against T. rubrum, M. gypseum and Epidermophyton floccosum when compared with naftifine, tolnaftate and clotrimazole; comparisons with bifonazole against these strains were not available. Assessment after 1 week's treatment in patients with tinea pedis revealed that mycological cure rates were greater in those who received twice-daily butenafine for 1 week or once-daily butenafine for 4 weeks than in placebo recipients. Mycological and overall cure rates were either further increased or maintained up to 5 weeks after treatment cessation compared with end-of-treatment values. In patients with tinea cruris or tinea corporis who received once-daily butenafine 1% for 2 weeks, the mycological and overall cure rates continued to increase for up to 4 weeks after treatment cessation.

Atovaquone. A review of its pharmacological properties and therapeutic efficacy in opportunistic infections.

Atovaquone has been investigated as an alternative agent for oral use in the treatment of both mild to moderate Pneumocystis carinii pneumonia (PCP) and toxoplasmosis, opportunistic infections commonly experienced by patients with AIDS. In patients with mild to moderate PCP, a dosage of 750mg 3 times daily (administered in tablet form) has similar overall therapeutic efficacy (defined as clinical response without a treatment-limiting adverse event) to the conventional therapies oral cotrimoxazole (trimethoprim-sulfamethoxazole) and intravenous pentamidine, respectively. Response rates to atovaquone are lower than those achieved with cotrimoxazole, but atovaquone has superior tolerability. Atovaquone recipients experienced significantly fewer treatment-limiting adverse effects than patients treated with cotrimoxazole (7 vs 20%) or pentamidine (4 vs 36%). Mortality rates were higher among atovaquone-treated patients than in cotrimoxazole recipients (7 vs 0.6%) 4 weeks after completion of therapy in a large comparative trial, although most deaths were caused by bacterial infections. However, a similar rate of mortality was reported for atovaquone- and pentamidine-treated patients (16 vs 17% 8 weeks after discontinuation of therapy) in another study. In predominantly small numbers of patients with toxoplasmosis, of whom most were unresponsive to conventional agents, atovaquone 750mg 4 times daily (administered as tablets) produced a complete or partial radiological response rate of 37 to 87.5% 52% of patients achieved a complete or partial clinical response after 6 weeks of treatment in the largest trial (n = 87), although the incidence of toxoplasmosis-related death was 24% 18 weeks after therapy was initiated. Thus, atovaquone will be a useful option for the treatment of patients with mild to moderate PCP who are intolerant or unresponsive to cotrimoxazole, especially if the increased plasma drug concentrations observed with the suspension further improve response rates. Atovaquone should also be considered a promising agent for the treatment of toxoplasmosis.

Iodixanol. A review of its pharmacodynamic and pharmacokinetic properties and diagnostic use as an x-ray contrast medium.

Iodixanol is an iso-osmolal nonionic dimeric hydrophilic contrast agent. It has similar diagnostic efficacy to that of other iodinated contrast media. Because of its physical properties, iodixanol would be expected to produce a lower incidence of adverse events than other nondimeric contrast media. Indeed, pharmacodynamic studies indicate that iodixanol has fewer cardiovascular effects, causes less renal damage and is associated with similar or smaller changes to the blood-brain barrier and neurological function when compared with nondimeric nonionic contrast media. In clinical trials, iodixanol had a similar tolerability profile to other nonionic contrast media but induced fewer adverse events than ioxaglate. Iodixanol appears to have an advantage over other contrast media in that it generally causes less frequent and less intense discomfort on injection. However, in common with other newer, and usually nonionic, contrast media, iodixanol is expensive. Studies investigating other nonionic contrast media (but not iodixanol) have shown that it is not cost-effective in all patients to replace older, usually ionic, contrast media with the more costly newer alternatives. Nonetheless, in selected patients who are considered at increased risk of contrast medium-associated adverse events, nonionic agents should be used. Iodixanol, with its lower intensity (and possibly frequency) of discomfort, may be a preferred option in these patients.

Gemfibrozil. A reappraisal of its pharmacological properties and place in the management of dyslipidaemia.

Gemfibrozil improves lipid and apolipoprotein profiles, particularly very low density lipoprotein (VLDL) triglyceride and high density lipoprotein (HDL) cholesterol levels, in patients with dyslipidaemia when administered at a total daily dose of 900 or 1200 mg. As demonstrated by the Helsinki Heart Study, these effects result in a reduction in some risk factors for coronary heart disease (CHD) and also a 34% reduction in the incidence of this disease after 5 years compared with placebo. Limited data suggest that gemfibrozil has beneficial effects on the fibrinolytic system and may slow the progression of atherosclerosis. Gemfibrozil has shown efficacy in the treatment of patients with type IIa, IIb, III, IV or V dyslipidaemia or hypoalphalipoproteinaemia, especially in patients with elevated triglyceride and low HDL cholesterol levels. It is also effective in patients with non-insulin-dependent diabetes mellitus (NIDDM) and dyslipidaemia and has no detrimental effects on glycaemic control. A small number of studies also showed gemfibrozil to be effective for the control of dyslipidaemia associated with renal failure, transplantation, nephrotic syndrome, arterial occlusive disease or systemic lupus erythematosus. However, patients with pre-existing CHD do not appear to derive the same benefits (reduced CHD mortality) from gemfibrozil therapy as these other patients, although results are based on studies of limited size and number. In general, gemfibrozil has at least similar efficacy to bile acid sequestrants and other fibric acid derivatives. Comparisons with HMG-CoA reductase inhibitors show these agents to produce different effects on lipid profiles from gemfibrozil. Thus, gemfibrozil would be expected to be superior in some patients (those with elevated triglyceride or VLDL cholesterol levels), but HMG-CoA reductase inhibitors should have greater benefits in those with elevated low density lipoprotein cholesterol levels. Thus, in patients with elevated triglyceride levels and low HDL cholesterol levels, and, particularly in patients with NIDDM, gemfibrozil is a useful treatment option, which has been shown to reduce the risk of CHD in middle aged men. However, limited available data prevents the accurate comparison of this agent with HMG-CoA reductase inhibitors in patients with this lipid profile.

Docetaxel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of metastatic breast cancer.

Docetaxel is a member of the taxoid class of antineoplastic agents. Its mechanism of action is primarily related to its ability to enhance microtubule assembly and to stabilise microtubules by preventing their depolymerisation, thus disrupting normal cell division. Docetaxel has significant cytotoxic activity against human breast cancer cell lines and freshly explanted human breast cancer cells in vitro. It has also shown activity in mice against mammary tumours and human mammary tumour xenografts. Docetaxel has been investigated in the treatment of patients with advanced and/or metastatic breast cancer in European and North American phase II trials using an initial dose of 100 mg/m2 infused over 1 hour every 3 weeks. As first-line treatment, monotherapy with docetaxel was associated with complete and partial response rates of 5 to 16% and 49 to 53%, respectively, with an overall (complete plus partial) response rate of 54 to 68%. The median overall survival time of patients in one study was > or = 71 weeks. Docetaxel monotherapy has shown impressive activity as second-line therapy in patients with metastatic breast cancer who had relapsed while receiving adjuvant therapy or who had progressive disease following previous treatment, with overall response rates of 53 and 58% reported in 2 studies. A number of issues need to be addressed before the ultimate place of docetaxel in the management of metastatic breast cancer is fully established. The efficacy of docetaxel compared with standard agents and in combination regimens and its effect on quality-of-life aspects require further evaluation. Nevertheless, docetaxel is a promising new agent which has produced impressive clinical results and should be considered an alternative second-line treatment of patients with metastatic breast cancer.

Diacerein.

Rhein, the active metabolite of diacerein, inhibits interleukin-1 activity. Consequently, collagenase production in articular cartilage is reduced. Rhein dose-dependently inhibits superoxide anion production, chemotaxis and phagocytic activity of neutrophils, and macrophage migration and phagocytosis. Articular cartilage damage is reduced by diacerein in animal models of osteoarthritis. Diacerein does not alter renal or platelet cyclooxygenase activity and may therefore be tolerated by patients with prostaglandin-dependent renal function. In clinical trials of < or = 6 months' duration, oral diacerein 50mg twice daily was associated with improvement in 57 to 85% of patients with osteoarthritis. Pain scores and measures of joint function were generally reduced compared with baseline and placebo. Diacerein had similar efficacy to NSAIDs, but a slower onset of action, in comparative trials of < or = 2 months' duration conducted in patients with osteoarthritis. The predominant adverse effects of diacerein are diarrhoea and related disorders.

Nisoldipine coat-core. A review of its pharmacodynamic and pharmacokinetic properties and clinical efficacy in the management of ischaemic heart disease.

Nisoldipine coat-core is an extended-release once-daily formulation of a dihydropyridine calcium antagonist effective in the treatment of chronic stable angina pectoris. With immediate-release formulations of nisoldipine, plasma drug concentrations that produce therapeutic effects result rapidly, but are not sustained and do not maintain the effects throughout a 12-hour dosage interval. In contrast, with nisoldipine coat-core, a gradual increase in plasma nisoldipine concentrations occurs over 12 hours and therapeutic concentrations are then maintained for the duration of a 24-hour dosage interval. In dosages of 10 to 60 mg once daily, nisoldipine coat-core controls symptoms of angina and improves exercise-induced signs of ischaemia in patients with stable angina. Compared with placebo, daily nisoldipine coat-core doses of > or = 20 mg provide statistically significant increases in total exercise time and time to produce angina and a trend towards an increase in the time to produce 1 mm ST segment depression, in exercise tests conducted approximately 23 hours postdose. When administered in 20 and 40 mg daily doses, nisoldipine coat-core produces improvements in exercise test parameters that are similar to those seen with amlodipine 5 or 10 mg/day or regular-release or sustained-release (SR) diltiazem 240 mg/day. The frequency of daily angina attacks and consumption of short-acting nitrates are also reduced by nisoldipine to a similar extent to that observed with these other agents. After longer term (1 year) administration of 10 to 60 mg daily, improvements in exercise test parameters are maintained, with equivalent anti-ischaemic efficacy seen in patients receiving nisoldipine coat-core alone or with background nitrate or beta-blocker therapy. Adverse events associated with nisoldipine coat-core are typical of the dihydropyridine class of calcium antagonists, with peripheral oedema and headache being most common. Nisoldipine coat-core appears to be associated with fewer deaths than placebo, notably in the DEFIANT-II (Doppler Flow and Echocardiography in Functional Cardiac Insufficiency: Assessment of Nisoldipine Therapy II) study, where only 1 death occurred with nisoldipine compared with 7 in the placebo group. Nisoldipine should not be taken during phenytoin therapy. In addition, grapefruit juice should be avoided during nisoldipine therapy and nisoldipine should not be taken concurrently with high-fat meals. Thus, the coat-core formulation of nisoldipine appears to have overcome the limitations of the shorter duration of action of immediate-release nisoldipine. Nisoldipine coat-core is well tolerated and once-daily administration produces a long duration of effective anti-ischaemic relief in patients with chronic stable angina pectoris.

Balsalazide.

Balsalazide is a prodrug of mesalazine which has an inert carrier molecule instead of the sulfapyridine moiety of sulfasalazine. Balsalazide 6.75 g/day was more effective than mesalazine 2.4 g/day in at least 1 trial and as effective as sulfasalazine 3 g/day for inducing remission in patients with acute ulcerative colitis in 8- and 12-week trials. Moreover, complete symptom relief occurred more promptly with balsalizide 6.75 g/day than with mesalazine 2.4g/day. In long term studies, balsalazide 2 g/day was as effective as sulfasalazine 2 g/day and balsalazide 6 g/day was as effective as mesalazine 1.5 g/day, in maintaining remission in patients with ulcerative colitis. The tolerability profile of balsalazide is significantly better than that of sulfasalazine; 70% of sulfasalazine-intolerant patients were able to tolerate balsalazide.

Enoxaparin. A review of its clinical potential in the management of coronary artery disease.

UNLABELLED: Enoxaparin (enoxaparin sodium) is a low molecular weight heparin (LMWH) that is widely used in the prevention of deep venous thrombosis and pulmonary embolism in patients undergoing orthopaedic or general surgery. Its efficacy in these indications has led to study of its use in patients with coronary artery disease, particularly those with unstable angina, who have a high risk of myocardial infarction and death. A double-blind multicentre study [ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q Wave Coronary Events)] showed that subcutaneous enoxaparin was more effective than intravenous unfractionated heparin (UFH) in reducing the incidence of the composite end-point of death, myocardial infarction or recurrent angina after 14 days in 3171 patients with recent-onset resting angina (i.e. unstable angina). There were no statistically significant between-group differences for the secondary end-point of death or myocardial infarction. Preliminary reports of long term follow-up data indicate that the clinical benefit of enoxaparin over UFH is maintained after 1 year. The only significant difference in tolerability between enoxaparin and UFH in ESSENCE was for minor haemorrhage (mostly injection-site ecchymosis), which was more common with the LMWH. Prospective pharmacoeconomic substudies of the ESSENCE trial suggest that total medical costs (including those for subsequent revascularisation procedures) for enoxaparin treatment are lower than those for UFH. The ESSENCE study is the first double-blind trial to show that a LMWH is more effective than UFH in patients with unstable angina. The superiority of enoxaparin was attributable mainly to its effects on recurrent angina. The level of anticoagulation achieved in the UFH group raises a number of issues which might have affected the apparent relative efficacy of enoxaparin and UFH. Preliminary data suggest that enoxaparin is at least as effective as UFH in reducing the incidence of subsequent cardiac events in patients receiving thrombolysis for acute myocardial infarction, and a randomised comparison with no additional treatment (other than aspirin) has demonstrated its efficacy in this indication. Enoxaparin has been ineffective in preventing restenosis after angioplasty CONCLUSIONS: The ESSENCE study has shown that enoxaparin is more effective than UFH in patients with unstable angina. Although clarification of some methodological issues would be beneficial, the available efficacy data, together with the practical advantages of LMWHs in general, suggest that enoxaparin is an effective and convenient means of treating unstable angina and should provide cost savings compared with UFH.

Salmeterol/fluticasone propionate combination.

Current evidence suggests that addition of the long-acting beta2-agonist salmeterol to an inhaled corticosteroid in patients with persistent asthma symptoms provides greater clinical benefit than doubling the dosage of the inhaled corticosteroid. Fixed combination salmeterol/fluticasone propionate in 3 different fluticasone propionate dosage strengths administered via the Diskus powder inhaler does not result in any untoward interaction that affects the pharmacodynamic or pharmacokinetic profiles of the individual drugs, or their adverse effect profiles - including the influence of the corticosteroid on plasma cortisol levels. Administration of fixed combination salmeterol/ fluticasone propionate to both adults and children with persistent asthma provides greater improvements in lung function than either agent alone, and at least equal effectiveness to the same dosages of the 2 agents given by separate powder inhalers. Preliminary reports indicate that combination therapy has also demonstrated superior efficacy to budesonide (fluticasone propionate dosages were 25% those of budesonide). The most commonly encountered adverse effects in clinical trials with combined salmeterol/fluticasone propionate therapy have been oropharyngeal candidiasis. hoarseness/dysphonia, throat irritation, headache, tachycardia/palpitations, tremor and dizziness (all in < or =5% of patients).

Miglitol: a review of its therapeutic potential in type 2 diabetes mellitus.

UNLABELLED: Miglitol, the first pseudomonosaccharide alpha-glucosidase inhibitor, smooths postprandial peak plasma glucose levels and thus improves glycaemic control, which is reflected in a reduced glycosylated haemoglobin (HbA1c) level. This oral antihyperglycaemic agent is indicated for the treatment of patients with type 2 diabetes mellitus. Miglitol is generally well tolerated and, unlike the sulphonylurea agents, is not associated with bodyweight gain or hypoglycaemia when administered as monotherapy. The drug is systemically absorbed but is not metabolised and is rapidly excreted via the kidneys. Clinical trials with miglitol (usually 50 or 100 mg 3 times daily) in patients with type 2 diabetes mellitus consistently demonstrated a significant improvement in glycaemic control for periods of 6 to 12 months. There were also marked reductions in postprandial serum insulin levels, although miglitol generally had no effect on fasting insulin levels. In comparative studies miglitol had similar efficacy to acarbose, but at lower therapeutic doses (50 and 100 mg 3 times daily, respectively). In addition, although sulphonylurea agents provided superior reductions in HbA1c levels, miglitol provided similar or superior reductions in fasting and postprandial plasma glucose levels. In combination with other oral antidiabetic agents or insulin, miglitol improved glycaemic control in patients in whom metabolic control was suboptimal despite dietary and pharmacological intervention. Most adverse events associated with miglitol treatment involve disturbances of the gastrointestinal tract (most common effects are flatulence, abdominal pain and diarrhoea). These symptoms are usually dose dependent, mild to moderate in severity, occur at the onset of treatment, decline with time and resolve promptly on discontinuation of the drug or with dosage adjustment. As monotherapy, miglitol is not associated with hypoglycaemia, but concomitant use with other oral antidiabetic agents may necessitate dosage adjustment of the other agents. Miglitol had no significant effects on renal, cardiovascular, respiratory or haematological parameters in long term studies. No dosage adjustments are required in elderly patients, in those with hepatic impairment or in those with mild to moderate renal insufficiency. CONCLUSIONS: In long term, well designed trials miglitol reduces fasting and postprandial plasma glucose levels, thus improving glycaemic control, which is reflected in a reduced HbA1c level in patients with type 2 diabetes mellitus. Most adverse events associated with miglitol involve disturbances of the gastrointestinal tract. This agent is a useful first-line therapy in patients with type 2 diabetes mellitus insufficiently controlled by diet alone and as second-line or as adjuvant therapy in those insufficiently controlled with diet and sulphonylurea agents. Miglitol may prove particularly beneficial in elderly patients and those with hepatic impairment or mild to moderate renal impairment, in whom other oral antidiabetic agents are contraindicated or need to be used with caution.

Ebastine: an update of its use in allergic disorders.

UNLABELLED: Ebastine is a second-generation antihistamine which undergoes transformation to its active metabolite, carebastine. Its antihistaminic and antiallergic effects have been demonstrated in in vitro and in vivo studies, in addition to data obtained from clinical trials. Patients with allergic rhinitis or chronic idiopathic urticaria experienced significant improvement in their symptoms with ebastine 10 or 20 mg once daily. Some studies in patients with seasonal allergic rhinitis (SAR) have indicated trends towards greater efficacy with the 20 mg than the 10 mg dose, although only 1 study has shown statistically significant benefits. In comparative trials in patients with SAR, ebastine 10 mg was as effective as most other second-generation antihistamines, including astemizole, azelastine, cetirizine, loratadine and terfenadine. Ebastine 20 mg/day was significantly superior to loratadine 10 mg/day in patients with SAR according to effects on secondary efficacy variables in comparative studies; 1 study found significantly greater changes from baseline in mean total symptom score with ebastine 20 mg (-43 vs -36% with loratadine, p = 0.045). In patients with perennial allergic rhinitis, ebastine 10 or 20 mg daily was significantly more effective than loratadine in reducing total symptom scores from baseline 1 comparative study. There have been no reports of serious adverse cardiac effects during ebastine therapy. Increases in corrected QT interval have been observed during clinical trials; however, these have not been considered clinically significant and were generally of similar magnitude to those seen with loratadine. The normal diurnal variation in QTc interval and the problems associated in correcting for changes in heart rate also complicate assessment of this issue. The incidence of adverse events during ebastine treatment is not significantly greater than that observed with placebo or other second-generation antihistamines. CONCLUSIONS: Ebastine 10 mg daily is a well tolerated and effective treatment for allergic rhinitis and chronic idiopathic urticaria. At this dosage, it is as effective as the other second-generation antihistamines against which it has been compared. Ebastine 20 mg has similar tolerability to the 10 mg dose, and trends towards greater efficacy with the higher dose have been shown in some studies. Ebastine does not appear to be associated with any significant cardiac adverse events. Ebastine is a useful treatment option for patients with allergic rhinitis or chronic idiopathic urticaria.

Bupropion: a review of its use in the management of smoking cessation.

UNLABELLED: Sustained release bupropion (amfebutamone) is a non-nicotine agent that is indicated as an aid to smoking cessation. In 2 large well designed clinical trials, sustained release bupropion 300 mg/day (the recommended dose) for 7 or 9 weeks was associated with considerably and significantly higher smoking abstinence rates (continuous abstinence and 7-day point prevalence rates) than placebo during treatment and at follow-up at 6 and 12 months. Point prevalence rates at 12 months in 2 studies were 23.1 and 30.3% with bupropion, whereas values for placebo were 12.4 and 15.6%. Continuous abstinence rates at 12 months, available from 1 trial, were 18.4% with bupropion and 5.6% with placebo. Furthermore, bupropion was associated with significantly higher quitting rates than nicotine patch in a comparative study. Combination therapy with bupropion and nicotine patch provided slightly higher abstinence rates than bupropion alone, although differences were not statistically significant. The combination was superior to nicotine patch alone. Data from a preliminary report of long term bupropion treatment (52 weeks) showed that the drug was associated with significantly higher continuous abstinence rates than placebo only to 6 months. However, point prevalence abstinence rates were significantly higher with bupropion than placebo to 18 months. Bupropion 300 mg/day recipients reported nicotine withdrawal symptoms during treatment; however, the symptoms were significantly less severe with bupropion than placebo. Patients receiving bupropion 300 mg/day or bupropion in combination with nicotine patch for smoking cessation generally gained less bodyweight than placebo recipients. The benefits of bupropion for preventing weight gain persisted after the completion of long term, but not short term therapy. Bupropion was well tolerated in clinical trials, and the only adverse events that were significantly more common with bupropion than placebo were insomnia and dry mouth. Data published so far suggest that sustained release bupropion has a low potential for inducing seizures (seizure rate approximately 0.1% in patients with depression). CONCLUSIONS: Bupropion is an effective and well tolerated smoking cessation intervention. Further studies with long term follow-up will be useful in determining whether abstinence rates are maintained with bupropion. In addition, clarification of its efficacy in comparison with other therapies used for smoking cessation would help to establish its clinical value. The reduced potential for weight gain with bupropion and the ability to use bupropion in combination with nicotine replacement therapy make the drug a useful treatment option for smoking cessation.

Levobupivacaine.

Levobupivacaine is an enantiomer of the long-acting local anaesthetic bupivacaine, which, although currently the most widely used agent in surgery and obstetrics, is associated with potentially fatal cardiotoxicity. Levobupivacaine 75 to 122 mg was less arrhythmogenic than the same dose range of bupivacaine in healthy volunteers. Its effects on the corrected QT interval were significantly weaker than those of bupivacaine, and it tended to have a weaker effect on QRS duration. The CNS depressant effect of intravenous levobupivacaine 40 mg was less than that of bupivacaine 40 mg in healthy volunteers, both in terms of the magnitude of the effect and the regions of the cortex affected. Clinical studies have demonstrated that epidural levobupivacaine produces a sensory and motor block clinically similar to that of bupivacaine in patients requiring anaesthesia during surgery. However, the duration of sensory block was significantly longer with levobupivacaine 0.75% than with levobupivacaine 0.5% or bupivacaine 0.5% or 0.75% in one study. Levobupivacaine 0.25% was as effective as bupivacaine 0.25% in women requiring epidural anaesthesia during labour with respect to time to onset of pain relief, overall quality of analgesia, extent of sensory blockade and number of patients reporting motor block. Levobupivacaine is as well tolerated as bupivacaine. In a clinical study involving 88 patients who received either drug, intraoperative hypotension was the most commonly reported adverse event with levobupivacaine and no serious arrhythmias occurred.

Milnacipran. A review of its use in depression.

UNLABELLED: Milnacipran is a cyclopropane derivative which acts by inhibiting noradrenaline (norepinephrine) and serotonin (5-hydroxytryptamine; 5-HT) reuptake at presynaptic sites; no postsynaptic receptor activity has been demonstrated. It is most commonly administered at a dosage of 50 mg twice daily for the treatment of major depressive disorder. Improvement usually occurs within 2 weeks of treatment initiation, but some patients do respond sooner. Most studies which evaluated milnacipran were of short (4 to 8 weeks) duration and results were not published in full with rigorous peer review. Nonetheless, the drug is significantly more effective than placebo for the treatment of in- or outpatients with moderate to severe major depressive disorder. Limited data suggest that it may prevent relapse and be effective for long term use, although this requires confirmation. Milnacipran 200 mg/day is generally not significantly different from amitriptyline 150 mg/day in terms of onset and efficacy. However, when doses are titrated (not a requirement for milnacipran), milnacipran 50 or 100 mg/day has a slower onset than the tricyclic antidepressant. At a dosage of 100 mg/day for 4 to 12 weeks, milnacipran generally has similar efficacy to imipramine and clomipramine 150 mg/day, although milnacipran 50 to 150 mg/day had a faster onset of activity than imipramine 50 to 150 mg/day in Japanese patients. In a 6-month trial, milnacipran was less effective than clomipramine. Milnacipran 50 or 100 mg twice daily was as effective as fluoxetine 20 mg once daily or fluvoxamine 100 mg twice daily in 4- to 12-week studies. At a dosage of 50 then 100 mg daily it was also as effective as mianserin 30 then 60 mg daily in a 4-week study. However, when administered once daily (in the evening), milnacipran 100 mg/day was not as effective as fluoxetine 20 mg/day after 6 weeks. The drug is generally well tolerated, producing no more adverse events (including anticholinergic events) than placebo, selective serotonin reuptake inhibitors or mianserin and fewer adverse events than tricyclic antidepressants in clinical trials. However, dysuria has been reported in 7% of male patients receiving milnacipran. CONCLUSIONS: Data from predominantly short term trials suggest that milnacipran generally has similar efficacy to tricyclic antidepressants and SSRIs. Although further published data are required to confirm its efficacy, good tolerability profile and pharmacokinetic profile which suggests a low potential for drug interactions, milnacipran should be considered a promising agent for the treatment of patients with major depressive disorder.