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Micafungin, an echinocandin antifungal agent with a novel mechanism of action, inhibits beta-(1,3)-D-glucan synthase interfering with fungal cell wall synthesis. It shows excellent antifungal activity against a broad range of Candida spp., including azole-resistant strains, and Aspergillus spp. in in vitro and animal studies. In HIV-positive patients, intravenous micafungin 50-150 mg/day dose-dependently eradicated endoscopically confirmed oesophageal candidiasis, with micafungin 100 and 150 mg/day being more effective than micafungin 50 mg/day and as effective as fluconazole 200 mg/day in a double-blind trial. In nonblind trials, micafungin (monotherapy or combination therapy) was effective against invasive aspergillosis, candidiasis and candidaemia in paediatric and adult patients with newly diagnosed or refractory infections. Micafungin 50 mg/day provided significantly better antifungal prophylaxis than fluconazole 400 mg/day in 882 haematopoietic stem cell transplant recipients in a randomised, double-blind trial. Respective overall success rates were 80% and 73.5%. Micafungin is generally well tolerated. Adverse events were not dose- or infusion-related with micafungin 12.5-900 mg/day; no histamine-like reactions occurred. Micafungin was as well tolerated as fluconazole, with numerically fewer micafungin recipients discontinuing treatment (4.2% vs 7.2%).

Memantine, an uncompetitive antagonist with moderate affinity for NMDA receptors, demonstrates voltage-dependency and relatively fast on/off receptor kinetics. Memantine 20 mg/day significantly slowed the rate of deterioration in outpatients with moderate to severe Alzheimer's disease in a 28-week US randomised, double-blind, placebo-controlled, multicentre study. Memantine 10 mg/day improved measures of dementia in care-dependent inpatients with Alzheimer's disease or vascular dementia in a 12-week randomised, double-blind study. Significantly more memantine than placebo recipients were responders according to Clinical Global Impression of Change scores and the Behavioural Rating Scale for Geriatric Patients Care Dependence subscale. Memantine 20 mg/day significantly improved cognition-related outcomes (cognitive subscale of the Alzheimer's Disease Assessment Scale) in patients with vascular dementia in two 28-week randomised, double-blind, placebo-controlled, multicentre trials. No statistically significant between-group difference was seen in other primary endpoints. Adverse events (incidence in memantine recipients greater than in placebo recipients) occurring in patients with moderately severe to severe dementia included diarrhoea, insomnia, dizziness, headache and hallucination.

Carvedilol (Dilatrend) blocks beta(1)-, beta(2)- and alpha(1)-adrenoceptors, and has antioxidant and antiproliferative effects. Carvedilol improved left ventricular ejection fraction (LVEF) in patients with chronic heart failure (CHF) in numerous studies. Moreover, significantly greater increases from baseline in LVEF were seen with carvedilol than with metoprolol in a double-blind, randomised study and in a meta-analysis. Carvedilol also reversed or attenuated left ventricular remodelling in patients with CHF and in those with left ventricular dysfunction after acute myocardial infarction (MI). Combined analysis of studies in the US Carvedilol Heart Failure Trials Program (patients had varying severities of CHF; n = 1094) revealed that mortality was significantly lower in carvedilol than in placebo recipients. In addition, the risk of hospitalisation for any cardiovascular cause was significantly lower with carvedilol than with placebo. Mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF in the Carvedilol Or Metoprolol European Trial (COMET) [n = 3029]. The Carvedilol Prospective Randomised Cumulative Survival (COPERNICUS) trial (n = 2289) demonstrated that compared with placebo, carvedilol was associated with significant reductions in all-cause mortality and the combined endpoint of death or hospitalisation for any reason in severe CHF. All-cause mortality was reduced in patients who received carvedilol in addition to conventional therapy compared with those who received placebo plus conventional therapy in the Carvedilol Post-Infarct Survival Control in LV Dysfunction (CAPRICORN) trial (enrolling 1959 patients with left ventricular dysfunction following acute MI). Carvedilol was generally well tolerated in patients with CHF. Adverse events associated with the alpha- and beta-blocking effects of the drug occurred more commonly with carvedilol than with placebo, whereas placebo recipients were more likely to experience worsening heart failure. In conclusion, carvedilol blocks beta(1)-, beta(2)- and alpha(1)-adrenoceptors and has a unique pharmacological profile. It is thought that additional properties of carvedilol (e.g. antioxidant and antiproliferative effects) contribute to its beneficial effects in CHF. Carvedilol improves ventricular function and reduces mortality and morbidity in patients with mild to severe CHF, and should be considered a standard treatment option in this setting. Administering carvedilol in addition to conventional therapy reduces mortality and attenuates myocardial remodelling in patients with left ventricular dysfunction following acute MI. Moreover, mortality was significantly lower with carvedilol than with metoprolol in patients with mild to severe CHF, suggesting that carvedilol may be the preferred beta-blocker.

Topical 3% diclofenac in 2.5% hyaluronic acid (HA) gel (diclofenac HA gel; Solaraze) is an NSAID approved for the treatment of actinic keratoses (AK). The efficacy of diclofenac HA gel (0.5g applied twice daily to each 5cm x 5cm treatment area) in patients with AK has been evaluated in three randomized, double-blind, HA gel vehicle-controlled trials. In each trial, efficacy was assessed 30 days after the end of treatment because an earlier study revealed that resolution of lesions was greater when measured after a 4 week interval, rather than at the end of treatment. In two fully published multicenter trials, there was no difference in baseline characteristics of the study groups. In a further single center study (not yet published), patients randomized to diclofenac HA gel had a significantly higher mean number of target lesions at baseline compared with HA gel vehicle. In the two published studies, the efficacy of diclofenac HA gel increased with increased treatment duration. When compared with HA gel vehicle recipients, significant improvements in total lesion number scores (TLNS), cumulative lesion number scores (CLNS), patient global improvement indices (PGII) and investigator global improvement indices (IGII) were obtained in patients treated for 60 and 90 but not 30 days with diclofenac HA gel. Fifty percent of patients treated for 90 days with diclofenac HA gel (vs 20% in HA gel vehicle recipients) and 33% of those treated for 60 days (vs 10%) had TLNS and CLNS of zero at the end of follow-up. In the third trial, in which treatment was applied for 90 days, there was no statistically significant difference in the proportion of patients with TLNS or CLNS of zero at the end of follow-up. However, when controlling for the significant difference in mean baseline target lesion scores by calculating the mean change from baseline in lesion counts, TLNS and CLNS were significantly lower in recipients of diclofenac HA gel than HA gel vehicle at the end of follow-up. Pruritus was the most frequently reported adverse event in all trials and the incidence was generally similar or lower in patients treated with diclofenac HA gel than HA gel vehicle. In conclusion, diclofenac HA gel produces significant reductions in the number of AK lesions, and can produce complete clearance of lesions when applied twice daily for 60 or 90 days. The product is well tolerated and did not produce serious adverse cosmetic effects in clinical trials. Thus, diclofenac HA gel represents a useful addition to the array of pharmacologic treatments available for AK.

One month after the last dose (i.e. at month 7), geometric mean titres (GMTs) of antibodies directed against hepatitis A virus (anti-HAV) were generally greater in participants (aged 12-15 years) receiving combined two-dose (0 and 6 months) hepatitis A and B vaccine (AmBirix) compared with the three-dose (containing one half the dose of the two active components per dose, given at 0, 1 and 6 months; Twinrix Paediatric) schedule. Moreover, at month 7 all patients had seroconverted to anti-HAV. GMTs of antibodies directed against hepatitis B surface antigen greatly exceeded the threshold for seroprotection (>/=10 mIU/mL) 1 month after the last dose of vaccine. Seroprotection rates against hepatitis B virus (HBV) were similar 1 month after completion of either a two- (97.9%) or three-dose (100%) vaccination schedule. At 24 months' follow-up, all patients tested remained positive for anti-HAV, and 93.3% and 96.2% of those treated with the two- and three-dose schedules, respectively, remained above the threshold for seroprotection against HBV. Administering the second dose in the two-dose series at 12 months rather than at 6 months did not compromise the immune response to the combined vaccine in adolescents aged 12-15 years in a randomised, multicentre trial. Local adverse events reported in the 4 days following administration of combined two-dose hepatitis A and B vaccine include pain or soreness, redness and swelling; systemic symptoms included headache, fatigue, gastrointestinal events and fever.

Travoprost is a synthetic ester prodrug of a prostaglandin F(2alpha) analogue used in the treatment of open-angle glaucoma and ocular hypertension. Intraocular travoprost 0.004% once daily was significantly more effective at reducing intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension than placebo or timolol 0.5% twice daily and was at least as effective as latanoprost 0.005% once daily in randomised, double-blind studies. When used as adjunctive therapy with timolol 0.5% twice daily in patients with elevated IOP not adequately controlled by timolol alone, travoprost 0.004% showed significant additional IOP reduction in a randomised double-blind trial. Travoprost 0.004% was well tolerated in clinical trials. The majority of adverse events such as ocular hyperaemia and eyelash changes were mild and resolved without treatment.

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, is a nonsteroid, has anti-inflammatory activity, and has demonstrated efficacy in reducing symptoms of atopic dermatitis in adult and pediatric patients when applied topically. Compared with vehicle, topical pimecrolimus 1.0% cream was significantly more effective at reducing symptoms of atopic dermatitis, as measured by the Eczema Area and Severity Index (EASI), in infants aged 3 to 23 months, children aged 2 to 17 years, and adults. The median reductions from baseline in the total EASI score in adults after treatment with pimecrolimus 1.0% or corresponding vehicle twice daily for 3 weeks were 47 and 0%, respectively. In infants and children, treatment with pimecrolimus 1.0% twice daily for 6 weeks resulted in significant decreases in mean EASI scores compared with vehicle. The severity of pruritus was significantly reduced in patients of all age groups after topical treatment with pimecrolimus 1.0% cream. Compared with vehicle, the incidence of eczematous flares was also reduced by intermittent long-term use of topical pimecrolimus 1.0% in adults, children and infants. Sixty-one percent of children treated with pimecrolimus for 1 year completed the first 6 months of treatment without experiencing a flare, compared with 35% of patients who received vehicle. Furthermore, the use of topical corticosteroids for the treatment of uncontrolled flares in adults, children and infants was lower in the pimecrolimus groups than in the vehicle groups. Topical pimecrolimus 1.0% cream is well tolerated in atopic dermatitis patients of all age groups. There were no clinically relevant systemic adverse events reported from any of the studies in patients with atopic dermatitis. The most frequently reported adverse events pertained to application site reactions, such as burning and a feeling of warmth. In conclusion, topical pimecrolimus 1.0% cream has shown efficacy in the treatment of mild to moderate atopic dermatitis in infants, children and adults. Although tolerability data concerning infants and children have not yet been published in full, the drug appears to be well tolerated in all age groups, and there have been no reports of clinically relevant systemic adverse events. Furthermore, pimecrolimus has shown no potential for skin atrophy, a problem commonly associated with treatment with topical corticosteroids. Topical pimecrolimus 1.0% provides a promising and well tolerated treatment option in the management of infants, children and adults with mild to moderate atopic dermatitis.

Unlabelled: The combination of candesartan cilexetil [an angiotensin II type 1 (AT(1)) receptor antagonist] plus hydrochlorothiazide (a thiazide diuretic), has been used in the treatment of patients with hypertension. The blood pressure (BP) lowering effect of various doses of this combination, administered orally once a day for 4 to 52 weeks, has been demonstrated in clinical trials. These studies showed that combinations of candesartan cilexetil 4 to 16 mg with hydrochlorothiazide 12.5 or 25 mg induced significant reductions reductions in systolic (S) BP and diastolic (D) BP from baseline in patients with mild to severe hypertension. Data from clinical trials indicated that reductions in BP induced by candesartan cilexetil 4 to 32 mg/hydrochlorothiazide 12.5 mg combinations were significantly greater than those observed after monotherapy with either drug. Treatment for 8 weeks with candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg or candesartan cilexetil 16 mg induced SBP/DBP reductions of 12.0/7.5 mm Hg and 7.5/5.5mm Hg, respectively (p < 0.05 both comparisons). Moreover, data from a randomised, double-blind, placebo-controlled, dose-finding study in 1038 patients with mild to moderate hypertension showed that the greatest reductions in SBP/DBP were achieved by candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg. Significant differences in BP reduction in favour of the combination were observed when hypertensive patients were given candesartan cilexetil 4 or 8 mg/hydrochlorothiazide 12.5 mg or hydrochlorothiazide monotherapy for 8 weeks. Additionally, greater efficacy of the combination compared to monotherapy with either drug was demonstrated by response rates to treatment. Moreover, a fixed combination of candesartan cilexetil 16 mg/hydrochlorothiazide 12.5 mg demonstrated a greater antihypertensive effect than losartan 50 mg/hydrochlorothiazide 12.5 mg in two clinical trials. Candesartan cilexetil 8 mg/hydrochlorothiazide 12.5 mg showed a similar antihypertensive effect compared with that of combined lisinopril 10 mg/hydrochlorothiazide 12.5 mg. Candesartan cilexetil/hydrochlorothiazide combination was well tolerated in patients with hypertension. Combined data from placebo-controlled trials showed that most adverse events were uncommon and not serious. Patients receiving combination therapy exhibited, among other adverse events, headache (3.2 vs 5.5% for candesartan cilexetil/hydrochlorothiazide and placebo, respectively), back pain (3.0 vs 2.4%), dizziness (2.6 vs 1.2%) and respiratory infection (2.5 vs 1.4%). Moreover, 3.3 and 2.7% of patients receiving candesartan cilexetil/hydrochlorothiazide or placebo, respectively, discontinued treatment because of adverse events., Conclusion: The combination of candesartan cilexetil and hydrochlorothiazide (AT(1)-receptor antagonist and thiazide diuretic, respectively) is an effective treatment for patients with hypertension. Data from randomised, double-blind, placebo-controlled clinical trials showed that this combination is significantly more efficacious than either agent alone. Moreover, the combination of these two agents showed an excellent adverse event profile. Current data support the use of this combination as an alternative when monotherapy with either agent is not effective, and there are no compelling or specific indications for other drugs. However, data from large clinical trials, evaluating morbidity and mortality outcomes, are needed to determine the precise role of candesartan cilexetil/hydrochlorothiazide combination in the treatment of patients with hypertension.

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, is a nonsteroid, has anti-inflammatory activity, and has demonstrated efficacy in reducing symptoms of atopic dermatitis in adult and paediatric patients when applied topically. Compared with vehicle, topical pimecrolimus 1.0% cream was significantly more effective at reducing symptoms of atopic dermatitis, as measured by the Eczema Area and Severity Index (EASI), in infants aged 3 to 23 months, children aged 2 to 17 years and adults. The median reductions from baseline in the total EASI score in adults after treatment with pimecrolimus 1.0% or corresponding vehicle twice daily for 3 weeks were 47 and 0%, respectively. In infants and children, treatment with pimecrolimus 1.0% twice daily for 6 weeks resulted in significant decreases in mean EASI scores compared with vehicle. The severity of pruritus was significantly reduced in patients of all age groups after topical treatment with pimecrolimus 1.0% cream. Compared with vehicle, the incidence of eczematous flares was also reduced by intermittent long-term use of topical pimecrolimus 1.0% in adults, children and infants. Sixty percent of children treated with pimecrolimus for 1 year completed the first 6 months of treatment without experiencing a flare, compared with 35% of patients who received vehicle. Furthermore, the use of topical corticosteroids for the treatment of uncontrolled flares in adults, children and infants was lower in the pimecrolimus groups than in the vehicle groups. Topical pimecrolimus 1.0% cream is well tolerated in atopic dermatitis patients of all age groups. There were no clinically relevant systemic adverse events reported from any of the studies in patients with atopic dermatitis. The most frequently reported adverse events pertained to application site reactions, such as burning and a feeling of warmth. In conclusion, topical pimecrolimus 1.0% cream has shown efficacy in the treatment of mild to moderate atopic dermatitis in infants, children and adults. Although tolerability data concerning infants and children have not yet been published in full, the drug appears to be well tolerated in all age groups, and there have been no reports of clinically relevant systemic adverse events. Furthermore, pimecrolimus 1.0% cream has shown no potential for skin atrophy, a problem commonly associated with treatment with topical corticosteroids. Pimecrolimus 1.0% cream provides a promising and well tolerated treatment option in the management of infants, children and adults with mild to moderate atopic dermatitis.

Etoricoxib is a cyclo-oxygenase (COX)-2-selective NSAID with a higher COX-1 to COX-2 selectivity ratio than the other COX-2-selective NSAIDs rofecoxib, valdecoxib or celecoxib. In patients with rheumatoid arthritis, improvements in tender and swollen joint counts and patient and investigator global assessment of disease activity were significantly greater in etoricoxib than in placebo recipients in two studies. Etoricoxib was also significantly more effective than naproxen in one of these studies. In patients with osteoarthritis of the hip or knee, etoricoxib was significantly more effective than placebo and had similar efficacy to naproxen with regards to improvements in pain and physical function scores and patient global assessment of disease status scores in two studies. Etoricoxib had similar efficacy to diclofenac in patients with osteoarthritis of the knee. Single-dose etoricoxib relieved pain in patients with postoperative dental pain in two studies. Similar scores assessing total pain relief over 8 hours (TOPAR8) were reported in etoricoxib and naproxen sodium or ibuprofen recipients, and higher TOPAR8 scores were reported with etoricoxib than with paracetamol (acetaminophen)/codeine. Pain relief was significantly better with etoricoxib than placebo in two studies in patients with chronic low back pain. Etoricoxib had similar efficacy to indomethacin in a study in patients with acute gout, and single-dose etoricoxib had similar efficacy to naproxen sodium in a study in women with primary dysmenorrhoea. Compared with non-COX-selective NSAIDs, etoricoxib was associated with significantly fewer upper gastrointestinal (GI) perforations, ulcers or bleeds, and was significantly less likely to result in treatment discontinuation because of NSAID-type GI symptoms or any GI symptoms.

Olmesartan medoxomil is a nonpeptide angiotensin II receptor antagonist which selectively and competitively inhibits the type 1 angiotensin II receptor without affecting other receptors regulating the cardiovascular system. In well designed randomised trials, olmesartan medoxomil was significantly more effective than placebo, and at dosages of 10 to 20 mg/day was at least as effective as atenolol 50 to 100 mg/day in reducing diastolic blood pressure (DBP). At dosages of 5 to 20 mg/day, olmesartan medoxomil was more effective than captopril 12.5 to 50mg twice daily at lowering seated DBP in patients with mild to moderate hypertension in a dose titration study. Reductions in seated DBP were greater with olmesartan medoxomil 10 to 20 mg/day than losartan 50 to 100 mg/day. Olmesartan medoxomil at 20 mg/day was more effective in lowering seated DBP than losartan 50 mg/day, valsartan 80 mg/day or irbesartan 150 mg/day, and was more efficacious than losartan 50 mg/day or valsartan 80 mg/day at reducing 24-hour ambulatory systolic blood pressure. Olmesartan medoxomil has shown no clinically important pharmacokinetic interactions with digoxin, warfarin or antacid (aluminium magnesium hydroxide). Adverse events were infrequent in clinical studies of olmesartan medoxomil and were similar to those attributed to placebo. With olmesartan medoxomil, the frequency of dizziness was higher than with placebo but similar to that occurring with losartan, valsartan and irbesartan.

The prodrug fenofibrate, a synthetic phenoxy-isobutyric acid derivative, is rapidly hydrolyzed in vivo to form fenofibric acid, which alters plasma lipid levels by activating the peroxisome proliferator-activated receptor alpha. The micronized fenofibrate 200 mg capsule formulation, and the recently developed micronized fenofibrate 160 mg tablet formulation, are bioequivalent. Micronized fenofibrate 200 mg/day (capsules) increased high density lipoprotein cholesterol (HDL-C) levels significantly from baseline in up to 7098 patients with various dyslipidemias in noncomparative studies. Micronized fenofibrate 200 mg/day (capsules) produced significantly greater elevations in HDL-C levels than a variety of HMG-CoA reductase inhibitors in small, randomized, double-blind and nonblind studies in patients with dyslipidemia (n = 91 to 227). This formulation of fenofibrate and gemfibrozil produced similar increases in HDL-C levels in a randomized, double-blind study (n = 234). Micronized fenofibrate 160 mg once daily (tablet) increased HDL-C levels significantly from baseline by 10.6 to 14.5% in patients with type IIa or IIb dyslipidemia (n = 353) in two noncomparative studies. Additionally, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and LDL-C to HDL-C and TC to HDL-C ratios were lowered significantly from baseline. The tablet and capsule formulations of fenofibrate were both generally well tolerated in two noncomparative studies in 375 or 9884 patients. In double-blind, placebo-controlled trials in a total of 804 patients, the pooled incidences of individual adverse events were generally similar with fenofibrate and placebo.

Unlabelled: Candesartan cilexetil is converted to the angiotensin II receptor antagonist candesartan during absorption from the gastrointestinal tract. The selective and competitive binding of candesartan to the angiotensin II type 1 (AT(1)) receptor prevents binding of angiotensin II, a key mediator in the renin-angiotensin system. Significant reductions in systolic BP and diastolic BP are achieved with a once-daily dosage of candesartan cilexetil 2 to 32 mg/day in patients with mild to moderate hypertension. In randomised studies, candesartan cilexetil 8 to 16 mg/day was at least as effective as therapeutic dosages of losartan or other angiotensin II receptor antagonists. At a dosage of up to 32 mg/day candesartan cilexetil demonstrated greater antihypertensive efficacy than losartan 50 or 100 mg/day. In comparative trials, candesartan cilexetil demonstrated similar or greater antihypertensive efficacy compared with enalapril or hydrochlorothiazide and equivalent efficacy compared with amlodipine. The efficacy of candesartan cilexetil is not affected by age, and the drug provided significant BP reductions in Black patients and in those with severe hypertension. Long-term clinical studies to assess the effects of treatment with candesartan cilexetil on cardiovascular morbidity and mortality are ongoing. Regression of left ventricular hypertrophy has been seen with candesartan cilexetil treatment in patients with hypertension. Furthermore, the drug has favourable effects on renal function in patients with hypertension with or without coexisting diabetes mellitus. Renal vascular resistance and albumin excretion were reduced following treatment with candesartan cilexetil. Glucose homeostasis and lipid metabolism were not affected by treatment in patients with type 2 diabetes mellitus. Candesartan cilexetil is well tolerated and is not associated with cough, a common adverse effect of angiotensin converting enzyme inhibitor treatment. A pooled analysis of clinical trials found that the tolerability profile of candesartan cilexetil is not significantly different from that of placebo. Adverse events are not dose-related and are generally of mild to moderate severity., Conclusions: Candesartan cilexetil is an effective antihypertensive agent with a tolerability profile similar to that of placebo. Comparative data indicate that candesartan cilexetil has antihypertensive efficacy equivalent to that of other major classes of antihypertensive agents and has a long duration of action. Therefore, candesartan cilexetil is a useful therapeutic option in the management of patients with hypertension.

Unlabelled: Tamsulosin is a selective alpha1A- and alpha1D-adrenoceptor antagonist. These alpha1-receptors are predominant in the prostate, prostatic capsule, prostatic urethra and bladder. The relaxation of prostate and bladder smooth muscles may result in improvement in maximum urine flow (Qmax) and reduction of lower urinary tract symptoms (LUTS). Tamsulosin 0.4 and 0.8 mg/day in a modified-release formulation was significantly more effective than placebo in large (n >250) double-blind, randomised, multicentre, 12- to 13- week clinical trials in patients with LUTS. A greater increase in Qmax from baseline was seen in patients receiving tamsulosin 0.4 or 0.8 mg/day (1.4 to 1.79 ml/sec from a baseline of 9.46 to 10.7 ml/sec) than in placebo recipients (0.4 to 0.93 ml/sec from a baseline of 9.75 to 10.4 ml/sec); the between-group difference was significant in two of three studies. Tamsulosin 0.4 or 0.8 mg/day improved total Boyarsky symptom scores from baseline by a significantly greater extent (by 3.0 to 5.2 points from a baseline of 9.5 to 11.1 points) than placebo (1.9 to 3.2 points from a baseline of 9.3 to 11.0 points). In noncomparative extension studies, the improvement in efficacy parameters with tamsulosin treatment was maintained for up to 4 years. Tamsulosin is effective in patients with mild to severe LUTS, patients with diabetes mellitus or those aged > or = 65 years and does not interfere with the antihypertensive action of nifedipine, enalapril or atenolol. Tamsulosin 0.4 mg/day for 12 weeks and tamsulosin 0.2 mg/day for 4 weeks were as effective as alfuzosin 2.5mg three times daily and terazosin 2 mg/day, respectively, in improving Qmax and symptom scores in randomised comparative trials. With the exception of a numberically greater incidence of abnormal ejaculation, dizziness and rhinitis, the incidence of adverse events with tamsulosin 0.4 mg/day was similar to that seen with placebo in randomised, double-blind studies. The overall incidence of symptoms indicative of orthostasis was 1.4% with tamsulosin 0.4 or 0.8 mg/day treatment. Tamsulosin had less effect on blood pressure than alfuzosin or terazosin., Conclusion: Tamsulosin, an alpha1-adrenoceptor antagonist, has a well established place in the treatment of LUTS and has a tolerability profile similar to that of placebo (apart from a higher incidence of abnormal ejaculation, dizziness and rhinitis). Comparative data have shown tamsulosin to be as effective as other alpha1-adrenoceptor antagonists at increasing Qmax and improving symptom scores. However, tamsulosin is unlikely to produce orthostatic hypotensive adverse effects or interfere with concomitant antihypertensive drug therapy. Therefore, tamsulosin is a useful therapeutic option in the management of patients with moderate to severe LUTS.

Unlabelled: Quinapril is rapidly de-esterified after absorption to quinaprilat (the active diacid metabolite), a potent angiotensin converting enzyme (ACE) inhibitor. Quinapril produces favourable haemodynamic changes, and improves ventricular and endothelial function in patients with various cardiovascular disorders; these effects are mediated through the binding of quinaprilat to both tissue and plasma ACE. Quinapril 10 to 40 mg/day provided effective blood pressure control in most patients with essential hypertension in clinical trials, but some patients required dosages of 80 mg/day and/or concomitant diuretic therapy. In general, quinapril provided similar blood pressure control to other standard antihypertensive therapies including other ACE inhibitors, calcium antagonists and beta-adrenoceptor antagonists in comparative clinical trials. Combined therapy with quinapril and hydrochlorothiazide had a significantly greater antihypertensive effect than either drug as monotherapy in two well designed studies. Quinapril has also been shown to reduce microalbuminuria in patients with hypertension and/or diabetes mellitus. In patients with congestive heart failure, quinapril

Rizatriptan is an orally active serotonin 5-HT(1) receptor agonist that potently and selectively binds to 5-HT(1B/1D) subtypes. Earlier clinical trials demonstrated that rizatriptan 5 or 10mg is more effective than placebo at providing pain relief and a pain-free state, relieving associated symptoms of migraine, normalising functional ability and improving patient quality of life, and showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recently, rizatriptan 10mg was shown to be more effective than zolmitriptan 2.5mg or naratriptan 2.5mg at producing a pain-free state 2 hours postdose. Furthermore, compared with naratriptan, significantly more patients who received rizatriptan were pain free or had pain relief from 1 hour onwards. The number of patients with normal functional ability at 2 hours was significantly higher after rizatriptan than after naratriptan or zolmitriptan. Rizatriptan was also generally more effective than zolmitriptan or naratriptan at relieving migraine-associated symptoms. Rizatriptan is generally well tolerated, and adverse events are usually mild and transient. The most common adverse events associated with rizatriptan in recent randomised trials were asthenia/fatigue, dizziness, somnolence and nausea. There was a trend towards a lower incidence of adverse events with rizatriptan compared with zolmitriptan (31.2 vs 38.8%). However, rizatriptan was associated with a significantly higher incidence of adverse events than naratriptan (39 vs 29%). The incidence of chest pain was similar after the administration of rizatriptan, zolmitriptan or naratriptan (2-4%). In conclusion, rizatriptan is an effective drug for the acute treatment of moderate or severe migraine. Oral rizatriptan 5 and 10mg have shown greater efficacy than placebo in providing pain relief, an absence of pain, relief from associated symptoms, normal functional ability and an improvement in patient quality of life. Earlier results showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recent studies have shown that rizatriptan 10mg provides faster pain relief and a higher percentage of patients with an absence of pain and normal functional ability at 2 hours than naratriptan 2.5mg or zolmitriptan 2.5mg. The efficacy of rizatriptan is retained when used in the long term, and the drug is generally well tolerated. Although well designed studies comparing rizatriptan with almotriptan, eletriptan and frovatriptan would further define the position of rizatriptan, current data suggest that rizatriptan should be considered as a first-line treatment option in the management of migraine.

Moxifloxacin is a fluoroquinolone antibacterial agent which attains good penetration into peripheral tissues and inflammatory fluids. The drug shows good in vitro activity against staphylococci and streptococci. Moxifloxacin is therefore a suitable option for the treatment of uncomplicated skin and skin structure infections of bacterial origin. In clinical trials, moxifloxacin was as effective as cephalexin in the treatment of uncomplicated skin and skin structure infections in patients aged >or=18 years. Moxifloxacin 400mg once daily or cephalexin 500mg three times daily for 7 days both resulted in clinical resolution in 84% of patients during a double-blind, randomised trial in 401 patients (intent-to-treat). The main infectious agent in this study was Staphylococcus aureus. Similar results were obtained in two other randomised, double-blind trials published as abstracts. The bioavailability of moxifloxacin is substantially reduced by coadministration with antacids or iron preparations. Moxifloxacin, however, does not show pharmacokinetic interaction with theophylline or warfarin. Dosage adjustments are not required in patients with renal impairment or in patients with mild to moderate hepatic insufficiency. The most common adverse events reported during moxifloxacin treatment are gastrointestinal disturbances. The potential for photosensitivity reactions during moxifloxacin treatment is low.

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

Rosuvastatin is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used in the treatment of patients with dyslipidaemia. Rosuvastatin is not extensively metabolised and has a low propensity for drug interactions. In well designed trials of between 6 and 52 weeks' duration, rosuvastatin was superior to atorvastatin, simvastatin and pravastatin in improving the lipid profile of patients with hypercholesterolaemia. In a 1-year dose-titration study, rosuvastatin 13.4mg daily (mean dose) allowed more patients to achieve US National Cholesterol Education Program (Adult Treatment panel II)[NCEP] target low-density lipoprotein (LDL)-cholesterol levels than atorvastatin 20.8mg daily (98 vs 87%) with the difference most marked in high-risk patients (97 vs 61%). Similarly, when compared with pravastatin and simvastatin 20 mg/day in a further 1-year trial, 88% of rosuvastatin recipients [9.5 and 13.8 mg/day (mean doses)] achieved NCEP target serum LDL-cholesterol levels compared with 60 and 73% of pravastatin and simvastatin recipients, respectively, with the difference more marked in high-risk patients. In further clinical trials, rosuvastatin improved the lipid profile of patients with heterozygous or homozygous familial hypercholesterolaemia, hypertriglyceridaemia or mixed dyslipidaemias. Rosuvastatin was well tolerated in clinical trials of up to 1 years' duration.

Unlabelled: Telmisartan is an angiotensin II receptor antagonist that is highly selective for type 1 angiotensin II receptors. It was significantly more effective than placebo in large (n >100), double-blind, randomised, multicentre clinical trials in patients with mild to moderate hypertension. Telmisartan 20 to 160 mg once daily produced mean reductions in supine trough systolic blood pressure and diastolic blood pressure of up to 15.5 and 10.5 mm Hg, respectively. Maximum blood pressure reduction occurred with a dosage of 40 to 80 mg/day. Telmisartan 40 to 120 mg/day was as effective as amlodipine 5 to 10 mg/day or atenolol 50 to 100 mg/day in dose-titration studies. Telmisartan 20 to 160 mg/day was generally similar in efficacy to enalapril 5 to 20 mg/day or lisinopril 10 to 40 mg/day in both titration-to-response and other studies. Hydrochlorothiazide was coadministered in most of the titration-to-response studies if patients remained hypertensive. Telmisartan 80 mg/day was more effective than submaximal dosages of losartan (50 mg/day) or valsartan (80 mg/day) and was as effective as a fixed-dose combination of losartan 50 mg plus hydrochlorothiazide 12.5 mg over the last 6 hours of the dosage interval and the whole 24-hour postdose interval. In patients with severe hypertension, telmisartan 80 to 160 mg/day was as effective as enalapril 20 to 40 mg/day (both agents could be titrated and combined sequentially with hydrochlorothiazide 25 mg and amlodipine 5 mg). The addition of hydrochlorothiazide to telmisartan was more effective than each agent alone at lowering blood pressure in patients with hypertension. Telmisartan was well tolerated in patients with mild to moderate hypertension and was significantly less likely to cause persistent, dry cough than lisinopril., Conclusion: Telmisartan is an effective antihypertensive agent with a tolerability profile similar to that of placebo. Comparative data have shown telmisartan to be as effective as other major classes of antihypertensive agents at lowering blood pressure. Compared with lisinopril, telmisartan is associated with a significantly lower incidence of dry, persistent cough. Therefore, telmisartan is a useful therapeutic option in the management of patients with hypertension.

Unlabelled: The mechanisms of action of silymarin involve different biochemical events, such as the stimulation of the synthetic rate of ribosomal RNA (rRNA) species through stimulation of polymerase I and rRNA transcription, protecting the cell membrane from radical-induced damage and blockage of the uptake of toxins such as alpha-amanitin. Studies in patients with liver disease have shown that silymarin increases superoxide dismutase (SOD) activity of lymphocytes and erythrocytes, as well as the expression of SOD in lymphocytes. Silymarin has also been shown to increase patient serum levels of glutathione and glutathione peroxidase. Silybin 20 to 48 mg/kg/day has shown promise as a clinical antidote to acute Amanita (deathcap mushroom) poisoning. Primary efficacy data from 3 trials which examined the therapeutic potential of silymarin in patients with cirrhosis, and included patient survival as an end-point, demonstrated that silymarin had no significant beneficial effect on patient mortality. However, upon subanalysis, silymarin 420 mg/day had a significantly beneficial effect on patient survival rate (compared with patients receiving placebo) in 1 randomised, double-blind trial in patients with alcoholic cirrhosis. Silymarin 420 mg/day was also shown to improve indices of liver function [AST, ALT, gamma-glutamyl transferase and bilirubin] in patients with liver disease of various aetiology, including those exposed to toxic levels of toluene or xylene; however, it was largely ineffective in patients with viral hepatitis. Reports of adverse events while receiving silymarin therapy are rare. However, there have been accounts of nausea, epigastric discomfort, arthralgia, pruritus, headache and urticaria. Silymarin has also been reported to have possibly caused a mild laxative effect., Conclusion: The antioxidant properties of silymarin (a mixture of at least 4 closely related flavonolignans, 60 to 70% of which is a mixture of 2 diastereomers of silybin) have been demonstrated in vitro and in animal and human studies. However, studies evaluating relevant health outcomes associated with these properties are lacking. Although silymarin has low oral absorption, oral dosages of 420 mg/day have shown some therapeutic potential, with good tolerability, in the treatment of alcoholic cirrhosis. Moreover, silybin 20 to 48 mg/kg/day has shown promise as an antidote for acute mushroom poisoning by Amanita phalloides; however, further studies paying attention to the amount of ingested mushroom and time elapsed before administration of treatment are needed to clarify its role in this indication. Studies in patients with the early onset of liver disease may demonstrate the liver regeneration properties that silymarin is promoted as possessing.

Clopidogrel is a selective inhibitor of ADP-induced platelet aggregation. A large, multicenter, randomized study in 12 562 patients with acute coronary syndromes without ST-segment elevation demonstrated that treatment with clopidogrel (loading dose of 300 mg followed by once daily treatment with 75 mg) in addition to standard therapy including aspirin (75 to 325 mg/day) significantly reduced the risk of the combined endpoint of cardiovascular death, myocardial infarction or stroke compared with treatment with standard therapy. Furthermore, the composite risk of these outcomes or refractory ischemia was also significantly reduced in patients treated with clopidogrel plus aspirin. The effects of clopidogrel were independent of background treatment with cardiovascular medications and/or interventions. The risk of severe ischemia, recurrent angina or heart failure was also significantly reduced in patients receiving clopidogrel plus aspirin. There was also a significant reduction in the need for coronary revascularization during the initial period of hospitalization. In patients undergoing percutaneous coronary intervention (PCI), the relative risk of the combined endpoint of cardiovascular death, myocardial infarction or urgent target-vessel revascularization within 30 days of the intervention was significantly reduced. Moreover, the relative risk of the single endpoint of myocardial infarction within 30 days of PCI was significantly in favor of clopidogrel-treated patients. Hemorrhagic events (both major and minor) were significantly more frequent in patients with acute coronary syndromes receiving treatment with clopidogrel plus aspirin than in patients treated with aspirin alone. This was largely attributable to an increased incidence in the rate of gastrointestinal hemorrhage and bleeding at the site of arterial puncture. However, there was no difference between the two groups in the incidence of bleeding episodes that were considered to be life-threatening.

Imatinib inhibits the BCR-ABL tyrosine kinase created by the Philadelphia chromosome (Ph+) in chronic myeloid leukaemia (CML). Complete haematological responses were achieved in 88% of patients and major cytogenetic responses were detected in 49% of patients with chronic phase CML treated with oral imatinib 400 mg/day in a multicentre noncomparative study of 532 patients. Administration of oral imatinib 400 or 600 mg/day to 235 patients with accelerated phase CML in a multicentre noncomparative study resulted in haematological responses in 63% of patients and major cytogenetic responses in 21% of patients. 26% of the 260 patients with blast crisis CML receiving imatinib 400 or 600 mg/day in a multicentre noncomparative trial sustained a haematological response and 13.5% of patients had a major cytogenetic response. Imatinib 400 or 600 mg/day orally achieved ahaematological response in 19 of 32 patients with Ph+ acute lymphoblastic leukaemia in a pilot study. Clinical improvement was demonstrated in 89% of 36 patients with gastrointestinal stromal tumours unresponsive to standard chemotherapy during treatment with 400 or 600 mg/day oral imatinib in a noncomparative phase II trial. Adverse events were frequent in clinical trials of imatinib but most events were mild or moderate in severity. Serious adverse events reported include severe fluid retention, cytopenias and hepatotoxicity.

Unlabelled: Tolterodine is a competitive muscarinic receptor antagonist that shows in vivo selectivity for the bladder over the salivary glands compared with oxybutinin. Results of randomised double-blind placebo-controlled studies indicate that tolterodine 4 mg/day (administered as immediate-release tablets 2mg twice daily or extended-release capsules 4mg daily) is superior to placebo in improving micturition diary variables in patients with overactive bladder. Moreover, tolterodine 2mg twice daily is as effective as oxybutynin 5mg 3 times daily. Maximum treatment effects with both drugs occurred after 5 to 8 weeks of treatment and improvements were maintained during long term treatment for up to 24 months. In a pooled analysis of four 12-week studies, equivalent and significant reductions in micturition frequency (-2.3 and -2.0 vs -1.4, p < 0.001) and the incidence of urge incontinence episodes (-1.6 and -1.8 vs -1.1, p < 0.05) were reported for tolterodine 2mg twice daily and oxybutynin 5mg 3 times daily compared with placebo. Functional bladder capacity was also significantly increased. Improvements in patient perceptions of their urgency symptoms and of problems caused by their bladder condition were significantly greater during treatment with tolterodine than with placebo. Tolterodine was generally well tolerated in clinical trials of up to 24 months' duration. Dry mouth was the most frequent adverse event. The incidence (40 vs 78%, p < 0.001) and intensity of this event was lower with tolterodine 2mg twice daily than oxybutynin 5mg 3 times daily. Additionally, a 23% lower incidence of dry mouth was reported with once daily extended-release tolterodine capsules than with twice daily immediate-release tablets (p < 0.02). The incidence of adverse CNS events with tolterodine was low and similar to that of placebo. Tolterodine was well tolerated in elderly patients and no serious tolerability concerns were identified., Conclusion: Tolterodine is the first antimuscarinic agent to specifically developed for the treatment of overactive bladder. The functional selectivity of tolterodine for the bladder translates into good efficacy and tolerability in patients, including the elderly, with overactive bladder. Tolterodine is as effective as oxybutynin in improving micturition diary variables but is associated with a significantly lower incidence and intensity of dry mouth. This favourable tolerability profile, together with sustained clinical efficacy during long term treatment, places tolterodine as valuable treatment for the symptoms of overactive bladder.

Repaglinide, a carbamoylmethyl benzoic acid derivative, is the first of a new class of oral antidiabetic agents designed to normalise postprandial glucose excursions in patients with type 2 diabetes mellitus. Like the sulphonylureas, repaglinide reduces blood glucose by stimulating insulin release from pancreatic beta-cells, but differs from these and other antidiabetic agents in its structure, binding profile, duration of action and mode of excretion. In clinical trials of up to 1-year's duration, repaglinide maintained or improved glycaemic control in patients with type 2 diabetes mellitus. In comparative, 1-year, double-blind, randomised trials (n = 256 to 544), patients receiving repaglinide (0.5 to 4mg before 3 daily meals) achieved similar glycaemic control to that in patients receiving glibenclamide (glyburide) < or = 15 mg/day and greater control than patients receiving glipizide < or = 15 mg/day. Changes from baseline in glycosylated haemoglobin and fasting blood glucose levels were similar between patients receiving repaglinide and glibenclamide in all studies; however, repaglinide was slightly better than glibenclamide in reducing postprandial blood glucose in I short term study (n = 192). Patients can vary their meal timetable with repaglinide: the glucose-lowering efficacy of repaglinide was similar for patients consuming 2, 3 or 4 meals a day. Repaglinide showed additive effects when used in combination with other oral antidiabetic agents including metformin, troglitazone, rosiglitazone and pioglitazone, and intermediate-acting insulin (NPH) given at bedtime. In 1-year trials, the most common adverse events reported in repaglinide recipients (n = 1,228) were hypoglycaemia (16%), upper respiratory tract infection (10%), rhinitis (7%), bronchitis (6%) and headache (9%). The overall incidence of hypoglycaemia was similar to that recorded in patients receiving glibenclamide, glipizide or gliclazide (n = 597) [18%]; however, the incidence of serious hypoglycaemia appears to be slightly higher in sulphonylurea recipients. Unlike glibenclamide, the risk of hypoglycaemia in patients receiving repaglinide was not increased when a meal was missed in 1 trial. In conclusion, repaglinide is a useful addition to the other currently available treatments for type 2 diabetes mellitus. Preprandial repaglinide has displayed antihyperglycaemic efficacy at least equal to that of various sulphonylureas and is associated with a reduced risk of serious hypoglycaemia. It is well tolerated in a wide range of patients, including the elderly, even if a meal is missed. Furthermore, glycaemic control is improved when repaglinide is used in combination with metformin. Thus, repaglinide should be considered for use in any patient with type 2 diabetes mellitus whose blood glucose cannot be controlled by diet or exercise alone, or as an adjunct in patients whose glucose levels are inadequately controlled on metformin alone.

Unlabelled: Reviparin (reviparin sodium) is a low molecular weight heparin (LMWH) that catalyses the inactivation of factors Xa and IIa by binding to antithrombin, which ultimately leads to the inhibition of the clotting cascade. It is administered subcutaneously. Reviparin 7,000 to 12,600 anti-XaIU/day was found to be as effective as intravenous unfractionated heparin in preventing the clinical recurrence of acute deep vein thrombosis (DVT) and/or pulmonary embolism in 1 large randomised, multicentre trial (COLUMBUS) and was significantly more effective than intravenous unfractionated heparin in the prevention of recurrent venous thromboembolism in another large randomised, multicentre trial (CORTES). Reviparin has also been compared with unfractionated heparin in children with established DVT. However, the trial was under-powered and no conclusion could be made regarding comparative efficacy. As prophylaxis, reviparin 1,750 anti-XaIU once daily was as effective as unfractionated heparin 5,000IU twice daily in 1,311 patients undergoing abdominal surgery and, in a once daily dosage of 4,200 anti-XaIU, was as effective as subcutaneous enoxaparin sodium 40 mg/day or acenocoumarol in patients undergoing hip replacement surgery. Reviparin 1,750 anti-XaIU also effectively prevented DVT. compared with no treatment, in patients undergoing knee arthroscopy. It was also more effective than placebo in patients with brace immobilisation of the lower extremity. Reviparin was compared with 'standard care' in children with central venous lines. However, the trial was too small to make conclusions regarding its efficacy. Comparative data indicate that reviparin is at least as well tolerated as heparin and enoxaparin sodium. However, in a large (n = 1,279) trial there were significantly fewer major bleeding episodes in patients receiving reviparin than in patients given the oral anticoagulant acenocoumarol. The most commonly reported adverse events in therapeutic trials have been intraoperative blood loss and postoperative bleeding complications such as wound haematoma, bruising and injection site haemorrhage. Reviparin was also well tolerated in 2 studies in children aged < or = 16 years., Conclusion: Reviparin has shown efficacy in the treatment of established DVT and in the prevention of postoperative DVT after moderate and high risk surgery and was as effective as enoxaparin sodium or acenocoumarol in patients undergoing hip replacement surgery. As an effective and well tolerated antithrombotic agent, reviparin is likely to assume a significant role in the treatment and prevention of DVT, as it appears to have a preferable tolerability profile to subcutaneous heparin after moderate risk surgery and is at least as effective as intravenous heparin in the treatment of established DVT.

Caspofungin is the first in a new class of antifungal agents, the glucan synthesis inhibitors, that interfere with fungal cell wall synthesis. Caspofungin exhibited in vitro and in vivo efficacy against a wide range of fungi and yeasts including Aspergillus and Candida species. A complete or partial response to caspofungin therapy was seen in 40.7% of immunocompromised adults with invasive aspergillosis who did not respond to, or did not tolerate, other antifungal agents in a noncomparative multicentre study. Caspofungin was effective in patients with oropharyngeal or oesophageal candidiasis, according to the preliminary results of 2 randomised double-blind trials. Caspofungin was generally well tolerated in a multicentre noncomparative trial involving patients with invasive aspergillosis. One or more drug-related clinical adverse effects were experienced by 13.8% of caspofungin recipients (the most common were fever, nausea, vomiting and complications associated with the vein into which caspofungin was infused). The tolerability of caspofungin appeared to be better than that of amphotericin B and similar to that of fluconazole in double-blind, randomised trials involving patients with mucosal candidiasis.

Unlabelled: Mometasone furoate is a corticosteroid with relatively high in vitro potency. Recent randomised, double-blind, multicentre trials have assessed the efficacy of mometasone furoate delivered by dry powder inhaler over 12 weeks in adults and adolescents with mild to severe persistent asthma. Mometasone furoate 200 microg twice daily or 400 microg once daily in the morning or 200 microg once daily in the evening improved lung function, asthma symptom scores and use of rescue medication to a significantly greater extent than placebo in patients who had previously received only short-acting inhaled beta2-adrenoceptor agonists alone as treatment in 3 trials (n = 195 to 306). In studies in 227 to 733 patients with mild to moderate asthma who were receiving ongoing treatment with inhaled corticosteroids prior to enrolment, mometasone furoate 100 to 400 microg twice daily was consistently better at improving the above indicators of asthma than placebo. Mometasone furoate 100 to 200 microg twice daily was as effective as beclomethasone dipropionate 200 microg twice daily or budesonide 400 microg twice daily and mometasone furoate 200 microg twice daily was as effective as fluticasone propionate 250 microg twice daily. Mometasone furoate 400 or 800 microg twice daily was also consistently more effective than placebo in reducing oral corticosteroid dosages and improving lung function and asthma symptoms in 132 patients with oral corticosteroid-dependent asthma. Once daily administration of mometasone furoate 400 microg appears to be as effective at improving indicators of asthma as twice daily administration of 200 microg. Patients receiving mometasone furoate < or =800 microg/day and recipients of placebo experienced a similar overall incidence of adverse events considered to be related to treatment. The most common of these events were oral candidiasis, headache, pharyngitis and dysphonia. Mometasone furoate 100 to 400 microg twice daily, beclomethasone dipropionate 200 microg twice daily, budesonide 400 microg twice daily or fluticasone propionate 250 microg twice daily were similarly tolerated., Conclusion: Inhaled mometasone furoate is well tolerated, with minimal systemic activity and is equally effective when administered as a divided dose or as a single daily dose. Use of the drug can result in a decrease in requirements for oral corticosteroids in patients with oral corticosteroid-dependent asthma and is as effective as other inhaled corticosteroids currently used in the treatment of mild to moderate persistent asthma. Thus mometasone furoate is suitable for the control of mild to severe persistent asthma in adults or adolescents.

Cetirizine is the carboxylated metabolite of hydroxyzine, and has high specific affinity for histamine H(1) receptors. Pseudoephedrine is a sympathomimetic drug that acts directly on alpha-adrenergic receptors. black triangle Cetirizine/pseudoephedrine 5/120 mg twice daily was significantly more effective than intranasal budesonide 100 microg or placebo at improving nasal obstruction, nasal patency and reducing the volume of nasal secretion, and was significantly more effective than intranasal xylometazoline 0.1% with respect to nasal secretion, during house dust mite faeces challenge in three randomised, cross- over studies among volunteers with seasonal or perennial rhinitis. The onset of action of cetirizine/pseudoephedrine was reported to be approximately 30 minutes. black triangle The bioavailability of cetirizine and pseudoephedrine is similar after administration of cetirizine/pseudoephedrine 5/120 mg bilayer tablets or coadministration of cetirizine 5 mg tablets plus pseudoephedrine sustained-release (SR) 120 mg caplets. black triangle Cetirizine 5mg plus pseudoephedrine SR 120 mg twice daily for 2 to 3 weeks was significantly more effective than each drug given alone at reducing mean total symptom scores for seasonal or perennial allergic rhinitis in two randomised, double-blind, multicentre trials. In both studies, the mean proportion of days during which the five measured symptoms (nasal obstruction, sneezing, rhinorrhoea, nasal pruritus and ocular pruritus) were absent or mild was significantly greater in recipients of the cetirizine plus pseudoephedrine SR. black triangle In one study, cetirizine 5 mg plus pseudoephedrine SR 120 mg was significantly more effective at reducing nasal obstruction than either drug alone. black triangle Cetirizine 5mg plus pseudoephedrine SR 120 mg twice daily for 2 to 3 weeks was well tolerated in patients with seasonal or perennial allergic rhinitis. The most common adverse events were dry mouth, insomnia, headache, somnolence, asthenia and nervousness.

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

Clobetasol propionate foam (clobetasol foam), a new formulation of the superpotent corticosteroid, has anti-inflammatory, antipruritic and vasoconstrictive properties. It was reported that the absorption rate of clobetasol was greater from the foam than from the solution in cadaver skin. In patients with moderate to severe scalp psoriasis, topical application of clobetasol 0.05% foam twice daily for 2 weeks induced significant improvement of all signs and symptoms of the disease compared with placebo. Compared with clobetasol 0.05% solution, clobetasol foam demonstrated greater improvement of scaling after 2 weeks of treatment and after 2 weeks of follow-up. The investigator's global assessment rated 74% of patients in the clobetasol foam group to be clear or almost clear (90 to 100%) of scalp psoriasis compared with 10% of the placebo foam group. Adverse events at the application site of clobetasol 0.05% foam were limited to one case each of dry skin, eczema, and skin hypertrophy. Clobetasol foam 7 g/day for 2 weeks induced reversible suppression of the hypothalamic-pituitary-adrenal axis in 3 out of 13 patients (methodology of assessment not provided).

Lansoprazole is an inhibitor of gastric acid secretion and also exhibits antibacterial activity against Helicobacter pylori in vitro. Current therapy for peptic ulcer disease focuses on the eradication of H. pylori infection with maintenance therapy indicated in those patients who are not cured of H. pylori and those with ulcers resistant to healing. Lansoprazole 30 mg combined with amoxicillin 1g, clarithromycin 250 or 500mg, or metronidazole 400 mg twice daily was associated with eradication rates ranging from 71 to 94%, and ulcer healing rates were generally >80% in well designed studies. In addition, it was as effective as omeprazole- or rabeprazole-based regimens which included these antimicrobial agents. Maintenance therapy with lansoprazole 30 mg/day was significantly more effective than either placebo or ranitidine in preventing ulcer relapse. Importantly, preliminary data suggest that lansoprazole-based eradication therapy is effective in children and the elderly. In the short-term treatment of patients with gastro-oesophageal reflux disease (GORD), lansoprazole 15, 30 or 60 mg/day was significantly more effective than placebo, ranitidine 300 mg/day or cisapride 40 mg/day and similar in efficacy to pantoprazole 40 mg/day in terms of healing of oesophagitis. Lansoprazole 30 mg/day, omeprazole 20 mg/day and pantoprazole 40 mg/day all provided similar symptom relief in these patients. In patients with healed oesophagitis. 12-month maintenance therapy with lansoprazole 15 or 30 mg/day prevented recurrence and was similar to or more effective than omeprazole 10 or 20 mg/day. Available data in patients with NSAID-related disorders or acid-related dyspepsia suggest that lansoprazole is effective in these patients in terms of the prevention of NSAID-related gastrointestinal complications, ulcer healing and symptom relief. Meta-analytic data and postmarketing surveillance in >30,000 patients indicate that lansoprazole is well tolerated both as monotherapy and in combination with antimicrobial agents. After lansoprazole monotherapy commonly reported adverse events included dose-dependent diarrhoea, nausea/vomiting, headache and abdominal pain. After short-term treatment in patients with peptic ulcer, GORD, dyspepsia and gastritis the incidence of adverse events associated with lansoprazole was generally < or = 5%. Similar adverse events were seen in long-term trials, although the incidence was generally higher (< or = 10%). When lansoprazole was administered in combination with amoxicillin, clarithromycin or metronidazole adverse events included diarrhoea, headache and taste disturbance. In conclusion, lansoprazole-based triple therapy is an effective treatment option for the eradication of H. pylori infection in patients with peptic ulcer disease. Preliminary data suggest it may have an important role in the management of this infection in children and the elderly. In the short-term management of GORD, lansoprazole monotherapy offers a more effective alternative to histamine H2-receptor antagonists and initial data indicate that it is an effective short-term treatment option in children and adolescents. In adults lansoprazole maintenance therapy is also an established treatment option for the long-term management of this chronic disease. Lansoprazole has a role in the treatment and prevention of NSAID-related ulcers and the treatment of acid-related dyspepsia; however, further studies are needed to confirm its place in these indications. Lansoprazole has emerged as a useful and well tolerated treatment option in the management of acid-related disorders.

Desloratadine is the orally active major metabolite of the nonsedating H1-antihistamine loratadine. The drug had no adverse cardiovascular effects in various animal models or when administered at 9 times the recommended adult dosage for 10 days in volunteers. Therapeutic dosages had no effects on wakefulness or psychomotor performance in healthy volunteers. No clinically significant interactions have been reported between desloratadine and drugs that inhibit the cytochrome P450 system, nor does the drug potentiate the adverse psychomotor effects of alcohol. Oral desloratadine 5 mg once daily for up to 4 weeks in patients with seasonal allergic rhinitis (SAR) significantly reduced nasal (including congestion) and non-nasal symptoms and improved health-related quality of life compared with placebo. Similar beneficial effects were observed in patients with SAR and coexisting asthma (in whom asthma symptoms and use of beta2-agonists were reduced). Desloratadine 5 mg once daily for 6 weeks significantly improved pruritus and reduced the number of hives compared with placebo in patients with chronic idiopathic urticaria (CIU). Sleep and daytime performance also improved. Desloratadine was well tolerated in clinical trials and had an adverse event profile similar to that of placebo in patients with SAR (with or without asthma) or CIU.

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

Methylphenidate is a CNS stimulant that is thought to block the reuptake of dopamine and noradrenaline (norepinephrine) into the presynaptic neuron. A sustained release (OROS formulation of the drug has been developed for use in children with attention deficit/hyperactivity disorder (ADHD). In children aged 6 to 12 years with ADHD, the maximum plasma concentration of OROS methylphenidate 18 to 54 mg was reached after approximately 7 to 8 hours. In adults, the plasma concentration-time profile of OROS methylphenidate differed markedly from that of the sustained release and immediate release (IR) methylphenidate formulations. In a clinical trial involving 282 children with ADHD, once daily OROS methylphenidate 18 to 54 mg was significantly more effective than placebo and demonstrated an effect similar to IR methylphenidate 5 to 15 mg 3 times daily in reducing the symptoms of ADHD. OROS methylphenidate demonstrated sustained efficacy in a 1-year noncomparative study involving children with ADHD. In clinical trials, the OROS formulation of methylphenidate had a tolerability profile similar to that of IR methylphenidate.

Unlabelled: Inhaled salmeterol is a long-acting, selective beta2-adrenoceptor agonist bronchodilator. The drug has been compared with placebo, ipratropium bromide and oral theophylline in patients with chronic obstructive pulmonary disease (COPD) in randomised, clinical trials. Inhaled salmeterol 50 microg twice daily produced significant improvement in forced expiratory volume in 1 second (FEV1), equivalent to that obtained with inhaled ipratropium bromide 40 microg 4 times daily and greater than that obtained with placebo or oral theophylline in randomised trials. Use of as-needed salbutamol (albuterol) was significantly reduced during treatment with inhaled salmeterol or ipratropium bromide compared with placebo or oral theophylline. The time to first COPD exacerbation was significantly longer during 12 weeks of treatment with inhaled salmeterol 50 microg twice daily than ipratropium bromide 40 microg 4 times daily. Compared with baseline and placebo, patients treated for 16 weeks with salmeterol 50 microg (but not 100 microg) twice daily reported significant improvement in total St George's Respiratory Questionnaire (SGRQ) scores. Similarly, more patients treated with inhaled salmeterol 50 microg twice daily or ipratropium bromide 40 microg 4 times daily experienced an increase of > or = 10 points in Chronic Respiratory Disease Questionnaire (CRQ) scores, the minimum clinically significant increment. Compared with placebo, inhaled salmeterol 50 microg twice daily alone, or concurrent with ipratropium bromide 40 microg 4 times daily improved lung function and reduced symptoms in patients with stable COPD in a 12-week, randomised, double-blind study. Clinically meaningful improvement in CRQ scores was documented in significantly more patients treated with the combination of the 2 drugs than either salmeterol monotherapy or placebo. Inhaled salmeterol 50 microg twice daily plus oral theophylline had additive effects on lung function, increased the proportion of symptom-free days and decreased requirements for as-needed salbutamol compared with either agent alone according to a pooled analysis of 2 multicentre, randomised, double-blind studies., Conclusion: When used at the optimal dosage, 50 microg twice daily, salmeterol provides symptomatic relief and improves lung function and health-related quality of life in patients with COPD. Available evidence suggests that the drug is as effective as ipratropium bromide and more effective than oral theophylline in patients with COPD. Moreover salmeterol has additive effects when used in combination with inhaled ipratropium bromide or oral theophylline. These qualities make the drug suitable for first-line use in patients with COPD who require regular bronchodilator therapy to manage symptoms.

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

Orlistat is a nonsystemically acting gastric and pancreatic lipase inhibitor that limits the absorption of dietary fat. A retrospective pooled analysis of three 2-year, double-blind, randomised, placebo-controlled trials involving patients with obesity revealed that orlistat recipients were more likely to experience an improvement, and less likely to experience a deterioration, in glucose tolerance status than placebo recipients. In comparison with placebo, orlistat recipients had significantly greater reductions in glycosylated haemoglobin and fasting plasma glucose levels in large, double-blind, randomised, placebo-controlled studies of 24 to 52 weeks' duration involving patients with obesity and type 2 diabetes mellitus. In one such study, the dosage of concomitant sulphonylureas was able to be reduced in more orlistat than placebo recipients (43.2 vs 28.9%), with discontinuation of sulphonylurea therapy achieved in 11.7% of orlistat recipients. The most common adverse effects reported in orlistat recipients with type 2 diabetes mellitus relate to the gastrointestinal system and are similar to those reported in studies involving patients without type 2 diabetes mellitus.

Current evidence suggests that the addition of the long acting inhaled beta2-agonist formoterol to low or moderate doses of the inhaled corticosteroid budesonide is effective in improving lung function and reducing the incidence of asthma exacerbations. Concurrent use of budesonide with formoterol does not result in any untoward interaction that affects the pharmacodynamic or pharmacokinetic profiles of the individual drugs, or their adverse effect profiles. The administration of combined budesonide/formoterol is effective in improving morning and evening peak expiratory flow rates in adults with persistent asthma. Control of asthma symptoms is also significantly improved. In children aged 4 to 17 years, combined budesonide/formoterol is effective in increasing both morning and evening peak expiratory flow rates and significantly improving forced expiratory volume in 1 second (FEV1). The most commonly encountered adverse effects in clinical trials with combination budesonide/formoterol therapy have been respiratory infection, pharyngitis and coughing. No adverse effects on pulse rate, blood pressure or serum potassium have been reported with combination therapy.

* Omalizumab is a recombinant humanised monoclonal antibody which specifically binds to the C epsilon3 domain of immunoglobulin (Ig) E, the site of high-affinity IgE receptor binding. * Improvements in asthma symptoms and health-related quality-of-life, and a significant reduction in the frequency of asthma exacerbations were seen in allergic asthmatic patients treated with omalizumab. * Omalizumab was also effective in the treatment of children with allergic asthma demonstrating improvements in health-related quality-of-life and significant dosage reductions of inhaled corticosteroids. * Administration of omalizumab to patients with allergic rhinitis resulted in a rapid dose-dependent suppression of serum free IgE levels. * Omalizumab significantly improved health-related quality-of-life and nasal symptoms in patients with seasonal allergic rhinitis. Antihistamine requirements were also significantly reduced following treatment. * Adverse events were infrequent in clinical trials of omalizumab, and not significantly different from placebo. The most frequent drug-related event was mild to moderate urticaria.

Unlabelled: The long-acting beta2-agonist salmeterol and the corticosteroid fluticasone propionate are available as a combination inhalation device for the treatment of persistent asthma. Well designed studies in adults, adolescents and children aged > or =4 years, demonstrate that combined salmetero/fluticasone propionate 50/100, 50/250 and 50/500 microg administered via a dry powder inhaler (DPI) is clinically equivalent to concurrent delivery of the same dosages of the 2 drugs via separate DPIs. In adults and adolescents, combined salmeterol/fluticasone 50/100 and 50/250 microg twice daily produced rapid improvements in lung function that were consistently greater than those in patients receiving monotherapy twice daily salmeterol 50 microg, fluticasone propionate 100 or 250 microg or placebo in 2 well designed studies. Recipients of the combination had a significantly greater probability of completing 12 weeks of treatment than patients receiving monotherapy or placebo. The combination also produced significant improvements between baseline and end-point in all secondary outcome variables (morning and evening peak expiratory flow, daytime symptom scores, days and nights without asthma symptoms and requirements for as-needed beta-agonists) and health-related quality of life (QOL). Combination therapy was superior to monotherapy with salmeterol and placebo for all outcomes in both studies, and was superior to fluticasone propionate 100 microg for all but 1 outcome (nights without awakenings) in 1 study. Similar results were obtained in patients who had previously been using short acting beta2-agonists alone. Combined twice daily salmeterolfluticasone propionate 50/100 and 50/250 microg produced greater improvements in lung function than inhaled budesonide at higher dosages than fluticasone propionate in the combination. Combined salmeterol/fluticasone propionate 50/250 microg produced similar improvements in lung function to concurrent budesonide 800 microg plus formoterol 12 microg when given twice daily for 12 weeks. In another 12-week trial, combined salmeterol/fluticasone propionate 50/100 microg was more effective than oral montelukast 10 mg/day plus fluticasone propionate 100 microg twice daily in patients with suboptimally controlled asthma. Salmeterol/fluticasone is more cost effective than monotherapy with fluticasone propionate or budesonide. The most frequent adverse events associated with salmeterol/fluticasone propionate are headache, throat irritation, hoarseness and candidiasis., Conclusion: Combined salmeterol/fluticasone propionate is as effective as the 2 drugs given concurrently via separate inhalers and significantly more effective than either drug given alone at the same nominal dosage. The combination is also significantly more effective than montelukast plus fluticasone propionate or monotherapy with inhaled budesonide. Furthermore, the combination is more cost effective than inhaled corticosteroid monotherapy.

Budesonide, a topically active corticosteroid, has a broad spectrum of clinically significant local anti-inflammatory effects in patients with inflammatory lung diseases including persistent asthma. In infants and young children with persistent asthma, day- and night-time symptom scores, and the number of days in which beta2-agonist bronchodilators were required, were significantly lower during randomised, double-blind treatment with budesonide inhalation suspension 0.5 to 2 mg/day than placebo in 3 multicentre trials. Significantly fewer children discontinued therapy with budesonide inhalation suspension than with placebo because of worsening asthma symptoms in a study that included children who were receiving inhaled corticosteroids at baseline. Recent evidence indicates that budesonide inhalation suspension is significantly more effective than nebulised sodium cromoglycate in improving control of asthma in young children with persistent asthma. At a dosage of 2 mg/day, budesonide inhalation suspension significantly reduced the number of asthma exacerbations and requirements for systemic corticosteroids in preschool children with severe persistent asthma. In children with acute asthma or wheezing, the preparation was as effective as, or more effective than oral prednisolone in improving symptoms. In children with croup, single 2 or 4mg dosages of budesonide inhalation suspension were significantly more effective than placebo and as effective as oral dexamethasone 0.6 mg/kg or nebulised L-epinephrine (adrenaline) 4mg in alleviating croup symptoms and preventing or reducing the duration of hospitalisation. Early initiation of therapy with budesonide inhalation suspension 1 mg/day appears to reduce the need for mechanical ventilation and decrease overall corticosteroid usage in preterm very low birthweight infants at risk for chronic lung disease. In adults with persistent asthma, budesonide inhalation suspension < or =8 mg/day has been compared with inhaled budesonide 1.6 mg/day and fluticasone propionate 2 mg/day administered by metered dose inhaler. Greater improvements in asthma control occurred in patients during treatment with budesonide inhalation suspension than with budesonide via metered dose inhaler, whereas fluticasone propionate produced greater increases in morning peak expiratory flow rates than nebulised budesonide. Several small studies suggest that the preparation has an oral corticosteroid-sparing effect in adults with persistent asthma and that it may be as effective as oral corticosteroids during acute exacerbations of asthma or chronic obstructive pulmonary disease. The frequency of adverse events was similar in children receiving budesonide inhalation suspension 0.25 to 2 mg/day or placebo in 12-week studies. During treatment with budesonide inhalation suspension 0.5 to 1 mg/day in 3 nonblind 52-week studies, growth velocity in children was generally unaffected; however, a small but statistically significant decrease in growth velocity was detected in children who were not using inhaled corticosteroids prior to the introduction of budesonide inhalation suspension. Hypothalamic-pituitary-adrenal axis function was not affected by short (12 weeks) or long (52 weeks) term treatment with nebulised budesonide. In conclusion, budesonide inhalation suspension is the most widely available nebulised corticosteroid, and in the US is the only inhaled corticosteroid indicated in children aged > or =1 year with persistent asthma. The preparation is suitable for use in infants, children and adults with persistent asthma and in infants and children with croup.

Unlabelled: Lercanidipine is a vasoselective dihydropyridine calcium antagonist which causes systemic vasodilation by blocking the influx of calcium ions through L-type calcium channels in cell membranes. It is a highly lipophilic drug and as such has a slower onset and longer duration of action than a number of other calcium antagonists. Preclinical evidence suggests that lercanidipine has antiatherogenic potential and it may also protect against end-organ damage. In well controlled clinical studies, once daily administration of lercanidipine 10 or 20mg effectively reduced blood pressure (BP) compared with placebo in patients with mild to moderate hypertension without affecting heart rate. Response rate (percentage of patients with diastolic BP < or =90mm Hg or reduced by > or =10mm Hg from baseline) ranged from 50 to 66% with lercanidipine 10 mg/day and up to 86% with lercanidipine 20 mg/day. The drug had a long duration of action: clinical measurements for diastolic BP yielded a trough/peak ratio of >0.8 for both lercanidipine dosages in 1 study. Comparative trials, either published in full or as abstracts, found lercanidipine 10mg once daily for > or =4 weeks to be at least as effective as atenolol 50mg once daily, candesartan cilexetil 16 mg/day, captopril 25mg twice daily, enalapril 20 mg/day, hydrochlorothiazide 12.5mg once daily, irbesartan 150 mg/day and slow release nifedipine 20mg twice daily in patients with mild to moderate hypertension. In addition, lercanidipine 20 mg/day was as effective as amlodipine 10 mg/day. Lercanidipine is effective in the treatment of elderly patients (aged 60 to 85 years) with mild to moderate essential hypertension and in those with isolated systolic hypertension. In addition, monotherapy with lercanidipine 20 or 40 mg/day has shown efficacy in patients with severe hypertension, and add-on therapy helped control BP in a large proportion of patients with severe hypertension not responding sufficiently to beta-blockers, diuretics or ACE inhibitors. Unpublished data indicate that the drug reduces blood pressure in patients with type 2 (non-insulin-dependent) diabetes mellitus, without adversely affecting glucose homeostasis. Lercanidipine was well tolerated in clinical trials, with most treatment-related adverse events typical of dihydropyridine calcium antagonists, namely headache, flushing, dizziness and ankle oedema., Conclusions: Lercanidipine is an effective and well tolerated once daily antihypertensive agent in patients with mild to moderate hypertension. In addition, the drug may reduce BP when used as monotherapy in patients with severe hypertension or when used adjunctively in patients with resistant hypertension. Importantly, lercanidipine appears to be at least as effective and well tolerated as other commonly used antihypertensive agents. The drug therefore represents a useful therapeutic option in the management of patients with hypertension and will be particularly useful in patients not responding to, or intolerant of, antihypertensive agents from other drug classes.

Unlabelled: Clopidogrel is an ADP receptor antagonist that is indicated for the reduction of atherosclerotic events including myocardial infarction, ischaemic stroke and vascular death in patients with atherosclerosis manifested by recent stroke, myocardial infarction or established peripheral vascular disease. In the 19 185 patients enrolled in the multicentre, randomised double-blind CAPRIE study, the annual risk of the combined end-point of ischaemic stroke, myocardial infarction and death from vascular disease (vascular death) was significantly lower during treatment with clopidogrel 75 mg/day than aspirin 325 mg/day [5.3 vs 5.8%/year, respectively; relative risk reduction (RRR) 8.7%, p = 0.043] after a mean follow-up of 1.9 years. Clopidogrel provided even greater reductions in the risk of recurrent ischaemic events than aspirin in patients with a history of coronary artery bypass surgery, diabetes mellitus and in those receiving concomitant lipid-lowering therapy. Moreover there was a significant reduction in the incidence of hospitalisation in patients treated with clopidogrel. In a patient population (Saskatchewan, Canada) with a greater risk of ischaemic events than the CAPRIE study population, the number of patients needed to be treated with clopidogrel to prevent 1 ischaemic event was estimated to be 70 (vs 200 in the CAPRIE study). In randomised trials and registry surveys, clopidogrel 75 mg/day plus aspirin had similar efficacy (as measured by adverse cardiac outcomes) to ticlopidine 250mg twice daily plus aspirin during the 30 days after placement of intracoronary stents. Tolerability of clopidogrel was significantly better than ticlopidine in the randomised, double-blind CLASSICS study. Among patients treated with clopidogrel or aspirin in the CAPRIE study, the overall gastrointestinal tolerability of clopidogrel was generally better than that of aspirin; the frequency of gastrointestinal haemorrhage was significantly lower among patients treated with clopidogrel than aspirin. Diarrhoea, rash and pruritus were significantly more common with clopidogrel than aspirin., Conclusion: Clopidogrel was significantly more effective than aspirin in the prevention of vascular events (ischaemic stroke, myocardial infarction or vascular death) [corrected] in patients with atherothrombotic disease manifested by recent myocardial infarction, recent ischaemic stroke or symptomatic peripheral arterial occlusive disease [corrected] in the CAPRIE study. The overall tolerability profile of the drug was similar to that of aspirin, although gastrointestinal haemorrhage occurred significantly less often in clopidogrel recipients. The drug is widely used in combination with aspirin for the prevention of atherothrombosis after placement of intravascular stents, and available data suggest that this combination is as effective as ticlopidine plus aspirin for this indication.

Unlabelled: Dalteparin is a low molecular weight heparin (LMWH) with a mean molecular weight of 5000. Compared with unfractionated heparin (UFH), the drug has markedly improved bioavailability and increased plasma elimination half-life, and exerts a greater inhibitory effect on plasma activity of coagulation factor Xa relative to its effects on other coagulation parameters. Dalteparin also has less lipolytic activity than UFH. Dalteparin 2500U once daily subcutaneously is of similar antithrombotic efficacy to UFH 5000IU twice daily, and 2 studies have shown superiority over UFH 2 or 3 times daily of dalteparin 5000U once daily in patients requiring surgical thromboprophylaxis. After total hip arthroplasty, dalteparin was superior to adjusted-dosage warfarin and was of greater thromboprophylactic efficacy when given for 35 than for 7 days. Intravenous or subcutaneous dalteparin is as effective as intravenous UFH when given once or twice daily in the initial management of established deep vein thrombosis (DVT). The drug is also effective in long term home treatment. Dalteparin has been shown to be effective in combination with aspirin in the management of unstable coronary artery disease (CAD), with composite end-point data from 1 study suggesting benefit for up to 3 months. Current data indicate potential of the drug in the management of acute myocardial infarction (MI). Dalteparin is also of similar efficacy to UFH, with a single bolus dose being sufficient in some patients, in the prevention of clotting in haemodialysis and haemofiltration circuits. Pharmacoeconomic data indicate that overall costs relative to UFH from a hospital perspective can be reduced through the use of dalteparin in patients receiving treatment for venous thromboembolism. Dalteparin has also been shown to be cost effective when used for surgical thromboprophylaxis. Overall, rates of haemorrhagic complications in patients receiving dalteparin are low and are similar to those seen with UFH., Conclusions: Dalteparin is effective and well tolerated when given subcutaneously once daily in the prophylaxis and treatment of thromboembolic disease. The simplicity of the administration regimens used and the lack of necessity for laboratory monitoring facilitate home or outpatient treatment and appear to translate into cost advantages from a hospital perspective over UFH or warfarin. Dalteparin also maintains the patency of haemodialysis and haemofiltration circuits, with beneficial effects on blood lipid profiles and the potential for prophylaxis with a single bolus injection in some patients. Data are also accumulating to show dalteparin to be an effective and easily administered alternative to UFH in patients with CAD.

Unlabelled: Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). The antidepressant efficacy of mirtazapine has been established in randomised, double-blind comparative studies. Mirtazapine has generally shown similar efficacy to other antidepressants. There is evidence for a faster onset of action with mirtazapine than with the selective serotonin (5-hydroxytryptamine; 5-HT) re-uptake inhibitors (SSRIs) on the basis of mean depression rating scale scores. Data from a long term (mean 240 days) clinical trial that was subsequently used in pharmacoeconomic analyses showed that mirtazapine was associated with significantly higher sustained remission rates and rates of discontinuation because of improvement than amitriptyline and placebo. Although differences were not statistically significant, mirtazapine had higher response rates at 6 weeks than the SSRI fluoxetine in an analysis that was also used as the basis of pharmacoeconomic studies. Mirtazapine improved quality of life to a similar extent to fluoxetine, citalopram and paroxetine in unpublished studies of 6 and 8 weeks' duration. Pooled analyses suggest that mirtazapine may be associated with greater improvement than fluoxetine and citalopram in quality of life after 2 and 4 weeks, although confirmation is required. In a decision analytical model of approximately 6 months' duration, mirtazapine was associated with a higher proportion of successfully treated patients and lower total direct costs than amitriptyline. The direct cost per successfully treated patient with mirtazapine was lower than that with amitriptyline by 33,112 Austrian schillings (S; year of costing not stated), 24,212 French francs (FF; 1995/1996 values), 13,851 Swedish kronor (SEK; 1997 values) and 553 Pounds (1997/1998 values) in Austrian, French, Swedish and UK analyses, respectively. Compared with fluoxetine, mirtazapine was associated with higher per-patient costs in all 4 countries but a higher proportion of successfully treated patients. Mirtazapine was more cost effective than fluoxetine: the direct cost per successfully treated patient was lower by S32,046 in Austria, FF25,914 in France, SEK9796 in Sweden and 327 Pounds in the UK. The additional cost of mirtazapine versus fluoxetine for each additional successfully treated patient at 6 months was S11,732, SEK17,229, 750 Pounds and FF3342 in the Austrian, Swedish, UK and French analyses, respectively. Mirtazapine was generally associated with lower indirect costs (for lost productivity of employed patients) than amitriptyline and similar indirect costs to fluoxetine in the analyses., Conclusions: Available data suggest that mirtazapine is a cost-effective alternative to amitriptyline and fluoxetine for the treatment of depression. Mirtazapine also has similar effects to SSRIs on quality of life with possibly a shorter time to onset of action, although published trial results are required to confirm these preliminary data.

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

Unlabelled: The ACE inhibitor lisinopril is a lysine derivative of enalaprilat, the active metabolite of enalapril. In patients with heart failure, maximum pharmacodynamic effects are produced 6 to 8 hours after administration of the drug and persist for 12 to 24 hours. High doses (32.5 to 35mg, administered once daily) of lisinopril in the Assessment of Treatment with Lisinopril and Survival (ATLAS) study demonstrated clinically important advantages over low doses (2.5 to 5mg, administered once daily) of the drug in the treatment of congestive heart failure. High doses of lisinopril were more effective than low doses in reducing the risk of major clinical events in patients with heart failure treated for 39 to 58 months. Compared with recipients of low doses, those receiving high doses of lisinopril had an 8% lower risk of all-cause mortality (p = 0.128), a 12% lower risk of death or hospitalisation for any reason (p = 0.002) and 24% fewer hospitalisations for heart failure (p = 0.002). These benefits were associated with significant cost savings. In short term (generally 12 weeks' duration) randomised, double-blind, parallel-group, multicentre clinical trials, lisinopril was significantly more effective than placebo and was at least as effective as captopril, enalapril, digoxin and irbesartan at improving symptomatic end-points and clinical status in patients with heart failure. Lisinopril is generally well tolerated by patients with heart failure. In controlled clinical trials, the most common adverse events occurring in recipients of the drug were dizziness, headache, hypotension and diarrhoea. Overall adverse event profiles for patients treated with high or low doses of lisinopril in the ATLAS study were similar. However, high doses of lisinopril used in the ATLAS study were associated with a higher incidence of adverse events, importantly hypotension and worsening renal function; nevertheless, these events were generally well managed by altering the dose of lisinopril or concomitant medications. Furthermore, despite the higher incidence of some adverse events with high doses of lisinopril, the frequency of treatment discontinuations because of adverse events was the same in the high and low dose groups., Conclusions: Lisinopril (when added to diuretics and/or digoxin) provides symptomatic benefits in patients with congestive heart failure. The ATLAS study demonstrated that high doses of lisinopril significantly reduced the risk of the combined end-point of morbidity and mortality compared with low doses of the drug. Importantly, there was no clinically significant decrease in the tolerability of the drug with use of a high dose. Lisinopril is at least as effective and as well tolerated as other members of the ACE inhibitor class for the treatment of congestive heart failure.

Unlabelled: Iomeprol is a nonionic, monomeric iodinated contrast medium. Unlike the older ionic agents, iomeprol has low chemotoxicity, osmolality and viscosity and high water solubility. Compared with other nonionic contrast media, the osmolality and viscosity are lower and the water solubility is reported to be higher with iomeprol. Most radiographs (about 67 to 100%) obtained with iomeprol (containing 150 to 400 mg/ml of iodine) were of good or excellent quality in noncomparative and comparative trials recruiting 40 to 6127 patients undergoing various radiographic procedures. As expected, the diagnostic efficacy of iomeprol did not differ significantly from that of other nonionic agents (iopamidol, iopromide, iohexol and iotrolan). Iomeprol (containing 150 to 400 mg/ml of iodine) was well tolerated in clinical trials. Most adverse events were transient and of mild to moderate intensity and were similar to those observed with other contrast media. The overall incidence of adverse events ranged from 3 to 49.7% and mainly included localised pain (< or =6%) and heat sensations (8 to 45%), taste disturbances (3 to 27%) and various pseudoallergic reactions (< or =20% for each type of event). The incidence of heat or pain and taste disturbances with iomeprol was similar to that observed with iopromide and iopamidol. Pain (but not heat sensations) was reported significantly less frequently and taste disturbances reported significantly more frequently with iomeprol than with iohexol in a comparative trial. Pseudoallergic reactions (such as nausea, vomiting, skin reactions, dizziness, headache) were significantly less common with iomeprol than with ioxaglate and occurred at a similar frequency to that with iopromide and iopamidol. Cardiovascular events were rarely observed with iomeprol. Currently available iomeprol solutions contain a range of iodine concentrations (150 to 400 mg/ml) and are approved for a wide variety of diagnostic procedures. Iomeprol solutions are chemically stable which negates the need for chelating agents. Formulations of this agent are therefore the first not to contain edetic acid (EDTA)., Conclusions: Iomeprol shows equivalent diagnostic efficacy, and a similar adverse event profile, to that of other nonionic contrast media. The availability of a range of iodine concentrations enables iomeprol to be used in a variety of diagnostic procedures. Iomeprol, like others in its class, is suitable for use in diagnostic imaging.

Montelukast is a cysteinyl leukotriene receptor antagonist used to treat persistent asthma in patients aged > or = 6 years. The drug has a rapid onset of action. Improvements in lung function and reductions in as-needed beta2-agonist usage are apparent within 1 day of initiating montelukast treatment in adults and adolescents (aged > or = 15 years treated with 10 mg/day) or children (aged 6 to 14 years treated with 5 mg/day) with persistent asthma as shown in clinical trials. In two 12-week, multicentre, randomised, double-blind studies in adults and adolescents aged > or = 15 years with persistent asthma [forced expiratory volume in 1 second (FEV1) = 50 to 85% predicted] there was significantly (p < 0.05) greater improvement in FEV1, symptom scores, peak expiratory flow (PEF), as-needed beta2-agonist use, peripheral eosinophil counts and health-related quality of life (QOL) in patients treated with montelukast 10 mg/day than in recipients of placebo. Improvements were significantly greater in patients treated with inhaled beclomethasone 400 microg/day than in recipients of montelukast 10 mg/day in 1 of these studies. Nonetheless, 42% of montelukast recipients experienced > or = 11% improvement in FEV1, the median improvement in this parameter in beclomethasone-treated patients. In an 8-week multicentre, randomised, double-blind, study in children aged 6 to 14 years with persistent asthma (FEV1 50 to 85% predicted), montelukast 5 mg/day produced significantly greater improvements in FEV1, clinic PEF, as-needed beta2-agonist use, peripheral eosinophil counts, asthma exacerbations and QOL scores than placebo. The combination of montelukast 10 mg/day plus inhaled beclomethasone 200 microg twice daily provided significantly better asthma control than inhaled beclomethasone 200 microg twice daily in adults with poorly controlled asthma (mean FEV1 = 72% predicted) despite 4 weeks treatment with inhaled beclomethasone. Patients receiving the combination experienced significant improvements in FEV1 and morning PEF, significant reductions in daytime symptom scores, as-needed beta2 agonist usage and night-time awakenings with asthma, and had significantly lower peripheral blood eosinophil counts after 16 weeks in this multicentre, randomised, double-blind, placebo-controlled study. Among adults (FEV1 > or = 70%) treated with montelukast 10 mg/day for 12 weeks, inhaled corticosteroid dosages were titrated downward by 47% (vs 30% in placebo recipients), 40% of patients were tapered off of inhaled corticosteroids (vs 29%), and significantly fewer patients (16 vs 30%) experienced failed corticosteroid rescues in a multicentre, randomised, double-blind study. During clinical studies, the frequency of adverse events in montelukast-treated adults, adolescents and children was similar to that in placebo recipients. In conclusion, montelukast is well tolerated and effective in adults and children aged > or = 6 years with persistent asthma including those with exercise-induced bronchoconstriction and/or aspirin sensitivity. Furthermore, montelukast has glucocorticoid sparing properties. Hence, montelukast, as monotherapy in patients with mild persistent asthma, or as an adjunct to inhaled corticosteroids is useful across a broad spectrum of patients with persistent asthma.