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

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

Spotlight on bicalutamide 150mg in the treatment of locally advanced prostate cancer.

Bicalutamide (Casodex) is a competitive androgen receptor antagonist that inactivates androgen-regulated prostate cell growth and function, leading to cell apoptosis and inhibition of prostate cancer growth. It is administered orally as a once-daily dose. In the EU and a number of other countries, bicalutamide 150 mg/day is approved in men with locally advanced nonmetastatic prostate cancer as immediate therapy either as an adjuvant to active treatment or as monotherapy as an alternative to surgical or medical castration. Combined analysis of the three trials that comprise the bicalutamide Early Prostate Cancer programme showed that bicalutamide administered in conjunction with standard care in men with locally advanced prostate cancer offers disease-free survival benefits over standard care alone and is generally well tolerated. Overall survival was improved to a greater extent in the subgroup of patients who received bicalutamide plus radiation therapy compared with radiation therapy alone. Men with localised prostate cancer do not benefit from the addition of bicalutamide to standard care. Combined analysis of two other studies in men with locally advanced prostate cancer show that bicalutamide monotherapy offers better tolerability and higher health-related quality-of-life scores for sexual interest and physical capacity compared with surgical or medical castration, while achieving disease-free and overall survival durations that were not significantly different. Thus, when treatment options are being evaluated, bicalutamide as adjuvant therapy or monotherapy should be considered as an alternative to other available hormonal therapies in men with locally advanced prostate cancer, especially in those who wish to maintain an active lifestyle.

Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer.

Bicalutamide (Casodex) is a competitive androgen receptor antagonist that inactivates androgen-regulated prostate cell growth and function, leading to cell apoptosis and inhibition of prostate cancer growth. It is administered orally as a once-daily dose. In the EU and a number of other countries, bicalutamide 150 mg/day is approved in men with locally advanced nonmetastatic prostate cancer as immediate therapy either as an adjuvant to active treatment or as monotherapy as an alternative to surgical or medical castration. Combined analysis of the three trials that comprise the bicalutamide Early Prostate Cancer (EPC) programme showed that bicalutamide administered in conjunction with standard care in men with locally advanced prostate cancer offers disease-free survival benefits over standard care alone and is generally well tolerated. Overall survival was improved to a greater extent in the subgroup of patients who received bicalutamide plus radiation therapy compared with radiation therapy alone. Men with localised prostate cancer do not benefit from the addition of bicalutamide to standard care. Combined analysis of two other studies in men with locally advanced prostate cancer show that bicalutamide monotherapy offers better tolerability and higher health-related quality-of-life (HR-QOL) scores for sexual interest and physical capacity compared with surgical or medical castration, while achieving disease-free and overall survival durations that were not significantly different. Thus, when treatment options are being evaluated, bicalutamide as adjuvant therapy or monotherapy should be considered as an alternative to other available hormonal therapies in men with locally advanced prostate cancer, especially in those who wish to maintain an active lifestyle.

Insulin glulisine.

Insulin glulisine is a rapid-acting human insulin analogue that has a faster onset of action and shorter duration of action than regular human insulin (RHI) in patients with type 1 or 2 diabetes mellitus and is efficacious in controlling prandial blood glucose levels in these patients. In large, well designed trials in patients with type 1 diabetes, insulin glulisine demonstrated a similar degree of glycaemic control, as measured by glycosylated haemoglobin (HbA(1c)) levels, to RHI after 12 weeks and insulin lispro after 26 weeks. Pre-meal insulin glulisine was also more effective than RHI at controlling 2-hour post-prandial glucose excursions in patients with type 1 or 2 diabetes over a period of 12 weeks. In patients with type 2 diabetes, insulin glulisine induced significantly greater reductions in HbA(1c) levels and 2-hour post-breakfast and post-dinner blood glucose levels than RHI over a period of 26 weeks. Insulin glulisine was generally well tolerated by patients with type 1 or 2 diabetes and had a similar safety profile to insulin lispro or RHI. Severe hypoglycaemia was experienced by similar proportions of insulin glulisine or comparator insulin (insulin lispro or RHI) recipients with type 1 or type 2 diabetes.

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

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

0.4% nitroglycerin ointment : in the treatment of chronic anal fissure pain.

0.4% Nitroglycerin ointment is an intra-anal formulation of nitroglycerin (glyceryl trinitrate) indicated for the treatment of chronic anal fissure pain.black triangle Nitroglycerin is a nitric oxide (NO) donor, which reduces the increased anal canal pressure caused by a hypertonic internal anal sphincter, improving anodermal blood flow. A twice-daily 375 mg application of 0.4% nitroglycerin ointment, delivering a daily nitroglycerin dose of 3mg, significantly increased the rate of decrease in mean visual-analogue-scale pain scores, recorded daily, versus placebo (actual vehicle) over the first 3 and 8 weeks of treatment in patients with chronic anal fissure pain participating in randomised double-blind trials. Most recipients of 0.4% nitroglycerin ointment experienced headache, which was transient but severe in 20-25% of patients in randomised double-blind trials; however, compliance was generally good with few study withdrawals. Features and properties of 0.4% nitroglycerin (Rectogesic) rectal ointment Indication Pain associated with chronic anal fissures Mechanism of action Donor of nitric oxide Mediates relaxation of internal anal sphincter Dosage and administration Dosage 375 mg of 0.4% nitroglycerin rectal ointment, delivering nitroglycerin 1.5 mg Frequency Twice daily Route of administration Intra-anal Pharmacokinetic profile Mean bioavailability (0.2% nitroglycerin ointment, 0.75 mg nitroglycerin dose)50%Maximum plasma concentration 0.1 to >1 microg/L Volume of distribution approximate, equals 3 L/kg Clearance approximate, equals 1 L/kg/min Elimination half-life approximate, equals 3 min Most common adverse event Headache.

Indapamide sustained release: a review of its use in the treatment of hypertension.

A low-dose sustained-release (SR) formulation of the thiazide-type diuretic indapamide, indapamide SR (Natrilix SR), retains the antihypertensive activity of the immediate-release (IR) formulation, with a smoother pharmacokinetic profile. In well controlled 12- to 52-week clinical trials, indapamide SR 1.5 mg/day was well tolerated and reduced blood pressure as effectively as therapeutic dosages of amlodipine, candesartan, enalapril, hydrochlorothiazide or indapamide IR. Indapamide SR was also more effective than enalapril in reducing left ventricular hypertrophy (LVH), and similar reductions in renal end-organ damage, assessed by microalbuminuria, were seen with indapamide SR- and enalapril-based antihypertensive strategies. Indapamide SR provides an effective option for initial antihypertensive monotherapy and a basis for multidrug antihypertensive strategies.

Ramelteon.

Ramelteon, approved in the US for the treatment of insomnia characterised by difficulty with sleep onset, is a highly selective agonist for the melatonin MT1/MT2 receptors, which are believed to mediate the circadian rhythm in mammals. Ramelteon has negligible affinity for the MT3 binding sites and other receptors in the brain, including the opiate, dopamine, benzodiazepine and serotonin receptors, which may explain the lack of significant adverse events and lack of abuse or dependence potential observed with ramelteon. In three clinical trials in patients with chronic insomnia, ramelteon 8mg was effective in reducing sleep latency, without being associated with any significant or clinically relevant residual effects. It also generally increased total sleep time and, where assessed, sleep efficiency. In a first-night-effect model of transient insomnia, ramelteon 8mg was significantly more effective than placebo at reducing sleep latency and increasing total sleep time. Ramelteon was generally well tolerated; the most commonly reported adverse events occurring in more ramelteon than placebo recipients were somnolence (5% vs 3%), fatigue (4% vs 2%) and dizziness (5% vs 3%). Adverse events were mostly mild or moderate in nature. Ramelteon has been shown to have no potential for abuse or dependence.

Naftidrofuryl: a review of its use in the treatment of intermittent claudication.

Naftidrofuryl (Praxilene) is a vasodilator that has been used in the treatment of intermittent claudication for >30 years in Europe to improve walking distance and provide symptomatic relief. However, earlier trials had inconsistencies in design and the clinical relevance of the treatment effect has been controversial. Recent randomised, double-blind, placebo-controlled trials, however, have generally been conducted in accordance with updated methodology guidelines. In these studies, naftidrofuryl 200mg three times daily improved pain-free and maximal walking distances and health-related quality of life by a significantly greater extent than placebo in patients with intermittent claudication. The magnitude of these effects appears to support claims that the effects of naftidrofuryl are clinically relevant in these patients.

Rotigotine: in Parkinson's disease.

Rotigotine is a nonergolinic dopamine D3/D2/D1 receptor agonist delivered via a transdermal system and has been evaluated for the treatment of idiopathic Parkinson's disease. Patients with early Parkinson's disease receiving rotigotine monotherapy experienced significantly greater improvements in parkinsonian symptoms (as measured by Unified Parkinson's Disease Rating Scale scores) compared to placebo in two large, well designed clinical trials. Significant beneficial effects versus placebo were observed with the 30 and 40 cm2 rotigotine patches in both trials.black triangle Patients with advanced Parkinson's disease receiving rotigotine as adjunctive therapy with levodopa experienced clinically significant reductions from baseline in 'off' time in two well designed clinical trials. In one trial, a large placebo effect was observed, therefore, there was no significant difference between placebo and active treatment (20, 40 and 60 cm2) for this primary efficacy variable, However, a recent study found a significant (p < or = 0.003) reduction in 'off' time in rotigotine 40 and 60 cm2 recipients versus that in the placebo group. Rotigotine was generally well tolerated in clinical trials as both monotherapy and when administered with levodopa; adverse events were generally mild or moderate in severity.

Palifermin: in myelotoxic therapy-induced oral mucositis.

Palifermin, a recombinant human keratinocyte growth factor (KGF), mimics the actions of endogenous KGF and has shown efficacy in the management of myelotoxic therapy-induced oral mucositis in cancer patients. In a randomised, double-blind trial in patients with haemtaological malignancies receiving conditioning radiochemotherapy before undergoing autologous stem cell transplant, intravenous palifermin 60 microg/kg/day (two 3-day cycles, administered before myelotoxic therapy and after transplant) significantly reduced the median duration (primary endpoint) [3 vs 9 days] and incidence (63% vs 98%) of WHO grade 3 or 4 oral mucositis, compared with placebo. Patient-reported outcomes also showed significant improvement with palifermin treatment, which was associated with significant reductions in healthcare resource utilisation, compared with placebo. The drug was generally well tolerated, with skin/oral toxicities, pain/arthralgias and dysaesthesia being the most common palifermin-related adverse reactions.

Fondaparinux sodium: a review of its use in the treatment of acute venous thromboembolism.

Fondaparinux sodium (fondaparinux) is a synthetic sulfated pentasaccharide anticoagulant developed from the antithrombin binding moiety of heparin. Through the activation of antithrombin it inhibits Factor Xa, the activation of thrombin, and the subsequent coagulation cascade. Fondaparinux is approved in Europe and the US for the treatment of acute venous thromboembolism (VTE), including both deep vein thrombosis (DVT) and pulmonary embolism (PE), when used in conjunction with warfarin. In phase III clinical trials, subcutaneous fondaparinux was noninferior to subcutaneous enoxaparin or intravenous unfractionated heparin (UFH) in the prevention of recurrent symptomatic VTE in patients with acute DVT and PE, respectively, and equally well tolerated. It thus provides a valuable alternative to UFH and low-molecular weight heparins in the treatment of acute VTE, particularly in the outpatient setting.

Rifaximin: a review of its use in the management of traveller's diarrhoea.

Oral rifaximin, a semisynthetic rifamycin derivative, is an effective and well tolerated antibacterial for the management of adults with non-invasive traveller's diarrhoea. Rifaximin was significantly more effective than placebo and no less effective than ciprofloxacin in reducing the duration of diarrhoea after treatment initiation for illness contracted during travel to diverse geographic locations. While rifaximin is effective in patients with Escherichia coli-predominant traveller's diarrhoea, it appears ineffective in patients infected with inflammatory or invasive enteropathogens. Rifaximin has a broad spectrum of antibacterial activity in vitro and undergoes negligible systemic absorption (<0.4%). In contrast to systemically absorbed antibacterials, such as the fluoroquinolones and macrolides, the acquisition of resistance to rifaximin would have limited consequences for global public health, as rifaximin has no role in the management of systemic infections. Rifaximin shows promise as chemoprophylaxis against traveller's diarrhoea and is a valuable new option for the management of traveller's diarrhoea caused by non-invasive bacterial strains.

Topical tazarotene: a review of its use in the treatment of plaque psoriasis.

Tazarotene (Tazorac) is a topical retinoid indicated for the treatment of plaque psoriasis. When used as monotherapy, topical tazarotene was effective at controlling signs and symptoms of plaque psoriasis, and had significantly lower post-treatment relapse rates than fluocinonide cream. The most common adverse events associated with tazarotene therapy are skin-associated events, such as pruritus, burning, and erythema. Combination therapy with tazarotene and mid-to-high potency topical corticosteroids generally resulted in a greater therapeutic effect than that with tazarotene alone, reduced the irritancy of tazarotene, and decreased the risk of post-treatment disease flare seen with corticosteroids; it also has the potential to reduce the degree of skin atrophy associated with topical corticosteroids. The combination of tazarotene and phototherapy also appears promising. Thus, tazarotene, as monotherapy or in combination with topical corticosteroids or UV light therapy, represents a useful treatment option in patients with plaque psoriasis.

Bivalirudin: a review of its use in patients undergoing percutaneous coronary intervention.

Bivalirudin (Angiox, Angiomax) is a synthetic 20-amino acid peptide analogue of hirudin. It is a direct thrombin inhibitor that binds specifically and reversibly to both fibrin-bound and unbound thrombin. Intravenous bivalirudin is approved in Europe for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI). In the US, bivalirudin is approved in patients with unstable angina pectoris undergoing percutaneous transluminal coronary angioplasty (PTCA) and has recently been approved for use with provisional glycoprotein (GP) IIb/IIIa inhibition in patients undergoing PCI. Bivalirudin plus provisional GP IIb/IIIa inhibition is effective in patients undergoing PCI. The large, well controlled REPLACE-2 (Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events) study showed that bivalirudin plus provisional GP IIb/IIIa inhibition was noninferior to heparin plus planned GP IIb/IIIa inhibition and that bivalirudin was associated with a reduced risk of bleeding complications. In patients with heparin-induced thrombocytopenia (HIT), bivalirudin was effective against ischaemic events and there was a low incidence of bleeding complications. Bivalirudin should be considered as an alternative to heparin plus planned GP IIb/IIIa inhibition in any patient undergoing urgent or elective PCI, especially in any patient with a high risk of bleeding complications.

Rosiglitazone/Metformin.

The thiazolidinedione rosiglitazone and the biguanide metformin are effective antihyperglycaemic agents with different modes of action; rosiglitazone primarily increases insulin sensitivity, whereas metformin primarily reduces hepatic glucose output. Antihyperglycaemic combination therapy is often required to achieve effective glycaemic control. A fixed-dose formulation of rosiglitazone/metformin was recently approved in the EU and the US for the treatment of type 2 diabetes mellitus in patients inadequately controlled on metformin monotherapy. Bioequivalence between the fixed-dose combination tablet and coadministration of rosiglitazone with metformin at the same dosage has been established in a pharmacokinetic study. Fixed-dose rosiglitazone/metformin 8 mg/2g per day reduced glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels to a significantly greater extent than metformin 3 g/day in patients with type 2 diabetes in a 24-week, randomised, double-blind study. Rosiglitazone plus metformin was significantly more effective than metformin alone at reducing HbA1c and FPG levels in patients with type 2 diabetes in three 26-week, randomised, double-blind, placebo-controlled studies. Rosiglitazone plus metformin was generally well tolerated in all studies and had a tolerability profile similar to that of metformin monotherapy. Mild or moderate symptomatic hypoglycaemia was reported in

Ipratropium bromide HFA.

Ipratropium bromide is a nonselective antagonist of the muscarinic receptors located on airway smooth muscle, and is delivered via a metered-dose inhaler (MDI). Because of the requirement to phase out chlorofluorocarbon (CFC)-propelled MDIs, the ipratropium bromide inhalation aerosol MDI has been redesigned with a hydrofluoroalkane as the propellant (ipratropium bromide HFA). Ipratropium bromide HFA has recently been approved in the US for the maintenance treatment of bronchospasm associated with COPD. Ipratropium bromide HFA 42 microg four times daily (one dose [42 microg] is delivered via two puffs of the inhaler) demonstrated comparable efficacy to that of ipratropium bromide CFC 42 microg four times daily, as measured by spirometric testing, in a large, randomized, double-blind, placebo-controlled, 12-week trial in patients with stable COPD. Similarly, four-times-daily ipratropium bromide HFA 42 microg and ipratropium bromide CFC 42 microg provided a comparable degree of bronchodilation in patients with stable COPD during a 1-year, open-label study primarily designed to assess safety. In both studies, the tolerability profiles of ipratropium bromide HFA and ipratropium bromide CFC were comparable. The most common adverse events were related to respiratory system disorders. During the 1-year study, dry mouth was reported by 1.3% and 0.7% of patients in the ipratropium bromide HFA or ipratropium bromide CFC groups.

Efalizumab.

Efalizumab is a humanized monoclonal antibody that binds to CD11a, the alpha-subunit of lymphocyte function-associated antigen-1, and consequently inhibits T-cell activation. In randomized, double-blind, placebo-controlled trials, efalizumab 1.0 mg/kg, administered subcutaneously once weekly for 12 weeks, significantly reduced disease activity in patients with chronic, moderate-to-severe plaque psoriasis. Significantly more efalizumab recipients had a > or =75% decrease in the Psoriasis Area and Severity Index (PASI) score [22.4-38.9%] than placebo recipients (2.4-4.9%); an additional 12 weeks of treatment resulted in sustained or increased PASI responses. The efficacy of weekly subcutaneous efalizumab was maintained during 15 months of treatment. Efalizumab significantly improved health-related quality of life in patients with chronic plaque psoriasis, with significant improvements in all the Dermatology Life Quality Index domains. Efalizumab was generally well tolerated in patients with chronic, moderate-to-severe plaque psoriasis, with few serious adverse events or treatment withdrawals. The most common adverse events were headache, chills, myalgia, pain, and fever; these most often occurred within 2 days of administration of the drug, were most frequent after the first or second dose, and decreased in frequency over time.

Lucinactant: in neonatal respiratory distress syndrome.

Lucinactant, formerly known as KL(4) surfactant, is a novel synthetic lung surfactant containing phospholipids and an engineered peptide, sinapultide, which is designed to mimic the actions of human surfactant protein B. It has been developed for use in the prevention or treatment of respiratory distress syndrome (RDS), a common problem in premature infants, which results from a deficiency or degradation of pulmonary surfactant. Lucinactant is administered intratracheally soon after birth as a replacement surfactant. In the pivotal randomized, double-blind, prophylaxis trial in premature infants, the incidence of RDS at 24 hours after birth was significantly lower in lucinactant recipients than in recipients of colfosceril palmitate, a synthetic non-protein-containing surfactant. RDS-related mortality at 14 days was significantly lower in lucinactant recipients than in recipients of colfosceril palmitate or beractant, a bovine-derived surfactant. In another randomized, double-blind, prophylaxis trial in premature infants, the rate of survival without bronchopulmonary dysplasia at 28 days of age in lucinactant recipients was not inferior to that in recipients of poractant alfa, a porcine-derived surfactant. Lucinactant was generally well tolerated. Adverse events were transient and related to the administration procedure. There were no differences in the incidences of complications of prematurity between lucinactant and the other surfactants.

Spotlight on cefditoren pivoxil in bacterial infections.

Cefditoren pivoxil (Spectracef, Meiact) is a third-generation oral cephalosporin with a broad spectrum of activity against pathogens, including both Gram-positive and -negative bacteria, and is stable to hydrolysis by many common beta-lactamases. Cefditoren pivoxil is approved for use in the treatment of acute exacerbations of chronic bronchitis (AECB), mild-to-moderate community-acquired pneumonia (CAP), acute maxillary sinusitis, acute pharyngitis/tonsillitis, and uncomplicated skin and skin structure infections (indications may differ between countries). In clinical trials in adults and adolescents, cefditoren pivoxil demonstrated good clinical and bacteriological efficacy in AECB, CAP, acute maxillary sinusitis, acute pharyngitis/tonsillitis, and uncomplicated skin and skin structure infections, and was generally well tolerated. Thus, cefditoren pivoxil is a good option for the treatment of adult and adolescent patients with specific respiratory tract or skin infections, particularly if there is concern about Streptococcus pneumoniae with decreased susceptibility to penicillin, or beta-lactamase-mediated resistance among the common community-acquired pathogens.