Spotlight on denosumab in postmenopausal osteoporosis.

Denosumab (Prolia®) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU, and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function, and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral, and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.

Denosumab: a review of its use in the treatment of postmenopausal osteoporosis.

Denosumab (Prolia®) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.

Indacaterol: in chronic obstructive pulmonary disease.

Indacaterol is a long-acting ß2-adrenoceptor agonist that is available in the EU for the maintenance treatment of airflow obstruction in adult patients with chronic obstructive pulmonary disease (COPD). Indacaterol has a 24-hour bronchodilatory effect, which allows for once-daily administration. The onset of bronchodilation after inhalation of indacaterol is fast, with significant improvements versus placebo seen 5 minutes after inhalation. In four large (n > 400), randomized, double-blind, placebo-controlled, multicentre phase III trials, patients with COPD who received indacaterol 150 or 300 µg once daily had a significantly higher mean trough forced expiratory volume in 1 second (FEV1) than placebo recipients after 12 weeks. Trough FEV1 differences between indacaterol and placebo recipients were 130-180 mL and exceeded the clinically relevant threshold of 120 mL in all trials. Furthermore, indacaterol recipients had significantly higher mean trough FEV1 values after 12 weeks than patients who received formoterol, salmeterol or open-label tiotropium. COPD exacerbations and symptoms, and health-related quality of life were also significantly improved for indacaterol versus placebo recipients in some studies. Indacaterol was generally well tolerated by adults with moderate to severe COPD.

Telmisartan/amlodipine: single-pill combination in hypertension.

Telmisartan/amlodipine is a single-pill combination of telmisartan, an angiotensin II receptor antagonist, and amlodipine, a dihydropyridine calcium channel antagonist, which is taken orally once daily for the treatment of hypertension. In the US and the EU, single-pill telmisartan/amlodipine can be used as a replacement for separate telmisartan and amlodipine tablets, and by patients not achieving BP goals with amlodipine monotherapy. In addition, the US indication includes patients not achieving BP goals with telmisartan (or another angiotensin II receptor antagonist or calcium channel antagonist other than amlodipine) alone, and as initial therapy in patients considered likely to require multiple drugs to achieve their BP goals. In an 8-week, randomized, double-blind, factorial-design, placebo-controlled, multicenter study in adult patients with hypertension (n = 1461), mean DBP was reduced from baseline to a significantly greater extent in recipients of telmisartan 40 or 80 mg/day plus amlodipine 5 or 10 mg/day than in those receiving equivalent dosages of telmisartan or amlodipine monotherapy. Single-pill telmisartan/amlodipine recipients had significantly greater reductions in BP than telmisartan or amlodipine monotherapy recipients in an 8-week, randomized, double-blind, multicenter study in adult patients with severe hypertension (n = 858), and in four 8-week, randomized, double-blind, multicenter trials in patients who had not responded to amlodipine (n = 1097, 947, and 531) or telmisartan (n = 314) monotherapy. Telmisartan/amlodipine was generally well tolerated in clinical trials, including two 36-week follow-up studies.

Vinflunine.

Vinflunine is a novel bifluorinated vinca alkaloid that appears to differ from other class members in terms of its tubulin-binding properties and inhibitory effects on microtubule dynamics. Notably, it demonstrated superior in vivo antitumour activity to that of vinorelbine in a range of transplantable murine and human tumours. In a randomized, open-label, multicentre phase III trial in adult patients with advanced transitional cell carcinoma of the urothelium who experienced progression after first-line platinum-containing chemotherapy (n = 370), median overall survival (OS; primary endpoint) was 6.9 months for intravenous vinflunine plus best supportive care (BSC) recipients versus 4.6 months for BSC alone recipients in the intent to treat (ITT) population. The difference in OS between treatment groups was not significant in the ITT population; however, there was a significant improvement in OS for vinflunine plus BSC recipients in the ITT population after adjusting for prespecified prognostic factors, and in the analysis of the eligible population (ITT population excluding baseline protocol violations). In the latter, median OS was 6.9 months with vinflunine plus BSC versus 4.3 months with BSC alone after a median follow-up of approximately 1.8 years and again after a median follow-up of approximately 3.6 years. Progression-free survival, objective response rate and disease control rate were significantly improved with vinflunine plus BSC versus BSC alone. The most frequent treatment-related adverse events in vinflunine recipients included myelosuppression (e.g. neutropenia) and gastrointestinal symptoms (e.g. constipation). In general, adverse events with vinflunine were noncumulative and medically manageable.

Bevacizumab: in previously treated glioblastoma.

Bevacizumab is a recombinant humanized monoclonal IgG(1) antibody that binds to human vascular endothelial growth factor and inhibits angiogenesis and hence tumour growth. It is available in the US and other countries for the treatment of several types of cancer, including glioblastoma that has recurred after previous treatment. Two prospective phase II trials have evaluated bevacizumab 10 mg/kg every 2 weeks for the treatment of previously treated glioblastoma. In the randomized, noncomparative, multicentre AVF3708g trial in patients with glioblastoma in first or second relapse, the rate of progression-free survival at 6 months was 42.6% and the objective response rate was 28.2% in recipients of bevacizumab alone (n = 85). In the bevacizumab plus irinotecan treatment arm (n = 82), the 6-month progression-free survival rate was 50.3% and the objective response rate was 37.8%. These rates were all significantly higher than historical control data. In the supporting, single-arm, single-centre, phase II NCI 06-C-0064E trial of bevacizumab in patients with glioblastoma that had recurred after radiotherapy and temozolomide chemotherapy (n = 48), the rate of progression-free survival at 6 months was 29% and the overall response rate based on Macdonald criteria was 35%. Given the nature of the disease, bevacizumab was generally well tolerated in these two phase II trials. In the AVF3708g trial, grade 3 or higher treatment-emergent adverse events occurred in 46.4% of bevacizumab and 65.8% of bevacizumab plus irinotecan recipients.

Topical diclofenac solution.

Topical diclofenac solution (Pennsaid) is a liquid formulation containing the NSAID diclofenac sodium (1.5% w/w). The solution base contains 45% w/w dimethyl sulfoxide (DMSO) to enhance the absorption of diclofenac through the skin. Topical diclofenac solution is applied directly to the knee for treatment of symptoms associated with osteoarthritis of the knee. In well designed 4- to 12-week trials in patients with primary osteoarthritis of the knee, topical diclofenac solution (40 drops four times daily) was significantly more effective than placebo or vehicle control (carrier solution without diclofenac) for improving Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index pain and physical function, and improving patient global assessment (PGA) and/or patient overall health assessment scores from baseline to the final assessments. Topical diclofenac solution (50 drops three times daily) was as effective as oral diclofenac 150 mg/day for improving WOMAC pain and physical function and PGA scores in a 12-week double-blind study in patients with osteoarthritis of the knee. Topical diclofenac solution was generally well tolerated. The most common treatment-emergent adverse event experienced by topical diclofenac solution recipients was dry skin at the application site. Gastrointestinal adverse events and abnormal laboratory parameters were less common with topical diclofenac solution than with oral diclofenac.

Dexmethylphenidate extended release: a review of its use in the treatment of attention-deficit hyperactivity disorder.

Dexmethylphenidate extended release (XR) [Focalin XR] is a CNS stimulant indicated for the treatment of attention-deficit hyperactivity disorder (ADHD) in patients aged > or = 6 years. Dexmethylphenidate contains the d-threo-enantiomer of methylphenidate. Dexmethylphenidate XR capsules have a bimodal release profile, which mimics two doses of dexmethylphenidate immediate release (IR) given 4 hours apart, and allows once-daily administration. Once-daily dexmethylphenidate XR was effective and generally well tolerated in the treatment of ADHD in children, adolescents and adults in placebo-controlled trials. Improvements in ADHD symptoms were significantly greater for dexmethylphenidate XR versus placebo throughout the day, from as early as 0.5 hours after drug administration up to 11-12 hours after administration. Furthermore, dexmethylphenidate XR showed greater efficacy than osmotic release oral system (OROS) methylphenidate over the first half of the laboratory classroom day in crossover trials; however, assessments late in the day (10-12 hours post-dose) favoured OROS methylphenidate. The once-daily administration regimen with dexmethylphenidate XR avoids the need for a midday dose to be administered at school; administration options are extended in that the contents of the dexmethylphenidate XR capsule can be sprinkled on apple sauce for patients unable to swallow the capsule whole. Although dexmethylphenidate XR is a controlled substance in the US, this formulation appears to have a low risk of abuse or misuse. Thus, dexmethylphenidate XR extends the range of first-line pharmacological treatment options for children, adolescents or adults with ADHD, particularly for patients who require a rapid onset and prolonged duration of action, including children who require a reduction in ADHD symptoms throughout the school day.

Ixabepilone: in locally advanced or metastatic breast cancer.

Ixabepilone, an analogue of the natural product epothilone B, stabilizes microtubules resulting in cell cycle arrest and apoptosis. It is indicated for the treatment of locally advanced or metastatic breast cancer in the US. Ixabepilone has shown antitumour activity in tumour cell lines in vitro and in several animal tumour models, including those that display key mechanisms of resistance to other anticancer agents. In a randomized, nonblind, multicentre, phase III trial in women with locally advanced or metastatic breast cancer that was pretreated with, or resistant to, anthracyclines and resistant to taxanes, progression-free survival was significantly longer in ixabepilone plus capecitabine recipients compared with recipients of capecitabine monotherapy (median 5.8 vs 4.2 months). The response rate to ixabepilone monotherapy was 11.5% in a noncomparative, multicentre, phase II trial in women with locally advanced or metastatic breast cancer resistant to anthracyclines, taxanes and capecitabine. The most common grade 3 or 4 treatment-related adverse events in both trials were myelosuppression and peripheral sensory neuropathy.

Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections.

Liposomal amphotericin B (AmBisome) is a lipid-associated formulation of the broad-spectrum polyene antifungal agent amphotericin B. It is active against clinically relevant yeasts and moulds, including Candida spp., Aspergillus spp. and filamentous moulds such as Zygomycetes, and is approved for the treatment of invasive fungal infections in many countries worldwide. It was developed to improve the tolerability profile of amphotericin B deoxycholate, which was for many decades considered the gold standard of antifungal treatment, despite being associated with infusion-related events and nephrotoxicity. In well controlled trials, liposomal amphotericin B had similar efficacy to amphotericin B deoxycholate and amphotericin B lipid complex as empirical therapy in adult and paediatric patients with febrile neutropenia. In addition, caspofungin was noninferior to liposomal amphotericin B as empirical therapy in adult patients with febrile neutropenia. For the treatment of confirmed invasive fungal infections, liposomal amphotericin B was more effective than amphotericin B deoxycholate treatment in patients with disseminated histoplasmosis and AIDS, and was noninferior to amphotericin B deoxycholate in patients with acute cryptococcal meningitis and AIDS. In adults, micafungin was shown to be noninferior to liposomal amphotericin B for the treatment of candidaemia and invasive candidiasis. Data from animal studies suggested that higher dosages of liposomal amphotericin B might improve efficacy; however, in the AmBiLoad trial in patients with invasive mould infection, there was no statistical difference in efficacy between the standard dosage of liposomal amphotericin B 3 mg/kg/day and a higher 10 mg/kg/day dosage, although the standard dosage was better tolerated. Despite being associated with fewer infusion-related adverse events and less nephrotoxicity than amphotericin B deoxycholate and amphotericin B lipid complex, liposomal amphotericin B use is still limited to some extent by these adverse events. Both echinocandins were better tolerated than liposomal amphotericin B. The cost of liposomal amphotericin B therapy may also restrict its use, but further pharmacoeconomic studies are required to fully define its cost effectiveness compared with other antifungal agents. Based on comparative data from well controlled trials, extensive clinical experience and its broad spectrum of activity, liposomal amphotericin B remains a first-line option for empirical therapy in patients with febrile neutropenia and in those with disseminated histoplasmosis, and is an option for the treatment of AIDS-associated cryptococcal meningitis, and for invasive Candida spp. or Aspergillus spp. infections. Amphotericin B, a macrocyclic, polyene antifungal agent, is thought to act by binding to ergosterol, the principal sterol in fungal cell membranes and Leishmania cells. This results in a change in membrane permeability, causing metabolic disturbance, leakage of small molecules and, as a consequence, cell death. In vitro and in vivo studies have shown that liposomal amphotericin B remains closely associated with the liposomes in the circulation, thereby reducing the potential for nephrotoxicity and infusion-related toxicity associated with conventional amphotericin B. Amphotericin B shows very good in vitro activity against a broad spectrum of clinically relevant fungal isolates, including most strains of Candida spp. and Aspergillus spp., and other filamentous fungi such as Zygomycetes. Liposomal amphotericin B has proven effective in various animal models of fungal infections, including those for candidiasis, aspergillosis, fusariosis and zygomycosis. Liposomal amphotericin B also shows immunomodulatory effects, although the mechanisms involved are not fully understood, and differ from those of amphotericin B deoxycholate and amphotericin B colloidal dispersion. In adult patients with febrile neutropenia, intravenous liposomal amphotericin B has nonlinear pharmacokinetics, with higher than dose-proportional increases in exposure being consistent with reticuloendothelial saturation and redistribution of amphotericin B in the plasma compartment. Liposomal amphotericin B is rapidly and extensively distributed after single and multiple doses, with steady-state concentrations of amphotericin B attained within 4 days and no clinically relevant accumulation of the drug following multiple doses of 1-7.5 mg/kg/day. In autopsy tissue, the highest concentrations of the drug were found in the liver and spleen, followed by the kidney, lung, myocardium and brain tissue. Elimination of liposomal amphotericin B, like that of amphotericin B deoxycholate, is poorly understood; its route of metabolism is not known and its excretion has not been studied. The terminal elimination half-life is about 7 hours. No dosage adjustment is required based on age or renal impairment. In several randomized, double-blind trials (n = 73-1095) in adult and/or paediatric patients, liposomal amphotericin B was effective as empirical therapy or as treatment for confirmed invasive fungal infections, including invasive candidiasis, candidaemia, invasive mould infection (mainly aspergillosis), histoplasmosis and cryptococcal meningitis. All agents were administered as an intravenous infusion; the typical dosage for liposomal amphotericin B was 3 mg/kg/day. Treatment was generally given for 1-2 weeks. Participants in trials evaluating empirical therapy had neutropenia and a persistent fever despite antibacterial treatment and had received chemotherapy or undergone haematopoietic stem cell transplantation. As empirical therapy in adult and paediatric patients, liposomal amphotericin B appeared to be as effective as amphotericin B deoxycholate (approximately 50% of patients in each group achieved treatment success) or amphotericin B lipid complex (approximately 40% of liposomal amphotericin B recipients experienced treatment success). Of note, in the first trial, results of the statistical test to determine equivalence between treatments were not reported. In the second trial, efficacy was assessed as an 'other' endpoint. In another trial, caspofungin was shown to be noninferior to liposomal amphotericin B, with approximately one-third of patients in each group experiencing treatment success. Liposomal amphotericin B was significantly more effective than amphotericin B deoxycholate for the treatment of moderate to severe disseminated histoplasmosis in patients with AIDS, with 88% and 64% of patients, respectively, having a successful response. Liposomal amphotericin B was noninferior to amphotericin B deoxycholate for the treatment of cryptococcal meningitis in terms of mycological success. Micafungin therapy was shown to be noninferior to liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidiasis. In a substudy in paediatric patients, which was not powered to determine noninferiority, liposomal amphotericin B was as effective as micafungin for the treatment of candidaemia or invasive candidiasis. In this patient population, within each trial, 90% of adult patients and approximately three-quarters of paediatric patients in both treatment groups experienced a successful response. In patients with invasive mould infection (mainly aspergillosis), there was no difference in efficacy between a higher dosage of liposomal amphotericin B (10 mg/kg/day) and the standard dosage (3 mg/kg/day), with 46% and 50% of patients experiencing a favourable overall response. In well designed clinical trials, liposomal amphotericin B was generally at least as well tolerated as other lipid-associated formulations of amphotericin B and better tolerated than amphotericin B deoxycholate in adult and paediatric patients. Compared with other amphotericin B formulations, liposomal amphotericin B treatment was associated with a lower incidence of infusion-related adverse events and nephrotoxicity. A higher than recommended dosage of liposomal amphotericin B (10 mg/kg/day) was associated with an increased incidence of nephrotoxicity compared with the standard dosage (3 mg/kg/day), although the incidence of infusion-related reactions did not differ between treatment groups. In general, liposomal amphotericin B treatment was not as well tolerated as echinocandin therapy in well designed clinical trials. As empirical therapy or for the treatment of confirmed invasive fungal infections in adult patients, liposomal amphotericin B recipients experienced more infusion-related events and nephrotoxicity than caspofungin or micafungin recipients. There was no difference in the incidence of these adverse events between the liposomal amphotericin B and micafungin groups in a study in paediatric patients.

Intravenous conivaptan.

*Conivaptan is an arginine vasopressin V1A and V2 receptor antagonist. The intravenous formulation is approved in the US for use in the treatment of euvolemic and hypervolemic hyponatremia. Conivaptan produces a dose-dependent electrolyte-sparing aquaresis (solute-free water excretion), increasing serum sodium levels. *In a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial in adults with euvolemic or hypervolemic hyponatremia, the area under the serum sodium concentration-time curve over a 4-day treatment duration (primary endpoint) was significantly greater in intravenous conivaptan 40 mg/day recipients than in placebo recipients. *The total time during treatment that patients had serum sodium levels > or = 4 mEq/L above baseline was significantly longer in intravenous conivaptan than placebo recipients. In conivaptan recipients, an increase in serum sodium levels of > or = 4 mEq/L above baseline was achieved approximately 1 day after the first dose of the drug. *In addition, the mean change from baseline in free water clearance and effective water clearance over the first day of treatment was significantly greater with intravenous conivaptan than with placebo. *Given the nature of the treatment, the tolerability profile for intravenous conivaptan was generally acceptable in patients with hyponatremia. The most common adverse events were injection related (e.g. injection-site phlebitis), hypotension, and pyrexia.

Raloxifene: a review of its use in the prevention of invasive breast cancer.

Raloxifene (Evista) is a second-generation selective estrogen receptor modulator (SERM) that functions as an estrogen antagonist on breast and uterine tissues, and an estrogen agonist on bone. It is available in many countries worldwide for the treatment and prevention of osteoporosis in postmenopausal women, and has also been approved in the US for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis or postmenopausal women at increased risk of invasive breast cancer.Raloxifene reduces the risk of invasive breast cancer in postmenopausal women at high risk of invasive breast cancer and in postmenopausal women with osteoporosis. In addition, it is a well established agent for the prevention and treatment of osteoporosis. There was no significant difference between raloxifene and tamoxifen in the reduction in the risk of invasive breast cancer achieved in postmenopausal women at high risk of such cancer. Raloxifene was associated with an increased, albeit rare, risk of venous thromboembolism across several placebo-controlled trials and an increased risk of fatal stroke in one placebo-controlled trial in postmenopausal woman at increased risk for major coronary events. However, raloxifene was associated with a lower risk of venous thromboembolic events and cataracts than tamoxifen in a head-to-head trial. The choice of chemoprevention agent must consider a risk-benefit assessment for each individual patient. In this context, raloxifene is a valuable option for the prevention of invasive breast cancer in postmenopausal women with osteoporosis or at high risk of invasive breast cancer.

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.

Imatinib: a review of its use in chronic myeloid leukaemia.

Imatinib (Gleevec, Glivec) is a synthetic tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia (CML). It is specifically designed to inhibit the breakpoint cluster region (BCR)-Abelson (ABL) fusion protein that results from the chromosomal abnormality known as the Philadelphia chromosome. CML is characterised by this abnormality, which leads to abnormalities of the peripheral blood and bone marrow including an increase in the number of granular leukocytes. Imatinib is approved in numerous countries worldwide for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase CML, Ph+ accelerated-phase or blast-crisis CML, and in patients with Ph+ chronic-phase CML who have failed to respond to interferon-alpha therapy. It is also indicated in paediatric patients with newly diagnosed Ph+ chronic-phase CML, in accelerated-phase or blast-crisis CML, or in chronic-phase CML after failure of interferon-alpha therapy or when the disease has recurred after haematopoietic stem cell transplantation (HSCT). Approved indications, however, may vary by country. Imatinib is effective and generally well tolerated in patients with Ph+ CML. In patients with newly diagnosed chronic-phase CML, imatinib was more effective than interferon-alpha plus cytarabine in preventing progression of the disease and in achieving haematological and cytogenetic responses. Overall survival rates remain high after 5 years of follow-up, and historical comparisons with other treatments demonstrate improved overall survival with imatinib in the long term. Patients with accelerated-phase or blast-crisis CML, or those who have not responded to prior interferon-alpha therapy also benefit from imatinib treatment. Some patients become resistant or intolerant to imatinib therapy; management strategies to overcome these problems include dosage adjustment, other treatments, or combination therapy with imatinib and other agents. Allogeneic HSCT is currently the only potentially curative treatment, but it is associated with high rates of morbidity and mortality and is not suitable for all patients. The introduction of imatinib has had a marked impact on outcomes in patients with CML. It remains a valuable treatment for all stages of the disease, especially initial treatment of newly diagnosed Ph+ chronic-phase CML, and is endorsed by European and US treatment guidelines as a first-line option.

Recombinant full-length parathyroid hormone (1-84).

Full-length parathyroid hormone (PTH) 1-84 is a recombinant version of human PTH. It is approved in the EU for the treatment of postmenopausal women with osteoporosis who have a high risk of fractures. Once-daily subcutaneous administration of PTH(1-84) stimulates new bone formation and increases bone mass. In the pivotal, randomised, double-blind, multicentre, 18-month TOP trial in 2532 postmenopausal women with osteoporosis, subcutaneous PTH(1-84) 100 microg/day significantly reduced the incidence of new or worsened vertebral fractures relative to placebo (primary endpoint). Moreover, the increase from baseline in bone mineral density (BMD) at the lumbar spine, total hip, femoral neck and trochanter was also significantly greater than in the placebo group. In another well designed study (PaTH; n = 238), 1 year of subcutaneous PTH(1-84) 100 microg/day followed by 1 year of alendronate 10 mg/day resulted in significantly greater increases in total spine, femoral neck and total hip BMD at 24 months compared with patients who received placebo for the second year. During the first year, PTH(1-84) in combination with alendronate was no more effective than PTH(1-84) monotherapy in terms of increasing areal lumbar spine BMD. PTH(1-84) is generally well tolerated, although patients should be monitored for elevated serum calcium.

Nebivolol: a review of its use in the management of hypertension and chronic heart failure.

Nebivolol is a third-generation beta-adrenoceptor antagonist. It differs from other beta-adrenoceptor antagonists as it combines highly selective beta(1)-adrenoceptor antagonist properties with nitric oxide-mediated vasodilatory actions and beneficial effects on endothelial function. Nebivolol is approved in Europe and several other countries for the treatment of essential hypertension and in Europe for the treatment of stable mild or moderate chronic heart failure (CHF) in addition to standard therapies in elderly patients aged >or=70 years. Nebivolol is an effective antihypertensive agent and is well tolerated in patients with hypertension. The drug also effectively decreased the composite endpoint of mortality and cardiovascular hospital admission in elderly patients with CHF and was generally well tolerated in this population. Nebivolol should be considered as an alternative first-line treatment option for patients with uncomplicated mild to moderate essential hypertension and in elderly patients with CHF.

Zolpidem extended-release.

Zolpidem extended-release, or controlled-release (CR), is a new formulation of zolpidem, a nonbenzodiazepine hypnotic. It is indicated in the US for the treatment of insomnia, characterised by difficulties with sleep onset and/or sleep maintenance. Zolpidem CR is a dual-layered tablet; one layer releases zolpidem immediately and a second layer provides a slower release of additional zolpidem for maintenance of plasma zolpidem concentrations. Efficacy of zolpidem CR was assessed in two 3-week, randomised, double-blind, placebo-controlled, phase III polysomnography trials in younger adult (aged 18-64 years) or elderly (aged > or =65 years) patients with primary insomnia. Patients received nightly zolpidem CR (12.5mg in younger adult and 6.25mg in elderly patients). Efficacy was assessed objectively on nights 1, 2, 15 and 16. Patients who received zolpidem CR had significantly improved objective latency to persistent sleep, wake time after sleep onset and sleep efficiency on assessment nights compared with placebo recipients. In subjective assessments of sleep quality on day 2 and nights 15 and 22, significantly more zolpidem CR than placebo recipients gave favourable responses on a Patient Global Impression scale in the study in younger adult patients. In the other study, significantly more elderly patients in the zolpidem CR group rated their sleep as improved compared with the placebo group. Zolpidem CR was generally well tolerated and appears to have a tolerability profile similar to that of the original formulation of zolpidem.

Sumatriptan fast-disintegrating/rapid-release tablets.

Sumatriptan is a serotonin 5-HT(1B/1D) receptor agonist that is used for the acute treatment of migraine attacks. A new fast-disintegrating/rapid-release sumatriptan tablet (sumatriptan FDT/RRT) has been developed with the goal of speeding absorption and onset of effect compared with standard sumatriptan tablets. Bioequivalence of sumatriptan FDT/RRT tablets to standard sumatriptan tablets was established in healthy volunteers. Initial data suggest that sumatriptan FDT/RRT tablets may disintegrate faster and get emptied from the stomach faster than standard sumatriptan tablets. In a randomised, double-blind, multicentre, early intervention trial in adults with mild migraine, significantly more sumatriptan FDT/RRT 50 and 100mg recipients than placebo recipients were pain free or migraine free 2 hours after receiving study medication. Compared with placebo, pain relief was significantly greater with sumatriptan FDT/RRT 100mg at 25 and 17 minutes following administration, and with sumatriptan FDT/RRT 50mg at 50 and 30 minutes following administration, in two randomised, double-blind, multicentre trials in adults with moderate to severe migraine. Sumatriptan FDT/RRT tablets were generally well tolerated; the tolerability profile was similar to that reported for standard sumatriptan tablets in other studies.