Spotlight on quetiapine in acute mania and depression associated with bipolar disorder.

Quetiapine (Seroquel), an atypical antipsychotic with established efficacy in the treatment of schizophrenia, shows efficacy in the treatment of acute mania and depression associated with bipolar disorder.Quetiapine, either as monotherapy or in combination with lithium or divalproex sodium (valproate semisodium), is generally well tolerated and effective in reducing manic symptoms in adult and adolescent patients with acute bipolar mania, and is approved for use in adults for this indication. As monotherapy, the drug is also effective in reducing depressive symptoms in patients with bipolar depression. It is associated with a low incidence of extrapyramidal symptom (EPS)-related adverse events and low EPS ratings in bipolar disorder. Quetiapine thus shows potential in the treatment of bipolar depression, and represents a useful agent for the treatment of acute bipolar mania.

Abacavir plus lamivudine: a review of their combined use in the management of HIV infection.

Abacavir and lamivudine (two nucleoside analogue reverse transcriptase inhibitors [NRTIs]), as separate formulations in combination with other antiretroviral agents, are effective in the reduction of HIV RNA levels in antiretroviral-naive patients with HIV infection, and are generally well tolerated. A fixed-dose combination tablet of abacavir/lamivudine (Epzicomtrade mark, Kivexatrade mark) has been developed for once-daily use and preliminary efficacy data are promising. Although further experience with this formulation is needed to fully determine its position in the management of HIV infection, a single, once-daily tablet that may be taken irrespective of food intake should aid adherence to treatment, a key factor in determining the success of an antiretroviral regimen. Thus, abacavir and lamivudine are two established components of first-line antiretroviral regimens for the management of HIV infection and the fixed-dose abacavir/lamivudine tablet has the potential to be an effective, easily adhered to and generally well tolerated component of first-line therapy.

Low-dose ethinylestradiol/levonorgestrel.

Low-dose ethinylestradiol/levonorgestrel 20 microg/100 microg is a combined oral contraceptive that prevents pregnancy primarily by inhibiting ovulation. The Pearl index (pregnancies per 100 woman-years of use) with ethinylestradiol/levonorgestrel 20 microg/100 microg was 0.88 and the cumulative pregnancy rate was 1.9% at the end of a 3-year open-label trial (1708 women with 26 554 evaluable cycles). The contraceptive efficacy of ethinylestradiol/levonorgestrel 20 microg/100 microg was similar to that of other low-dose combined oral contraceptives containing ethinylestradiol 20 or 35 microg in a 6-cycle trial (463 evaluable women). Ethinylestradiol/levonorgestrel 20 microg/100 microg is well tolerated; adverse events were those commonly associated with combined oral contraceptives. Headache and metrorrhagia (2% of women) were the most common adverse events leading to treatment discontinuation in the 3-year trial. Cycle control in open-label trials in women receiving up to 36 cycles of ethinylestradiol/levonorgestrel 20 microg/100 microg was generally good, with the incidence of intermenstrual bleeding being highest during the first few cycles of use and decreasing thereafter.

Quetiapine: a review of its use in acute mania and depression associated with bipolar disorder.

Quetiapine (Seroquel), an atypical antipsychotic with established efficacy in the treatment of schizophrenia, shows efficacy in the treatment of acute mania and depression associated with bipolar disorder.Quetiapine, either as monotherapy or in combination with lithium or divalproex sodium (valproate semisodium), is generally well tolerated and effective in reducing manic symptoms in adult and adolescent patients with acute bipolar mania, and is approved for use in adults for this indication. As monotherapy, the drug is also effective in reducing depressive symptoms in patients with bipolar depression. It is associated with a low incidence of extrapyramidal symptom (EPS)-related adverse events and low EPS ratings in bipolar disorder. Quetiapine thus shows potential in the treatment of bipolar depression, and represents a useful agent for the treatment of acute bipolar mania.

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.

Once-monthly ibandronate.

Ibandronate is a nitrogen-containing bisphosphonate that has been approved for once-monthly administration in women with post-menopausal osteoporosis. Animal data suggest that the efficacy of the drug is determined by the cumulative dose rather than the frequency of administration. After treatment for 1 year in a large, randomized, double-blind, multicenter trial in women with postmenopausal osteoporosis, once-monthly ibandronate 150 mg was non-inferior to once-daily ibandronate 2.5 mg in terms of increases in mean lumbar spine (primary endpoint) and hip bone mineral density (BMD). In addition, once-monthly ibandronate 150 mg was significantly more effective than once-daily ibandronate for mean increase from baseline in lumbar spine BMD after 1 and 2 years. In another large, randomized, double-blind trial in women with osteoporosis, both once-daily and intermittent (>2-month between-dose interval [not approved]) ibandronate were significantly more effective than placebo in reducing the risk of new vertebral fractures, after treatment for 3 years. Once-daily and intermittent ibandronate also increased mean lumbar spine and hip BMD from baseline by significantly more than placebo. Oral once-monthly, once-daily, and intermittent ibandronate were generally well tolerated. Monthly ibandronate had a similar tolerability profile to once-daily ibandronate. The incidence of adverse events, including gastrointestinal events, with once-daily and intermittent ibandronate did not differ significantly from that with placebo. Significantly more women with osteoporosis preferred once-monthly ibandronate and found it more convenient than once-weekly alendronate, according to data from a 6-month, randomized, open-label, crossover study.

Enfuvirtide.

Enfuvirtide is the first of a new class of drugs, the fusion inhibitors. It is a synthetic peptide which binds to the HIV glycoprotein 41 (gp41), blocking fusion of the viral and cellular membranes. HIV isolates with reduced susceptibility to enfuvirtide have been recovered from patients receiving enfuvirtide in combination with other antiretroviral agents. Enfuvirtide 90mg (subcutaneously, twice daily) in combination with optimised background (OB) antiretroviral therapy significantly reduced plasma HIV RNA levels compared with OB alone after treatment for 24 weeks in two randomised trials involving adults with advanced HIV infection. The antiviral efficacy of enfuvirtide was maintained through to 48 weeks. At 24 and 48 weeks, the increase from baseline in the CD4+ cell count was significantly greater for patients receiving enfuvirtide plus OB than for those receiving OB alone. Enfuvirtide 30 mg/m(2) or 60 mg/m(2) in combination with other antiretroviral agents reduced plasma HIV RNA levels and increased CD4+ cell counts in a small trial involving paediatric patients with HIV infection. Local injection-site reactions were common. Lymphadenopathy and pneumonia occurred more often in patients receiving enfuvirtide plus OB than in the control group. The incidence of most other events was similar in each group.

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

Aprepitant (Emend) is the first commercially available drug from a new class of agents, the neurokinin NK(1) receptor antagonists. Oral aprepitant, in combination with other agents, is indicated for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV) associated with highly emetogenic chemotherapy in adults. In three randomised, double-blind, placebo-controlled trials comparing aprepitant (125 mg day 1, 80mg once daily on days 2 and 3 or 2-5) plus standard therapy (intravenous ondansetron and oral dexamethasone) with standard therapy plus placebo, overall complete responses (primary endpoint, defined as no emesis and no rescue therapy) were seen in significantly more patients in the aprepitant arms (63-73% versus 43-52%, p < 0.01 for all comparisons). Complete responses and complete protection during the acute and delayed phase, and overall complete protection were also observed in significantly more patients in the aprepitant arms. The difference between treatment groups was more marked in the overall and delayed phases than in the acute phase. The antiemetic efficacy of aprepitant plus standard therapy in the prevention of CINV was maintained for up to six cycles of chemotherapy. Where assessed, more patients in the aprepitant plus standard therapy arms than the standard therapy plus placebo arms reported no impact of CINV on daily life, as assessed by the Functional Living Index-Emesis. Aprepitant is generally well tolerated. The most common adverse events in randomised trials were asthenia or fatigue. Other adverse events experienced by aprepitant recipients include anorexia, constipation, diarrhoea, nausea (after day 5 of the study) and hiccups. In addition to being a substrate for cytochrome P450 (CYP) 3A4, aprepitant is also a moderate inhibitor and inducer of this isoenzyme as well as an inducer of CYP2C9. Thus, aprepitant has the potential to interact with other agents metabolised by hepatic CYP isoenzymes. In one trial, there was a higher incidence of serious infection or febrile neutropenia in the aprepitant plus standard therapy arm than the standard therapy plus placebo arm; this was attributed to a pharmacokinetic interaction between aprepitant and dexamethasone. In subsequent trials, a modified dexamethasone regimen was used. In conclusion, when added to standard therapy (a serotonin 5-HT(3) receptor antagonist and a corticosteroid), aprepitant is effective and generally well tolerated in the prevention of CINV associated with highly emetogenic chemotherapy in adults. Despite marked advances in the prevention of CINV, standard therapy does not protect all patients. The addition of aprepitant to standard therapy provides an advance in the prevention of both acute and delayed CINV in adults with cancer.

Intravenous lansoprazole: in erosive oesophagitis.

An intravenous formulation of lansoprazole, a proton pump inhibitor, is approved for use in patients with erosive oesophagitis who are temporarily unable to take oral lansoprazole. In healthy volunteers, oral and intravenous lansoprazole 30 mg/day were equivalent in suppressing basal and pentagastrin-stimulated maximum gastric acid output. Moreover, the mean 24-hour intragastric pH did not differ significantly following oral or intravenous administration of lansoprazole and was significantly higher with both formulations than with intravenous polyethylene glycol vehicle. After treatment for 7 days in patients with erosive oesophagitis, intravenous lansoprazole (30 mg/day) recipients had significantly lower median stimulated and basal gastric acid output measurements than placebo recipients. Median pentagastrin-stimulated gastric acid output levels were equivalent after 7 days treatment with intravenous or oral lansoprazole. Intravenous lansoprazole is generally well tolerated. All adverse events experienced by patients with erosive oesophagitis who received intravenous lansoprazole were mild or moderate in severity.

Emtricitabine/tenofovir disoproxil fumarate.

The nucleoside analogue reverse transcriptase inhibitor (RTI) emtricitabine and the nucleotide analogue RTI tenofovir disoproxil fumarate (tenofovir DF) have each shown antiviral activity against a number of HIV clinical isolates and cell lines. HIV variants with reduced susceptibility to emtricitabine and tenofovir have been selected for in vitro and have also been isolated from patients receiving the agents. Low rates of these variants have been observed in patients experiencing virological failure in large studies of emtricitabine- or tenofovir DF-containing therapy. Co-formulated oral emtricitabine/tenofovir DF was bioequivalent to the two agents as separate formulations in a pharmacokinetic trial in healthy volunteers. There are no published data on the clinical antiviral efficacy of co-formulated oral emtricitabine/tenofovir DF. However, each agent is effective in combination regimens with other drugs. Ongoing studies in antiretroviral-naive patients are evaluating the efficacy of the individual formulations given together in combination with efavirenz or lopinavir/ritonavir. In the latter trial, HIV RNA levels were reduced and CD4+ cell counts were increased at 24 and 48 weeks. Emtricitabine and tenofovir DF are generally well tolerated. Diarrhoea, nausea and vomiting were the most common adverse events reported with coadministered emtricitabine and tenofovir DF as separate formulations as part of combination therapy.

17 beta-estradiol/levonorgestrel transdermal system.

Hormone replacement therapy with continuous 17 beta-estradiol/levonorgestrel (estradiol/levonorgestrel), administered once weekly as a transdermal system, has shown efficacy in the treatment of vasomotor symptoms associated with menopause. Transdermal estradiol/levonorgestrel (4.4/2.74 and 4.5/3.75mg) significantly reduced the mean weekly (primary endpoint) and daily number of hot flashes (flushes) compared with placebo in a 12-week, randomized, double-blind trial in postmenopausal women (both of the dosages used are higher than the approved dosage). The same endpoints were also numerically reduced from baseline by estradiol/levonorgestrel (4.4/1.39 [approved dosage], 4.4/2.74, and 4.5/3.75mg), as well as 17 beta-estradiol (estradiol) in a substudy of a 12-month randomized trial in postmenopausal women; however, there were no significant between-group differences. Estradiol/levonorgestrel also reduced the mean daily maximal severity of hot flashes. In the 12-week study, mean daily hot flash severity improved from severe to mild for estradiol/levonorgestrel recipients, but remained moderately severe for placebo recipients. None of the recipients of estradiol/levonorgestrel 4.4/1.39mg and 12.8% of women treated with estradiol developed endometrial hyperplasia (primary endpoint) in a large, 12-month, randomized, double-blind trial in postmenopausal women. Over 12 months, estradiol/levonorgestrel and estradiol significantly improved mean quality-of-life total scores (women's health questionnaire) from baseline; there were no significant between-group differences. The estradiol/levonorgestrel transdermal system was generally well tolerated. In two trials, application-site reactions were common in all treatment groups (estradiol/levonorgestrel, estradiol, and placebo).

Clodronate : a review of its use in the prevention of bone metastases and the management of skeletal complications associated with bone metastases in patients with breast cancer.

Clodronate (clodronate disodium, Bonefos) is a non-nitrogen-containing bisphosphonate that inhibits osteoclast activity, and thereby inhibits bone resorption. Clodronate has been extensively used in patients with advanced breast cancer, and is generally well tolerated. In patients with primary breast cancer, clodronate is currently the only bisphosphonate shown to improve survival rates and to reduce the incidence of bone metastases in randomised controlled trials. Further trials in patients with early breast cancer are warranted to confirm results to date and to determine the optimal duration of treatment, as well as the efficacy of the drug compared with other bisphosphonates. In the meantime, clodronate is a well established bisphosphonate which has shown beneficial effects in the prevention of bone metastases and on survival in patients with primary breast cancer.