Drugs
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Vandetanib, an orally active, small-molecule, multitargeted tyrosine kinase inhibitor, demonstrates potent inhibitory activity against vascular endothelial growth factor receptor (VEGFR)-2 and -3, epidermal growth factor receptor (EGFR) and the rearranged during transfection (RET) tyrosine kinase receptor. The large (n=331), randomized, double-blind, multinational ZETA trial compared vandetanib at a dosage of 300 mg once daily with placebo in patients with unresectable, locally advanced or metastatic, hereditary or sporadic, medullary thyroid cancer. During a median follow-up period of 2 years, vandetanib demonstrated statistically significant clinical benefits over placebo with respect to the primary endpoint, namely progression-free survival (PFS), and a range of secondary endpoints, which included objective response rate, disease control rate, time to worsening of pain and calcitonin biochemical response rate. ⋯ Although the correlation between RET mutation status and clinical outcome could not be clearly evaluated in this trial, it is notable that, among patients with sporadic disease, vandetanib not only demonstrated a PFS benefit in the subgroup confirmed as having a RET mutation, but also in the subgroup for whom the RET mutation status was unknown. Vandetanib was generally well tolerated in the ZETA trial; the majority of adverse events were manageable according to standard clinical practice alone or in combination with vandetanib dose reductions. The adverse event of most concern is corrected QT interval prolongation, particularly in view of the long terminal elimination half-life of the drug.
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Extended-release intramuscular paliperidone palmitate (Xeplion®; Invega® Sustenna®) [henceforth referred to as intramuscular paliperidone palmitate] is a long-acting injectable (LAI) formulation of the well established atypical antipsychotic agent paliperidone (9-hydroxyrisperidone), which is the major active metabolite of risperidone. This article reviews, from an EU perspective, the therapeutic efficacy and tolerability of intramuscular paliperidone palmitate in the treatment of adults with schizophrenia, and the pharmacology of paliperidone that is relevant to the intramuscular formulation. Intramuscular paliperidone palmitate 25-150 mg equivalents (mg eq.) effectively reduced symptoms of schizophrenia in most short-term (9-13 weeks) placebo-controlled trials, as demonstrated by improvements in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint that were significantly greater in intramuscular paliperidone palmitate than placebo recipients. ⋯ The tolerability of intramuscular paliperidone palmitate was generally acceptable in clinical trials of schizophrenia. No new safety concerns were revealed compared with oral paliperidone, except for injection site-related reactions. In conclusion, intramuscular paliperidone palmitate is a useful option for the treatment of patients with schizophrenia.
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Bevacizumab is a recombinant, humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody that neutralizes the biological activity of VEGF and inhibits tumour angiogenesis. In two pivotal, well designed, phase III, clinical trials (GOG-0218 and ICON7) in women with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer, first-line treatment with bevacizumab in combination with standard chemotherapy (carboplatin plus paclitaxel) followed by maintenance treatment with bevacizumab alone significantly prolonged progression-free survival relative to standard chemotherapy. ⋯ In ICON7, HR-QOL did not differ to a clinically significant extent between patients receiving bevacizumab plus standard chemotherapy followed by bevacizumab maintenance and those receiving standard chemotherapy alone. Bevacizumab combination therapy had generally acceptable tolerability in these studies, with the nature of adverse events generally similar to that observed in previous clinical trials in patients with other solid tumours.
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This article reviews the pharmacology, therapeutic efficacy and tolerability profile of intramuscularly injected onabotulinumtoxinA (onaBoNTA; BOTOX®) for headache prophylaxis in adults with chronic migraine, with a focus on UK labelling for the drug. The pharmacological actions of onaBoNTA include a direct antinociceptive (analgesic) effect; while not fully understood, the mechanism of action underlying its headache prophylaxis effect in chronic migraine is presumed to involve inhibition of peripheral and central sensitization in trigeminovascular neurones. Pooled findings from two large phase III studies of virtually identical design (PREEMPT [Phase III REsearch Evaluating Migraine Prophylaxis Therapy] 1 and 2) showed that treatment with up to five cycles of onaBoNTA (155-195 units/cycle) at 12-week intervals was effective in reducing headache symptoms, decreasing headache-related disability, and improving health-related quality of life (HR-QOL) in patients with chronic migraine, approximately two-thirds of whom were overusing acute headache medications at baseline. ⋯ Debate surrounding the PREEMPT studies has centred on the small treatment effect of onaBoNTA relative to placebo, the possibility that blinding was inadequate and the relevance of the evaluated population. Nonetheless, the totality of the data showed that onaBoNTA therapy produced clinically meaningful improvements in headache symptoms, functioning and HR-QOL; on the basis of these trials, it has become the first (and so far only) headache prophylactic therapy to be specifically approved for chronic migraine in the UK and US. Overall, onaBoNTA offers a beneficial, acceptably tolerated and potentially convenient option for the management of this highly disabling condition, for example in patients who are refractory to oral medications used for prophylaxis.
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Intra-abdominal infection (IAI) is a complex disease entity in which different aspects must be balanced in order to select the proper antimicrobial regimen and determine duration of therapy. A current classification indicates different faces of peritonitis. Primary peritonitis implies an intact gastrointestinal tract without overt barrier disruption. ⋯ The basis of antimicrobial therapy for IAI is that both Gram-negative and anaerobic bacteria should always be covered. In recent years, some newer agents such as doripenem, moxifloxacin and tigecycline have been added to the antimicrobial armamentarium for IAI. For patients in whom the source can be adequately controlled, antimicrobial therapy should be restricted to a short course (e.g. 3-7 days in peritonitis).