Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine

Aim The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis. Methods We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (−2 days to +3 days of menses onset) and ≥5 moderate or severe migraines per month prior to entering the trial. Results Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥3× normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥8× normal. In the efficacy subset there was no significant effect of telcagepant ( n = 887) vs placebo ( n = 447) in mean monthly headache days (treatment difference −0.5 day (95% CI: −1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference −0.4 day (95% CI: –0.5, –0.2), nominal p < 0.001). Conclusions Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations . Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.

Adjustable Tongue Advancement for Obstructive Sleep Apnea: A Pilot Study

Objectives: Surgical treatment of obstructive sleep apnea (OSA) caused by hypopharyngeal collapse of the upper airway can be considered in patients who are intolerant to continuous positive airway pressure (CPAP). The present procedures addressing the hypopharynx are invasive and have substantial morbidity and limited efficacy. Methods: Ten patients (mean age, 44 years) with moderate to severe OSA, ie, an apnea-hypopnea index (AHI) between 15 and 50, with CPAP intolerance were included in a prospective, nonrandomized, multicenter study to evaluate the feasibility, safety, and efficacy of a novel tongue advancement procedure. The procedure consists of the implantation of a tissue anchor in the tongue base and an adjustment spool at the mandible. Titration of this tissue anchor results in advancement of the tongue and a patent upper airway. Results: The mean AHI decreased from 22.8 at baseline to 11.8 at the 6-month follow-up (p = 0.007). The Epworth Sleepiness Scale score decreased from 11.4 at baseline to 7.7 at the 6-month follow-up (p = 0.094), and the snoring score decreased from 7.5 at baseline to 3.9 at the 6-month follow-up (p = 0.005). Four technical adverse events were noted, and 1 clinical adverse event occurred. Conclusions: Adjustable tongue advancement is a feasible and relatively safe way to reduce the AHI and snoring in selected patients with moderate to severe OSA and CPAP intolerance. Technical improvements and refinements to the procedure are ongoing.

Non-pegylated liposomal doxorubicin and docetaxel as front line treatment in HER2-neu negative metastatic breast cancer: Safety and efficacy results

10659 Background: First line docetaxel (D) and doxorubicin (DXR) yield up to 55% response rates in controlled studies, in relapse situation for patients who have received anthracyclin in adjuvant setting, with the risk to run on cardiotoxicity regarding anthracyclin cumulative dose.The objective of the study is to determine efficacy and tolerance of Myocet (M) and D as frontline chemotherapy in her2-neu negative metastatic breast cancer (MBC) patients (pts) who have received anthracyclin in adjuvant setting. Methods: Eligible pts were above 18 years, with MBC relapsing at least 12 month after anthracyclin given in adjuvant setting. WHO = 0–1-2, normal left ejection fraction (LEF), measurable targets, cumulative dose of DXR or epirubicin or mitoxantron previously administred respectively under 300, 600, 75 mg/m2. Ongoing hormonotherapy or radiotherapy had to be stop at least 4 weeks before treatment: M = 60 mg/m2 was given as 90 minutes infusion, followed by D = 75 mg/m2 given as 60 minutes infusion, the both 21 days cycles for 6 cycles. Clinical adverse event review, haematology was performed each cycle, LEF each two cycles, tumor assessment, at day 50 and day 120. Results: Between 04/04 and 05/05: 21 pts with median age 55 (33–72) entered the study. All pts were metastatic (liver 10 pts, bone 9, lung 4, soft tissue 2, skin 2, pleural 1, multiples 6). Premenopausal 6 pts , negative oestrogen receptor: 5 pts. A total of 108 MD infusion has been given, infusions delayed 11, omitted 1, reduced dose 15. Use of neutrophils growth factors 11 pts. No treatment related death has been reported. Grade 3/4 toxicity: febrile neutropenia 6 pts (28%), thrombocytopenia 1, alopecia 21, nausea-vomiting 0, gastritis 1, dental infection 1, one cardiac heart failure grade 3 was observed 6 month after the end of 9 cycles of MD, responsive to angiotensin conversion inhibitor. Efficacy: 10 partials responses, 5 completes responses and 2 progressive disease. RR = 71% Binomial 95% CI (53–85). Conclusions: MD is clinically well tolerated with however 28 % grade 3/4 neutropenia and a large use of neutrophils growth factors, no life threatening aplasia was observed. The high response rate had to be confirm with the safety results at the end of the accrual (50 pts planed). No significant financial relationships to disclose.

Pharmacogenetics-Based Coumarin Therapy

To reduce the risk of hemorrhage, experts advocate prescribing the anticipated therapeutic dose to patients who are beginning coumarin therapy, but until now there was no accurate way to estimate that dose. Using pharmacogenetics-based coumarin therapy, clinicians can now estimate the therapeutic dose by genotyping their patients for single nucleotide polymorphisms (SNPs) that affect coumarin metabolism or sensitivity. SNPs in the cytochrome P450 complex (CYP2C9) affect coumarin metabolism. Patients with either of two common variants, CYP2C9*2 or CYP2C9*3, metabolize coumarins slowly and are twice as likely to have a laboratory or clinical adverse event, unless their initial coumarin doses are reduced. SNPs in vitamin K epoxide reductase (VKORC1) correlate with coumarin sensitivity. Patients known to be homozygous for a common VKORC1 promoter polymorphism, −1639 G>A (also designated as VKOR 3673, haplotype A, or haplotype*2), should be started on lower coumarin doses than genotype GG patients. By providing an estimate of the therapeutic coumarin dose, pharmacogenetics-based therapy may improve the safety and effectiveness of coumarin therapy.