Drugs in R & D最新文献

Azathioprine leads to changes in mean corpuscular volume (MCV) and white blood cell (WBC) indices reflecting efficacy or toxicity. Understanding the interactions between bone marrow stem cells and azathioprine could highlight abnormal response patterns as forerunners for hematologic malignancies. This study gives a statistical description of factors influencing the relationship between MCV and WBC in children with inflammatory bowel disease treated with azathioprine. We found that leukopenia preceded macrocytosis. Macrocytosis is therefore not a good predictor of leukopenia. Further studies will be necessary to determine the subgroup of patients at increased risk of malignancies based on bone marrow response.

Background: There are limited prospective data on clopidogrel resistance and clinical outcome of patients with selective coronary drug-eluting stent (DES) implantation.

Objective: To investigate whether clopidogrel resistance is associated with long-term thrombotic events in patients with selective coronary DES implantation.

Methods: A total of 154 patients who underwent selective percutaneous coronary intervention (PCI) with DES were enrolled in this study. Platelet aggregation was measured using light transmittance aggregometry (LTA) before clopidogrel administration (baseline) and 24 hours after loading with clopidogrel 300 mg. Clopidogrel resistance was defined as ≤10% absolute difference between baseline aggregation and post-administration aggregation. All patients who received the same anti-platelet treatment were followed up for 1 year after discharge for the incidence of a composite endpoint consisting of cardiovascular death, myocardial infarction (MI) and revascularization, and secondly for the incidence of stent thrombosis.

Results: The incidence of clopidogrel resistance is 20.28% in our study population. Patients who are complicated by diabetes mellitus, smoke, or have a higher body mass index (BMI) tend to have clopidogrel resistance. Patients in the clopidogrel-resistant group have significantly higher incidences of composite endpoints (21.88% vs 4.92%; p = 0.006) and stent thrombosis (12.5% vs 1.64%; p = 0.017) than patients in the clopidogrel-response group during 1-year follow-up.

Conclusions: Diabetes, smoking, and high BMI are associated with clopidogrel resistance, and clopidogrel resistance indicates an increased risk of long-term thrombotic events in patients implanted with DES.

Background: Transient lower esophageal sphincter relaxations (TLESRs) have been identified as a primary cause of reflux events in patients with gastroesophageal reflux disease (GERD). GABA(B) receptor agonists such as lesogaberan (AZD3355) have been shown to inhibit TLESRs in healthy subjects and patients with GERD, and, therefore, offer a novel therapeutic add-on strategy to acid suppression for the management of GERD. As lesogaberan is being developed as an add-on treatment for the management of patients with GERD who have a partial response to proton pump inhibitor (PPI) therapy, it is important to rule out any clinically important pharmacokinetic drug-drug interaction between lesogaberan and PPIs.

Objective: To evaluate the effect of esomeprazole on the pharmacokinetics and safety of lesogaberan and vice versa.

Study design: This was an open-label, randomized, three-way crossover study. The study was open to healthy adult male and female subjects. The study subjects received treatment with, in random order, lesogaberan (150 mg twice daily [dose interval 12 hours]), esomeprazole (40 mg once daily), and a combination of both, during 7-day treatment periods.

Main outcome: The presence or absence of pharmacokinetic interactions between lesogaberan and esomeprazole was assessed by measuring the steady-state area under the plasma concentration-time curves during the dosing interval (AUC(τ)) and the maximum observed plasma concentration (C(max)) for lesogaberan and esomeprazole.

Results: Thirty male subjects (mean age 23.2 years, 97% Caucasian) were randomized to treatment and 28 subjects completed the study (one subject was lost to follow-up, and one subject discontinued due to an adverse event). The 95% confidence intervals of the geometric mean ratios for AUC(τ) and C(max) of lesogaberan and esomeprazole administered alone and concomitantly were within the recognized boundaries of bioequivalence (0.8-1.25). No new safety concerns were raised during this study. The number of patients with adverse events during treatment with lesogaberan alone (n = 17) and concomitantly with esomeprazole (n = 18) were comparable but higher than with esomeprazole alone (n = 10). Paresthesia (episodic, mild, and transient), pharyngitis, and flatulence were the most frequently reported adverse events.

Conclusions: There was no observed pharmacokinetic interaction between lesogaberan and esomeprazole when concomitantly administered to healthy subjects, and concomitant therapy was well tolerated. TRIAL REGISTRATION NUMBER (clinicaltrials.gov): NCT00684190.