Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin-releasing hormone antagonist Cetrorelix in healthy female volunteers

The gonadotrophin-releasing hormone antagonist Cetrorelix is in advanced clinical development for the control of endogenous gonadotrophin secretion during the course of a fertility programme. The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of Cetrorelix following single and multiple s.c. administration of different doses. Thirty-six healthy female volunteers received either 0.25, 0.50 or 1.00 mg Cetrorelix, in a first menstrual cycle as single dose and in a second cycle as multiple dose (daily between cycle days 3 and 16). Frequent blood samples were collected for determination of Cetrorelix, follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and progesterone concentrations. Follicular growth was measured by transvaginal ultrasonography. After single administration of each dose, maximum Cetrorelix concentrations (Cmax) were reached after 1 h, and Cmax and area under curve (AUC) increased linearly with the dose. The median terminal half-life ranged from 5 to 10 h in the three different dose groups. FSH, LH, oestradiol and progesterone concentrations were suppressed, with a nadir at 6-12 h after Cetrorelix administration. During multiple administration, Cmax and AUC also showed dose-linearity. The median terminal half-life of Cetrorelix varied between 20 and 80 h. A dose-dependent suppression of FSH, LH and oestradiol concentrations was observed during treatment. After multiple administration, ovulation was delayed for 5, 10 and 13 days in the 0.25, 0.50 and 1.00 mg dose groups, respectively. In conclusion, Cetrorelix showed linear pharmacokinetics, and effectively delayed the LH surge.      

Cutaneous hyperpigmentation induced by omeprazole mimicking ashy dermatosis

BACKGROUND: Omeprazole has been associated with multiple adverse effects including skin reactions but, to date, cutaneous hyperpigmentation has not been described as an adverse effect of this drug. OBSERVATIONS: We describe a case of a 52-year-old Caucasian woman who developed skin hyperpigmentation in the upper trunk, mimicking ashy dermatosis, 2 months after initiating omeprazole treatment. Histopathologic examination of a skin biopsy taken from a pigmented macule showed dermal macrophages containing golden-brown granules, which also displayed a sulphur peak on energy-dispersive X-ray microanalysis. High-performance liquid chromatography (HPLC) and mass spectrometry were also performed on the drug and on a biopsy specimen revealing the same chromatograms as well as the same mass spectra. CONCLUSIONS: According to our results, omeprazole itself may induce cutaneous pigmentation and, to our knowledge, this is the first report of this finding.     

The relationship between psychosocial work characteristics and fatigue and psychological distress

OBJECTIVES: To examine the associations between psychosocial work characteristics and fatigue in employees in the Maastricht Cohort Study. A second objective was to compare the relationships for fatigue versus psychological distress with these psychosocial work characteristics. METHODS: The design was cross-sectional and included 11,020 employees who responded to the self-administered baseline questionnaire of the Maastricht Cohort Study. Fatigue was measured with the Checklist Individual Strength, a 20-item self-report instrument. Psychological distress was measured with the 12-item version of the General Health Questionnaire. Psychosocial work characteristics comprised: psychological demands, decision latitude, and social support at work as measured by the Job Content Questionnaire, as well as emotional demands at work, physical demands at work, job insecurity, and conflict with supervisor/co-worker, which were assessed with items from existing Dutch questionnaires. RESULTS: Low decision latitude and low social support at work were associated with fatigue in both men and women. Associations were also found between emotional demands at work, job insecurity, physical demands and conflict with supervisor and fatigue in men; and high psychological demands and fatigue in women. As regards psychological distress, there was no association with low decision latitude, but strong associations with emotional demands and conflict with supervisor in both genders. CONCLUSIONS: The study provides strong support for associations between psychosocial work characteristics and fatigue in men and women, even after adjustment for psychological distress. Moreover, it suggests some differential effects of psychosocial work characteristics on fatigue and psychological distress.     

Myocardial reperfusion injury and oxidative stress: Therapeutic opportunities

Acute myocardial infarction(AMI) is the leading cause of death worldwide. Its associated mortality, morbidity and complications have significantly decreased with the development of interventional cardiology and percutaneous coronary angioplasty(PCA) treatment, which quick-ly and effectively restore the blood flow to the area previously subjected to ischemia. Paradoxi-cally, the restoration of blood flow to the ischemic zone leads to a massive production of reactive oxygen species(ROS) which generate rapid and severe damage to biomolecules, generating a phenomenon called myocardial reperfusion injury(MRI). In the clinical setting, MRI is associated with multiple complications such as lethal reperfusion, no-reflow, myocardial stunning, and reperfusion arrhythmias. Despite significant advances in the understanding of the mechanisms accounting for the myocardial ischemia reperfusion injury, it remains an unsolved problem. Although promising results have been obtained in experimental studies(mainly in animal models), these benefits have not been translated into clinical settings. Thus, clinical trials have failed to find benefits from any therapy to prevent MRI. There is major evidence with respect to the contribution of oxidative stress to MRI in cardiovascular diseases. The lack- of consistency between basic studies and clinical trials is not solely based on the diversity inherent in epidemiology but is also a result of the methodological weak-nesses of some studies. It is quite possible that pharmacological issues, such as doses, active ingredients, bioavailability, routes of administration, co-therapies, startup time of the drug intervention,and its continuity may also have some responsibility for the lack- of consistency between different studies. Furthermore, the administration of high ascorbate doses prior to reperfusion appears to be a safe and rational therapy against the development of oxidative damage associated with myocardial reperfusion. In addition, the association with N-acetylcysteine(a glutathione donor) and deferoxamine(an iron chelator) could improve the antioxidant cardioprotection by ascorbate, mak-ing it even more effective in preventing myocardial reperfusion damage associated with PCA following AMI.     

Primary Sclerosing Cholangitis: A Clinical Review

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by fibro-obliterative inflammation of the entire biliary tree. It is a slowly progressive disease with an undulating course, resulting in terminal biliary cirrhosis after a median period of about 12 years after diagnosis. The etiology of the disease is unknown and there is no effective therapy that can halt disease progression. Around 8% of PSC patients develop cholangiocarcinoma, which, by the time it is diagnosed, cannot be treated curatively. The purpose of this article is to review the current knowledge about primary sclerosing cholangitis and to speculate on future strategies to address the issues of etiology and therapy.