ABSTRACT
AIMS: Insufficient erythropoietin (EPO) synthesis is a relevant cause of renal anaemia in patients with chronic kidney disease. Molidustat, a selective hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, increases endogenous EPO levels dose dependently in preclinical models. We examined the pharmacokinetics, safety, tolerability and effect on EPO levels of single oral doses of molidustat in healthy male volunteers. METHODS: This was a single-centre, randomized, single-blind, placebo-controlled, group-comparison, dose-escalation study. Molidustat was administered at doses of 5, 12.5, 25, 37.5 or 50 mg as a polyethylene glycol-based solution. RESULTS: In total, 45 volunteers received molidustat and 14 received placebo. Molidustat was absorbed rapidly, and the mean maximum plasma concentration and area under the concentration-time curve increased dose dependently. The mean terminal half-life was 4.64-10.40 h. A significant increase in endogenous EPO was observed following single oral doses of molidustat of 12.5 mg and above. Geometric mean peak EPO levels were 14.8 IU l-1 (90% confidence interval 13.0, 16.9) for volunteers who received placebo and 39.8 IU l-1 (90% confidence interval: 29.4, 53.8) for those who received molidustat 50 mg. The time course of EPO levels resembled the normal diurnal variation in EPO. Maximum EPO levels were observed approximately 12 h postdose and returned to baseline after approximately 24-48 h. All doses of molidustat were well tolerated and there were no significant changes in vital signs or laboratory safety parameters. CONCLUSIONS: Oral administration of molidustat to healthy volunteers elicited a dose-dependent increase in endogenous EPO. These results support the ongoing development of molidustat as a potential new treatment for patients with renal anaemia.
Subject(s)
Anemia/drug therapy , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Prolyl-Hydroxylase Inhibitors/administration & dosage , Pyrazoles/administration & dosage , Renal Insufficiency, Chronic/complications , Triazoles/administration & dosage , Administration, Oral , Adult , Anemia/blood , Anemia/etiology , Area Under Curve , Erythropoietin/blood , Half-Life , Healthy Volunteers , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Male , Prolyl-Hydroxylase Inhibitors/adverse effects , Prolyl-Hydroxylase Inhibitors/pharmacokinetics , Proof of Concept Study , Pyrazoles/adverse effects , Pyrazoles/pharmacokinetics , Renal Insufficiency, Chronic/blood , Single-Blind Method , Triazoles/adverse effects , Triazoles/pharmacokinetics , Young AdultABSTRACT
The German regulations for opioid prescriptions have been changed in February 1998. The regulations have been made much more easier and should therefore have improved the pain management in Germany. We investigated the knowledge of the WHO analgesic ladder and how they have been followed in a nation-wide survey among physicians not specialised in pain management. Only 9% of the questionnaires were returned. Although the majority of the physicians (93%) reported knowledge about the WHO recommendations for the treatment of cancer pain, more than 15% of the participating physicians rated transdermal fentanyl as a weak opioid or even as a non-opioid. A negative pain management index in 15% of the patients gave evidence of poor quality in pain management. The majority of patients (84%) did not receive immediate release analgesics for the treatment of breakthrough pain. Continuous medical education is still necessary before a further alleviation of regulations will help to reduce the undertreatment of patients suffering from cancer pain in Germany.
Subject(s)
Analgesics, Opioid/therapeutic use , Neoplasms/physiopathology , Pain/drug therapy , Aged , Analgesics, Opioid/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug and Narcotic Control/legislation & jurisprudence , Female , Germany , Humans , Male , Middle Aged , Palliative Care , Patient Care Team , Quality Assurance, Health Care , Surveys and Questionnaires , Treatment Outcome , World Health OrganizationABSTRACT
Oral vaccination against poliomyelitis, which was carried out worldwide, lead to eradication of poliomyelitis in the United States, in South America and parts of Europe; in other parts of the world, paralytic poliomyelitis is still a severe risk of health. In those countries where poliomyelitis has been eradicated, it is presently discussed whether the vaccination schedules should be changed to an inactivated polio vaccine (IPV), as in polio-free countries only cases of paralytic poliomyelitis after vaccinations have been reported. Behringwerke's data from a 30-year period of analysing adverse drug reaction reveal the following: using the trivalent oral polio vaccine (OPV), based on WHO case definition, the risk for vaccine-associated paralytic poliomyelitis with permanent damage is approximately 1 case for 4.5 million vaccinations (0.22 per million) in vaccinees, and approximately 1 case for 11 million (0.09 per million) in contact persons. This low risk is in line with the data ascertained worldwide.
