Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656

The anticholinergic antiparkinson drug orphenadrine is an antagonist at central and peripheral muscarinic receptors. Orphenadrine intake has recently been linked to QT prolongation and Torsade-de-Pointes tachycardia. So far, inhibitory effects on I _Kr or cloned HERG channels have not been examined. HERG channels were heterologously expressed in a HEK 293 cell line and in Xenopus oocytes and HERG current was measured using the whole cell patch clamp and the double electrode voltage clamp technique. Orphenadrine inhibits cloned HERG channels in a concentration dependent manner, yielding an IC₅₀ of 0.85 μM in HEK cells. Onset of block is fast and reversible upon washout. Orphenadrine does not alter the half-maximal activation voltage of HERG channels. There is no shift of the half-maximal steady-state-inactivation voltage. Time constants of direct channel inactivation are not altered significantly and there is no use-dependence of block. HERG blockade is attenuated significantly in mutant channels lacking either of the aromatic pore residues Y652 and F656. In conclusion, we show that the anticholinergic agent orphenadrine is an antagonist at HERG channels. These results provide a novel molecular basis for the reported proarrhythmic side effects of orphenadrine.     

Randomized placebo-controlled trial of metformin for adolescents with polycystic ovary syndrome

OBJECTIVE: To determine whether metformin or placebo could, in conjunction with healthy lifestyle counseling, decrease serum testosterone levels and related aberrations in adolescents with hyperandrogenism, hyperinsulinemia, and polycystic ovarian syndrome. DESIGN: Randomized, placebo-controlled, double-blind trial. SETTING: Pediatric university teaching hospital. PARTICIPANTS: Twenty-two adolescents aged 13 to 18 years with hyperinsulinemia and polycystic ovarian syndrome. INTERVENTION: Participants were randomly assigned to take a 12-week course of either metformin or placebo. MAIN OUTCOME MEASURES: Pretreatment and posttreatment oral glucose tolerance tests, fasting lipid profiles, and clinical measurements. RESULTS: There was a significant decline in mean serum testosterone concentration with metformin (-38.3 ng/dL) compared with placebo (-0.86 ng/dL) (95% confidence interval, -infinity to -0.29 for the mean difference between groups). At completion, the relative risk of menses was 2.50 times higher in the metformin group compared with the placebo (95% confidence interval, 1.12 to 5.58). Measures of insulin sensitivity, including insulin area under the curve and HOMA (homeostasis model assessment), demonstrated improvement only with metformin, but these did not reach statistical significance. High-density lipoprotein cholesterol levels increased by 6.98 mg/dL with metformin vs a decrease of -2.33 mg/dL with placebo (95% confidence interval, 0.78 to 18.23 for the mean difference between groups). There were no significant changes in body mass index, hirsutism, triglyceride levels, or total and low-density lipoprotein cholesterol levels. CONCLUSION: Metformin significantly lowered total testosterone concentrations, increased the likelihood of menses, and improved high-density lipoprotein cholesterol levels without affecting measures of insulin sensitivity or body weight.     

Concomitant oral findings in children after cardiac transplant

Heart transplantations have been performed in the Centre for Paediatric Heart Surgery at the Justus Liebig University in Giessen (Germany) since 1988. For further consultation and therapy, some affected children subsequently present at the Polyclinic for Paediatric Dentistry. In all these cases problematic oral findings were diagnosed. It was the aim of this study to describe the different findings and to create a concept for avoiding them in the future. Altogether, 10 children with cardiac transplants (three girls, seven boys) were examined and, where necessary, treated. At the time they first presented, they were between 23 and 119 months old (average = 72.2) and had all been operated on (organ transplant) in the first 6 months of life. Each child showed evidence of gingival hyperplasia in the area of the front teeth, which was because of ongoing immunosuppression. In three patients, reactive mucosal caps avoided the age-related penetration of a permanent incisor in the upper jaw. In addition, the primary teeth of six children were affected by caries; in two of these cases, the damage was because of the nursing-bottle syndrome. The results show that any infant with cardiac transplant has to be subjected to careful dental examination and offered comprehensive medical care in cooperation with the competent centre for child cardiac surgery. Furthermore, the parents of such children should be informed prior to transplantation about the possibility of subsequent findings and how these findings can be either avoided or, if necessary, adequately treated.     

A modified version of tinnitus retraining therapy: observing long-term outcome and predictors

Tinnitus retraining therapy (TRT) in Germany includes not only directive counseling and sound therapy but also stress management and facultative psychotherapeutic treatment. The aim of the present study was to investigate the impact of this modified version of TRT on certain tinnitus-related aspects of distress and variables that may predict treatment outcome. Clinical data from 92 patients undergoing outpatient TRT in the Charité Tinnitus Centre were evaluated retrospectively over 1 year. Treatment outcome was defined by changes in specific areas of tinnitus-related distress and assessed by the Tinnitus Questionnaire. Changes in audiometric frequency and loudness of tinnitus were examined by regular audiometric testing. The overall Tinnitus Questionnaire score was significantly reduced after 1 year. Severely affected tinnitus sufferers (decompensated tinnitus) profited more than less affected patients (compensated tinnitus). In cases of indicated psychotherapy, improvement was significant for the patients who took advantage of psychotherapeutic treatment during TRT but was not significant for those who interrupted or dismissed an indicated psychotherapy. Changes in tinnitus-specific areas of distress were most pronounced in the scales for emotional and cognitive distress and intrusiveness. Significant changes in sleep disturbances, auditory perceptual difficulties and somatic complaints were observed in patients with decompensated tinnitus. In patients with chronic tinnitus, modified TRT may lead to significant subjective improvement in certain tinnitus-related symptoms like emotional and cognitive distress and intrusiveness. Particularly patients suffering from severe tinnitus distress take advantage of therapy. Careful psychotherapeutic diagnostics and therapies and, if necessary, motivation to make use of psychotherapy seem to be essential preconditions for therapeutic success in patients with severe psychosomatic comorbidity.     

Insulin: a model system for nanomedicine?

One of the predominant aims of insulin therapy for diabetes is to appropriately mimic physiological insulin secretion levels and their correlation with glucose concentration in healthy individuals. This report outlines current methods and their limitations in glycemic control and their possible relationship to insufficient knowledge about the structure and dynamics of the insulin hormone itself. Based on recent experimental and computational work, a possible approach to less-invasive insulin administration is sketched.     

Physician-induced torsade de pointes--therapeutic implications

Torsade de pointes (TdP) is a clinico-electrocardiographic syndrome characterized by an abnormally prolonged QT interval and the occurrence of potentially life-threatening ventricular tachyarrhythmias. Two mayor causes can be distinguished: congenital and acquired long QT syndrome. Whereas the former has recently been identified as an ion channelopathy, the mechanisms underlying acquired long QT syndrome are far from being understood. It has been suggested that patients with the acquired form of the disease may suffer from a clinically hidden form of the congenital variant. However, recent studies have yielded only a small number of individual cases in whom genetic analyses revealed the presence of an ion channel gene mutation.Since acquired long QT syndrome is most often induced by drugs prolonging myocardial repolarization, it is largely an iatrogenic disease. In order to prevent unwitting exposure to risk, physicians prescribing agents that may prolong repolarization need to be aware of the typical clinico-electrocardiographic characteristics of drug-induced TdP, and its diagnosis and management. A clearer delineation of the risk factors predisposing to abnormal prolongation of repolarization, and a more precise quantification of the torsadogenic potency of individual drugs appear mandatory in order to prevent or at least minimize the occurrence of this potentially fatal adverse effect of certain drugs.