Pharmacokinetics of the anxiolytic beta-carboline derivative abecarnil in the mouse, rat, rabbit, dog, cynomolgus monkey and baboon. Studies on species differences

The pharmacokinetics of abecarnil (isopropyl 6-(benzyloxy)-4-(methoxymethyl)-9H-pyrido [3,4-b] indole-3-carboxylate, ZK 112 119) were studied in the mouse, rat, rabbit, dog, cynomolgus monkey and baboon using 14C-labeled drug and HPLC with fluorescence detection for measurement of unchanged drug. Abecarnil was rapidly and completely absorbed after oral doses of 10 mg/kg. At higher doses, absorption was prolonged and incomplete in the cynomolgus monkey. The bioavailability of abecarnil was 20-30% in all the species investigated. The terminal half-life of the unchanged drug in plasma was relatively similar in all species (0.6-1.7 h). Abecarnil was able to pass the blood-brain barrier achieving concentrations in the brain similar to those in plasma. Tissue distribution of labeled compounds was rapid with highest concentrations in the liver, adrenals, kidneys and pancreas followed by the bone marrow, lungs, heart, fat, spleen, ovaries and thyroid gland. Excretion of radiolabeled compounds proceeded predominantly in the feces of the rat, the rabbit and the cynomolgus monkey.     

Ein Fragebogen zur infertilitätsbedingten Belastung andrologischer Patienten

The infertility distress scale (IBS) has been designed to assess the stress perceived by andrological patients resulting from infertility. This review presents findings from different studies with a total of 769 patients. The scale consists of eight items. The stability of scores is very high even for a mean follow-up of 2 years. The scale correlates highly with an already validated measure of infertility distress. Correlations with measures of depressiveness are in the low to medium range. All in all, the psychometric results indicate that the IBS is a factor-stable, reliable and valid instrument for assessing chronic infertility distress in andrological patients. After the presentation of normative data, the usefulness of the IBS as a screening instrument for identifying highly distressed patients is discussed. Findings supporting the scale's sensitivity to change are also presented. The scale is a useful tool in clinical practice as well as in research.     

THE EFFECT OF HYPERTENSIVE EPISODES AND CARDIAC HYPERTROPHY ON THE CANINE CARDIAC BAROREFLEX

1. Left ventricular (LV) hypertrophy has been implicated in the reduction of baroreflex sensitivity present in hypertension. The aim of the current study was to investigate the mean arterial pressure-heart rate reflex (MAP-HR) in a model which induced left ventricular hypertrophy but no sustained blood pressure elevation. 2. Five mongrel dogs were exposed to transient blood pressure elevation of between 20 and 30 mmHg, through hindlimb compression using a pneumatic pressure suit, for 7 h per day, 6 days per week for 6 weeks. Resting blood pressure was not altered by the 6 week hindlimb compression intervention. 3. Echocardiographically determined LV mass (mean ± s.e.m.) was 116.0 ± 7.4 g prior to hindlimb compression (baseline) and elevated to 125.4 ± 8.1 g (P= 0.003) after 6 weeks of compression. A reduction in the early (E) to late (A) transmitral diastolic flow ratio (E/A) from 1.80 ± 0.06 at baseline to 1.54 ± 0.09 (P = 0.037) after the 6 week intervention suggested that cardiac compliance was reduced. 4. The maximum gain of the MAP-HR reflex, studied using the ‘steady-state’ drug technique, when blood pressure was normal, showed a trend for reduction from 3.85 ± 0.43 beats/min per mmHg at baseline to 3.10 ± 0.45 beats/min per mmHg (P= 0.067) after 6 weeks of compression. This gain reduction became significant after β-adrenoceptor blockade with propranolol (3.13 ± 0.55 vs 2.32 ± 0.25 beats/min per mmHg; P= 0.039). Covariant analysis showed a significant inverse correlation between LV mass and maximum gain (r= 0.96; P<0.001) during the 6 week compression period. 5. The MAP-HR reflex changes in this model mimic those present in hypertension and implicate cardiac hypertrophy as one possible mediator.     

Risk of acquiring influenza A in a nursing home from a culture-positive roommate.

Influenza A was cultured in 62 double rooms. The roommate was infected in 12 (19.4%). During 3,294 resident-seasons, influenza was cultured in 208 single rooms (6.3%). Those who lived in double rooms with a culture-positive roommate had a 3.07 relative risk (CI95, 1.61-5.78) of acquiring influenza.     

Applicability of the SHBG androgen sensitivity test in the differential diagnosis of 46,XY gonadal dysgenesis, true hermaphroditism, and androgen insensitivity syndrome.

The sex hormone-binding globulin (SHBG) androgen sensitivity test has been used as a simple method to assess androgen receptor function in vivo. After a short term oral administration of the anabolic-androgenic steroid stanozolol the mean nadir serum concentration of SHBG is used as a measure of androgen response. We performed this test in order to evaluate its applicability in 16 patients with intersexual genital status: eleven with 46,XY gonadal dysgenesis and three with true hermaphroditism (group I), and in two patients with androgen insensitivity syndrome (AIS, group II). Ten healthy adult volunteers served as controls. In the two patients with AIS (group II) we found a diminished decrease of serum SHBG to 80.1 % and 80.7 %, respectively, indicating slight residual androgen responsiveness. In eleven patients of group I who were not on hormone replacement therapy, a mean nadir level of 51.7 +/- 8.7 % was found. In the controls the mean nadir serum SHBG level was significantly higher (62.7 +/- 5.2 %), probably due to interference of endogenous androgens and contraceptive medication with the stanozolol-induced SHBG decrease. In three gonadectomised patients who were on hormone replacement therapy the initial SHBG concentration was increased (513.5 +/- 239.1 nmol/l); the mean nadir SHBG concentration of 45.6 +/- 9.8 % of the initial level indicates an increased sensitivity of the test in patients in whom the counteracting ovarian androgens are absent. Our findings confirm that under standard test conditions the SHBG androgen sensitivity test is a simple diagnostic tool for the detection of androgen receptor malfunction.     

Long-term benefit to pallidal deep brain stimulation in a case of dystonia secondary to pantothenate kinase-associated neurodegeneration.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal recessive disorder with onset in childhood and rapid progression. There is no causative and insufficient symptomatic drug therapy. Deep brain stimulation (DBS) of the internal pallidum (GPi) has been reported to improve motor function. Most case reports, however, are limited to short observational periods. The impact of DBS on the progression and life expectancy in PKAN is unknown. We present a 5-year outcome and video documentation of bilateral GPi-DBS of an adolescent patient suffering from genetically defined PKAN.     

Quantitative whole-body autoradiographic analysis of the tissue distribution of orally-administered [14C]cholesterol in hypercholesterolemic rats

The cholesterol-fed rat model has been used to examine the distribution of radiolabeled cholesterol by whole-body autoradiographic and quantitative videodensitometric methods. Animals were fed a hypercholesterolemic diet for 7 days, and were subsequently killed at 3, 6, 12, 24, or 72 h following a single oral dose of [14C]cholesterol. Maximum blood and tissue levels were observed at 12 h, while liver and adrenals were the most intensely labeled tissues. Liver maintained consistently high levels over the course of the study, while activity in other tissues declined moderately by 72 h, indicating the long half-life of cholesterol radioequivalents in tissue. The results of these experiments suggest that autoradiographic examination of cholesterol distribution in animals treated with pharmaceutical agents designed to modify cholesterol absorption or clearance will be useful in providing supplemental or confirmatory information on the drugs' mode of action.