Pharmacokinetic analysis of pegylated megakaryocyte growth and development factor in humans

Phase I studies with pegylated megakaryocyte growth and development factor (PEG-rHuMGDF), a c-Mpl ligand that stimulates megakaryopoiesis, have demonstrated that PEG-rHuMGDF is biologically active alone and causes a dose-related enhancement of platelet recovery when administered after chemotherapy. Here we report the dose-ranging pharmacokinetics of PEG-rHuMGDF. Pre-injection blood samples were drawn daily for pharmacokinetic studies on 43 patients. An ELISA, established using PEG-rHuMGDF as the standard, was able to quantitate Mpl ligand at concentrations > 0.02 ng/mL. Over the dose range 0.03 to 5.0 microg/kg/day, subcutaneous administration produced linear increases in steady-state serum levels. Maximum levels of PEG-rHuMGDF attained after 5.0 microg/kg/day were 5.88 to 10.9 ng/mL. After discontinuation of PEG-rHuMGDF, concentrations of Mpl ligand returned to baseline within 5 days. The pharmacokinetics were best described by a one-compartment model with first-order absorption, an absorption delay, and non linear clearance over the first 48 hours. The mean terminal half-life was 33.3 + 16.7 hours, and the average apparent at steady state was 27.7 + 14.0 mL/h/kg; both were independent of administered dose. The apparent clearance of PEG-rHuMGDF was not predicted by platelet count. Administration of chemotherapy and Filgrastim did not alter the pharmacokinetics of PEG-rHuMGDF.     

Neural regulation of electrical and mechanical activities in the rat tail artery

Stimulation of the perivascular nerves elicited two types of electrical responses in the rat tail artery—excitatory junction potentials (e.j.p.s) and slow depolarization—and two types of mechanical responses—fast and slow contractions. Fast phasic contractions were triggered whenever action potentials were generated from either the e.j.p. or the slow depolarization reaching threshold. Slow tonic contractions and slow depolarizations were sensitive to -adrenergic blockade. However the slow contraction always preceded the slow depolarization. Bolus doses of exogenous noradrenaline also induced slow contraction and slow depolarization and the development of tension also preceded the membrane potential change. Increasing the external KCl also induced membrane depolarization however, contractions were not observed until the membrane was depolarized positive of –49 mV. In contrast, tension developed readily with membrane potential more negative than –49 mV with exogenous noradrenaline and neural stimulation, suggesting that the action of noradrenaline was not mediated by electromechanical coupling. It was concluded that vascular activity in the rat tail artery could be regulated by the e.j.p., the slow depolarization and also by pharmacomechanical coupling.     

Jasmine green tea epicatechins are hypolipidemic in hamsters (Mesocricetus auratus) fed a high fat diet.

These studies were designed to test the hypolipidemic activity of green tea epicatechins (GTE) isolated from jasmine green tea. In Experiment 1, three groups of hamsters were given a semisynthetic diet containing 200 g lard/kg and 1 g cholesterol/kg for 4 wk. The control group received distilled water, and the other two groups received either 15 g/L green tea water extract (GTWE) or 5.0 g/L GTE solution. Both the GTWE and GTE groups had lower concentrations of serum total cholesterol (TC) and triacylglycerols (TG) than the controls (P < 0.05). In Experiment 2, four groups of hamsters received tap water as the drinking fluid, but they were given the same high fat and cholesterol diet supplemented with 0 (control), 1.1, 3.4 or 5.7 g GTE/kg diet. The hypolipidemic effect of jasmine GTE was dose dependent. In Experiment 3, the time-course of changes in serum TC and TG was monitored in hamsters given the high fat diet supplemented with 5.7 g GTE/kg in comparison with that of controls. The hypolipidemic effects of dietary GTE were evident after feeding for 2 wk. Dietary supplementation of GTE did not affect liver fatty acid synthase. However, GTE-supplemented hamsters had higher fecal excretions of total fatty acids, neutral sterols and acidic sterols compared with the control group. In Experiment 4, hamsters were fed nonpurified diet; the control group drank distilled water, and the GTE group drank distilled water containing 5.0 g GTE/L. No differences in activities of 3-hydroxy-3-methyl glutaryl coenzyme A reductase and intestinal acyl CoA:cholesterol acyltransferase were observed. This study suggests that the hypolipidemic activity of GTE is not due to inhibition of synthesis of cholesterol or fatty acid but is most likely mediated by its influence on absorption of dietary fat and cholesterol.     

Hypertrophic olivary degeneration following surgical excision of brainstem cavernous hemangioma: a case report

Hypertrophic olivary degeneration (HOD) is a rare type of neuronal degeneration involving the dento-rubo-olivary pathway. It is distinguished from other types of neuronal degeneration in that hypertrophy, rather than atrophy, takes place in the neurons in the inferior olivary nucleus. Prior to the invention of Magnetic Resonance Imaging (MRI), HOD was difficult to be detected, and a firm diagnosis could only be made at autopsy. We present a case of bilateral HOD following surgical excision of a cavernous hemangioma in the brainstem. The literature and imaging findings of this uncommon condition are reviewed.     

Cognitive Behavioral Therapy of Minor Depressive Symptoms in Elderly Chinese Americans: A Pilot Study

There is a high prevalence of suicide amongelderly Chinese, and particularly among elderly Chinesewomen in Mainland China with a prevalence of 19.6 perhundred thousand. Since Chinese individuals may much more highly value education, acognitive-behavioral package originated by RicardoMunoz, Ph.D. was adapted for Chinese American subjects.The material was videotaped in eight sessions,approximately 25 minutes in length, to be shown to communitysubjects who were at least 40 years and over. Inaddition, a videotape of muscular relaxation techniqueswas made. A manual written in Chinese about the content of each class, was given to each subject whenhe/she attended. The experimental group showedsignificant improvement in the scores in the HamiltonDepression Scale, including the Somatic Subscale in the Hamilton Anxiety Scale. There was nosignificant improvement in the control group on any ofthe measures. Thus the study suggests the efficacy ofpsychoeducational classes in reducing symptoms ofdepression in non-patient community elderly. Other studiesare being conducted among Korean Americans and JapaneseAmericans in the United States, and also in the Orientamong Japanese elderly.     

Buprenorphine pharmacokinetics: relative bioavailability of sublingual tablet and liquid formulations.

Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM-III-R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration-time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.