Design of pharmacogenetic studies of drug metabolism.
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Biomedical subjects
Publications and source records attributed to E Nelson.
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The pharmacokinetics and bioavailability of phenobarbital were examined in six healthy adult subjects after a 2.6 mg/kg intravenous and a 2.9 mg/kg oral dose. Serum concentrations of phenobarbital were followed by means of a high pressure liquid chromatographic assay for 21 days after drug administration. After the intravenous dose, the mean distribution half-life was 0.18 hour and the mean elimination half-life was 5.8 days. Mean total body clearance and mean renal clearance were 3.0 ml/hr/kg and 0.8 ml/hr/kg, respectively. The apparent volume of distribution was 0.60 liter/kg. After administration of phenobarbital tablets, the maximum phenobarbital serum concentration was 5.5 mg/liter at 2.3 hours after the dose. Adjusted absolute availability of phenobarbital from the tablets studied was 94.9 per cent (range 81-111.9 per cent). The elimination half-life averaged 5.1 days for the oral dose. There was no evidence of autoinduction of phenobarbital elimination over the study period.
Three-day-old chick embryos (Hamburger-Hamilton stages 18-19) were exposed to a dose of ethyl alcohol (0.32 ml of 50% ethanol) that causes cardiac malformations in 96.6% of the animals. Ethanol was administered into the air sac after 72-80 h of incubation. Samples of albumin at the opposite pole of the egg were drawn 0-50 h after treatment and quantitated for ethanol concentration with capillary gas-liquid chromatography. Ethanol concentrations in the albumin increased significantly (P < 0.05) at 2, 5 and 15 h after injection of ethanol, reached a maximum mean ethanol concentration at 20 h (217.3 +/- 23.5 mg dl-1), decreased significantly at 30 h to 175.4 +/- 27.5 mg dl-1, then increased again and stabilized at 40-50 h. Individual sample concentrations ranged from 0 mg dl-1 (at 0.5-2 h) to 286.5 mg dl-1 at 40 h. Ethanol concentrations in the albumin were comparable to human blood alcohol levels during intoxication (> 150 mg dl-1). Our results suggest that a potent cardioteratogenic dose of ethanol in the chick embryo is reasonable in terms of potential human embryo exposure.
Our studies indicate that, in the presence of particular isoforms of adenylyl cyclase (i.e., type 7 AC), moderately intoxicating concentrations of ethanol will significantly potentiate transmitter-mediated activation of the cAMP signaling cascade. Activation of this signaling cascade may have important implications for the mechanisms by which ethanol produces intoxication, and/or for the mechanisms of neuroadaptation leading to tolerance to, and physical dependence on, ethanol. We initiated a series of studies to investigate the phosphorylation of AC7 by PKC, the role of this phosphorylation in modulating the sensitivity of AC7 to activation by Gsalpha, and the PKC isotype(s) involved in the phosphorylation of AC7. The T7 epitope-tagged AC7 expressed in Sf9 and HEK293 cells was found to be phosphorylated in vitro by the catalytic subunit of PKC. Treatment of AC7-transfected HEK293 cells with phorbol dibutyrate (PDBu) or ethanol increased the phosphorylation of AC7 and its responsiveness to Gsalpha. In human erythroleukemia (HEL) cells, which endogeneously express AC7, ethanol and PDBu increased AC activity stimulated by PGE(1). The potentiation by both PDBu and ethanol was found to be sensitive to the PKC delta-selective inhibitor, rottlerin. The potentiation of AC activity by ethanol in HEL cells was also selectively attenuated by the RACK inhibitory peptide specific for PKC delta, and by expression of the dominant negative, catalytically inactive, form of PKC delta. These data demonstrate that AC7 can be phosphorylated by PKC, leading to an increase in functional activity, and ethanol can potentiate AC7 activity through a PKC delta-mediated phosphorylation of AC7.
Pathologic hair-pulling (trichotillomania) has been described in the dermatologic and psychiatric literature for the last century, but has become the focus of increased attention in the last few years. Once thought to be either a wholly benign condition or a symptom of obsessive-compulsive disorder, more recently hair-pulling has been noted in the context of numerous types of psychopathology, and has been reported to respond to several different types of intervention, both psychological and somatic. Estimates of its prevalence have varied widely. Because of the disparate conclusions of the literature on this condition, a more careful assessment of diagnostic validity is recommended.
Both in vitro and in vivo methods are used to test the validity of techniques for storing platelet concentrates for transfusion. In this study, the characteristics of platelet concentrates stored for 5 days at 22 degrees C in two different containers were evaluated by paired comparison using two in vitro measurements and two in vivo measurements. On two occasions, 10 normal subjects donated concentrates that were stored in containers of either the CLX system or the PL-146 system. The first plastic used was chosen at random. If necessary, a concentrate platelet count was reduced to 1,200,000 per microliters by addition of plasma to avoid pH fall. Mean recoveries were 48.2 +/- 10.6 percent (mean +/- 1 SD) and 42.4 +/- 7.8 percent for platelets stored in containers of the CLX and PL-146 systems, respectively. Similarly, survivals (T 1/2 in days) were 3.4 +/- 0.8 and 3.0 +/- 0.7, respectively. Since a paired design was used, the superiority of the CLX system was demonstrable with a one-tailed paired t test. If a paired design had not been used, a pooled t test would have been appropriate and the differences would not have been significant. This result emphasizes the value of the paired design. Furthermore, two in vitro measurements that reflect platelet morphology, dispersion of the size distribution and extent of shape change with adenosine diphosphate, were superior for platelets stored in CLX containers as well, suggesting a relationship between these measurements and in vivo viability.(ABSTRACT TRUNCATED AT 250 WORDS)
The clinical pharmacokinetics and pharmacodynamics of enalapril and its de-esterified active metabolite, MK 422, were determined in eight patients with congestive cardiomyopathy and five patients with hypertension. After administration of single doses of 2.5, 5, and 10 mg enalapril in the congestive heart failure patients and 20 or 40 mg in the hypertensive patients, serum levels and urine elimination of enalapril and MK 422 were determined. Standing and supine heart rate and blood pressure were measured as was ejection fraction in the congestive heart failure group and renin activity, aldosterone levels, and converting enzyme activity in the hypertensive group. Apparent oral clearance after administration of 5 and 10 mg enalapril was lower in the congestive heart failure patients (0.6 +/- 0.2 and 0.7 +/- 0.4 L/min) than after 20 and 40 mg given to hypertensive patients (2.5 +/- 1.3 and 2.7 +/- 2.7 L/min). The elimination of MK 422 was also slower in the congestive heart failure patients (7.8 +/- 5.0 and 6.8 +/- 2.5 h after 5 and 10 mg enalapril, respectively, vs. 4.6 +/- 2.0 and 5.3 +/- 1.1 h after 20 and 40 mg, respectively, in the hypertension group). The enalapril area under the concentration-time curve increased disproportionately to dose increments in both groups, but was more pronounced in congestive heart failure. Twenty and 40 mg enalapril lowered the blood pressure by 2 h after dosing in the hypertension group, and peak effects were seen 4-5 h after dosing. Peak effects correlated with peak serum MK 422 concentrations but not with enalapril (MK 421) levels. Supine heart rates were unchanged after 20 mg, but increased after 40 mg; standing heart rates were transiently increased after 20 and 40 mg enalapril. Blood pressure was not significantly changed in the congestive heart failure group, and cardiac ejection fraction was unchanged. In the hypertension group, renin stimulation and converting enzyme activity inhibition were seen at 4 h and persisted for at least 24 h after administration of 40 mg enalapril. In summary, the clearance of enalapril and elimination of MK 422 was slower in congestive heart failure patients versus hypertensive patients. Therefore, slower onset and longer duration of drug effect might be anticipated in patients with congestive heart failure versus patients with hypertension during enalapril administration.
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Scanning electron microscopic observations of the luminal surface of the rabbit common carotid artery subjected to occlusion for 30 minutes or two hours revealed crater-like and balloon-like defects in the endothelial surface. The frequency of occurrence of these abnormalities was significantly decreased by pretreatment with heparin or aspirin in doses considered to have antiplatelet aggregating activity.
Shoulder rotator cuff impingement syndrome is a common and disabling problem for the wheelchair athlete. In this study we investigated the role of shoulder strength imbalance as a factor for the development of this syndrome. Nineteen paraplegic male athletes underwent clinical and isokinetic examination of both shoulders with peak torque values measured in abduction, adduction, and internal and external rotation. Twenty athletic, able-bodied men without shoulder problems were tested as controls. Ten (26%) of the paraplegic athletes had rotator cuff impingement syndrome. The results of the isokinetic testing demonstrated that 1) the paraplegics' shoulders were stronger than the controls in all directions (P < 0.05); 2) the strength ratio of abduction: adduction was higher for paraplegic athletes (P < 0.05); 3) paraplegics' shoulders with rotator cuff impingement syndrome were weaker in adduction and external and internal rotation than the paraplegic athletes without impingement syndrome (P < 0.05); and 4) paraplegics' shoulders with rotator cuff impingement syndrome had higher abduction:adduction and abduction:internal rotation strength ratios than the shoulders of paraplegics without impingement syndrome (P < 0.05). We concluded that shoulder muscle imbalance, with comparative weakness of the humeral head depressors (rotators and adductors), may be a factor in the development and perpetuation of rotator cuff impingement syndrome in wheelchair athletes.
PURPOSE: The purpose of this study was to compare the incidence and progression of periodontal disease in HIV-infected children to HIV-negative household peers. This paper reports the findings after two years. METHODS: Children diagnosed as HIV-infected and their household peers were recruited from the Children's Hospital AIDS Program in Newark NJ. A periodontal examination was performed at baseline and at six-month intervals for two years. A total of 121 subjects were examined two years after baseline (68 HIV-infected and 53 controls). These children ranged in age from 2-15 years at baseline. RESULTS: Plaque assessment (PHP-M) in HIV-infected cases showed a seven-fold increase over controls for the period. However, there were no significant differences between the two groups in changes over the two years for Bleeding on Probing, Gingival Index or Pocket Depths. There was virtually no recession or pathologic mobility in either group. One-fourth of the HIV-infected group exhibited Linear Gingival Erythema at both baseline and year two. Although the number of subjects with LGE did not increase, there was an increase in the severity of LGE at year 2. CONCLUSION: This study suggests that in a medically well-controlled HIV-infected population, with the exception of the prevalence of Linear Gingival Erythema, the periodontal findings are similar to their HIV-negative household peers and to the general pediatric population.
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This study describes mothers' choice between General Practitioner (GP) and hospital clinics for the six week postnatal check and elucidates influencing factors for their choice, using structured interviews with mothers within one week of discharge from hospital. Intended uptake of the six week check was high overall. For mother's own check, 203 (45%) planned to attend hospital clinics and 116 (26%) planned to attend the GP, while for the baby's check 115 (26%) planned to attend hospital clinics and 245 (55%) planned to attend the GP. The remainder planned to attend a consultant privately or had been referred to the specialised gynaecological/paediatric clinic. Factors influential for those choosing GPs were: convenience, familiarity and opportunity for discussion. Hospital instructions and the expected quality of examination were important for those choosing the hospital. Some possible misconceptions regarding provision of aspects of postnatal care were uncovered. This study highlights underuse of the GP service for the routine six week check and makes recommendations in relation to this.
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