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Biomedical subjects

J Posner

Publications and source records attributed to J Posner.

At least 73 records · Page 4Linked to original sources
PubMed1988

A preliminary study of the pharmacodynamics and pharmacokinetics of a novel enkephalin analogue [Tyr-D.Arg-Gly-Phe (4NO2).Pro.NH2 (BW443C)] in healthy volunteers.

We have studied 16 healthy men to evaluate preliminary pharmacodynamics and kinetics of BW443C given by i.v. infusions. Four volunteers received escalating doses at weekly intervals, starting at 0.1 microgram.kg-1 for 60 min and increasing to a maximum of 2.0 micrograms.kg-1.min-1 for 180 min. Subsequently 12 different subjects received single i.v. infusions of 10 micrograms.kg-1.min-1 for 20 min. Subjective effects were reported and objective measurements made of central nervous and cardiovascular effects. Blood was sampled at intervals on all occasions, plasma concentrations were determined by radioimmunoassay and pharmacokinetic profiles were analysed using NONLIN. Dry mouth and some nasal stuffiness were reported and postural hypotension occurred in 5/16 subjects at plasma concentrations greater than 0.8 microgram.ml-1. Supine blood pressure was well maintained in all subjects and hypotension resolved within 60-90 min of discontinuing the infusion. There was no evidence of sedation, mood change, nausea, vomiting, miosis, change in accommodation or respiratory depression. Rapid infusions produced transient feelings of warmth, heavy eyelids, heavy legs, and increased bowel sounds, which resolved despite increasing plasma concentrations. The disposition of the peptide was adequately described by a 2-compartment model with a mean +/- SD plasma clearance of 123 +/- 18 ml.min-1 and a half-life of 2.0 +/- 0.4 h.

Adult↗
PubMed1987

The disposition of antipyrine and its metabolites in young and elderly healthy volunteers.

1 Oxidative metabolism of antipyrine (AP) was compared in 11 elderly (greater than 65 years) and 12 young (less than 40 years) volunteers. All subjects were non-smokers, consumed little if any alcohol and were in good health. 2 After a single dose of AP 500 mg, its clearance from saliva and profiles of the parent drug and its major metabolites in urine were determined using high-performance liquid chromatography. 3 Mean total AP clearance from saliva was lower in the elderly (P less than 0.05). Mean weight-normalised volume of distribution was also smaller (P less than 0.01) so that elimination half-life in the elderly was not significantly different from that in the young. 4 The percentage dose excreted in 48 h urine as norantipyrine (NORA) and its clearance for production were lower in the elderly (P less than 0.001 and P less than 0.01 respectively). Urinary 3-hydroxymethylantipyrine (HMA) and free antipyrine were present in greater quantities in 48 h urine in the elderly (P less than 0.001 and P less than 0.05) while the amounts of 4-hydroxyantipyrine (OHA) were almost identical in the two age groups. 5 The findings suggest that there is a selective impairment of N-demethylation in the elderly which may have important implications for dosage of elderly patients with drugs metabolised by this route.

Adult↗
PubMed1986

Comparative disposition of codeine and pholcodine in man after single oral doses.

Four healthy male subjects received single oral doses of 15, 30 and 60 mg of codeine and pholcodine according to a balanced cross-over design with an interval of 7 days between the six treatments. Blood samples were collected for 8 h after each drug administration. In phase 2 of the study six different male volunteers received single oral doses of 60 mg of codeine and pholcodine with a 14 day interval between successive drug treatments. Blood was sampled for 12 h after codeine and 121 h after pholcodine administration. Plasma concentrations of free (unconjugated) and total (unconjugated plus conjugated) codeine, pholcodine and morphine were determined by radioimmunoassay and selected pharmacokinetic parameters were derived from these data. Pharmacokinetics of both drugs were independent of dose. Codeine was absorbed and eliminated relatively rapidly [elimination t1/2 = 2.3 +/- 0.4 h (mean +/- s.d.)]. While codeine kinetics were adequately described by a one-compartment open model with first-order absorption, a two-compartment model was required to describe pholcodine elimination from plasma (t1/2,z = 37.0 +/- 4.2 h). Plasma concentrations of conjugated codeine were much greater than those of the unconjugated alkaloid. By contrast, pholcodine appeared to undergo little conjugation. Biotransformation of codeine to morphine was evident in all subjects, although the extent of this metabolic conversion varied considerably between subjects. Morphine was not detectable in the plasma of any subject after pholcodine administration.

Administration, Oral↗
PubMed1985

The effects of naloxone on opiate and placebo analgesia in healthy volunteers.

Two double blind cross-over studies were performed using a submaximal effort tourniquet test (SETT) in healthy volunteers to investigate the role of endogenous opioids in placebo analgesia. In the first study IV naloxone significantly inhibited analgesia, miosis and sedation produced by the opioid dipipanone 10 mg in 12 subjects. In the second naloxone, which did not produce hyperalgesia, failed to inhibit significant placebo analgesia in 12 subjects. The results do not support the involvement of endogenous opioids in ischemic limb pain or placebo analgesia under these conditions.

Adult↗
PubMed1985

The disposition of bupropion and its metabolites in healthy male volunteers after single and multiple doses.

The pharmacokinetics of bupropion and 3 of its basic metabolites were determined in 8 young, healthy, male volunteers after single and multiple oral doses of bupropion. Plasma profiles were obtained: 1) after a single 100 mg oral dose of bupropion hydrochloride, 2) following administration of 100 mg 8-hourly for 14 days and 3) again after a single 100 mg dose 14 days later. Plasma concentrations of the parent drug and metabolites were determined by high-performance liquid chromatography. Saliva secretion and pupil diameters were measured, subjective assessments of sleep made using visual analogue scales and side effects, blood counts and biochemistry were monitored. After the first dose mean elimination half lives (t1/2) of bupropion, and metabolites I and II were 8, 19 and 19 h respectively. On repeated administration there was little accumulation of the parent drug and no evidence for induction of its own metabolism. Accumulation of I was consistent with its rate of elimination after single doses while that of II was greater than predicted with prolongation of t1/2 to 35 h. Metabolite III was barely detectable after single doses but its accumulation on multiple dosing was consistent with its long half life (35 h) determined on occasion 2. Saliva secretion was significantly reduced during the multiple dosing period but there were no complaints of dry mouth. Subjective assessments of sleep were not significantly altered though one subject reported vivid dreams. There were no other adverse reactions.

Adult↗
PubMed1984

Alcohol and bupropion pharmacokinetics in healthy male volunteers.

A study was performed to determine whether there is a pharmacokinetic interaction between alcohol and the novel antidepressant bupropion. In the first part 8 healthy male volunteers received single doses of 100 mg bupropion hydrochloride orally on 2 occasions accompanied by either ethanol in orange or plain orange drink according to a balanced cross over design. Plasma bupropion concentrations were determined by radioimmunoassay and kinetics analysed with the aid of NONLIN. Blood alcohol levels were assessed by breathalyser. The disposition of bupropion was adequately described by a 2 compartment model and kinetic parameters were not significantly altered by the presence of alcohol. In the second part of the study the same subjects received 40 ml ethanol in orange drink 3.5 h after ingestion of 100 mg bupropion or dummy tablet in a double blind cross over fashion. Bupropion did not affect alcohol kinetics. In contrast to many other psychotropic drugs there is no evidence for a kinetic interaction between bupropion and alcohol.

Adult↗
PubMed1984

Tolerance and pharmacokinetics of A515U, an acyclovir analogue, in healthy volunteers.

A515U (6-deoxyacyclovir) is an analogue of acyclovir devoid of antiviral activity in vitro but which is well absorbed and undergoes conversion to acyclovir after oral administration to rats. The tolerance and pharmacokinetics of various doses of A515U have been studied in 8 healthy volunteers. Single oral doses of 25, 50, 100, 200 and 400 mg A515U and 400 mg acyclovir for comparison were administered to the volunteers at weekly intervals. Concentrations of the parent drug and acyclovir were determined in plasma and urine. The prodrug was well tolerated and did not cause adverse reactions or changes in haematological or biochemical variables. It was well absorbed and conversion to acyclovir was rapid and extensive at all doses. Plasma concentrations of acyclovir achieved with 50 mg A515U orally were comparable to and less variable than those produced by 400 mg acyclovir. A515U was rapidly cleared with a short plasma elimination half life of approximately 0.5 h. The attainment of high plasma concentrations of acyclovir by oral administration of a prodrug may represent an important advance in antiviral chemotherapy.

Absorption↗
PubMed1984

A comparison of methods for assessing the sedative effects of diphenhydramine on skills related to car driving.

A double blind cross-over study was performed to compare the sensitivity of "oof road" driving with that of laboratory tests of driving-related skills to drug induced sedation. Twelve experienced drivers (6 M, 6 F) received single oral doses of the H1-antagonist diphenhydramine 25, 50 and 100 mg and placebo. Each treatment was administered on 2 separate occasions, once in the driving school when real driving skills were assessed and again in the laboratory when performance of an adaptive tracking task, body sway and visual reaction were measured. On all occasions subjects assessed their own performance and alertness/sedation using visual analogue scales. Data were subjected to analysis of variance and differences assessed by Newman Keul's test. Diphenhydramine failed to impair driving performance at any dose while all doses produced significant changes in each of the 3 laboratory tests. Subjects rated themselves sedated after all 3 doses of active drug in the laboratory but only after the 100 mg dose in the driving school. Tests performed in the psychopharmacology laboratory appear to be more sensitive to the sedative effects of diphenhydramine than tests of "off road" driving. The implications are discussed.

Adult↗
PubMed1984

A modified submaximal effort tourniquet test for evaluation of analgesics in healthy volunteers.

Three double blind, placebo controlled, cross-over studies were conducted to assess the activity of analgesics in healthy volunteers using a modified submaximal effort tourniquet test (SETT). On each study day tests were performed in a silent cubicle at 21 degrees C immediately before and then hourly after drug administration. After exsanguination of the dominant arm trained subjects performed intermittent, isometric hand-grip exercise for 1 min and then rated pain intensity continuously on a visual analogue scale generated and scored by microcomputer. Tests were terminated by the subjects when pain became unbearable. Tourniquet times and cumulative analgesia scores were significantly increased by small doses of opiates, dipipanone and codeine but not by aspirin, indomethacin or diazepam. Scores on visual analogues scales for alertness and reports of side effects as well as the absence of analgesic activity of diazepam showed that analgesia was not related to sedation. The computerisation of pain ratings and standardisation of experimental conditions probably account for the sensitivity of this model. The difference between responses to opiates and anti-inflammatory drugs is discussed.

Adult↗
PubMed1984

Effect of amiodarone on thyroid hormone economy.

Serum thyroxine (T4), triiodothyronine (T3), resin uptake of T3 (RT3U), thyroid stimulating hormone (TSH) and TSH response to thyrotropin releasing hormone (TRH) were measured in 92 patients treated with amiodarone for up to 4 years. Two patients developed thyrotoxicosis, while euthyroid hyperthyroxinemia occurred in 29 (32%). Hypothyroidism was diagnosed in 11 patients (12%), and a further 11 had tests consistent with a "failing thyroid." Of 39 patients with normal values of T4, 15 had abnormal responses to TRH. Of the 92 patients, 24 were tested before administration of amiodarone and then sequentially; alterations in thyroid function were frequent within the first 3 months. A scheme is proposed for early recognition of disturbed thyroid function due to amiodarone.

Adult↗
PubMed1983

Systolic time intervals in diabetes.

The systolic time intervals at rest of 16 Type 1 (insulin-dependent) and 30 Type 2 (non-insulin-dependent) otherwise healthy adult diabetic patients selected from primary health care clinics were compared with those of age- and sex-matched normal subjects by paired analysis. There was no significant difference in prevalence of smoking, body mass index, fasting serum cholesterol or mean blood pressure between the diabetic and control groups. Mean rate-corrected pre-ejection period (diabetic patients: 132.7 +/- 2.1 ms, normal subjects: 134.6 +/- 3.5 ms (+/- SEM), left ventricular ejection time (diabetic patients: 413.9 +/- 3.0 ms, normal subjects: 421.5 +/- 4.7 ms) electromechanical systole (diabetic patients: 544.9 +/- 2.5 ms, normal subjects: 548.0 +/- 3.5 ms) and pre-ejection period/left ventricular ejection time ratio (diabetic patients: 0.36 +/- 0.01, normal subjects: 0.34 +/- 0.01) were not significantly different between the two groups (p greater than 0.05) and systolic time intervals did not correlate with duration of diabetes or type of treatment. Thus, we did not detect subclinical cardiomyopathy in healthy diabetic patients by this technique. However, a statistically significant skew in the distribution of systolic time intervals in the diabetic group (p less than 0.025) suggests the possibility of an 'at risk' population in which a more sensitive technique might demonstrate impaired ventricular performance.

Cardiomyopathies↗
PubMed1983

Comparison of digoxin-induced cardiac toxicity in resistant and sensitive species.

We have examined the species-specific arrhythmogenic effects of digoxin in the rat (resistant species) and in the guinea-pig (sensitive species). 26 adult rats and 23 adult guinea-pigs were anaesthetized with pentobarbitone and injected subcutaneously with varying doses of digoxin. Electrocardiograms were monitored continuously for 4 1/2 h following digoxin administration. The arrhythmogenic dose (AD50) and lethal dose 50 under anaesthesia (LD50) were determined using the method of Litchfield & Wilcoxin. AD50 in rats was 13.0 +/- 1.0 mg kg-1 (mean +/- s.d.) compared with 0.60 +/- 0.04 (P less than 0.01) in the guinea-pig and LD50 was 30.0 +/- 1.9 mg kg-1 in the rat compared with 0.60 +/- 0.04 (P less than 0.01) in the guinea-pig. The onset of arrhythmias was not dose-dependent in the rat but was clearly so in the guinea-pig; for example 102 +/- 15 min (mean +/- s.e.m.) following 0.5 mg kg-1, and 43 +/- 2 min following 1 mg kg-1. In the rat the onset of arrhythmias was 54.0 +/- 11.5 min. Supraventricular arrhythmias (paroxysmal atrial tachycardia) appeared in 73% of rats compared with only 18% of guinea-pigs whereas ventricular arrhythmias (ventricular tachycardia), multiple premature ventricular contractions and or multifocal PVC's occurred in 100% of guinea-pigs compared with only 32% of rats. All guinea-pigs that developed arrhythmias died whereas several rats recovered from supraventricular tachycardias. In conclusion, the guinea-pig is much more sensitive to digoxin toxicity than the rat, develops arrhythmias at much lower doses and these arrhythmias are much more likely to be ventricular in origin and cause fatality.

Animals↗
PubMed1979

Neurological complications of malignant germ cell tumors of testis: biology of brain metastases (I).

Central nervous system metastases are a common complication of disseminated germ cell tumors of the testis. They occurred in 16% of 242 patients treated and in 25% of the patients who died in our VAB chemotherapy series. Pulmonary metastases preceded or coincided with the development of brain metastases. The frequency of brain metastases differed with the histology of the primary tumor. They occurred in 13% of pure embryonal carcinomas, 18% of mixed tumors containing embryonal or choriocarcinoma elements, and 83% of pure choriocarcinomas. Embryonal carcinoma and choriocarcinoma were the principle histologies found in brain metastases. Characteristically, pure choriocarcinoma deposits in the brain were multiple (8/9) and cerebellar involvement was common (5/9). Pure embryonal carcinoma CNS metastases were typically single (6/8) or very few and cerebellar involvement was not observed. The interval from the diagnosis of malignancy to the diagnosis of brain metastases was longer for embryonal carcinoma than for pure choriocarcinoma (23 mos. vs. 6.5 mos.). Survival following the diagnosis of brain metastases was poor. There was a tendency toward longer survival for histologically pure embryonal carcinoma deposits in the brain than for the pure choriocarcinomas (6.5 mos. vs. 1 mo.).

Brain Neoplasms↗