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Biomedical subjects

D A Thomas

Publications and source records attributed to D A Thomas.

At least 91 records · Page 5Linked to original sources
PubMed1988

Determination of a novel antiarrhythmic agent ACC-9358 in human plasma by high-performance liquid chromatography.

A liquid chromatographic method for the determination of ACC-9358, an antiarrhythmic agent, in human plasma is described. ACC-9358 was extracted from plasma into chloroform and back extracted into 0.01 N hydrochloric acid. ACC-9358 in the acidic extract was eluted from a Novapak C18 column using a 87:13:0.1 (by volume) mixture of phosphate buffer (pH 3.0), acetonitrile, and triethylamine as the mobile phase and measured at 280 nm. The average extraction recoveries were 78.4 and 85.4% at the 0.5- and 5-micrograms/ml level, respectively. Standard curves were linear and reproducible over the concentration range of 0.01-10 micrograms/ml, with coefficients of determination better than 0.999. Coefficients of variation for both within-day and day-to-day analysis were less than 11%. The assay method is sensitive, reproducible, and suitable for disposition studies of ACC-9358 in humans.

Anti-Arrhythmia Agents↗
PubMed1987

Toxicity and pharmacokinetics of the nonprotein amino acid L-canavanine in the rat.

The toxicity of L-canavanine was investigated because of its demonstrated potential as an antitumor drug. This natural product was only slightly toxic to Sprague-Dawley rats following a single sc injection: the LD50 was 5.9 +/- 1 8 g/kg in adult rats and 5.0 +/- 1.0 g/kg in 10-day-old rats. Following a single dose of 2.0 g/kg, the systemic clearance value for canavanine in adult rats was 0.114 liter/hr, the volume of distribution at steady state was 0.154 liter, and the half-life was 1.56 hr. Forty-eight percent of the dose was excreted unaltered in the urine following an iv injection, and 16% of a sc dose was recovered in the urine. Bioavailability of a 2.0 g/kg sc dose was 72%. Single oral doses of canavanine were less toxic to adult rats than sc injections. Bioavailability of a 2.0 g/kg po dose was 43%, and only 1% of the administered canavanine was recovered in the urine. Twenty-one percent of the administered canavanine remained in the gastrointestinal tract 24 hr after an oral dose. Less than 1% of a 2.0 g/kg dose of L-[guanidinooxy-14C]canavanine was incorporated into the proteins of adult and neonatal rats 4 or 24 hr following administration. Repeated sc administration of canavanine resulted in more severe toxicity. Weight loss and alopecia were observed in rats given daily sc canavanine injections for 7 days. Food intake was decreased by 80% in adult rats subjected to this dosing regimen, but returned to normal after canavanine injections were terminated. Histological studies of tissues from adult rats treated with 3.0 g/kg canavanine daily for 6 days revealed pancreatic acinar cell atrophy and fibrosis. Serum amylase and lipase levels were elevated following one sc injection of 2.0 g/kg canavanine; after three daily injections both serum enzymes were depleted. Elevations in serum glucose and urea nitrogen, and depletion of cholesterol, were observed. The most significant changes were severe attenuations of serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase activity.

Alopecia↗
PubMed1987

Metabolism of L-[guanidinooxy-14C]canavanine in the rat.

The metabolism of L-canavanine, a nonprotein amino acid with significant antitumor effects, was investigated. L-Canavanine, provided at 2.0 g/kg, was supplemented with 5 microCi of L-[guanidinooxy-14C]canavanine (58 microCi/mumol) and administered iv, sc, or orally to female Sprague-Dawley rats weighing approximately 200 g. 14C recovery in the urine at 24 hr was 83, 68, or 61%, respectively, of the administered dose. Another 5-8% of the 14C was expired as 14CO2. The gastrointestinal tract contained 21% of orally administered 14C. Serum, feces, tissues, and de novo synthesized proteins only accounted for a few percent of the original dose by any administrative route. Analysis of the 14C-containing urinary metabolites revealed that [14C] urea accounted for 88% of the urinary radioactivity for an iv injection, 75% for sc administration, and 50% following an oral dose. By all routes of administration, [14C]guanidine represented 5% of the radioactivity in the urine and [14C]guanidinoacetic acid accounted for 2%. Serum and urine amino acid analysis showed a markedly elevated ornithine level. Basic amino acids such as histidine, lysine, and arginine were also higher in the urine. Plasma ammonia levels were determined following oral canavanine doses of 1.0, 2.0, and 4.0 g/kg. A rapid but transient elevation in plasma ammonia was observed only at the 4.0 g/kg dose. This indicates that elevated plasma ammonia is not a likely cause of canavanine toxicity at the drug concentrations used in this study.

Administration, Oral↗
PubMed1986

Dorsal horn opiate administration attenuates the perceived intensity of noxious heat stimulation in behaving monkey.

In monkeys trained to detect and discriminate noxious heat stimuli, morphine microinjected into the medullary dorsal horn attenuated the perceived intensity of noxious heat in a dose- and stimulus-dependent fashion. These data demonstrate a pharmacologically specific effect of opiates on the sensory intensity component of pain at the earliest central relay pathway transmitting noxious information.

Animals↗
PubMed1986

Incidence of fever and bacteremia following transbronchial needle aspiration.

Fiberoptic bronchoscopy and transbronchial needle aspiration were performed on 50 occasions in 47 afebrile patients. The aspirations were followed by endobronchial or transbronchial biopsies in 22 patients, as well as bronchial brushings and washings where appropriate. Blood for cultures was drawn at 5 and 30 minutes following needle aspiration, as well as at the time of any temperature above 38 degrees C during the 24 hours following the procedure. In five (10 percent) of the 50 cases, there was temperature greater than 38 degrees C (100.4 degrees F) in the 24 hours following the bronchoscopy; in no patient were cultures of blood positive, whether done early after the procedure or at the time of fever. We conclude that transbronchial needle aspiration, a new procedure gaining widespread popularity in diagnostic thoracic medicine, is not associated with clinically detectable bacteremia. This procedure should not require antimicrobial prophylaxis in patients susceptible to endocarditis.

Adult↗
PubMed1986

Growth inhibition of a rat colon tumor by L-canavanine.

The effects of L-canavanine, a higher plant nonprotein amino acid, on the growth of a rat colon carcinoma were assessed. The 1 and 10% lethal dose values following a single s.c. injection in Fischer rats were 4.75 and 5.57 g/kg, respectively. Rats received s.c. injections of a 10% (w/v) tumor cell suspension. When the tumors reached a size of 500 to 1000 mm3, the rats received canavanine, 2.0 g/kg or 3.0 g/kg s.c. daily for 5 or daily for 9 days. Control animals received a 0.9% NaCl solution. Administration of canavanine, 2.0 g/kg for 5 days produced a treated versus control of 23%; the treated versus control for 9 days was 14%. The 3.0-g/kg dosing regimen resulted in a treated versus control value of -13% after 5 days and -8% after 9 days. The negative values indicated regression of the tumor. The reduction in tumor volume, expressed as the percentage of regression, was 22% in animals receiving canavanine, 3.0 g/kg daily for 5 days and 60% in the 3.0-g/kg-daily-for-9-days treatment group. Cumulative toxicity caused death in 2 of 5 animals in the 3.0-g/kg-for-9-days treatment group; the average weight loss was 31%. The 3.0-g/kg-for-5-days treatment also produced undesirable cumulative toxicity as indicated by a weight loss of 19%. Cumulative toxicity was reduced greatly when canavanine was administered at a dose level of 2.0 g/kg for 5 days (weight loss of 13%). Analysis of the relationship of caloric deprivation to tumor growth reduction established that canavanine-mediated curtailment of tumor growth was not caused by reduced food intake and its associated loss in body weight. Histological examination of tissues from rats receiving canavanine, 2.0 or 3.0 g/kg daily for 5 or 9 days failed to reveal lesions in any of the examined tissues, except for varying degrees of pancreatic acinar atrophy. All other tissues appeared normal. The white and red blood cell values of canavanine-treated rats were also normal following 1, 3, or 6 injections of canavanine, 2.0 or 3.0 g/kg. The results indicated that canavanine induced marked growth inhibition of the rat colon carcinoma. Our experiments also disclosed that further studies must be conducted to optimize the dosing schedule to enhance drug efficacy and to reduce its cumulative toxicity.

Animals↗
PubMed1986

The medullary dorsal horn: a target for the expression of opiate effects on the perceived intensity of noxious heat.

We examined the effects of morphine microinjected into the medullary dorsal horn (MDH) on the ability of monkeys to detect temperature increases in the noxious heat range. Behavioral detection latency and the percentage of correct detections were used as measures of the perceived intensity of noxious heat stimuli. Three monkeys were trained to detect a change (T2) of 0.4, 0.6, or 1.0 degrees C from a previous noxious heat level of 46 degrees C (T1). Effects on attentional, motivational, and motoric aspects of the monkeys' behavior were assessed by having them detect innocuous cooling and visual stimuli in tasks of similar difficulty. Morphine (1, 3, and 10 micrograms) microinjected into the MDH produced a dose-dependent and stimulus-intensity-dependent increase in the latency to detection of the T2 stimuli. These effects were opiate receptor-mediated since they were antagonized by systemically administered naloxone (0.5 mg/kg, i.m.) given 40 min after the microinjection of morphine. There were no effects of morphine on the behavioral detection latencies to the innocuous cooling and visual stimuli, indicating that the effects of morphine were modality-specific and independent of changes in motivation, attention, or motoric ability. These data demonstrate a pharmacologically specific effect of opiates on the perceived intensity of noxious heat stimuli at the earliest central relay pathway transmitting noxious information.

Animals↗
PubMed1985

A radiometric assay for determining the incorporation of L-canavanine or L-arginine into protein.

Procedures for a radiometric assay of L-[guanidinooxy-14C]canavanine were developed which provide a convenient and accurate measure of the incorporation of [14C]canavanine into de novo-synthesized proteins. These methods are also applicable to determining [14C]arginine incorporation into protein. These procedures have been employed to study the synthesis of L-[guanidinooxy-14C]canavanine- and L-[guanidino-14C]arginine-containing proteins from the hemolymph of Manduca sexta and Heliothis virescens, two highly destructive insect pests.

Animals↗
PubMed1985

Differential effects of perinatal androgen treatment on sexually dimorphic characteristics in rats.

Rats were treated with testosterone propionate (TP) or oil (O) beginning in midgestation (group TTT), late gestation (group OTT), neonatally (group OOT), or were left untreated until adulthood (group OOO). At 40 days of age all animals were gonadectomized, received implants of TP in silastic capsules, and were tested in subsequent weeks for masculine copulatory behavior and ex copula phallic responses. Postmortem measures were taken of genital structures and of sexually dimorphic spinal nuclei. Males treated perinatally with androgen were unaffected or exhibited reduced masculinization except on two measures, i.e., number of penile flips and number of cells in the dorsolateral motor nucleus of the lumbar spinal cord, which reflected virilization greater than in normal males. All perinatally androgenized females showed virilization on almost every measure taken of their morphology and behavior. Relative to OOO females, the greatest increases in masculinization were evident in OOT and OTT females. No additional masculinization was detected in TTT females. Only among the TTT rats were males not reliably more masculine than females, but that usually was due to the reduced masculinization of TTT males. Four broad classes of influence characterized the effects of perinatal androgen treatment; these classes may reflect differences in the developmental courses of the variables measured.

Animals↗
PubMed1984

Levamisole as adjuvant to chemotherapy of ovarian cancer. Results of a randomized trial and 4-year follow-up.

The results of a randomized trial, stratified according to age and stage of disease, in 140 patients with ovarian cancer are presented. The drug, levamisole, or a placebo was given as adjuvant to cytotoxic chemotherapy for 12 months after maximal surgical reduction of tumor. Because of severe side effects, levamisole treatment was discontinued in 8 of 69 patients (marked neutropenia in 5, severe skin rashes in 3). There were no significant differences in the survival curve and mean duration of survival between levamisole-treated and placebo-treated groups during the 4 years of follow-up, except for patients with Stage II disease. Among these latter patients, the survival rate became progressively much lower in the levamisole-treated group and the difference reached statistical significance after the second year of follow-up (P less than 0.01). In view of the inconclusive evidence that levamisole provides a beneficial effect (in fact, there is concern of a deleterious effect) and the serious side effects, the drug should not be used in patients with ovarian cancer.

Adjuvants, Immunologic↗
PubMed1984

Do pup ultrasonic cries provoke prolactin secretion in lactating rats?

Marked prolactin (PRL) secretion in response to the ultrasonic distress vocalizations of rat pups in lactating dams deprived of their pups for 6 hr was reported by others. In two experiments, this phenomenon could not be confirmed under our testing conditions at either 1 or 2 weeks postpartum, although behavioral responses to the ultrasounds were noted. In addition, suckling-induced PRL secretion did not differ consistently as a function of the tape recording (pup ultrasounds, 45 kHz artificially produced ultrasounds, or blank tape) heard prior to the return of pups. The functional significance of rat pup ultrasounds is considered.

Animals↗
PubMed1984

Sex role orientation, personality structure, and adjustment in women.

In an effort to clarify and expand the theoretical foundation for behavioral researches on androgyny the present study, through an extensive literature review, attempted to establish personality structure as a function of masculine instrumentality (M) and feminine expressivity (F) in females. Results were strong and confirming, suggesting that considerable relationship may exist between certain sex role socialization practices and general personality development. In addition, the implications of instrumentality and expressivity for adjustment were investigated through a planned contrast of clinical and normal groups, with the expectation that feminine females would appear more frequently in the clinical group. However, results clarified that it is the lack of masculine instrumentality in the personality, not the feminine role per se, which is implicated in mental illness. These findings lend clarity to previous researches on androgyny and adjustment. Implications for feminine socialization and ego psychology are considered.

Adolescent↗