Search PubMed⌕ Search

Biomedical subjects

J S Walker

Publications and source records attributed to J S Walker.

At least 73 records · Page 4Linked to original sources
PubMed1989

Kinetics of drug action in disease states. XXXII: Effect of experimental hypertension on the pharmacodynamics of phenobarbital in rats.

The purpose of this investigation was to determine the effect of experimental hypertension on the concentrations of phenobarbital required to produce a defined hypnotic effect (loss of righting reflex) in adult, female Lewis rats. Hypertension was induced with deoxycorticosterone acetate (DOCA), administered by im injection (first experiment) or by pellet implant (second experiment), and 1% NaCl in the drinking water. There were two control groups: one that received im injections of water or a drug-free pellet implant plus 1% NaCl in the drinking water, the other that received water injections or drug-free pellet implants and no NaCl in the drinking water. These treatments were carried out for 3 months and resulted in appreciable elevation of blood pressure and increased heart weight in the DOCA + NaCl-treated (but not in the NaCl alone) rats. All animals then received an infusion of phenobarbital until onset of loss of righting reflex. The concentrations of phenobarbital in the serum, serum water, brain, and CSF of the hypertensive rats at the pharmacologic endpoint did not differ significantly from corresponding concentrations in the control groups (except for a marginal difference of the drug concentration in serum water between the DOCA pellet group and the drug-free pellet control group). It is concluded that DOCA-induced hypertension has no apparent effect on the sensitivity of the central nervous system to the hypnotic action of a barbiturate in female rats.

Animals↗
PubMed1989

Phenylpropanolamine potentiates caffeine neurotoxicity in rats.

Numerous case reports have documented that phenylpropanolamine (PPA) stimulates the central nervous system with symptoms ranging from anxiety and hallucinations to grand mal seizures produced by overdoses. Most of these reports have occurred following concomitant use of caffeine which in high doses is known to cause seizures and psychotic episodes. The purpose of this investigation was to determine if PPA could potentiate caffeine-induced seizures in the rat. First, the input rate dependence of caffeine-induced neurotoxicity was determined by infusing rats intravenously with caffeine at one of three different rates (1.65-8.12 mg/min) until the onset of maximal seizure. This occurred after an average of 12 to 60 min of infusion. The PPA concentrations in serum, brain, and cerebrospinal fluid (CSF) at this pharmacologic endpoint were independent of infusion rate. In another experiment, rats were pretreated with an anorexiant dose of PPA (30 mg/kg ip) either acutely or chronically for 6 d, while control animals received saline solution. All groups were then infused with caffeine at a rate of 4.18 mg/min until onset of seizures. Caffeine concentrations at that time in serum, brain, and CSF were significantly lower in the PPA-pretreated animals than in the control group. It is concluded that both acute and chronic pretreatment with PPA increases the sensitivity of rats to the neurotoxic effects of caffeine.

Animals↗
PubMed1989

Induction of experimental thyroid dysfunction in rats with implantable pellets of thyroxine or propylthiouracil.

Subcutaneously implanted pellets containing the thyroid hormone thyroxine or the thyrotoxic agent propylthiouracil were used to induce hyper- or hypothyroidism in rats. The results obtained were compared to those produced by daily subcutaneous injection of these substances. The thyroxine pellets caused substantial elevation of serum thyroxine concentrations for at least 25 days, whereas the propylthiouracil pellets caused a pronounced decrease of serum thyroxine concentrations. Changes in heart weight and rectal temperature were consistent with the observed alterations of serum thyroxine concentrations. Treatment with propylthiouracil was associated with small elevations of serum total protein, urea nitrogen, and creatine concentrations regardless of the method of administration of this agent. It is concluded that implantable pellets are an effective and convenient means of administering drugs for producing thyroid dysfunction in rats.

Animals↗
PubMed1989

Kinetics of drug action in disease states. XXXI. Effect of experimental hyperthyroidism on the hypnotic activity of a benzodiazepine (oxazepam) in rats.

This investigation was designed to determine the effect of experimental hyperthyroidism on the hypnotic activity of a benzodiazepine and on the binding characteristics of the benzodiazepine receptor complex. Rats were made hyperthyroid by subcutaneous implantation of slow release pellets containing L-thyroxine. This treatment produced the characteristic symptoms of hyperthyroidism: increased serum thyroxine concentrations, increased heart weight and body temperature, and decreased serum protein concentrations. The hyperthyroid rats and a parallel group of normal animals (with drug-free pellets implanted subcutaneously) were slowly infused intravenously with oxazepam until they lost their righting reflex. The hyperthyroid rats required a significantly larger dose of the benzodiazepine and their total serum and cerebrospinal fluid concentrations of oxazepam (but not the serum concentration of free drug and the brain concentration) at the onset of loss of the righting reflex were modestly but statistically significantly lower than those of the normal rats. The receptor density and affinity for diazepam in hyperthyroid rats were not significantly different from those of the normal animals. Hyperthyroidism apparently affects the pharmacokinetics of oxazepam but has, at best, only a small effect on the pharmacodynamics (hypnotic activity) of the drug.

Animals↗
PubMed1989

Confocal fluorescence microscopy with the tandem scanning light microscope.

Applications of the tandem scanning confocal microscope (TSM) to fluorescence microscopy and its ability to resolve fluorescent biological structures are described. The TSM, in conjunction with a cooled charge-coupled device (cooled CCD) and conventional epifluorescence light source and filter sets, provided high-resolution, confocal data, so that different fluorescent cellular components were distinguished in three dimensions within the same cell. One of the unique features of the TSM is the ability to image fluorochromes excited by ultraviolet light (e.g. Hoechst, DAPI) in addition to fluorescein and rhodamine. Since the illumination is dim, photobleaching is insignificant and prolonged viewing of living specimens is possible. Series of optical sections taken in the Z-axis with the TSM were reproduced as stereo images and three-dimensional reconstructions. These data show that the TSM is potentially a powerful tool in fluorescence microscopy for determining three-dimensional relationships of complex structures within cells labeled with multiple fluorochromes.

Animals↗
PubMed1989

Kinetics of drug action in disease states. XXXIV. Effect of experimental thyroid disorders on the pharmacodynamics of phenobarbital, ethanol and pentylenetetrazol.

To determine the effect of thyroid disorders on the concentration-activity relationship of certain drugs acting on the central nervous system, rats were made hyperthyroid by administration of L-thyroxine and hypothyroid by administration of propylthiouracil. They then received a slow i.v. infusion of phenobarbital or ethanol until they lost their righting reflex, or of pentylenetetrazol until the onset of maximal seizures. Drug concentrations in serum, brain and cerebrospinal fluid (CSF) were determined at these pharmacologic endpoints. Hyperthyroidism was associated with a statistically significant increase in the infused hypnotic dose and brain concentration of phenobarbital but had no apparent effect on concentrations of the drug in serum and CSF. The hypnotic dose of ethanol was increased significantly in hyperthyroid rats and decreased in hypothyroid animals; ethanol concentrations in serum, brain and CSF at onset of effect were generally not affected by thyroid dysfunction except for a small but statistically significant increase of serum ethanol concentrations in the hyperthyroid rats. The convulsant dose of pentylenetetrazol was reduced significantly in hypothyroid animals and unaltered in hyperthyroid rats; the concentrations of the convulsant in serum, brain and CSF were not apparently changed by the thyroid dysfunctions. In general, experimental thyroid disorders had no pronounced effect on the pharmacodynamics (concentration-effect relationship) of phenobarbital, ethanol and pentylenetetrazol in rats.

Animals↗
PubMed1988

The reversal of midazolam sedation with the benzodiazepine antagonist flumazenil (Anexate).

Flumazenil (Anexate) was used to reverse midazolam sedation in a series of 108 patients undergoing minor diagnostic or therapeutic procedures. At a mode dose of 0.5 mg IV, flumazenil was shown to rapidly and predictably reverse the sedation produced by a mode dose of 5 mg midazolam. Amnesia for the procedure was excellent in all but three cases, and side effects were infrequent and minor. In the endoscopy clinic, the use of flumazenil was perceived by clinicians to significantly improve the speed and quality of recovery.

Anesthesia Recovery Period↗
PubMed1988

Pyrethrin poisoning from commercial-strength flea and tick spray.

A case of acute poisoning followed inhalation and cutaneous exposure to an over-the-counter flea and tick insecticide containing 0.15% pyrethrins. A self-limited syndrome of cutaneous paresthesias, upper respiratory tract irritation, dyspnea with productive cough, and repetitive vomiting and diarrhea occurred. The patient recovered uneventfully with conservative therapy. A review of the pharmacology and toxicity of pyrethrins and related products is discussed, as well as management of pyrethrin poisoning.

Acute Disease↗
PubMed1988

Heat production of rat anococcygeus muscle during isometric contraction.

Heat production, unloaded shortening velocity (Vus), and load-bearing capacity (LBC) were studied in the isolated rat anococcygeus muscle during isometric contractions at 27 degrees C. The relation between the total suprabasal heat produced and the stress-time integral for isometric contractions of various durations was curvilinear, demonstrating a decreasing slope as contractile duration increased. The rate of heat production at 600 s was approximately 68% of the peak value of 6.55 mW/g that occurred at 10 s. At the same time, force rose from a mean of 92 mN/mm2 at 10 s to a value of 140 mN/mm2 at 600 s. This produced a nearly threefold increase in the economy of force maintenance. The decline in the rate of heat production was accompanied by a decline in Vus from 0.56 Lo/s at 10 s to 0.28 Lo/s at 600 s, where Lo is the length for optimal force development. This suggests the fall in the rate of heat production was caused, at least in part, by a slowing of cross-bridge kinetics. The ratio of LBC to developed tension at 10 s was not significantly different from the ratio at 600 s, suggesting that the increase in tension was due to an increased number of attached cross bridges. The decline in heat production, therefore, appears contradictory, since an increased number of attached cross bridges would predict an increased rate of energy expenditure. The observations can be reconciled if either 1) the increase in force is caused by a progressive increase in the attachment time of a constant number of cross bridges that cycle at a lower frequency or 2) the decline in energy expenditure caused by the slowing of cross-bridge cycling is sufficient to mask the increase caused by the recruitment of additional cross bridges.

Animals↗
PubMed1988

Diflunisal pharmacodynamics in experimental arthritis in rats.

The analgesic response-serum concentration relationship (pharmacodynamics) of a representative nonsteroidal antiinflammatory drug, diflunisal, was examined after an acute dose in adjuvant arthritic and control rats. The analgesic response was 2-fold higher in the arthritic animals compared to controls. In parallel with this, there was a 2-fold increase in the serum free concentrations of diflunisal in the arthritic rats. Thus, the increase in diflunisal analgesic response in arthritis may be attributed to pharmacokinetic perturbations, resulting from alterations in serum protein binding and not to changes in drug pharmacodynamics. Endogenous binding inhibitors in adjuvant arthritis may contribute to the observed decreased in diflunisal protein binding.

Animals↗
PubMed1987

Alcuronium pharmacodynamics in dogs: effect-concentration relationships in the diaphragmatic and limb muscles.

Previous studies suggest that the muscles of the diaphragm are less sensitive to neuromuscular blocking agents than the limb muscles. However, this difference has not been characterized directly in terms of relaxant drug plasma concentrations. The pharmacodynamics of the non-depolarizing muscle relaxant alcuronium were therefore investigated in nine dogs using a constant-rate infusion regimen with simultaneous measurement of muscle paralysis in the limb and diaphragm. Maximum paralysis between 95 and 100% was achieved in both muscle groups, within approximately the same time interval. However, during onset of and offset of effect, the pharmacodynamic parameters ECp50 and ECp95 for the limb muscle were lower than in the diaphragm. From a pharmacodynamic effect model it was also predicted that Css(50) and Css(95) for the limb muscles are half those values for the diaphragm. Thus, the diaphragm is less sensitive to the action of alcuronium than are limb muscles. The half-time for equilibration of alcuronium between plasma and the effect site was two-fold lower for the diaphragm, and the rate of recovery from paralysis in diaphragmatic muscles was twice that observed in limb muscles. Collectively, these data suggest that there is a greater margin of safety in the diaphragmatic muscles and that the response of the peripheral limb muscles to nerve stimulation provides only a conservative index of recovery from competitive neuromuscular block in the diaphragmatic muscles.

Alcuronium↗
PubMed1987

Enzyme-linked immunosorbent assay for detection of antibodies to Rift Valley fever virus in ovine and bovine sera.

An enzyme-linked immunosorbent assay (ELISA) was developed for the rapid detection of antibodies to Rift Valley fever virus (RVFV) in ovine and bovine sera. Conditions to reduce nonspecific reactions were optimized. The ELISA results correlated with those of a plaque-reduction neutralization test, revealing 100% specificity and 90.7% sensitivity. In sera from sheep and cattle inoculated against RVFV, the hemagglutination-inhibition test in combination with the ELISA provided a better indication of response to killed RVFV vaccine than did either test alone.

Animals↗
PubMed1986

Reversed-phase high-performance liquid chromatographic assay for the determination of potency and impurities in tazadolene succinate bulk drug and capsules.

A reversed-phase assay based on high-performance liquid chromatography with a water-acetonitrile-tetrahydrofuran (THF)-triethylamine (TEA)-perchloric acid (pH 2.5) mobile phase and a Zorbax C8 column has been validated for the determination of the purity of tazadolene succinate (I) [E-(+/-)-1-(2-benzylidenecyclohexyl)azetidine succinate, U-53996H] bulk drug, the potency of tazadolene succinate hard-filled capsule formulations and impurity levels in bulk drug. The system resolves E- and Z-isomers and other structurally related molecules. Retention of these compounds is mainly dependent on the amount of acetonitrile and THF in the mobile phase. An amine must be present in the mobile phase to bring about elution of I. The potency assay utilizes testosterone as internal standard. Potency assays exhibited relative standard deviations (R.S.D.) of less than 1%. Quantitative recovery from hard-filled capsules (HFC) is obtained by using a simple extraction procedure. Potential process impurities, potential degradation products, and formulation excipients are resolved. The assay is linear for tazadolene succinate concentrations equivalent to 50-150% of the assay concentration. Impurities can be quantitated to levels equivalent to about 0.1% by weight with R.S.D. less than 5%. The estimated limit of detection for I is about 2 ng for a 20 microliters injection.

Analgesics↗
PubMed1985

Pediatric carbon monoxide toxicity.

We report a series of 28 pediatric carbon monoxide exposures. Sixteen patients (57%) were judged to have potentially toxic carboxyhemeglobin (COHb) levels (greater than 15%). In this group the range of COHb blood levels was 16.7% to 44.0% (mean = 26.5%). An unusually high incidence of syncope (56.3%, 9/16) and lethargy (68.7%, 11/16) was observed. Every patient with a COHb level greater than or equal to 24% experienced syncope; a marked departure from published adult values. Lethargy was reported at a mean COHb concentration of 25.9%. All patients with levels over 25% COHb, neurologic findings, acidosis, or syncope were considered candidates for hyperbaric oxygen therapy (HBOT). No morbidity from HBOT was encountered. Eighty-nine percent (25/28) of the patients are reportedly doing well, with no late sequelae identified. Delayed neurologic sequelae in three patients include chronic headaches, memory difficulties, or decline in school performance.

Adolescent↗