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Biomedical subjects

W J Murray

Publications and source records attributed to W J Murray.

At least 37 records · Page 2Linked to original sources
PubMed1988

Biochemical and functional effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the heart of female rats.

Biochemical, functional and morphologic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on the hearts of female rats were examined. Six days after the treatment of rats with TCDD, the blood pressures and resting heart rates were significantly less than in control animals. Treated animals were also less responsive to the effects of the beta-1 agonist, (-)isoproterenol. No histopathologic changes were observed in the heart although extensive centrilobular necrosis occurred in the liver after TCDD administration. Serum levels of thyroxine were 66% less than in control animals. Marked lipid peroxidation was produced in the liver with small but significant increases occurring in the heart. TCDD administration had no effect on catalase activity in the heart, but produced a 20% decrease in superoxide dismutase activity relative to control animals. The effects of TCDD on cardiac function do not appear to be due to a direct action of the xenobiotic on the heart but possibly to a down-regulation of beta-receptors in the heart as a result of the hypothyroid state.

Animals↗
PubMed1988

Double-blind comparison of nalbuphine and meperidine in combination with diazepam for intravenous conscious sedation in oral surgery outpatients.

Nalbuphine and meperidine were compared as analgesic components of intravenous conscious sedation in a double-blind, prospective trial of 47 patients undergoing elective oral surgery. Subjects were evaluated for pain intensity, pain relief, anxiety, sedation, recall, and vital signs at systematic observation points intraoperatively and postoperatively. At the conclusion of surgery 83% of patients who had received nalbuphine and 86% of patients treated with meperidine indicated complete pain relief. One observed adverse reaction was attributed to meperidine and another to the sedative component diazepam. No statistically significant differences were observed between nalbuphine and meperidine treatments.

Adult↗
PubMed1988

Comparison of nalbuphine and fentanyl in combination with diazepam for outpatient oral surgery.

Nalbuphine and fentanyl were compared as analgesic components of intravenous conscious sedation with diazepam in a double-blind, prospective trial of 50 patients undergoing elective oral surgery. Subjects were evaluated for intensity of pain, pain relief, sedation, anxiety, recall, and vital signs at systematic observation points intraoperatively and postoperatively. At the conclusion of surgery, 88% who received nalbuphine and 87% treated with fentanyl indicated complete pain relief. One observed adverse reaction was attributed to the combination of fentanyl and the sedative component diazepam. No statistically significant differences were observed between nalbuphine and fentanyl treatments.

Adult↗
PubMed1988

Searching for the endogenous benzodiazepine using the graph theoretical approach.

The graph theoretical indices of several compounds with reported benzodiazepine receptor binding affinities were calculated. Our results demonstrate a structural similarity among diazepam, triazolam, and the beta-carboline nucleus and a structural dissimilarity to the purines and nicotinamide. This result correlates with their respective binding affinities. Using the graph theoretical indices as structural descriptors of the benzodiazepines and the significant ligands of the beta-carbolines, a search for peptide sequences as potential ligands was explored. Single amino acids through pentapeptides with all possible amino acid substitutions and chemical modifications were calculated. The peptides generated were subjected to graph theoretical analysis, and their indices were compared to those of the benzodiazepines. Comparisons resulted in seven dipeptides and six tripeptides that are topologically similar to the benzodiazepines and beta-carbolines. The dipeptides are histidine- or tryptophan-containing compounds with pyroglutamine, phenylalanine, and tyrosine residues in the second position. The tripeptides have two aromatic amino acid residues and a pyroglutamine or glycyl terminal residue. These structures are promising candidates because (1) they are structurally (topologically) similar to the benzodiazepines, represented by diazepam and triazolam, and to the beta-carbolines; and (2) they are sequences that may reasonably form a part of a larger peptide or that may be formed metabolically by proteolysis.

Anti-Anxiety Agents↗
PubMed1988

Quantitative structure-activity study on human pharmacokinetic parameters of benzodiazepines using the graph theoretical approach.

The graph theoretical indices for a series of 13 benzodiazepines were calculated using a graph-path topological method. The total molecule, the ring fragments, and combinations of ring fragments were subjected to a quantitative structure-activity analysis using eight pharmacokinetic parameters. The metabolic clearance and the blood-to-plasma concentration ratios were most highly correlated with the graph theoretical indices, with R values of 0.975 and 0.938, respectively. These correlations were found when the diazepine + benzo fragment and phenyl fragment were used to calculate the graph-path indices. Terminal disposition half-life was correlated with the benzo + diazepine fragment, with R = 0.969. Truncating the graph-path codes by eliminating cycles in the total molecule markedly improved the correlation coefficients. When compared to the graph-path indices for the total molecule, the correlation coefficients for the terminal disposition half-life and metabolic clearance data rose from 0.721 to 0.935 and from 0.770 to 0.968, respectively, using the graph-path indices of the truncated molecule. Intrinsic clearance of unbound drug also was poorly correlated with the total molecule (r less than 0.7) but rose significantly using the graph-path indices of the truncated molecule (r = 0.971 and 0.975 for the well-stirred and parallel-tube models, respectively).

Anti-Anxiety Agents↗
PubMed1988

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induced perturbation of calcium distribution in the rat.

Altered calcium homeostasis may play a central role in the liver injury produced by some toxicants. Therefore, the dose and time dependent effects of TCDD on calcium distribution in whole homogenate and subcellular fractions of liver were examined. Groups of female rats were treated with 40 micrograms TCDD/kg for 1, 2 or 3 days. Animals treated with TCDD for 1 and 2 days were killed 1 day after treatment. Rats treated for 3 days were killed on days 1, 3, 5, 7, 9 and 12 post-treatment. A 2-fold increase in calcium content in whole homogenate occurred 5 days post-treatment. Increases in mitochondrial calcium were noted 3 days post-treatment, and significant increases in microsomal calcium were observed one day post-treatment. Small increases in cytosolic calcium also occurred. Thus, TCDD produces disturbances in the content and subcellular distribution of calcium which may contribute to the promotion of toxic manifestations by this xenobiotic.

Animals↗
PubMed1987

Comparative effects of BHA and ascorbic acid on the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in rats.

1. The abilities of BHA and ascorbic acid to prevent the toxic manifestations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were examined in female Sprague-Dawley rats. 2. Rats treated with BHA were partially protected from TCDD-induced lipid peroxidation, inhibition of glutathione peroxidase activity, and losses in liver, thymus and body weights. 3. Ascorbic acid had no effect on TCDD-induced alterations in glutathione peroxidase and aryl hydrocarbon hydroxylase activities, or body, liver and thymus weight changes. Ascorbic acid was unable to protect against the lethality of TCDD. 4. Some of the toxic manifestations of TCDD may be mediated by reactive oxygen species and free radical processes.

Animals↗
PubMed1987

In vivo and in vitro intervention with L-carnitine prevents abnormal energy metabolism in isolated diabetic rat heart: chemical and phosphorus-31 NMR evidence.

The beneficial effects of in vivo injections (200 mg/kg, twice daily) or in vitro perfusion (5.0 mM) of L-carnitine on an intrinsic abnormality in energy metabolism was investigated in isolated, perfused diabetic rat heart. Hearts were aerobically perfused for 60 min with elevated fatty acid substrate to simulate diabetic conditions. Phosphorus-31 nuclear magnetic resonance spectroscopy revealed a temporal decline in myocardial ATP levels (to approx 82%) during perfusion of diabetic hearts, but not in control hearts. This reduction was prevented by prior treatment in vivo with L-carnitine or by providing L-carnitine acutely in the perfusion medium. Chemical analysis of tissue extracts indicated that L-carnitine injections were effective in replenishing the decrease in total myocardial carnitine content which was present in diabetic hearts and in preventing the accumulation of long chain fatty acyl CoA. Perfusion with L-carnitine also attenuated the elevation of long chain fatty acyl CoA in diabetic hearts. This study gives additional support to the hypothesis that decreases in ATP which occur in the isolated, perfused diabetic heart are correlated with a concomitant elevation in long chain fatty acyl CoA, a known inhibitor of adenine nucleotide translocase. In the presence of elevated exogenous fatty acids, a primary deficiency in the total myocardial carnitine pool would result in elevations in tissue concentrations of long chain fatty acyl CoA since carnitine is a required carrier for transport of fatty acids into mitochondria. Replenishment of the carnitine in vivo was shown to be sufficient to prevent subsequent alteration in long chain fatty acyl CoA and ATP in isolated perfused diabetic hearts despite the burden of elevated fatty acid substrates.

Animals↗
PubMed1987

Spectrophotometric study of the photodecomposition kinetics of nifedipine.

Nifedipine is a photosensitive compound. Irradiation for 4 h under a fluorescent lamp placed 30 cm from a solution of nifedipine in 95% ethanol leads to complete photo-oxidation as determined spectrophotometrically. The disappearance of the reduced form and appearance of the oxidized form is best described by zero-order kinetics at concentrations higher than 4 x 10(-4) M. At lower concentrations pseudo-first order kinetics are followed. Monochromatic irradiation of nifedipine at wavelengths 400 to 700 nm in 25 nm increments showed no change in the absorbance at 280 nm, and, except for a hyperchromic effect at 237 nm, no other spectral changes were observed. Its photo-oxidation was dependent on the intensity of light and increased exponentially as solutions were irradiated progressively closer to a fluorescent light source. The pH studies showed that aqueous solutions of nifedipine photo-oxidized fastest at pH 2.

Drug Stability↗
PubMed1987

Effect of thyroidectomy on 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced lipid peroxidation.

Thyroid hormones have been implicated in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Therefore, the effects of methimazole (MMI) and propylthiouracil (PTU) induced hypothyroidism and surgical thyroidectomy on several toxic manifestations of TCDD were investigated. Female rats were treated with MMI (0.50 mg/kg) for 10 or 28 days, or PTU (5.0 mg/kg) for 10 days. Other animals were surgically thyroidectomized. The animals received TCDD (100 micrograms/kg) orally or the corn oil vehicle 6 days prior to sacrifice. MMI and PTU decreased serum thyroxine (T4) levels by 27-33% while surgical thyroidectomy decreased T4 levels by 66%. TCDD alone decreased T4 levels by 67%, and similar effects occurred in MMI and PTU treated animals. TCDD produced a 9% increase in serum triiodothyronine (T3) concentrations, and neither MMI or PTU treatment for 10 days modified this effect. Neither antithyroid drug prevented TCDD induced weight loss. TCDD administration resulted in over a 300% increase in hepatic malondialdehyde (MDA) content and a 60% decrease in glutathione peroxidase activity. Neither antithyroid compound affected TCDD-induced alterations in these two parameters. TCDD enhanced MDA content by 220% and inhibited glutathione peroxidase activity by 39% in surgically thyroidectomized rats. Thus, only severe hypothyroidism produced by surgical thyroidectomy was able to partially prevent the effects of TCDD on hepatic MDA content and glutathione peroxidase activity.

Animals↗
PubMed1986

Glutathione peroxidase and reactive oxygen species in TCDD-induced lipid peroxidation.

Previous studies have shown that high doses of TCDD induce hepatic lipid peroxidation and inhibit selenium dependent glutathione peroxidase (GSH-Px) activity. The dose dependent effects of TCDD on hepatic lipid peroxidation (malondialdehyde content) and GSH-Px activity were determined. A dose as low as 1 microgram/kg induced hepatic lipid peroxidation and inhibited GSH-Px. Based on the use of scavengers of reactive oxygen species, lipid peroxidation (malondialdehyde formation) by hepatic microsomes from both control and TCDD-treated rats appears to be due primarily to H2O2. The results indicate that superoxide, hydroxyl radical and singlet oxygen are also involved. The differences in the reactive oxygen species involved in microsomal lipid peroxidation between control and TCDD treated animals appear to be quantitative rather than qualitative. A 5.9-fold greater rate of malondialdehyde (MDA) formation by microsomes from TCDD treated animals occurred as compared to controls, while livers of TCDD rats had an MDA content that was 5.0-fold greater than the controls. These differences may be due in part to an enhanced production of H2O2 as well as a decrease in the activity of selenium dependent glutathione peroxidase which metabolizes H2O2.

Animals↗
PubMed1986

Synthesis and biological evaluation of cyclic analogues of 1-carnitine as potential agents in the treatment of myocardial ischemia.

A series of cyclic rigid analogues of l-carnitine has been synthesized and examined for activity as substrates for the carnitine-acylcarnitine translocase, the enzyme that mediates transport of fatty acids into the mitochondria. Synthetic steps to seven of these analogues are described in this paper. Bioassay of these compounds is conducted in a preparation of isolated heart mitochondria that have been previously loaded with [14C]-l-carnitine. Efflux of radioactivity from the mitochondria is then monitored in the presence of the compound being evaluated in order to assess the amount of enzyme activity initiated. The palmityl ester of l-N,N-dimethyl-trans-2-carboxy-4-hydroxypyrrolidinium chloride elicited a 13.63 and 63.07% efflux of [14C]-l-carnitine at concentrations of 3 and 50 mM, respectively. This represents the first instance in which a nonnaturally occurring analogue of l-carnitine has been shown to undergo transport via this mitochondrial translocase, suggesting the possibility that cyclic carnitine analogues may find utility as agents in the treatment of myocardial ischemia.

Animals↗
PubMed1986

Plasma cell balinitis of Zoon.

Superficial lesions of the glans penis can pose diagnostic difficulties. Plasma cell balanitis is such a condition and it may be confused clinically with erythroplasia of Queyrat. It is unresponsive to topical medication and curable only by circumcision.

Aged↗
PubMed1985

Possible mechanism of the synergistic effect of heparin and dihydroergotamine.

A combination of heparin and dihydroergotamine mesylate (Heparin-Dihydergot) has been shown to be more effective than either of these drugs alone in preventing postoperative venous thromboembolism. The possible mechanism for the synergistic effect of heparin and dihydroergotamine was assessed. Phlebograms obtained after administration of 0.5 mg of dihydroergotamine showed marked constriction of the tibial and soleal veins with a significant reduction in the mean diameter of the femoral vein. The effect on the coagulation mechanism was assessed in 28 patients. Blood samples were withdrawn from the femoral vein during varicose vein operations. A significant difference was observed in antithrombin III activity, kaolin-cephalin clotting time, beta-thromboglobulin, and fibrino-peptide levels between the control, dihydroergotamine, heparin, and the combination groups.

Antithrombin III↗