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Biomedical subjects

C E Wright

Publications and source records attributed to C E Wright.

At least 91 records · Page 5Linked to original sources
PubMed1992

Pharmacokinetic and pharmacodynamic comparison of immediate-release and sustained-release adinazolam mesylate tablets after single- and multiple-dose administration.

The effect of adinazolam release rate on psychomotor performance and sedation was assessed by administering 40 mg adinazolam mesylate immediate-release (CT) tablets, 60 mg sustained-release (SR) tablets, and placebo in a double-blind crossover study in 15 healthy male subjects. A separate panel of 16 subjects received the above single doses and multiple-dose regimens of 40 mg CT tablets every 8 hr and 60 mg SR tablets every 12 hr according to a crossover design. Psychomotor performance was assessed by digit symbol substitution test, card sorting tasks, and sedation ratings. Following single-dose administration, dose-corrected adinazolam and N-desmethyladinazolam (NDMAD) AUC values were equivalent for SR and CT tablets. Peak adinazolam and NDMAD levels were lower and occurred later for the SR tablets. Decrements in card sorting were 50 and 3% at 1 hr and 17 and 20% at 6 hr for the CT and SR tablets, respectively. Maximal sedation scores were lower for the SR tablets compared to the CT. Dose-corrected AUC was comparable between single and multiple doses for both adinazolam and NDMAD; no differences were observed in 24-hr AUC at steady-state between CT and SR tablets. Fluctuation ratios were reduced for both adinazolam and NDMAD following SR tablets. Psychomotor and sedative effects were attenuated upon multiple dosing. Thus, the reduction in peak plasma NDMAD following SR tablet administration results in a lesser sedation and psychomotor impairment on acute administration, and tolerance to these effects occurs on multiple dosing.

Adult↗
PubMed1992

Protective and pathological roles of nitric oxide in endotoxin shock.

OBJECTIVE: The aim was to investigate the effects of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of both the constitutive (Ca2+ dependent) and inducible (Ca2+ independent) nitric oxide (NO) synthases, or of pretreatment with the glucocorticoid dexamethasone, an inhibitor of the induction of the Ca2+ independent NO synthase, on lipopolysaccharide induced shock in the anaesthetised rabbit. METHODS: Mean arterial blood pressure, and blood flow in the portal vein, hepatic artery, and hindquarter vascular beds were measured in 49 halothane anaesthetised New Zealand White rabbits given lipopolysaccharide (Salmonella minnesota, 500 micrograms.kg-1 intravenously). The effects of pre- or post-lipopolysaccharide treatment with L-NMMA (300 mg.kg-1 intravenously) and of pretreatment with dexamethasone (3 mg.kg-1 intravenously) were determined. The effect of the NO donor S-nitroso-N-acetyl-penicillamine (SNAP, 300 micrograms.kg-1.h-1 intravenously) in animals treated with lipopolysaccharide and L-NMMA was also studied. RESULTS: Lipopolysaccharide elicited an initial transient fall in mean arterial pressure and decreases in blood flow in the vascular beds, followed by a progressive fall in mean arterial pressure. L-NMMA when given either before or after lipopolysaccharide markedly exacerbated its effects and resulted in severe hypotension, intense vasoconstriction, and increased mortality. Pretreatment with dexamethasone had no effect on the initial haemodynamic changes following lipopolysaccharide, but prevented the subsequent fall in mean arterial pressure observed in animals treated with lipopolysaccharide alone. Dexamethasone failed, however, to protect animals also treated with L-NMMA before lipopolysaccharide. Animals pretreated with L-NMMA and SNAP showed reduced haemodynamic changes when compared with controls (lipopolysaccharide only) or lipopolysaccharide and L-NMMA treated animals. CONCLUSIONS: Inhibition of both constitutive and inducible NO synthases during endotoxaemia is deleterious. This can be overcome by replacing NO intravenously with a donor of NO. Selective inhibition of the inducible NO synthase may, however, be beneficial in shock.

Animals↗
PubMed1992

Release of endothelium-derived relaxing factor from resistance arteries in hypertension.

Aortic rings from SHR are reported to have a decreased relaxation response to the endothelium-dependent agent acetylcholine compared with rings from WKY rats. Thus, a reduced EDRF (nitric oxide) response could contribute to hypertension. We found that in mesenteric small resistance arteries (200 microns I.D.) taken from 5- to 50-week old rats and mounted in a Mulvany-Halpern myograph, that the concentration-response curves to acetylcholine were similar in range and sensitivity (EC50) in arteries from SHR and WKY rats at the same age. Similarly, in small resistance arteries from human buttock skin, the relaxation to acetylcholine was not different between vessels from normotensive volunteers (mean BP = 95.2 +/- 1.5 mm Hg) and patients with untreated essential hypertension (mean BP = 116.5 +/- 2.5 mm Hg). In rabbits with chronic renovascular hypertension (cellophane renal wrap), acetylcholine and adenosine infusions into the lower abdominal aorta caused falls in hindquarter resistance that were enhanced in range, but with no change in sensitivity compared with normotensive rabbits. In normotensive rabbits, nitric oxide synthase inhibition with N omega-nitro-L-arginine infusion caused a rise in blood pressure, fall in hindquarter conductance and blockade of the acetylcholine responses. These experiments suggest that at the level of resistance arteries in vivo and in vitro, a defect in the receptor-stimulated response to EDRF associated with hypertension could not be detected. Apparently, basal nitric oxide is important in resting vasodilator tone, but its role in chronic hypertension is still unclear.

Acetylcholine↗
PubMed1992

A pharmacokinetic evaluation of the combined administration of triazolam and fluoxetine.

The influence of fluoxetine on triazolam pharmacokinetics was studied because of changes in diazepam pharmacokinetics reportedly produced by fluoxetine. Twenty-four healthy volunteers received a single 0.25-mg triazolam tablet alone, and another 0.25-mg tablet after 8 days of fluoxetine therapy 60 mg/day. All subjects received these treatments in the same sequence. Several blood samples were drawn from the subjects after the triazolam doses and were assayed by high-performance liquid chromatography (HPLC). Blood samples were drawn immediately before the last three fluoxetine doses to determine the concentration of fluoxetine and its metabolite norfluoxetine, also by HPLC. The pharmacokinetics of triazolam did not change significantly when the tablets were administered after multiple doses of fluoxetine. These results indicate that no pharmacokinetic interaction exists between triazolam and fluoxetine or norfluoxetine. However, each patient's clinical response to therapy should be monitored when triazolam tablets and fluoxetine capsules are administered concomitantly.

Adult↗
PubMed1991

The role of home environment in infant diarrhea in rural Egypt.

In 1982 and 1983, a descriptive environmental survey was conducted in 317 households with newborn infants in rural Bilbeis, Egypt. The incidence of infant diarrhea in these households was ascertained by twice-weekly home visits for a 1-year period (1981-1982). Using univariate and multivariate analyses, the authors identified household factors that were statistically associated with infant diarrhea incidence, including number of children in the house under 4 years of age; number of persons per household; incidence of diarrhea in other family members; having a dirt (vs. concrete) dining room floor; having multiple living areas in the house; having a house or roof in need of repair; using well water rather than tap water for cooking or bathin; the absence of a sewer for waste bathwater; food being left out at room temperature between meals; and having many rodents in the house. Two practices involving interaction with the environment appeared to be protective: butchering of cattle by the family for home consumption, and protection of the infant from flies by a veil during napping. The combined household variables explained 25% of the variance in the total incidence of diarrhea. Categories of variables that accounted for most of the total variance explained by environmental factors are, in decreasing order: house structure (28%); water usage (24%); toilet and bathing area (12%); animal management (11%); food preparation area (10%); hygiene (8%); and wastewater management (6%). This approach may be useful in identifying environmental characteristics whose change would reduce diarrheal illness among infants.

Abattoirs↗
PubMed1991

Crystallization of and preliminary X-ray data for the mouse major urinary protein and rat alpha-2u globulin.

Crystals of the mouse major urinary protein (MUP) and rat alpha-2u globulin (AMG) have been grown from solutions of polyethylene glycol 3350 and CdCl2, respectively. The crystals differ both in their morphologies and space groups but have very similar unit cell sizes. AMG crystallized in P2(1) (a = 56.6 A, b = 103.8 A, c = 62.7 A, beta = 95.1 degrees) with four subunits/asymmetric unit, while MUP gave crystals in P4(1)2(1)2 or P4(3)2(1)2 (a = 57.3 A, c = 109.9 A) with one subunit/asymmetric unit. Both crystal forms diffract beyond 2.8 A resolution.

Alpha-Globulins↗
PubMed1990

Differences in regional vascular sensitivity to endothelin-1 between spontaneously hypertensive and normotensive Wistar-Kyoto rats.

1. The systemic and regional haemodynamic effects of porcine endothelin-1 (endothelin) have been measured in anaesthetized spontaneously hypertensive (SH) rats rendered areflexic by ganglion blockade; comparisons were made with age-matched Wistar-Kyoto (WKY) control animals. 2. In both SH and WKY rats endothelin (0.1-1 nmol kg-1 i.v.) elicited an initial, short-lived (less than 2 min), fall in blood pressure which was associated with substantial increases in hindquarter and carotid vascular conductances. Both the blood pressure falls and the peripheral vasodilator responses were greater in SH than in WKY rats. 3. The initial depressor effects of endothelin were followed by marked and sustained increases in blood pressure associated with constriction in carotid, hindquarter, renal and mesenteric vascular beds. Vasoconstrictor responses were quantitatively similar in the two rat strains. 4. Pretreatment with indomethacin (5 mg kg-1 i.p. or i.v.) did not alter the responses to endothelin, 1 nmol kg-1, in SH rats. 5. The regional haemodynamic effects of intravenously administered acetylcholine (0.01-1 microgram kg-1), nitroprusside (0.3-10 micrograms kg-1) and angiotensin II (0.01-0.1 microgram kg-1) were similar in SH and WKY rats. 6. Endothelin (10(-10)-3 x 10(-8) M) contracted aortic rings from both SH rats and WKY control animals. Removal of the endothelium enhanced significantly the sensitivity of tissues from both WKY and SH rats to endothelin; the increase in sensitivity was greater in tissues from SH than WKY rats. 7. The results demonstrate qualitative similarities in the complex haemodynamic effects of endothelin in SH rats and WKY control animals. However, the SH rats display substantially greater vasodilator responses to endothelin than WKY. Eicosanoid generation is not the mechanism of the vasodilator action of endothelin in SH rats under the conditions of our experiments.

Acetylcholine↗
PubMed1989

The pharmacokinetics of 2.5- to 10-mg oral doses of minoxidil in healthy volunteers.

The dose proportionality of minoxidil was investigated by studying its pharmacokinetics after administration of single, oral doses of 2.5, 5.0, and 10.0 mg. The study, which was a Latin square cross-over design, was performed in 30 young, nonobese, normal subjects. Treatments were separated by a 4-day washout period. Serum and urine levels of minoxidil were determined by high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA). Supine blood pressure and pulse were monitored during each study phase. Minoxidil concentrations determined by RIA were highly correlated with concentrations determined by HPLC; only the HPLC data was used in the pharmacokinetic analyses. No significant effects were observed for dose normalized Cmax, tmax, volume of distribution, minoxidil renal clearance, or the percentage of the dose excreted as either minoxidil or minoxidil glucuronide. Significant differences in apparent oral clearance, dose normalized AUC, and terminal elimination rate constant (beta) were observed between the 2.5-mg dose and the higher doses, but no differences in these parameters between the 5.0- and 10.0-mg doses were apparent. Thus, the available data support dose-independent pharmacokinetics for minoxidil over this range of doses. Repeated measures analysis of variance detected significant time and treatment effects on supine blood pressure and pulse rate, but the effects were generally small and of little clinical significance. The results support the hypothesis that minoxidil has little effect on blood pressure in normotensive subjects.

Adolescent↗
PubMed1989

Disposition of minoxidil in patients with various degrees of renal function.

The disposition of minoxidil was evaluated after a 5 mg oral dose in 24 subjects with various degrees of renal function. Patients were divided into four groups based on a 24-hour ambulatory creatinine clearance (Clcr): Group I (n = 6) Clcr greater than 90 mL/min, Group II (n = 6) Clcr 50-80 mL/min, Group III (n = 5) Clcr of 30-49 mL/min, and Group IV (n = 7) Clcr less than 30 mL/min. Blood and urine samples obtained over 36 hours were analyzed for minoxidil by a high pressure liquid chromatography technique. Maximum plasma concentration (Cmax) and time to reach Cmax did not differ among the four groups. The terminal elimination half-life was prolonged in Group IV subjects (8.87 +/- 6.12 hours) (mean +/- SD) compared to those in Groups I, II and III (1.38 +/- 0.16, 1.99 +/- 0.45 and 2.42 +/- 0.53 hours, respectively). Apparent total body clearance (Clp/F) decreased as renal function declined; Clp/F = 0.82(Clcr) + 21.8, r = 0.739, P = 0.0001. Renal clearance and apparent nonrenal clearance also were significantly correlated with Clcr. The apparent volume of distribution significantly increased as renal function declined. Thus, the disposition of minoxidil is significantly delayed and dosage adjustment may be necessary in patients with renal insufficiency.

Administration, Oral↗
PubMed1989

A radiotracer probe to study metal interaction with human lactate dehydrogenase isoenzymes.

The electrophilic Ag+ ion was found to destroy completely the enzymatic activity of lactate dehydrogenase isoenzyme LDH-1 while other transition metal ions reduced its activity in varying degrees. A radiotracer probe involving 110mAg-labeled silver ion was used to understand the mechanism of denaturation of LDH and also to determine the number of active sites, if any, for substrate binding with the enzyme. Purified LDH-l was reacted with 110mAg-labeled silver ion and the mixture was passed through the sephadex G-75-120 gel to separate the 110mAg-LDH complex that might be formed during the reaction. The resulting elution curve revealed that a stable complex was formed. From the total radioactivity of 110mAg bound LDH, the specific activity of labeled Ag+ and the amount of LDH used the ratio of the number of moles of Ag+ reacted with 1 mol of LDH was computed. This was found to be approximately 4.0, indicating that there are four binding sites in LDD, probably one on each subunit. Kinetic studies of LDH catalysis of L-P reaction in the presence and absence of Ag+ ion suggest that silver ion is involved in competitive inhibition and that the interaction conforms to the "lock-and-key" model. The inhibition of catalysis by other metals is presumably of a noncompetitive type.

Binding Sites↗
PubMed1989

Urinary tract infection following instrumentation for urodynamic testing.

After identifying a temporal cluster of urinary tract infections in patients who had undergone urodynamic procedures, we examined the techniques within the urodynamic laboratory and retrospectively reviewed charts of all 155 patients tested in the previous six months. The rate of acquired urinary tract infections was 18.7%. Risk factors for infection included undergoing cystometrograms and being subject to the first procedure performed in a day. Technical errors in the performance of the urodynamic studies included failure to completely disassemble the apparatus upon completion of a procedure, failure to use sterile components, and lapses in aseptic technique. Bacteria implicated in the outbreak were isolated from tubing, transducers, and flush solutions. After the institution of appropriate technique, all patients tested in the subsequent six months were followed. The rate of acquired urinary tract infection dropped to 5%. Urodynamic apparatus should be completely disassembled following the completion of a procedure; reassembly using sterile components should occur immediately prior to the next procedure; aseptic technique should be maintained; and patients should undergo routine urine screening before a procedure. Surveillance of urodynamic procedures may reveal correctable flaws in technique.

Disease Outbreaks↗
PubMed1989

Effect of the bile-acid sequestrant colestipol on postprandial serum bile-acid concentration: evaluation by bioluminescent enzymic analysis.

Chronic ingestion of bile-acid sequestrants has been shown to decrease the serum cholesterol concentration and coronary events in hypercholesterolaemic patients. To develop improved sequestrants, a rapid, convenient method for testing the bile-acid binding efficacy of sequestrants is needed. Serum bile-acid concentrations could be used to detect bile-acid binding by an administered sequestrant, since the serum bile-acid concentration is determined largely by the rate of intestinal absorption in healthy individuals. To test this, serum bile-acid concentrations were measured at frequent intervals over 24 h in five otherwise healthy hypercholesterolaemic subjects during the ingestion of three standard meals, with or without the addition of 5 g colestipol granules administered 30 min before each meal. Total serum bile-acid concentration was measured with a previously reported bioluminescent enzymic assay, that uses a 3 alpha-hydroxysteroid dehydrogenase, an oxido-reductase, and a bacterial luciferase co-immobilized on to Sepharose beads. Bile acids in 1 ml of serum were isolated by solid-phase extraction chromatography with reversed-phase C18 cartridges. Colestipol lowered the postprandial elevation of serum bile acids by one half, with a subsequent decrease in the cumulative area under the curve. The data suggest that measurement of serum bile-acid concentrations by bioluminescence is a rapid, simple way to document the efficacy of bile-acid sequestrants.

Adolescent↗
PubMed1989

5-carboxamidotryptamine elicits 5-HT2 and 5-HT3 receptor-mediated cardiovascular responses in the conscious rabbit: evidence for 5-HT release from platelets.

The selective "5-HT1-like" receptor agonist 5-carboxamidotryptamine (5-CT, 0.2-1.6 micrograms/kg bolus i.v.), serotonin (5-HT, 3-10 micrograms/kg), and phenylbiguanide (10-40 micrograms/kg) all elicited the "Bezold-Jarisch-like" bradycardia reflex in conscious rabbits. This reflex was antagonised by the 5-HT3 receptor antagonist, MDL 72222. After autonomic blockade (mecamylamine), 5-CT and 5-HT infusion (i.v.) caused renal artery spasm (Doppler flowmeter) that was antagonised by ketanserin, a 5-HT2-receptor antagonist. Both 5-CT and 5-HT caused 5-HT1-like receptor mediated increases in hindquarter conductance that were unaltered by ketanserin (0.5 mg/kg). The anomalous 5-HT3 and 5-HT2 receptor actions of 5-CT were completely prevented by 16 h pretreatment with reserpine (5 mg/kg) that lowered total serum serotonin to less than 3% of normal but did not reduce the cardiovascular actions of 5-HT. Fluoxetine (1 mg/kg i.v.), an inhibitor of 5-HT uptake into platelets, significantly attenuated the Bezold-Jarisch-like reflex evoked by 5-CT but not by 5-HT. These studies suggest that 5-CT is carried into platelets where it releases 5-HT. This illustrates how apparent receptor selectivity asserted in in vitro assays can be destroyed in vivo.

Animals↗
PubMed1988

13C-NMR study of taurine and chlorotaurine in human cells.

13C-NMR with 13C-enriched taurine [( 13C]taurine) has been utilized to study the formation and reactions of N-chlorotaurine in solution and in human cells. Taurine reacts instantaneously with HOCl at pH 7.0 to form N-chlorotaurine, which is stable in solution by itself. In the presence of alpha-amino acids, a chlorine transfer reaction taken place to produce N-chloroamino acids, which quickly convert to the corresponding aldehydes. [13C]Taurine was incubated with human neutrophils and with cultured human lymphoblastoid cells and 13C-NMR spectra of the whole cell mixtures were acquired in order to examine the formation of N-chlorotaurine from reaction between taurine and the endogenous HOCl produced by myeloperoxidase-catalyzed reactions (Zgliczynski, J.M., et al. (1968) Eur. J. Biochem. 4, 540; Weiss, S.J., et al. (1982) J. Clin. Invest. 70, 598). The presence of N-chlorotaurine in the cells was not detected on the 13C-NMR spectra. On the other hand, N-chloro[13C]taurine incubated with the cells was found to be converted to taurine, which must have been produced by a chlorine transfer reaction of the N-chlorotaurine to other cellular components such as amino acids, peptides or proteins. A 13C-NMR study of taurine uptake in human lymphoblastoid cells indicated that taurine is incorporated into a freely mobile intracellular pool. These results suggest that the presence of abundant taurine in a freely mobile intracellular pool may serve as a buffer in preventing oxidative damage to the cells from attacks by HOCl or other oxidants.

Biological Transport↗