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Biomedical subjects

A J Wood

Publications and source records attributed to A J Wood.

At least 19 recordsLinked to original sources
PubMed1992

Sensitive assay for triazolam in plasma following low oral doses.

At low doses of triazolam currently recommended increased assay sensitivity is required for measurement of low plasma concentrations. A highly sensitive capillary gas chromatographic analytical method with a limit of detection of 0.02 ng/ml was developed and used to describe the pharmacokinetics of triazolam following the oral intake of 0.125, 0.250 and 0.375 mg. Six male subjects were studied with blood sampling at the following times: 0, 15, 30 and 45 min and 1, 1.5, 2.0, 2.5, 3, 4, 5, 6 and 8 h. The mean pharmacokinetic parameters for the three doses, respectively, were as follows: half-life, 2.7 +/- 0.4, 3.2 +/- 0.5 and 3.2 +/- 0.6 h; apparent oral clearance, 302.3 +/- 59.0, 260.2 +/- 67.9 and 328.6 +/- 77.8 ml/min; apparent volume of distribution, 64.3 +/- 9.6, 62.0 +/- 12.6 and 73.3 +/- 7.7 l; time to maximum concentration, 0.7 +/- 0.2, 0.6 +/- 0.1 and 0.8 +/- 0.3 h; maximum concentration, 2.2 +/- 0.3, 4.3 +/- 0.6 and 5.0 +/- 0.5 ng/ml; and the area under the concentration-time curve (AUC) up to 8 h, 6.8 +/- 1.2, 16.8 +/- 2.9 and 19.6 +/- 3.5 ng/ml h; and AUC extrapolated to infinity, 8.5 +/- 1.7, 21.4 +/- 4.4 and 26.3 +/- 7.2 ng/ml h. There were no significant differences in the half-life, clearance, volume of distribution and time to maximum concentration among the three doses. The AUC was significantly different on the three occasions and was linearly correlated with dose: r = 0.64 (p less than 0.005).

Administration, Oral↗
PubMed1992

Optimization of high-performance liquid chromatographic assay for catecholamines. Determination of optimal mobile phase composition and elimination of species-dependent differences in extraction recovery of 3,4-dihydroxybenzylamine.

This paper describes the application of a window diagram technique to optimize the four components of eluent (sodium acetate, sodium heptanesulfonate, acetonitrile and pH adjusted by monochloroacetic acid), for complete separation of five catecholamine compounds and the internal standard (3,4-dihydroxybenzylamine, DHBA). In addition, studies were performed to address the problem of the variable recovery of DHBA from dog plasma due to a time-dependent loss of DHBA. We found that this phenomenon can be prevented by pH adjustment prior to addition of DHBA, allowing development of an accurate high-performance liquid chromatographic assay for plasma catecholamines in dogs.

Animals↗
PubMed1992

Differing effect of atropine on heart rate in Chinese and white subjects.

To determine if differences exist between Chinese and white subjects in their response to atropine and if the intrinsic heart rate and the autonomic contribution to the heart differ between the two races, eight white and eight Chinese males were studied. In all subjects the heart rate decreased after the first dose of atropine (0.003 mg/kg) with no difference in the bradycardia between the two races. However, as further doses were administered, the heart rate increased in both groups, resulting in a significantly (p less than 0.05) greater increase in Chinese subjects than in white subjects. The increase in heart rate for each nanogram per milliliter of atropine was 2.8-fold higher (p less than 0.05) in the Chinese subjects (19.24 +/- 4.41 beats/min) compared with white subjects (6.83 +/- 1.62 beats/min). There was no difference in the intrinsic heart rate, in the relative vagal contribution, or in relative sympathetic contribution to the heart rate between the Chinese and white subjects. These data indicate that Chinese subjects are more sensitive to the effect of atropine, which is not related to the contribution of autonomic tone to the heart.

Adult↗
PubMed1992

Identification of the pharmacogenetic determinants of alfentanil metabolism: cytochrome P-450 3A4. An explanation of the variable elimination clearance.

There is considerable variability in the elimination clearance of the opioid analgesic alfentanil. It has been shown previously that alfentanil clearance is independent of the polymorphic debrisoquine hydroxylase (P-450 2D6), and it is therefore of interest to identify the human cytochrome P-450 enzymes involved in noralfentanil formation, the primary reaction involved in the oxidative N-dealkylation at the piperidine nitrogen. Purified human P-450 3A4 showed appreciable catalytic activity, and yeast recombinant P-450 3A4 also showed alfentanil oxidation activity. When microsomes prepared from different human liver samples were compared, noralfentanil formation activity was well correlated (r = 0.95,P less than 0.005) with nifedipine oxidation (a P-450 3A4 marker) but not with markers of other P-450s, including phenacetin O-deethylation (P-450 1A2), chlorzoxazone 6-hydroxylation (P-450 2E1), and (S)-mephenytoin 4'-hydroxylation (a P-450 2C enzyme). Using antibodies that recognize specific human P-450 enzymes (immunoinhibition techniques), it was possible to demonstrate that anti-P-450 3A4 nearly completely inhibited alfentanil oxidation activity in the human liver microsomes, but no other antibodies showed a measurable inhibitory effect. Selective chemical inhibitors of P-450 3A4, gestodene and troleandomycin, inhibited as much as 90% of the microsomal noralfentanil formation activity, but other chemical inhibitors did not show a detectable inhibitory effect. 7,8-Benzoflavone inhibited as much as 90% of the alfentanil oxidation activity of the microsomal or reconstituted P-450 3A4 system. This work indicates that P-450 3A4 contributes significantly to human liver microsomal alfentanil oxidation, whereas P-450 2D6 does not contribute.(ABSTRACT TRUNCATED AT 250 WORDS)

Alfentanil↗
PubMed1992

Lack of effect of ageing on the stereochemical disposition of propranolol.

The elderly are more resistant to the effects of propranolol than the young. To determine whether the decreased sensitivity in the elderly could be due to stereoselective alteration in propranolol metabolism, we investigated the effect of age on the oral clearance of (-)- and (+)-propranolol. Six young (aged 24-32, mean 27.3 +/- 1.3 years) and six elderly (65-80, mean 71.3 +/- 2.7 years) white male volunteers were given a single 80 mg oral dose of racemic propranolol. The mean peak plasma concentrations of both (+)- and (-)-propranolol were significantly higher (P less than 0.05) in the elderly (105.7 +/- 19.7 and 165.0 +/- 29.7 nmol l-1) compared with the young subjects (68.6 +/- 10.1 and 115.7 +/- 18.1 nmol l-1). The oral clearances of both (+)- and (-)-propranolol were significantly higher (P less than 0.05) in the young (6933 +/- 598 and 4554 +/- 372 ml min-1) than in the elderly (4548 +/- 712 and 2941 +/- 473 ml min-1). Age had no effect on the relative concentration of the two isomers. Thus, the ratio of (+)-propranolol to (-)-propranolol was 0.67 +/- 0.05 in the young compared with 0.65 +/- 0.02 in the elderly.

Adult↗
PubMed1992

Increase in Na+/K+ pump numbers in vivo in healthy volunteers taking oral lithium carbonate and further upregulation in response to lithium in vitro.

1. We have measured [3H]-ouabain binding to lymphocyte membranes in eight healthy volunteers before and after they had taken lithium carbonate for 14 days in doses which maintained the serum lithium concentration in the range 0.5-1.0 mmol 1-1. 2. There was a statistically significant increase in the [3H]-ouabain binding capacity of the lymphocyte membranes (reflecting the number of Na+, K+-ATPase molecules) after 14 days of lithium administration in vivo. This suggests that a failure to increase pump numbers after similar exposure to lithium in vivo in patients with manic-depressive psychosis is a primary abnormality associated with the disease. 3. In vivo lithium administration did not alter the normal adaptive (upregulatory) response of lymphocyte Na+, K+-ATPase to standard pharmacological challenges, involving in vitro incubation for 3 days with lithium chloride (8 mmol 1-1) or sodium ethacrynate (1 mumol 1-1). 4. We have previously found that there is an impaired response of the Na+, K+-ATPase to these in vitro stimuli in patients with manic-depressive psychosis, and our present data suggest that this abnormality is attributable to the disease itself and not to in vivo lithium therapy. 5. The data also suggest that the increase in vivo Na+/K+ pump activity which we have previously described in healthy volunteers after 21 days of lithium administration is at least partly due to an increase in Na+/K+ pump numbers.

Administration, Oral↗
PubMed1992

Elemental mercury vapour toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers. Part I: History, neuropsychological findings and chelator effects.

Mercury poisoning occurred after the acute, prolonged exposure of 53 construction workers to elemental mercury. Of those exposed, 26 were evaluated by clinical examination and tests of neuropsychological function. Patients received treatment with chelation therapy in the first weeks after exposure. Eleven of the patients with the highest mercury levels were followed in detail over an extended period. Observations included the evaluation of subjective symptoms of distress, using the 'Symptom Check List 90-Revised' (SCL-90R) and tests of visual-motor function such as 'Trailmaking Parts A and B', 'Finger Tapping', 'Stroop Colour Word Test' and 'Grooved Pegboard.' On day 85 +/- 11 (mean +/- s.d.) after exposure, these 11 men again received either 2,3-dimercaptosuccinic acid (DMSA) or N-acetyl-D, L-penicillamine (NAP) in a short-term study designed to compare the potential to mobilize mercury and the incidence of drug-induced toxicity of these two chelating agents. Rapidly resolving metal fume fever was the earliest manifestation of symptoms. CNS symptoms and abnormal performance on neuropsychological tests persisted over the prolonged period of follow-up. There were significant correlations between neuropsychological tests and indices of mercury exposure. Serial mercury in the blood and urine verified the long half-life and large volume of distribution of mercury. Chelation therapy with both drugs resulted in the mobilization of a small fraction of the total estimated body mercury. However, DMSA was able to increase the excretion of mercury to a greater extent than NAP. These observations demonstrate that acute exposure to elemental mercury and its vapour induces acute, inorganic mercury toxicity and causes long-term, probably irreversible, neurological sequelae.

Adult↗
PubMed1992

Elemental mercury vapour toxicity, treatment, and prognosis after acute, intensive exposure in chloralkali plant workers. Part II: Hyperchloraemia and genitourinary symptoms.

Exposure to elemental mercury vapour is known to influence renal function; however, severe renal disease has not been consistently identified. Eleven men were evaluated for renal disease after acute, massive mercury poisoning. Significant hyperchloraemia was identified in this group of patient and a reversible renal tubular defect was suggested by low normal serum bicarbonate, a normal serum anion gap and a positive urinary anion gap. The only other evidence of renal dysfunction was transient, mild proteinuria in one of the 11 patients. During this same time period, neuropsychological impairment was identified on a test of cognitive and visual-motor function, 'Trailmaking B', in seven of the 11 patients. Additionally, dysuria and ejaculatory pain occurred without evidence of urological disease. These complaints were more frequent in those patients with impairment on 'Trailmaking B' suggesting a neurological basis for these symptoms. The findings of this study support earlier observations that the brain rather than the kidney is the critical target organ after elemental mercury vapour exposure.

Adult↗
PubMed1991

Altered in vitro adaptive responses of lymphocyte Na+,K(+)-ATPase in patients with manic depressive psychosis.

When lymphocytes from healthy subjects are incubated in lithium (8 mM) or ethacrynate (1 microM) they show a time-dependent adaptive response, which consists of a significant increase in the number of Na+,K(+)-ATPase molecules in the lymphocyte membrane. We have studied the lymphocytes from nine euthymic drug-free patients with a history of manic depressive psychosis, and have found that this normal adaptive response was absent. It was also absent from the lymphocytes of euthymic patients taking lithium. We conclude that this altered in vitro adaptive response of lymphocyte Na+,K(+)-ATPase represents an enduring trait marker in manic depressive psychosis.

Bipolar Disorder↗
PubMed1991

Increased suppression of exercise-induced increase in renin by propranolol in Chinese subjects.

Sensitivity to the hypotensive effect of propranolol differs between Chinese subjects and white subjects. To explore the pharmacodynamic explanation for this difference, eight Chinese subjects (age range, 25 to 42 years) and eight white subjects (age range, 22 to 36 years) were given single doses of 10, 20, 40, and 80 mg propranolol on separate occasions at least 3 days apart. Heart rate, mean blood pressure, norepinephrine, epinephrine, and plasma renin activity were measured at the end of treadmill exercise 2 hours after medication was administered. Propranolol produced a concentration-dependent reduction in mean blood pressure and heart rate in both groups. Concentration-response curves were shifted significantly to the left in Chinese subjects, confirming the increased sensitivity to propranolol of the Chinese. The baseline exercise plasma renin activity was twofold higher (p less than 0.05) in Chinese than in white subjects. The sensitivity to beta-blockade-induced suppression of plasma renin activity was increased in the Chinese, which resulted in a sevenfold higher concentration being required in white subjects than in Chinese to produce the same 50% suppression of exercise plasma renin activity (84.8 +/- 23.2 versus 12.7 +/- 7.4 ng/ml, p less than 0.05). The reduction in exercise heart rate and mean blood pressure produced by propranolol were well correlated to the reduction in exercise plasma renin activity in both populations. There was no significant effect of either race or propranolol on plasma catecholamine concentration after exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

Dose-related effect of triazolam on postural sway.

Measurement of clinically relevant benzodiazepine drug effects at hypnotic and anxiolytic doses has been difficult because most measures are subjective, difficult to interpret, or relate to anesthetic doses. A potentially useful measure of drug effect is postural sway, which is a manifestation of the corrective mechanisms associated with the maintenance of upright posture. Postural sway was measured over 8 hours, with a biomechanics force platform, in six healthy male volunteers who received triazolam, 0.125, 0.250, or 0.375 mg, or placebo in a randomized double-blind study. Our results show a dose-dependent increase in postural sway measured as the elliptical area or the 95% confidence ellipse for the area covered by the subjects' sway. After triazolam, 0.250 and 0.375 mg, the area under the sway-time curve and peak effect increased significantly compared with placebo (p less than 0.05). The number of losses of balance when subjects stood on one foot also showed a significant increase with increased dose (p less than 0.05). The rate of loss of balance was positively correlated with the extent of postural sway (r = 0.802; p less than 0.001). The extent of sway when the subjects were drug free predicted this increase in a subject's postural sway with triazolam. Thus at hypnotic or anxiolytic doses of triazolam, computer-assisted force platform measures of sway provide a clinically relevant measure of drug effect. Measurement of drug-induced postural sway may be useful in persons at risk for falls, such as the elderly.

Adult↗
PubMed1991

Effect of i.v. anaesthesia with propofol on drug distribution and metabolism in the dog.

We have studied the effect of i.v. anaesthesia with propofol in the emulsion (Intralipid) formulation on drug distribution and metabolism in six dogs using dual-route administration of propranolol as a model compound. Each dog was studied on two consecutive days: day 1 awake and day 2 during propofol anaesthesia (6 mg kg-1 followed by an infusion of 0.8 mg kg-1 min-1). Propofol anaesthesia was associated with reduced intrinsic clearance by 40% (P less than 0.05) but no significant difference in systemic clearance or hepatic plasma flow. Propofol produced marked changes in drug distribution; volume of distribution (Vss) of propranolol increased 54% from 82.5 (SEM 7.3) litre awake to 127.3 (27) litre during propofol anaesthesia (P less than 0.05). This change was accompanied by an increase (P less than 0.05) in the free fraction of propranolol from 8.5 (0.7) % in awake to 14.0 (0.7) % in propofol-anaesthetized dogs. The combination of the effects of both drug clearance and protein binding resulted in a 65% decrease in the intrinsic clearance of unbound drug (P less than 0.05). In contrast with the effects of propofol on drug distribution, infusion of Intralipid alone in another group of six dogs had no significant effects on drug distribution, protein binding or drug metabolism. We conclude that propofol is a modest inhibitor of drug metabolism, but has major effects on propranolol distribution, possibly by changing plasma protein binding.

Anesthesia, Intravenous↗
PubMed1991

Effects of anesthesia on norepinephrine kinetics. Comparison of propofol and halothane anesthesia in dogs.

Alteration of sympathetic function is a major determinant of the cardiovascular effects of anesthetic agents. Plasma norepinephrine (NE) concentrations are determined not only by the rate of NE release from sympathetic nerves but also by NE clearance rate. Therefore, NE concentration in plasma may be an inadequate index of sympathetic activity. We used an isotope dilution technique to investigate the effects of halothane and propofol anesthesia on NE kinetics. A relationship of NE kinetics to halothane dose was determined in six dogs. Halothane 1.0 MAC reduced plasma NE concentration by 35 +/- 9% versus awake (P less than 0.05). This was due to a reduction of 52 +/- 9% in NE spillover (P less than 0.05) accompanied by a reduction of 27 +/- 5% in NE clearance (P less than 0.005). The clearance changes were dose-dependent: reductions were 34 +/- 4% at 1.5 MAC (P less than 0.05 vs. 1.0 MAC) and 45 +/- 5% at 2.0 MAC (P less than 0.05 vs. 1.5 MAC). Six dogs were studied with a single halothane dose (1.0 MAC) and NE concentration, spillover, and clearance were found to be stable over a period of 5.5 h of anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗