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Biomedical subjects

S H Curry

Publications and source records attributed to S H Curry.

At least 19 recordsLinked to original sources
PubMed1998

Quantitative electroencephalographic evaluation of non-fatal and fatal traumatic coma.

Diffuse axonal injury (DAI) is an important cause of morbidity and mortality after traumatic brain injury (TBI), and its severity is therefore a major determinant of outcome. There have been suggestions that the extent of DAI may be reflected in quantitative measures of cerebral function, including the electroencephalogram (EEG) and brain-stem auditory evoked potentials (BAEPs). It has therefore been proposed that these quantitative methods of analysis may provide objective predictors of outcome following TBI. We prospectively investigated the relationship between quantitative EEG and BAEP measures and outcome, in 60 comatose patients (47 male and 13 female; age range 1-80 years, mean 36.4) after severe, closed head injury (post-resuscitation Glasgow Coma Scale (GCS) of 8). The Spearman correlation coefficients (rs) have been calculated for quantitative EEG measures (mean regional power and interhemispheric coherence) and BAEPs with patient outcome on the Glasgow Outcome and Disability Rating Scales at 6 months and 1 year. The measures most significantly correlated with outcome (P < 0.001) are over the left hemisphere, beta activity power (amplitude squared) in the fronto-central and centro-temporal regions, and alpha activity power in the centro-temporal region. We found no correlation between interhemispheric coherence (a statistical measure of cross-correlation in the frequency domain) and outcome at either 6 months or 1 year post-injury. In 10 fatalities, we examined the relationship between interhemispheric EEG coherence prior to deaths and the histopathological severity of DAI, in concordant regions. The only significant correlation between DAI and interhemispheric coherence is seen in the alpha band at the temporo-occipital site (rs = -0.79, P = 0.007). Our data indicate that there is regional information in EEG power spectra over the left hemisphere, which could be used in prognostic predictions for patients in coma after severe TBI. We were unable to demonstrate a correlation between interhemispheric coherence and outcome, or any clear and consistent evidence of a relationship between interhemispheric coherence and the severity of DAI.

Adolescent↗
PubMed1997

Pharmacokinetics of dichloroacetate in adult patients with lactic acidosis.

The pharmacokinetic properties of the lactate-lowering drug dichloroacetate were investigated in 111 adult patients with lactic acidosis who were randomized to receive dichloroacetate as part of a placebo-controlled clinical trial. The clinical symptoms and etiology of lactic acidosis varied markedly among patients. Dichloroacetate, at a dose of 50 mg per kilogram of body weight, was administered in a 30-minute intravenous infusion into a peripheral vein. A second dose, identical to the first, was administered 2 hours after beginning the first infusion. Plasma levels of dichloroacetate were determined from blood samples collected periodically up to 288 hours after administration and the data were subjected to pharmacokinetic modeling. The pharmacokinetic properties of dichloroacetate in these acutely ill patients were complex and differed markedly from those in healthy volunteers, whose data fitted a one-compartment pharmacokinetic model. In contrast, the data from patients fitted one-, two-, or three-compartment pharmacokinetic models or even none of these, depending on the individual. Drug clearance in plasma tended to decrease as the number of compartments required to fit the data increased or as the number of drug treatments increased.

Acidosis, Lactic↗
PubMed1996

Event-related potentials--neurophysiological tools for predicting emergence and early outcome from traumatic coma.

OBJECTIVE: To determine the prognostic value of multimodal evoked potentials (EPs) and event-related (ERPs) potentials in coma (Glasgow Coma Score <8), after severe traumatic brain injury (TBI). DESIGN: Prospective, longitudinal study of neurophysiological responses recorded during traumatic coma. SETTING: Intensive Care Unit, Frenchay Hospital, Bristol, UK. PARTICIPANTS: Fifty-four comatose TBI patients (age range 1-80 years, mean 36.4). METHODS: Neurophysiological responses were recorded from 11 scalp electrodes with earlobe reference. Conduction times were measured for brainstem auditory, flash visual and somatosensory, short-latency EPs. Peak latencies and amplitudes were determined for long-latency components of visual and auditory ERPs, generated by passive "oddball" paradigms. These neurophysiological and various clinical parameters were correlated with patient outcome using Pearson's coefficient. MAIN OUTCOME MEASURE: Three month Glasgow Outcome Scale (GOS). RESULTS AND CONCLUSION: Highly significant (P <0.001) correlations exist between long-latency ERP components and 3-month outcome. Short-latency EPs, brainstem (wave I-V) and somatosensory conduction times also correlate significantly with the GOS (P <0.01). Of the clinical measurements, pupillary response patterns, APACHE II and Glasgow Coma Scores (GCS) correlate significantly with outcome, as do the retrospective measures of duration of coma and post-traumatic amnesia (PTA) in survivors. Unfortunately, due to variance of long-latency responses, even in controls, absolute values cannot be relied upon as prognosticators. The presence of "mismatch negativity" predicted the return of consciousness (89.7% sensitivity and 100% specificity) and preceded changes in GCS. Its latency was the single best indicator of 90-day outcome from coma (r = -0.641).

Acoustic Stimulation↗
PubMed1995

Whole body autoradiography of CCK-8 in rats.

Rats were given i.v., intranasal or intraperitoneal doses of CCK-8 (sulfated) labelled with 125I-labeled Bolton and Hunter reagent. Radioactivity was found mainly in the liver, kidney, and the intestinal contents. No radioactivity was detected in the brain. In animals dosed i.v., specific localization occurred in the tissue of the pyloric region of the stomach, and in the pancreas. Label persisted within the pyloric region of the stomach for longer than 30 min, in spite of the reported half-life of CCK-8 in plasma of approximately 1 min. Intranasal and intraperitoneal doses had limited bioavailability. The binding to the sites in the pyloric region of the stomach, which required systemic delivery, may have identified receptors associated with appetite control.

Administration, Intranasal↗
PubMed1995

Pharmacokinetics of promazine in patients with hepatic cirrhosis--correlation with a novel galactose single point method.

We examined promazine pharmacokinetics in nine patients with hepatic cirrhosis and in six healthy subjects. A specific and sensitive HPLC method was used to measure promazine concentrations in plasma, plasma water (free drug), red blood cells, and urine after oral administration of promazine (2 x 50 mg tablet). There were highly significant reductions in total plasma clearance (p < 0.01), free drug total plasma clearance (p < 0.01), metabolic clearance (p < 0.01), metabolic clearance of free drug (p < 0.01), and fraction bound (p < 0.01) in the cirrhotic patients. The elimination half-life and the area under the plasma concentration-time curve were significantly increased (p < 0.001 and p < 0.05, respectively) in the cirrhotic patients. However, the overall excreted promazine in urine, time to the promazine peak concentration, distribution half-life, renal clearance, apparent volume of distribution, and the promazine concentration ratio between plasma and red blood cells were not different. Thus caution is needed in using promazine for patients with hepatic cirrhosis. A newly developed galactose single point (GSP) method was applied to quantitatively measure the residual liver function in cirrhosis patients and successfully correlated it with promazine elimination half-life (r = 0.770, p < 0.01), total plasma clearance of free drug (r = 0.899, p < 0.005), metabolic clearance of free drug (r = 0.902, p < 0.005), and plasma protein binding (r = 0.822, p < 0.005). GSP may be a convenient index for promazine routine dosage adjustment in patients with liver cirrhosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

A prodrug approach to increasing the oral potency of a phenolic drug. Part 2. Pharmacodynamics and preliminary bioavailability of an orally administered O-(imidomethyl) derivative of 17 beta-estradiol.

The O-saccharinylmethyl prodrug of 17 beta-estradiol was about nine times as potent, based on 50% effective dose (ED50) values, as 17 beta-estradiol when each was given as an oral dose to ovariectomized rats. Similarly, a significant lowering of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels at 24 h was observed when an ED50 dose of the prodrug was given but not when an equimolar dose of 17 beta-estradiol was given orally. However, when given intravenously, there was no difference in potency between the two drugs. In the bioavailability studies, a significantly longer half-life (approximately 5-7 times) for 17B-estradiol was observed when the prodrug was given orally than when 17 beta-estradiol was given orally or when the prodrug or 17 beta-estradiol were given intravenously. This result was consistent with an observed five-fold enhancement in the oral bioavailability of 17 beta-estradiol when the prodrug was given.

Administration, Oral↗
PubMed1994

Natural history and course of acquired lactic acidosis in adults. DCA-Lactic Acidosis Study Group.

STUDY OBJECTIVE: To determine the pathogenesis and clinical course of lactic acidosis in adults receiving standard medical care. DESIGN: Placebo arm of a 5-year prospective, randomized, blinded study comparing placebo and dichloroacetate as specific lactate-lowering therapy. Each patient received intravenous saline placebo in addition to conventional therapy. SETTING: Intensive care units of 10 tertiary care hospitals in North America. PATIENTS: One hundred twenty-six patients with lactic acidosis, defined as arterial blood lactate greater than or equal to 5 mmol/L and either arterial pH of less than or equal to 7.35 or base deficit greater than 6 mmol/L. Patients were followed for up to 6 months. MEASUREMENTS AND MAIN RESULTS: Mean +/- SD demographic entry data for 126 patients included: age 56 +/- 17 years, lactate 10.4 +/- 5.5 mmol/L, pH 7.24 +/- 0.14, calculated base deficit 14.1 +/- 5.4, arterial systolic blood pressure 103 +/- 29 mm Hg, Glasgow Coma score 7.9 +/- 4.9, and APACHE II score 19.2 +/- 8.1. Despite fluids and pressors, 32% of patients had systolic blood pressures of less than or equal to 90 mm Hg in association with sepsis (59%), cardiac failure (18%), or hemorrhage (18%). The most common causes of lactic acidosis in the absence of shock were sepsis (49%), liver disease (15%), and respiratory failure (12%). The median survival was 38.5 hours. Survival at 24 hours was 59%. Arterial pH predicted 24-hour survival better than base deficit or bicarbonate level. Percent survival was 41% at 3 days and 17% at 30 days. Only 21% of patients survived to leave the intensive care unit, and 17% were discharged from the hospital. In patients receiving sodium bicarbonate, neither acid-base nor hemodynamic status improved. CONCLUSIONS: In this first prospective study of the clinical course of acute lactic acidosis in adults, nearly all subjects had both hemodynamic and nonhemodynamic (metabolic) underlying causes, many of which independently predicted survival and most of which were refractory to standard care.

Acidosis, Lactic↗
PubMed1994

Pharmacokinetics and pharmacodynamics of acepromazine in horses.

A specific, sensitive, reverse-phase high-performance liquid chromatographic assay for acepromazine, with analytic sensitivity as low as 5 ng/ml of plasma, and electrochemical detection with an oxidation potential of 0.7 V, was used to study the pharmacokinetics of acepromazine given at a dosage of 0.15 mg/kg of body weight in horses. The relation between effect and pharmacokinetics of the drug was examined. The effects studied included those on blood pressure, pulse, PCV, measures of respiration function, and sedation. Intravenously administered doses led to a biphasic concentration decay pattern with an alpha-phase distribution half-life of < 3 minutes. The beta-phase half-life was in the range of 50 to 150 minutes. The CNS effects peaked at 20 minutes after administration, and the hemodynamic effects peaked at 100 minutes. In all horses, the most sensitive variable was the PCV, which decreased by up to 20% (P < 0.0001). Systolic, diastolic, and mean blood pressures decreased (P < 0.0001); heart rate was unchanged (P > 0.05). Neither blood gas tensions nor blood pH changed noticeably (P > 0.05). In all horses studied, acepromazine had a significant (P < 0.0001) sedative effect, as observed by posture and alertness. None of the observed pharmacodynamic effects correlated well with plasma acepromazine concentration. These effects persisted beyond the time of detectable acepromazine concentration, indicating that they might be caused by active metabolites, or that their timing could result from complex pharmacokinetic compartment influences.

Acepromazine↗
PubMed1993

Plasma concentrations and hemodynamic effects of intravenous, sublingual, and aerosolized nitroglycerin in patients undergoing cardiac catheterization.

Intravenous, sublingual, or aerosolized nitroglycerin was administered to 19 patients with coronary artery disease during clinically indicated cardiac catheterization. Eight blood samples were collected over 15 min from each patient, and analyzed for content of nitroglycerin, 1,2-glycerol dinitrate, and 1,3-glycerol dinitrate. Simultaneously, heart rate (HR), systolic blood pressure (SBP), and left ventricular end-diastolic pressure (LVEDP) were recorded. Plasma concentrations of nitroglycerin were highest after intravenous injection and lowest after sublingual tablets. Metabolite concentrations were highest after intravenous injection at early time-points; at later time-points, no between-group differences could be detected. SBP was minimally affected by intravenous nitroglycerin but was significantly reduced by sublingual and aerosolized formulations. Minor fluctuations in HR were observed in association with all three formulations. LVEDP was reduced by all three formulations of nitroglycerin but most rapidly by the intravenous form. Overall, no differences were detected in hemodynamic responses caused by sublingual and aerosolized nitroglycerin. Efficacy of sublingual and aerosolized nitroglycerin in patients undergoing cardiac catheterization is equivalent.

Administration, Inhalation↗
PubMed1993

Red blood cell partitioning, protein binding and lipophilicity of six phenothiazines.

Hexane-water partition coefficients, pKa values, protein binding and red blood cell partitioning were studied with six phenothiazine drugs. Red cell partitioning was independent of drug concentration, and there was no correlation between partitioning and physicochemical characteristics. Red cell partitioning could be used indirectly to estimate protein binding, but two potential pitfalls of general importance were found. Failure to consider drug binding of glassware and haematocrit changes were shown to induce incorrect estimates of both red cell partitioning and protein binding, as well as hexane-water partition coefficients.

Blood Proteins↗
PubMed1992

A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group.

BACKGROUND: Mortality is very high in lactic acidosis, and there is no satisfactory treatment other than treatment of the underlying cause. Uncontrolled studies have suggested that dichloroacetate, which stimulates the oxidation of lactate to acetyl-coenzyme A and carbon dioxide, might reduce morbidity and improve survival among patients with this condition. METHODS: We conducted a placebo-controlled, randomized trial of intravenous sodium dichloroacetate therapy in 252 patients with lactic acidosis; 126 were assigned to receive dichloroacetate and 126 to receive placebo. The entry criteria included an arterial-blood lactate concentration of > or = 5.0 mmol per liter and either an arterial-blood pH of < or = 7.35 or a base deficit of > or = 6 mmol per liter. The mean (+/- SD) arterial-blood lactate concentrations before treatment were 11.6 +/- 7.0 mmol per liter in the dichloroacetate-treated patients and 10.4 +/- 5.5 mmol per liter in the placebo group, and the mean initial arterial-blood pH values were 7.24 +/- 0.12 and 7.24 +/- 0.13, respectively. Eighty-six percent of the patients required mechanical ventilation, and 74 percent required pressor agents, inotropic drugs, or both because of hypotension. RESULTS: The arterial-blood lactate concentration decreased 20 percent or more in 83 (66 percent) of the 126 patients who received dichloroacetate and 45 (36 percent) of the 126 patients who received placebo (P = 0.001). The arterial-blood pH also increased more in the dichloroacetate-treated patients (P = 0.005). The absolute magnitude of the differences was small, however, and they were not associated with improvement in hemodynamics or survival. Only 12 percent of the dichloroacetate-treated patients and 17 percent of the placebo patients survived to be discharged from the hospital. CONCLUSIONS: Dichloroacetate treatment of patients with severe lactic acidosis results in statistically significant but clinically unimportant changes in arterial-blood lactate concentrations and pH and fails to alter either hemodynamics or survival.

Acidosis, Lactic↗
PubMed1992

Pharmacokinetics of nitroglycerin and its metabolites after administration of sustained-release tablets.

Nitroglycerin was administered to eight healthy volunteers in the form of sublingual tablets, oral sustained-release tablets, and an oral solution. Blood samples were collected for measurement of nitroglycerin and its two isomeric glyceryl dinitrate metabolites. Blood pressure and pulse rate were monitored; subjective evaluations of headache, dizziness, facial flushing, skin irritation, and gastrointestinal upset were made. Nitroglycerin itself was virtually undetectable after the solution and tablet preparations; the metabolites were consistently detectable from a few minutes after dosing to 24 h later. Mean total (nitroglycerin plus metabolite) concentrations were comparable in the 15 min following sublingual administration, and the 8 h following tablet administration. The relative bioavailability of the tablets in comparison with the oral solution was 70 per cent based on metabolite concentrations. Nitroglycerin sustained-release tablets appear to exert their beneficial effects in the prolonged prophylaxis of angina through active metabolites.

Administration, Oral↗
PubMed1992

In vivo folate kinetics during chronic supplementation of human subjects with deuterium-labeled folic acid.

Six healthy men (22-31 y) were supplemented for 4 wk with folic acid labeled with deuterium [3',5'-2H2; 3.6 mumol/d (1.6 mg/d)] to permit evaluation of in vivo kinetics of this vitamin. Total folate in urine, serum and erythrocytes was determined by microbiological assay, and isotopic labeling of urinary and erythrocyte folate was determined by gas chromatography-mass spectrometry. During supplementation, serum folate reached maximal concentration in approximately 18 d, whereas excretion of total and deuterium-labeled folates increased rapidly and reached isotopic steady state in 1-2 wk. Isotopic labeling of erythrocyte folate increased continually over the entire supplementation period. Upon cessation of supplementation, red blood cell folate and urinary folate excretion (total and labeled) decreased linearly. The decline in total serum folate could be described with a biexponential model that yielded a slow-phase half-life of 18.7 +/- 2.3 d. This model also indicated a turnover of 4.5% of the total body folate pool per day. Pool sizes of total body folate before and after supplementation (at steady state) were calculated to be 10 mumol (4.4 mg) and 98.9 mumol (43.7 mg), respectively. These kinetic data and stable isotope methodology may be used to address a wide range of experimental questions related to folate metabolism.

Adult↗
PubMed1991

Disposition and pharmacodynamics of dichloroacetate (DCA) and oxalate following oral DCA doses.

Healthy volunteers received intravenous and/or oral doses of sodium dichloroacetate (DCA) in various single and multiple dose regimens. A crossover bioavailability study proved abortive because second and subsequent doses showed significantly longer terminal elimination half-lives (means 3.64 h and 9.9 h, respectively) than was the case for initial doses (1.58 h). A parallel bioavailability comparison failed to show that oral doses were significantly different from 100 per cent bioavailability (AUCoral, 604 micrograms h-1 ml-1; AUCi.v., 489 micrograms h-1 ml-1). The time required to elapse between individual doses, in order to prevent second doses having relatively long half-life values, varied in different individuals from 1 week to greater than 3 months. No cardiac or central nervous system effects were recorded by echocardiography and digit symbol substitution tests, respectively. The mean renal clearance of DCA was 42.9 ml h-1. No differences were observed in DCA kinetics between male and female subjects.

Administration, Oral↗
PubMed1991

Haemodialysis studies with dichloroacetate.

Seven patients undergoing routine thrice weekly haemodialysis for endstage renal failure participated in 12 investigations of dichloroacetate (DCA) pharmacokinetics and pharmacodynamics. DCA doses were 50 mg/kg by i.v. infusion over 30 min. In each investigation single doses were administered to each subject on two consecutive days, one being a day during which the patient was dialyzed. The timing of drug administration, relative to dialysis, was varied to assess the effect of dialysis on the apparent volume of distribution and elimination rate constants of DCA and on its effect on blood glucose and lactate. Dialysis increased the clearance of DCA by approximately 60%, but had no effect on its apparent volume of distribution. Dialysis did not reduce the maximal lactate-lowering effect of DCA, but slightly decreased the duration of this effect. Blood glucose levels were not significantly altered by DCA and no adverse drug effects were observed. We conclude that dialysis increases plasma clearance of DCA, but has little influence on the metabolic effects of the drug when given at 50 mg/kg doses. DCA can safely and effectively be given to hemodialysis patients who may require the drug for treatment of lactic acidosis.

Adult↗