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Biomedical subjects

C A Duncan

Publications and source records attributed to C A Duncan.

At least 19 recordsLinked to original sources
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

Fluctuation in mixed venous oxygen saturation in critically ill medical patients: a pilot study.

OBJECTIVE: To determine fluctuation in mixed venous oxygen saturation in critically ill medical patients during a period of rest. DESIGN: Nonexperimental, descriptive. SETTING: The medical and coronary intensive care units in a large county hospital in south-central Texas. PATIENTS: Twenty critically ill patients, aged 19 to 85, who had placement of a pulmonary artery catheter capable of continuous monitoring of mixed venous oxygen saturation. The majority had a diagnosis of respiratory failure and required mechanical ventilation. METHODS: Mixed venous oxygen saturation was recorded each minute for a 2-hour period in either early morning or late afternoon hours. Minute-by-minute values obtained during a 30-minute period of rest were used to determine fluctuation. The lowest and highest mixed venous oxygen saturation values during the period were used to calculate percent changes from average values (fluctuation). RESULTS: The range of fluctuation was +/- 6% of the average mixed venous oxygen saturation value for 80% of the sample. Four patients had a greater range of fluctuation: however, their actual mixed venous oxygen saturation values were within a clinically acceptable range. No significant differences in percentage of low or high fluctuation were noted for the following variables: time of day, medication administration, oxygen delivery, oxygen consumption and average mixed venous oxygen saturation. The percentage of low fluctuation was significantly lower for four patients who were not mechanically ventilated. CONCLUSIONS: Knowledge of normal fluctuation enables the care giver to evaluate changes in mixed venous oxygen saturation in response to activities and/or treatments. Additional study of fluctuation in homogenous groups of critically ill patients is warranted.

Adult↗
PubMed1991

Studies on the metabolic inversion of the 6'chiral center of simvastatin.

In two simvastatin (SV) metabolites the 6' alpha-methyl of SV is oxidized to either 6' beta-CH2OH (I) or 6' beta-COOH (II). A possible intermediate is 6' exomethylene SV (III). When Sprague Dawley rats received an i.v. dose of [14C] III (1 mg/kg) metabolite II was excreted in bile. When dogs received an i.v. dose of [14C] III together with either [3H] SV (1 mg/kg) or its hydroxy acid form, [( 3H] SVA) (10 mg/kg), both 3H and 14C I and II were excreted in bile. These results strongly indicate that I and II are secondary metabolites of SV formed from III perhaps via a common aldehyde intermediate.

Animals↗
PubMed1991

Effects of age on rat glutathione metabolism.

The authors hypothesized that rat plasma or tissue glutathione metabolism could change with age due to possible decreases in glutathione-related enzyme activities. To test this hypothesis, the authors measured plasma and tissue concentrations of glutathione and glutathione-related enzymes. Animals were 3 months, 12 months, or 24 months old at the time of experiments. Plasma glutathione was found to be significantly increased in both the 12-month-old and 24-month-old groups compared to the 3-month-old rats. Tissue enzyme measurements showed no significant differences between the groups in lung or liver glutathione peroxidase or glutathione S-transferase. gamma-Glutamyl transpeptidase activity was significantly decreased in kidney and lung with aging. Decreases in tissue gamma-glutamyl transpeptidase activity occur with age; this may contribute to increases in plasma glutathione concentrations.

Age Factors↗
PubMed1991

Protection from hyperbaric oxidant stress by administration of buthionine sulfoximine.

To explore the role of glutathione in protecting rats from hyperbaric hyperoxia, we administered buthionine sulfoximine (BSO) to block gamma-glutamyl cysteine synthase activity and decrease tissue glutathione synthesis. We then exposed these animals and their vehicle-treated matched controls to 100% oxygen at 4 ATA or room air at 1 ATA. After BSO treatment, glutathione concentrations in air-exposed controls decreased 62% in lung, 76% in liver, 28% in brain, and 62% in plasma. Paradoxically, BSO-treated rats were protected from hyperbaric hyperoxia. The BSO-treated animals seized significantly later and had a markedly prolonged time of survival compared with the vehicle-treated controls. We conclude that BSO treatment protects rats from hyperbaric hyperoxia, despite its effects of lowering plasma and tissue glutathione concentrations. This protection may be related to a direct effect of the compound in decreasing free radical-mediated tissue injury, increasing tissue antioxidant defenses, or increasing seizure threshold.

Animals↗
PubMed1991

Interobserver variability in the interpretation of pulmonary artery catheter pressure tracings.

STUDY OBJECTIVE: We evaluated the ability of three independent reviewers (R1, R2, R3) using waveform analysis to accurately identify confirmed valid PCWP tracings, and their ability to consistently report the PCWP numerical value. DESIGN: Sixty PA and PCWP tracings were prospectively obtained and blindly reviewed by three independent critical care physicians. SETTING: The medical ICU of Wilford Hall USAF Medical Center. PATIENTS OR PARTICIPANTS: Twenty mechanically ventilated patients with PA catheters inserted for hemodynamic assessment. INTERVENTIONS: Sixty PA and PCWP tracings were reviewed blindly and independently for acceptability using waveform criteria by three critical care physicians. While recording all 60 tracings, blood was aspirated from the distal port of the PA catheter with the balloon "wedged" and blood gas analysis was done. Each reviewer analyzed the PCWP tracings for validity using waveform criteria, and reported a numerical PCWP reading for those tracings judged valid by waveform criteria. Reviewer sensitivity, specificity and accuracy in performing waveform analysis were assessed by comparing their predictions with those tracings that were confirmed their predictions with those tracings that were confirmed valid by the aspiration of pulmonary capillary blood. Inter-reviewer agreement upon which validity of PCWP tracings was based and reviewer agreement on the numerical PCWP reading were also assessed. All tracings were blindly reviewed by each physician, first without and then with an AP tracing to define end-expiration. MEASUREMENT AND RESULTS: Thirty-eight of 60 PCWP tracings were confirmed valid by the aspiration of pulmonary capillary blood. In the remaining 22 tracings, mixed venous blood was aspirated with the balloon wedged, and tracing validity was unconfirmed. Reviewer accuracy in identifying was 50 percent for R1, 65 percent for R2 and 57 percent for R3. No reviewer's accuracy was significantly different from a random guess which would yield an accuracy of 50 percent. Agreement by all three reviewers in identifying valid PCWP tracings using waveform analysis varied from 37 percent in the absence of an AP tracing to 66 percent when an AP tracing was available to identify end-expiration (p less than 0.003). Agreement by all three reviewers on the PCWP numerical reading (within 4 mm Hg) was 79 percent without an AP tracing and 96 percent with an AP tracing (p = NS). The numerical reading reported by the ICU nurses and house staff correlated closely with the reviewers' readings. Agreement with the reported PCWP reading was improved only for R2 by the addition of an AP tracing. CONCLUSION: We conclude that the validation of PCWP tracings by waveform analysis is subject to interobserver variability, and reviewer accuracy in identifying confirmed valid tracings was no better than a random guess. Agreement on the numerical PCWP reading was high among the reviewers as was agreement by each individual reviewer with the reported PCWP. Finally, the presence of an AP tracing, to define end-expiration, adds little to the interpretation of the PCWP numerical reading by experienced physicians.

Adult↗
PubMed1990

Depletion of tissue glutathione with diethyl maleate enhances hyperbaric oxygen toxicity.

Rats exposed to hyperbaric hyperoxia experience severe central nervous system and lung toxicity. Exogenous glutathione administration has been shown to protect rats from the effects of hyperbaric hyperoxia. To explore the hypothesis that decreases in tissue glutathione (GSH) could increase the susceptibility of rats to hyperbaric hyperoxia, we administered diethyl maleate (DEM) (a compound that conjugates with GSH and rapidly lowers tissue levels) and measured tissue GSH levels. DEM administration decreased plasma GSH by 86%, liver GSH by 82%, and brain GSH by 45% between 2 and 4 h after injection with values returning to normal by 24 h. We then treated rats with DEM or saline and began exposure at 2 h after treatment to 100% oxygen at 4 ATA. Time-to-convulsion and time-to-death were recorded. Rats that received DEM 2 h before exposure seized earlier and died earlier than controls. Intraperitoneal administration of GSH to DEM-treated rats abolished the enhanced toxicity occurring during a hyperbaric hyperoxic exposure. DEM appears to increase the toxicity of rats exposed to hyperbaric hyperoxia by lowering tissue GSH levels, and replenishment of lung and brain GSH by exogenous administration reverses these effects.

Animals↗
PubMed1989

Effects of selenium deficiency on glutathione-induced protection from hyperbaric hyperoxia in rat.

Exposure of rats to 100% O2 at high pressure (greater than 2.0 ATA) results in generalized convulsions and death within several hours. The tripeptide, glutathione, has been shown to protect rats exposed to hyperbaric hyperoxia with delayed onset of seizures and prolonged survival. To investigate the hypothesis that glutathione exerts its protective effects via the glutathione redox cycle, we injected selenium-deficient rats and their selenium-supplemented controls with either glutathione (1 mmol/kg) or an equivolume of saline before exposure to 100% O2 at 4 ATA. Selenium-deficient rats exhibit marked reduction in liver glutathione peroxidase activity (GSH-Px). Glutathione administration significantly delayed both the onset of seizures and time to death in the control animals. In selenium-deficient rats, however, glutathione administration was not protective, having no significant effects on time to seizure or time to death. We also measured changes in glutathione concentrations in lung, liver, and brain of these same groups of animals exposed either to hyperbaric hyperoxia or to room air. In control rats, lung and brain glutathione concentrations did not change with the hyperbaric exposure regardless of glutathione pretreatment status, but hepatic glutathione concentration declined significantly during the exposure when glutathione was not supplied. If these animals were pretreated with glutathione, the decline in hepatic glutathione concentrations did not occur. In selenium-deficient rats, the hyperbaric exposure did not result in changes in lung, brain, or liver glutathione concentrations either in the glutathione-pretreated or in the saline-pretreated animals. Exogenous GSH administration does not protect selenium-deficient rats from hyperbaric hyperoxia.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Lung metabolism of xenobiotic compounds.

Many different therapeutic compounds are associated with pulmonary toxicity. Although the mechanism of injury for many of these compounds is poorly defined, several compounds are believed to produce alterations in normal lung biochemistry. These mechanisms of injury in both clinical and experimental models are discussed.

Bleomycin↗
PubMed1988

Single-breath DLCO maneuver causes cardiac output to fall during and after cycling.

The purpose of this study was to evaluate the influence of the single-breath pulmonary diffusing capacity (DLCO) breath-hold maneuver on central hemodynamics. Ten men (mean age 24 yr) were studied at rest, during 40 min of cycling at 40 and 60% of peak O2 uptake, and 10 min into recovery. DLCO was measured in the seated position during a 10-s breath hold at total lung capacity. At rest the breath hold caused a significant fall in stroke volume (SV, -16%) and an increase in heart rate (HR, +20%) with no change in cardiac output (Q). The resting DLCO of 36.5 ml.min-1.mmHg-1 increased by 28 and 48%, respectively, during the low- and moderate-intensity cycling. The breath hold while cycling caused a significant decrease in SV and Q, but HR did not change. Likewise, during recovery SV and Q fell with the breath hold but again HR did not change. A significant fall in systolic (-17%), diastolic (-12.5%), and mean arterial pressure (-15%) occurred during the breath hold at rest and during and after the exercise. The reduction observed in SV and blood pressure most likely reflected a decrease in venous return. The differences observed in the HR response before, compared with during and after exercise, were consistent with a resetting or shift in the operating point of the arterial baroreflex. Because blood flow fell during the exercise and recovery breath-hold maneuver, the "true" DLCO may have been underestimated during and after cycling.

Adult↗
PubMed1987

Rat lung glutathione release: response to oxidative stress and selenium deficiency.

We performed experiments to characterize the glutathione-dependent metabolism occurring during tert-butyl hydroperoxide infusion in isolated perfused rat lungs and to examine the effect of selenium deficiency on this metabolism. Selenium deficiency resulted in decreased lung glutathione peroxidase activity but normal glutathione reductase activity and glutathione content. Infusion of the hydroperoxide into control lungs caused a proportional increase in tissue glutathione disulfide (GSSG) concentration and release of GSSG into the perfusate up to an infusion rate of 250 nmol of tert-butyl hydroperoxide X min-1 X 100 g body wt-1. Infusion rates greater than this resulted in continued rise of tissue GSSG concentrations but GSSG release into the perfusate plateaued. Infusion of tert-butyl hydroperoxide into selenium-deficient rat lungs resulted in much lower concentrations of tissue GSSG and GSSG release into the perfusate; however, release in the selenium-deficient rat lung was also found to be saturable at infusion rates of 450 nmol of tert-butyl hydroperoxide X min-1 X 100 g of body wt-1. Selenium deficiency in the rat decreases the rate of reduction of infused tert-butyl hydroperoxide by glutathione and may predispose the lung to free radical damage.

Animals↗
PubMed1986

Transbronchial needle aspiration staging of bronchogenic carcinoma.

Transbronchial needle aspiration (TBNA) has been advocated as a reliable technique in the nonsurgical staging of patients with bronchogenic carcinoma. Some have questioned the reliability of TBNA, however. We used TBNA directed by computed tomography (CT) in 88 consecutive patients with bronchogenic carcinoma who had undergone chest CT. Chest CT was 94% sensitive, 79% specific, and 85% accurate in evaluating the mediastinum for malignant lymphadenopathy. There were 19 malignant aspirates in 44 patients with malignancy and apparent adenopathy evaluated by chest CT. No malignant carinal aspirates were obtained in any patient with a normal mediastinum evaluated by chest CT. There were 2 false positive needle aspirates. One patient with apparent right paratracheal adenopathy and malignant needle aspirate had no mediastinal neoplasm detected at surgery. The other false positive aspirate had been contaminated by tracheal debris. The overall sensitivity, specificity, and accuracy of TBNA mediastinal staging were 50, 96, and 78%, respectively. We conclude that CT scanning is a useful adjunct in the staging of patients with bronchogenic carcinoma, and that TBNA is a sensitive and highly specific staging technique that may negate the need for surgical staging in a large number of patients with bronchogenic carcinoma.

Adenocarcinoma↗
PubMed1985

Acute respiratory failure: mortality associated with underlying disease.

The hospital and ICU course of 98 patients who required mechanical ventilatory support longer than 72 h was reviewed to determine if mortality rates were influenced by admitting diagnosis. Patients with malignant diagnoses were compared to patients with nonmalignant diagnoses and to those admitted to the ICU after myocardial infarction or cardiorespiratory arrest. Although there was no significant intergroup difference in incidence of multiple organ system failure, age, and length of ICU and hospital stay, there was a much higher incidence of sepsis (p less than .05) and mortality (p less than .01) in the cancer group. Cancer patients and their families should be made aware of the extremely poor prognosis if prolonged acute respiratory failure develops.

Adult↗
PubMed1985

Carnitine and glucuronic acid conjugates of pivalic acid.

The [1-14C]pivaloyloxyethyl ester of methyldopa administered to man and cynomolgus monkeys resulted in the elimination in the urine of 14C-pivalic acid metabolites. Pivaloyl glucuronide and pivaloyl carnitine were identified as the major radioactive urinary metabolites in monkey urine and human urine, respectively. N.m.r. analysis indicated that pivaloyl carnitine had a cyclic structure. Although the role of carnitine is in the transport of fatty acids across mitochondrial membranes, it may also function in the conjugation of carboxylic acid xenobiotics in humans.

Animals↗
PubMed1979

GLC determination of S-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine in human plasma.

S-2-(3-tert-Butylamino-2-hydroxypropoxy)-3-cyanopyridine was recovered (approximately 90%) from human plasma and detected by conversion to a diheptafluorobutyryl derivative for electron-capture GLC. A homolog served as an internal standard. The method measures plasma drug concentrations at the 5-ng/ml level and is suitable for plasma analysis from humans who receive a therapeutic oral dose.

Antihypertensive Agents↗
PubMedDate not supplied

Metabolic disposition studies on simvastatin, a cholesterol-lowering prodrug.

The biosynthesis of cholesterol is mainly regulated by 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. Because the liver is the major site of cholesterol synthesis, it is the primary target of the class of drugs known as HMG-CoA reductase inhibitors. Simvastatin (SV) is a lactone prodrug which undergoes reversible metabolism. In the hydroxy acid form (SVA) it is a potent inhibitor of HMG-CoA reductase. SV is well absorbed by rats, dogs, and humans. After an oral dose of SV, tissue distribution studies were consistent with high hepatic extraction of SV and relatively poor tissue penetration of SVA. The majority of a radioactive dose of SV is eliminated in bile. A high portal/systemic gradient for 6'-OH-SVA, an active biliary metabolite, suggests its probable reentry and indicates potential for prolongation of HMG-CoA reductase inhibition. AUC comparisons in dogs after simultaneous iv (3H) and intraportal (14C) infusions indicate that hepatic extraction is high with only 8% of SV reaching the systemic circulation unchanged. Approximately 98% and 96% of SV was bound to human and dog plasma protein, respectively. The physiological disposition of SV in dog appears to be a suitable paradigm for man. Because of its high hepatic extraction SV should be both specific and selective with respect to the inhibition of HMG-CoA reductase.

Animals↗
PubMedDate not supplied

In vitro and in vivo biotransformation of simvastatin, an inhibitor of HMG CoA reductase.

Simvastatin (SV), an analog of lovastatin, is the lactone form of 1', 2', 6', 7', 8', 8a'-hexahydro-3,5-dihydroxy-2', 6'-dimethyl-8' (2", 2"-dimethyl-1"-oxobutoxy)-1'-naphthalene-heptanoic acid (SVA) which lowers plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase. SV but not its corresponding hydroxy acid form SVA underwent microsomal metabolism. Major in vitro metabolites were 6'-OH-SV (I) and 3"-OH-SV (III) formed by allylic and aliphatic hydroxylation, respectively, and 6'-exomethylene-SV (IV) formed by dehydrogenation. In rats, dogs, and humans, biliary excretion is the major route of elimination. Biliary metabolites (as both hydroxy acids and lactones) also included 6'-CH2OH-SV (V) and 6'-COOH-SV (VI) in both of which the 6'-chiral center had been inverted. High levels of esterase in rodent plasma favored the formation of SVA from SV. The formation of 1', 2', 6', 7', 8', 8a'-hexahydro-2', 6'-dimethyl-8'-(2",2"-dimethyl-1-oxobutoxy)-1'-naphthalene-pentano ic acid (VII) only in rodents represented a species difference in the metabolism of SV. It is proposed that VII is formed by beta-oxidation pathways of fatty acid intermediary metabolism. Several metabolites resulting from microsomal oxidation (after subsequent conversion from lactones to hydroxy acids) are effective inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase and may contribute to the cholesterol lowering effect of SV. Qualitatively, the metabolism of SV closely resembles that of lovastatin.

Aged↗