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Biomedical subjects

A Roux

Publications and source records attributed to A Roux.

At least 37 records · Page 2Linked to original sources
PubMed1997

Inhibition by omeprazole of proguanil metabolism: mechanism of the interaction in vitro and prediction of in vivo results from the in vitro experiments.

Both the antimalarial prodrug proguanil and the gastric proton pump inhibitor omeprazole are substrates for cytochrome P450 (CYP)2C19 and CYP3A. However, the relative contribution of each enzyme to proguanil bioactivation to cycloguanil and to the metabolism of omeprazole, as well as their potential to interact, remains to be examined. The bioactivation of proguanil to its active metabolite cycloguanil was studied in vitro in human liver microsomes and in vivo in 12 healthy subjects, in the absence and in the presence of omeprazole. The formation of cycloguanil from proguanil exhibited biphasic kinetic behavior in four of six human livers, indicating that at least two enzymes are responsible for this metabolic step. Cycloguanil formation activity did not correlate with immunoreactive CYP3A4 content or with CYP3A4 activity, as measured by testosterone 6beta-hydroxylation, suggesting that CYP3A4 plays a limited role in cycloguanil formation. Furthermore, troleandomycin (10 microM) inhibited only 10 to 17% of cycloguanil formation at proguanil concentrations of 100 and 500 microM. At a proguanil concentration of 20 microM, omeprazole at 10 microM inhibited cycloguanil formation in vitro by 47 +/- 59%. These in vitro results were consistent with the results of our in vivo study in healthy subjects, which showed a 32 +/- 11% decrease in proguanil apparent oral clearance and a 65 +/- 8% decrease in proguanil partial metabolic clearance to cycloguanil in the presence of omeprazole (both P < .001). We conclude that in vitro studies of proguanil metabolism and interactions are predictive of in vivo situations, that CYP2C19 is the main enzyme responsible for proguanil bioactivation to cycloguanil and that omeprazole inhibits this biotransformation in vitro and in vivo by inhibiting this enzyme.

Aryl Hydrocarbon Hydroxylases↗
PubMed1996

Metabolism of quinine in children with global malnutrition.

Malnutrition and malaria are two important public health problems in Africa. Quinine is one of the major treatments of chloroquine-resistant malaria. Although some authors have shown that quinine clearance is decreased in kwashiorkor, this type of malnutrition is caused by protein deficiency that differs from global protein-energy malnutrition. In rats, hepatic metabolism of many drugs is decreased in protein deficiency and increased in global food restriction. Several studies have found that human hepatic metabolism of many drugs is decreased in kwashiorkor, but, as yet, no study has focused on human global energy-protein malnutrition. Thus, as quinine is a drug with a narrow therapeutic index, we compared the pharmacokinetics of quinine in two groups. One group included children with global malnutrition and the other was a control group of children with normal nutrition. Volume of distribution and plasma concentrations of unbound quinine did not differ between children with global malnutrition and children with normal nutritional status. Clearance was significantly faster, half-life shorter, and concentrations, 12 h after the beginning of treatment, lower in malnourished children compared with control subjects. The ratio between area under the curve of hydroxyquinine (metabolite of quinine in man) and area under the curve of quinine was significantly increased in malnourished children and correlated with mid-arm/ head circumference ratio (marker of malnutrition in children). Thus, as metabolism of quinine is increased in children with global malnutrition, we suggest that the administration interval should be reduced in these children to obtain the same plasma concentrations of quinine found in normally nourished children. A safe and effective dosing strategy is postulated.

Animals↗
PubMed1994

Biochemiluminescence and biomedical applications.

Although used for analytical purposes for more than 40 years it is only recently that biochemiluminescence (BCL) has found widespread acceptance. Methods employing BCL reactions now play an important role in biomedical research and laboratory medicine. The main attractions for the assay technology include exquisite sensitivity (attomole-zeptomole), high selectivity, speed and simplicity. In biomedical research, the most important applications of BCL are: (1) to estimate microbial numbers and to assess cellular states (e.g., after exposure to antibiotic or cytotoxic agents) and in reporter gene studies (firefly luciferase gene); (2) NAD(P)H involved in redox/dehydrogenase studies using Vibrio luciferase complex; (3) BCL labels and CL detection of enzyme labels in immunoassays are the most widespread routine application for this technology. BCL enzyme immunoassays represent the most active area of development, e.g., enhanced BCL method for peroxidase and BCL assays for alkaline phosphatase labels using adamantyl 1,2-dioxetane.

Bacteria↗
PubMed1993

Contribution of preoperative investigations to the anaesthetic management of adult trauma patients.

In a prospective study of 50 adult trauma patients, the effects of a protocol calling for eight rapidly available special investigations and 11 laboratory, electrocardiographic and radiological investigations were assessed as to their influence on anaesthetic management. The only investigation which gave information additional to that obtained by the clinical examination was the arterial blood gas, especially the pH, arterial oxygen tension and arterial carbon dioxide tension. Other contributory investigations were the protocol haemoglobin and protocol blood sugar estimation. The protocol electrolytes and clotting profile as well as the laboratory full blood count, urea and electrolytes, electrocardiograph and chest radiograph did not make a contribution to the assessment and anaesthetic management of this patient group.

Adolescent↗
PubMed1992

The Johannesburg Hospital mobile anaesthesia service.

At a teaching hospital such as the Johannesburg Hospital with an air ambulance service, the need may arise for the administration of an anaesthetic outside the hospital. The occurrence of just such an event prompted the authors to review the literature regarding anaesthesia in adverse circumstances and to assemble, in a portable container, the equipment and drugs considered necessary to cope with the situation. In addition, the responsible anaesthetic personnel are receiving training in the use of the equipment and techniques required.

Aircraft↗
PubMed1992

Intramedullary epidermoid cysts of the spinal cord. Case report.

Epidermoid cysts are tumors familiar to neurosurgeons, but intramedullary epidermoid cysts are rare. The authors report the case of a 6-year-old girl presenting with progressive paraparesis. A midthoracic intramedullary mass was revealed on myelography and magnetic resonance (MR) imaging and confirmed as an intramedullary epidermoid cyst at surgery, at which time the cyst was removed. This is the fourth report documenting a purely intramedullary epidermoid cyst occurring in a child. The pathology and etiology, epidemiology, clinical features, radiology (including MR image characteristics), and surgical treatment of such rare intramedullary benign tumors are discussed. Magnetic resonance imaging reduces the delay in diagnosis of spinal cord tumors but should be guided by clinical judgment.

Child↗
PubMed1992

Postoperative hypoxaemia--its causes and prevention.

Postoperative hypoxaemia presents with varying degrees of severity. Aetiology of the condition is diverse and may originate in the pre-, intra- or postoperative periods. However, induction of anaesthesia and the type of operation are important initiating factors over which there is little control. The impact of postoperative hypoxaemia, especially when detected early, can be alleviated. This article attempts to explain the pathophysiology and provide suggestions as to detection and management of postoperative hypoxaemia.

Age Factors↗
PubMed1991

Natural inhibitors of T-cell activation in Hodgkin's disease.

Secondary immunodeficiency is frequently observed in Hodgkin's disease (HD) and is due in part to impaired T-cell function. Using monoclonal antibodies that bind to triggering molecules of human T lymphocytes (CD3/Ti antigen receptor; CD2 E-rosette receptor) and exert functional effects on T-cell activation, we have investigated in vitro immune responses of circulating lymphocytes from patients with HD in progression (n = 9) and in remission (n = 14). In patients with progressive HD, a severe dysfunction of the alternative CD2-mediated T-cell activation pathway was detected (49.3 +/- 14.2 v 9.4 +/- 5.1 cpm x 10(-3), in controls, P less than .01; n = 9) that parallels the reduced capacity of T lymphocytes to form rosettes with sheep red blood cells. Diminished alternative pathway activation in HD is not only due to a defect at the cellular level but also due to soluble mediators in the patients' plasma. Plasma from patients in progression markedly reduces CD2 mediated activation (P less than .01). These activities interfere, at least in part, with CD2/CD58 interactions and, therefore, reduce T-lymphocyte triggering through this amplifier mechanism.

Adult↗
PubMed1991

Liquid chromatographic analysis of propranolol enantiomers in human blood using precolumn derivatization with (+)-1-(9-fluorenyl)ethyl chloroformate.

A method for the determination of the R-(+) and S-(-) enantiomers of propranolol in blood was developed. After extraction with heptane-isopentanol and derivatization with (+)-1-(9-fluorenyl)ethyl chloroformate, excess reagent was removed using solid-phase extraction. The enantiomers were separated on an achiral, reversed-phase, radially compressed column, and detected by fluorescence with excitation and emission wavelengths of 260 and 340 nm, respectively. The limit of quantification was 0.5 ng/ml. This method was used for pharmacokinetic analysis of propranolol enantiomers after administration of immediate-release (80 mg) or sustained-release (160 mg) racemic propranolol.

Chromatography, High Pressure Liquid↗
PubMed1991

Influence of amiodarone on genetically determined drug metabolism in humans.

Amiodarone has been shown to interact with the nongenetically determined hepatic elimination of several drugs, including phenytoin and digoxin. Its influence on genetically determined metabolic pathways has not been studied in humans. We examined the effects of oral amiodarone therapy on the genetically determined metabolism of isoniazid (N-acetyltransferase), mephenytoin (cytochrome P450MEPH), and dextromethorphan (CYP2D6). Eight patients with arrhythmias were studied before and 76 +/- 16 days after amiodarone (loading dose of 1000 mg/day for 10 days followed by a maintenance dose of 200 to 400 mg/day). Genetically determined enzyme activity was assessed indirectly by calculating the metabolic ratio (parent drug/metabolite in 8-hour urine for CYP2D6 and P450MEPH and N-acetylisoniazid/isoniazid in plasma for N-acetyltransferase) after oral administration of the parent compounds. At the time of phenotyping, plasma concentrations of amiodarone and N-desethylamiodarone were 0.66 +/- 0.35 micrograms/ml and 0.65 +/- 0.26 micrograms/ml, respectively. Amiodarone increased the log(metabolic ratio) of dextromethorphan from a median of -2.5 (range, -2.9 to -2.0) to a median of -1.9 (range, -2.5 to -1.5; p less than 0.02) but did not alter the metabolic ratio of mephenytoin or isoniazid. The amount of dextromethorphan excreted in urine increased from a median of 0.084 mumol/8 hours (range, 0.041 to 0.161 mumol/8 hours) to a median of 0.205 mumol/8 hours (range, 0.064 to 0.288 mumol/8 hours; p less than 0.02) and the amount of its metabolite (dextrorphan) tended to decrease from a median of 26 mumol/8 hours (range, 15 to 37 mumol/8 hours) to a median of 20 mumol/8 hours (range, 7 to 27 mumol/8 hours; p less than 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Combination of long-acting furosemide and instant-acting amiloride: pharmacokinetics and pharmacodynamics in human subjects.

The pharmacokinetics and pharmacodynamics of the combination of amiloride (2 x 2.5 mg) and long-acting furosemide (2 x 10 mg) were compared with amiloride (5 mg) and furosemide (20 mg) in 12 healthy male volunteers aged 26.2 +/- 1.6 years and weighing 68.8 +/- 6.2 kg, after random order administration. Furosemide and amiloride plasma or urine concentrations were determined by HPLC with fluorimetric detection. The rate of absorption (tmax = 3 h) and the bioavailability of the two diuretics were not significantly modified by their combination. Furosemide plasma half-life was 2.77 +/- 1.04 h after the combination treatment and 2.76 +/- 0.98 h alone, amiloride plasma half-life was respectively 15.7 +/- 4.6 h and 14.6 +/- 3.7 h. The urinary elimination of furosemide was significantly higher in the 2-4 h interval in the combination treatment, accompanying its delayed maximum effect of diuresis. A synergistic effect was observed after the combination administration of the two diuretics; between the 2nd and the 8th hour, the sodium elimination was significantly increased (P less than 0.01) and the potassium excretion was significantly decreased (P = 0.05). After a single dose, no modification of plasma or erythrocyte magnesium levels was observed. This study shows that the combination of the two drugs entails a synergy of their activities which does not involve pharmacokinetic changes.

Adult↗
PubMed1991

Vasoconstrictor effects of adrenaline in human septic shock.

In an open prospective study, adrenaline administration in ten patients with eleven episodes of septic shock was studied. Appropriate supportive therapy (antibiotics, laparotomies, parenteral alimentation, ventilation) was given as needed. Haemoglobin was kept at or about 12 g%, pulmonary capillary wedge pressure kept at approximately 15 mmHg, and cardiac index at greater than 4.5 l/min/m2. Only when systemic vascular resistance (SVR) dropped below 600 dyn. s. cm-5 was adrenaline given to raise the latter to no higher than 800 dyn. s. cm-5 and the adrenaline was titrated to this end point. Adrenaline was used at doses up to 0.47 microgram/kg/min for up to nineteen days. There was no reliable dose response curve for adrenaline: each septic insult needed different dosages. However, if high enough doses were given, SVR eventually increased. There was no deterioration in cardiac index nor further increase in pulse rate and no renal damage was demonstrated. Only one patient died in septic shock. Two others died from causes not directly related to sepsis and another two while still in hospital, but again not septic. Five patients were eventually discharged from hospital. Adrenaline can thus be used as a vasoconstrictor in septic shock without adverse effects, but initial doses have to be high and the effects measured and titrated carefully. Used this way, adrenaline provides time for the eradication of sepsis.

Adult↗
PubMed1991

[Pharmacokinetics of aspirin in African children with normal nutrition and malnutrition].

Pharmacokinetics of aspirin given orally at antipyretic dose (12 mg/kg) were studied in 11 African children aged 4-48 months. In order to examine the influence of nutritional status on aspirin kinetics, children were classified according to Waterlow criteria. Blood samples were collected during the 8 hours following the initial dose. Albumin, prealbumin and transferrin plasma levels were measured and plasma salicylic acid (SA) concentrations determined by a fluorometric method. Nutritional status seemed to have no prominent effect on plasma concentrations of SA. The volume of distribution found in our study was lower than those obtained in other studies. This could be explained by lower plasma aspirin esterase activities in black children. There were large individual variations in plasma salicylate concentrations. For example, even at antipyretic doses, saturation phenomena appeared in two children.

Aspirin↗
PubMed1991

Spinal man after declaration of brain death.

Complex spinal automatism in a patient who was declared brain dead is described. These movements tend to appear once cerebrospinal shock has abated. We postulate that these manifestations are a reflection of the physiological potential of the isolated spinal cord. These spinal movements should be included in the revised guidelines for the determination of cerebral death.

Adult↗
PubMed1990

[Treatment with sustained theophylline release. Monitoring by salivary assay in children].

We have tested the possibility of replacing plasma assays by salivary assays of theophylline for the monitoring of sustained-release theophylline therapy in asthmatic children. In a first group of 40 children aged 7.2 +/- 3.3 years (mean +/- SD) treated with sustained-release theophylline in mean daily doses of 18.8 +/- 5 mg/kg, 77 plasma and saliva samples were taken simultaneously 6 hours after the morning dose (6 H). Saliva was collected after mouth-wash and stimulation with 10 mg of citric acid. Assays were performed using the EMIT method. Theophylline plasma concentrations (P) and salivary concentrations (S), both expressed as mumol/l, were found to correlate: P = 1.58 S + 8.7 (P less than 0.0001). In a second group of 33 children, 39 simultaneous samples were taken at 6 H. From the equation previously obtained the plasma concentration corresponding to each salivary concentration was calculated, and the calculated value was compared with the measured value. The difference between the two values was 7.1 +/- 9 mumol/l. On this basis, and because the method is non-invasive and painless, were are now using salivary assays (under strict conditions of collection and measurement) to verify the patients' compliance and to maintain or adjust dosage in asthmatic children.

Adolescent↗