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Biomedical subjects

M R Wright

Publications and source records attributed to M R Wright.

At least 37 records · Page 2Linked to original sources
PubMed1993

Transplacental and nonplacental clearances, metabolism and pharmacodynamics of labetalol in the fetal lamb after direct intravenous administration.

Labetalol has been previously shown to cause significant maternal and fetal metabolic effects in pregnant sheep after maternal administration. To investigate these observations further, the present study describes the pharmacokinetics, metabolism and pharmacodynamics of labetalol in the fetal lamb after direct fetal i.v. bolus (4 mg) administration. The fetal total body clearance of labetalol (50.45 +/- 1.37 ml m-1 kg-1), which was significantly higher than that previously determined in the ewe, was composed of transplacental and nonplacental CLs of 23.4 +/- 8.99 ml m-1 kg-1 and 27.05 +/- 10.36 ml m-1 kg-1, respectively. The maternal to fetal plasma labetalol area under the curve ratio was 0.031 +/- 0.002 and the CLmp and CLmn were 7.27 +/- 2.11 ml m-1 kg-1 and 30.5 +/- 5.94 ml m-1 kg-1, respectively. Labetalol concentrations in fetal tracheal fluid were consistently higher than that in fetal plasma. The glucuronide conjugate of labetalol was found in the amniotic fluid at up to 20 times the free drug concentration but the oxidative metabolite, 3-amino-1-phenyl-butane, was not detected in plasma or amniotic fluid samples. The fetal effect of labetalol was characterized by an acute lactic acidosis. The calculated hind limb arteriovenous lactate flux showed a net output of lactic acid equal to 3.85 +/- 2.05 g from the hind limb over 24 h after labetalol administration. Although the fetal exposure to labetalol in this study was roughly 4 times that after a 100-mg maternal bolus administration, the magnitude of fetal lactic acidosis was not significantly different in these studies. The clinical implications of the observations made in this study remain to be investigated.

Animals↗
PubMed1992

Improved high-performance liquid chromatographic assay method for the enantiomers of ibuprofen.

A rapid, inexpensive and sensitive high-performance liquid chromatographic method for the quantitation of ibuprofen enantiomers from a variety of biological fluids is reported. This method uses a commercially available internal standard and has significantly less interference from endogenous co-extracted solutes than do previously reported methods. The method involves the acid extraction of drug and internal standard [(+/-)-fenoprofen] from the biological fluid with isooctane-isopropanol (95:5) followed by evaporation and derivatization with ethylchloroformate and R-(+)-alpha-phenylethylamine. Excellent linearity was observed between the peak-area ratio and enantiomer concentration (r > 0.99) over a concentration range of 0.25-50 micrograms/ml. This method is suitable for the quantitation of ibuprofen from single-dose pharmacokinetic studies involving either rats or humans.

Animals↗
PubMed1992

Pharmacokinetics and pharmacodynamics of labetalol in the pregnant sheep.

The maternal-fetal disposition of labetalol, a combined alpha-1 and beta adrenergic blocker, and its pharmacodynamics in pregnancy are not well understood. This study describes the pharmacokinetics, cardiovascular and metabolic effects of labetalol in the mother and in utero fetus after a 100-mg maternal i.v. bolus administration, in the chronically instrumented pregnant sheep. Labetalol shows a triexponential decline in the mother with a total body clearance of 30.8 +/- 3.83 ml/min/kg, an apparent steady-state volume of distribution (nonparametric) of 3.02 +/- 0.18 liters/kg and terminal elimination half-life of 2.79 +/- 0.66 hr. These estimates are similar to the reported values in pregnant women. Labetalol rapidly crosses the sheep placenta. The peak fetal plasma concentration was 33.7 +/- 5.8 ng/ml, the fetal exposure to labetalol as calculated by the fetal to maternal area under the curve ratio was 14.37 +/- 1.54% and the apparent fetal elimination half-life was 3.71 +/- 0.5 hr. Labetalol persists in the amniotic and fetal tracheal fluids up to 24 hr with concentrations reaching 2- to 4 times the fetal plasma concentration. Whereas there were no significant maternal or fetal cardiovascular effects, some very significant metabolic effects were observed, including fetal and maternal lactic acidosis and hyperglycemia. Lactic acid accumulates in the fetal blood and amniotic fluid with peak concentrations (6.0 +/- 0.31 and 5.5 +/- 0.26 mM, respectively) showing a more than 300% increase over control values. The exact mechanism by which labetalol causes these metabolic effects is not clear, but it may involve its partial beta-2 agonist activity.

Animals↗
PubMed1992

Metabolic effects of ritodrine in the fetal lamb.

Ritodrine infusion to fetal lambs causes numerous metabolic perturbations including hypoxemia. To investigate these changes further and to elucidate a mechanism for the development of hypoxemia, ritodrine was infused at rate of 2.6 micrograms/min into nine chronically catheterized fetal lambs for 8, 12 or 24 hr. Plasma levels of ritodrine (20.0 +/- 2.7 ng/ml) were within the range of those reported in human fetuses exposed to ritodrine tocolysis. Fetal arterial glucose levels nearly doubled (0.72 +/- 0.07 to 1.29 +/- 0.18 mM), whereas lactate levels rose more than 5-fold (1.54 +/- 0.11 to 8.67 +/- 1.12 mM), with the latter change leading to a decline in fetal arterial pH from 7.370 +/- 0.004 to 7.273 +/- 0.033. Fetal oxygen consumption (VO2) rose from 342 +/- 35 to 407 +/- 30 mumol/min.kg via an increase in fetal fractional O2 extraction (32.0 +/- 1.1 to 49.0 +/- 1.7%). The rise in fetal O2 extraction contributed to concurrent declines in fetal arterial PO2 (21.9 +/- 0.6 to 17.0 +/- 0.5 mm Hg) and O2 content (3.7 +/- 0.2 to 2.1 +/- 0.1 mM). Umbilical venous PO2 and O2 content also fell resulting in a decline in fetal O2 delivery (DO2) from 1115 +/- 97 to 838 +/- 68 mumol/min.kg. The rise in fetal VO2 was reflected by a similar rise uterine VO2 (not significant), with the latter being accompanied by a significant increase in uterine O2 extraction and decrease in uterine venous PO2 and O2 content, perhaps contributing to the fall in fetal DO2. In conclusion, fetal hypoxemia during the infusion of ritodrine results from an increase in fetal VO2 that is not compensated for by a similar increase in umbilical or uterine DO2. These metabolic effects may put the fetus at risk, particularly in situations in which fetal DO2 is already reduced, as may occur in compromised pregnancies.

Animals↗
PubMed1991

Determination of ritodrine in biological fluids of the pregnant sheep by fused-silica capillary gas chromatography using electron-capture detection.

A sensitive and selective gas chromatographic assay method employing splitless injection, fused-silica capillary columns and electron-capture detection is reported for the quantitation of the tocolytic drug, ritodrine, in a variety of biological fluids obtained from the pregnant ewe and fetus. This method has improved sensitivity and selectivity over previously published assay procedures. A 25 m x 0.31 mm I.D., cross-linked 5% phenylmethylsilicone, fused-silica capillary column was employed for all analyses. Linearity of response was observed over the range 2.5-75 ng of ritodrine base per 0.05-0.5 ml of biological fluid, representing approximately 1-75 pg at the detector. The coefficient of variation was less than 10% over the range 2.5-75 ng of added ritodrine. The minimum quantifiable amount is approximately 2.5 ng from a 0.5-ml biological fluid sample. Applicability of this method to biological fluids, obtained from ovine subjects, is demonstrated by the analysis of samples obtained during the course of ritodrine placental transfer studies.

Amniotic Fluid↗
PubMed1991

Drug disposition and effects in the fetus.

Surveys of drug use in pregnancy demonstrate that a significant proportion of human fetuses are exposed to prescription and non-prescription drugs antenatally or during labor, although recently a decrease in licit drug consumption during pregnancy may have occurred. However, legitimate medical reasons for drug therapy of the mother or fetus remain and there is an increasing problem with illicit drugs. Several approaches are used to examine placental transfer of and fetal exposure to drugs, including studies on pregnant women, the use of chronically catheterized pregnant animals (particularly sheep), acute studies on small animals (e.g. guinea pig and rabbit) and the use of the perfused placenta. Fetal drug exposure is affected by large number of maternal, placental and fetal factors. For long term maternal drug administration, drug binding in maternal and fetal plasma, and fetal drug elimination seem particularly important. Thus, the rate of non-placental clearance of morphine, methadone, acetamionophen, metoclopramide, ritodrine and diphenhydramine in the fetal lamb is comparable to that in the ewe, although the routes of fetal elimination are not fully elucidated. The fetal liver may be of lesser importance in overall drug elimination than in the adult, but conjugated drug metabolites in the fetus may persist because of limited placental transfer. Hence, we have observed that the glucuronide conjugate of ritodrine accumulates in amniotic fluid after intravenous ritodrine administration. Accumulation of intact drugs in amniotic fluid also occurs via fetal renal excretion and perhaps via the fetal membranes. Also, a number of basic amine drugs are also concentrated in fetal tracheal fluid, probably as a consequence of pulmonary uptake, which also takes place in the adult. However, this could result in high fetal lung levels of agents, such as beta 2-adrenergic agonists, that have potent effects on pulmonary function and maturation. When digoxin, metoclopramide and diphenhydramine are injected into amniotic fluid, they are preferentially distributed to the fetus and, for the latter 2 drugs, uptake by the chorioallantoic membranes appears to be important. Thus, there is the possibility of recycling of drugs from amniotic fluid to the fetal circulation and their persistence in the fetus. Many of the therapeutic agents given to pregnant women in late pregnancy have effects on fetal CNS, cardiovascular or metabolic functions. Alterations in fetal behaviour are elicited by prescription sedatives and anesthetics and illicit drugs, and also by the antihistamine, diphenhydramine, present in various nonprescription medications.

Adrenergic beta-Agonists↗
PubMed1991

Clearance and disposition of ritodrine in the fluid compartments of the fetal lamb during and after constant rate fetal intravenous infusion.

The disposition of the beta-2 adrenoreceptor agonist, ritodrine, has been examined in the fetal lamb during and after constant rate fetal intravenous infusion (8-24 h). Samples were collected from the fetal femoral artery, umbilical vein, maternal femoral artery, uterine vein, fetal trachea and the amniotic activity for ritodrine quantitation. The amniotic fluid was also analyzed for conjugated metabolites of ritodrine. Ritodrine appears to be cleared across the sheep placenta only to a limited extent (placental clearance 9.2 +/- 2 ml/min/kg; mean +/- S.E.M.). There is, however, significant fetal nonplacental clearance of ritodrine (fetal nonplacental clearance 52.8 +/- 8.0 ml/min/kg). At least part of this clearance appears to be due to fetal drug metabolism, as evidenced by the accumulation of glucuronide conjugates of ritodrine in the amniotic fluid. Ritodrine was also shown to accumulate in the amniotic and fetal tracheal fluids and persist after fetal arterial plasma ritodrine concentrations became undetectable. The accumulation of ritodrine in the tracheal fluid may be of pharmacologic significance, given the well documented, potent effects of beta-2 agonists on fetal lung function and development.

Animals↗
PubMed1988

Linearity of metoclopramide kinetics at doses of 5-20 mg.

The disposition of metoclopramide was studied on a four-way crossover basis in six healthy non-smoking volunteers. The linearity of kinetic parameters and absolute bioavailability of metoclopramide were examined. In contrast to previous reports, metoclopramide obeyed linear kinetics over oral doses ranging from 5 to 20 mg. The absolute bioavailability of metoclopramide was 0.76 +/- 0.38 (mean +/- s.d.) from the oral dosage forms examined in this study.

Biological Availability↗
PubMed1988

Effect of haemodialysis on metoclopramide kinetics in patients with severe renal failure.

The kinetics of metoclopramide and the effects of haemodialysis on metoclopramide kinetics were examined in eight uraemic subjects 1 h and 24 h prior to the onset of dialysis. In spite of the relatively minor contribution of renal clearance to total body clearance in normals, metoclopramide kinetics were substantially altered in uraemia. The total body clearance was decreased by 2-4 fold, terminal elimination half-life proportionately increased, while the volume of distribution appeared to be unaffected compared with that previously demonstrated in normal healthy subjects. Haemodialysis does not appear to be effective in removing metoclopramide from the body and metoclopramide clearance subsequent to dialysis is unaltered. The kinetic parameters in the uraemic subjects are not significantly different between drug administrations 1 or 24 h prior to the time of onset of haemodialysis. Following kidney transplantation, in one subject, there appeared to be a rapid return to apparently normal kinetics from the uraemic state.

Female↗
PubMed1987

The male aesthetic patient.

Just like their female counterparts, men are increasingly turning to facial plastic surgery, but male patients bring to the surgeon an array of unexplored motivations and expectations along with unresolved emotional conflicts. These feelings of ambivalence, emotional instability, and sometimes even hostility toward the surgeon make the male aesthetic patient more of a psychological risk than the female aesthetic patient. This article focuses on how the surgeon can recognize and control the male patient's emotional disturbances and, consequently, better serve his patient and protect himself.

Emotions↗
PubMed1986

Surgical addiction. A complication of modern surgery?

Today the concept of surgery has changed dramatically. No longer is surgery limited to emergency or lifesaving procedures. We now have surgery by choice, which, despite marked advantages, may well encourage a certain type of individual to have surgery for reasons for which it is not intended. This article discusses the underlying characteristics of the patient who seeks repetitive surgery. The author points out that it is the surgeon's, not the patient's, responsibility to prevent unnecessary surgery.

Female↗
PubMed1984

The elective surgeon's reaction to change and conflict.

The social and technologic advancements that have caused elective surgery to flourish and seem like an ideal specialty have also placed considerable strain and burden on the surgeon. The elective surgeon, whose expertise is not clearly established and whose roles are ambiguous, is especially affected by the changes and attendant conflicts that are occurring in the spectrum of modern medicine. Data from objective studies indicate that the surgeon's rigorous training and personality characteristics cause him to react defensively to impending threat and thus make him vulnerable to litigation. This article offers a positive approach to change and conflict.

Clinical Competence↗
PubMed1984

How to recognize and control the problem patient.

All surgery has a psychological impact, but nowhere does the patient's psyche come into play more prominently than in the field of elective surgery. Psychological manifestations related to elective surgery must be recognized and controlled preoperatively, lest they control the operative outcome. This article discusses the personality characteristics associated with the potential problem patient; counseling and evaluative techniques; common psychogenic conditions; cause and management of patient dissatisfaction; and psychology of the terminal patient.

Anxiety↗
PubMed1980

Self-perception of the elective surgeon and some patient perception correlates.

This study investigated the personality characteristics of the elective surgeon, the realism of the surgeon's role concept, and the relationships between these variables and the occurrence of litigation. Data obtained from 125 surgeons and 65 of these surgeons' patients were computer analyzed to answer three specific questions. The surgeon's personality needs were found to differ significantly from those of the general population. Both the surgeons and the patients viewed the surgeon's role unrealistically. No specific physician-patient interaction variable was found to be related significantly to the occurrence of litigation. Findings showed that the elective surgeon is aware of the documented causes for litigation but unaware of how his own personality may affect his vulnerability to litigation.

Adult↗