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Biomedical subjects

G D Olsen

Publications and source records attributed to G D Olsen.

At least 37 records · Page 2Linked to original sources
PubMed1992

In utero cocaine exposure: effect on neonatal breathing in guinea pigs.

Cocaine (COC) abuse during pregnancy may be a factor in the development of neonatal breathing abnormalities. To examine this possibility, pregnant Dunkin-Hartley guinea pigs were treated daily with s.c. injections of saline or 2, 6 or 12 mg/kg of COC during the second half of gestation. Treatments were assigned randomly to pregnant dams. Neonatal weight, breathing, ECG and EEG were recorded in unsedated animals using noninvasive techniques at intervals for 3 weeks after birth. Neonatal weight on Day 1 was decreased by exposure to the two highest doses of COC (P less than .05). The effects of drug treatment, day of study and response to inhalation of 5% CO2 were analyzed by repeated measures analysis of variance. A significant drug-, day- and CO2-effect on tidal volume (VT) and inspiratory minute volume (VI) was observed (P less than .01). COC exposure in utero increased the weight-normalized neonatal VT and VI on room air and 5% CO2 during the first 2 weeks of life in the absence of a measurable effect of drug exposure upon breathing frequency, heart rate or EEG power. The increase in VT and VI may be caused by an increase in metabolic rate (hyperpnea) or an alteration of ventilatory control (hyperventilation). Either mechanism could represent functional teratogenesis and either results in a greater ventilatory effort which increases the work of breathing and the consumption of oxygen. An increase in oxygen demand due to an increase in metabolism or an increase in ventilatory effort might compromise some neonates and contribute to an increased incidence of sudden-infant-death.

Animals↗
PubMed1992

Cocaine and metabolite concentrations in the fetal guinea pig after chronic maternal cocaine administration.

To determine the disposition of cocaine (COC) and metabolites after chronic COC exposure in the late gestation guinea pig, six time-bred Dunkin-Hartley guinea pigs were given 10 daily 6 mg/kg COC s.c. injections from day 50 of gestation. Maternal blood and urine, fetal cord blood, and brain and amniotic fluid were collected 1 hr after the last injection. There was no difference between maternal and fetal plasma COC concentrations. This may be due to the combined effect of lower protein binding and ion trapping of COC in the fetus. Benzoylecgonine was higher in maternal plasma, but benzoylnorecgonine was higher in fetal plasma. COC brain-to-plasma ratios were similar in the dam and fetus. Benzoylecgonine was the only metabolite that could be detected in the brain, but levels were too low to quantitate. COC accumulated 3 to 4 times plasma concentrations in the amniotic fluid and was directly proportional to fetal plasma COC concentrations. Benzoylnorecgonine in amniotic fluid accumulated to 2 times fetal plasma levels. The in vitro half-life of COC in amniotic fluid was 30 times longer than plasma elimination half-life in vivo. The high level and long duration of COC in amniotic fluid serve as a reservoir for prolonged fetal COC exposure.

Amniotic Fluid↗
PubMed1991

Cocaine pharmacokinetics in the pregnant guinea pig.

The pharmacokinetics of cocaine (COC) were studied during late gestation in guinea pigs. Clearance (Cl) was not dose-dependent and the average +/- S.D. was 59 +/- 16 ml/min/kg over the i.v. dose range of 2 to 12 mg/kg. Volume of distribution at steady state (Vdss), mean resident time (MRT) and elimination half-life (T1/2) were dose-dependent over this dose range with changes occurring between the 2 and the 4 mg/kg dose of COC. Vdss was 2.1 and 3.9 l/kg. MRT time was 42 and 57 min, and elimination T1/2 was 34 and 49 min at the 2 and 4 mg/kg dose, respectively. Cl and Vdss values after 2 to 20 mg/kg of COC s.c. were similar to those after i.v. administration, whereas MRT was significantly greater as a result of delayed absorption. Absorption of COC s.c. was nearly complete (84%) and had a T1/2 of 51 min. Benzoylecgonine (BE) and benzoylnorecgonine (NOR) were major and persistent metabolites of COC. Norcocaine was present after COC doses of 4 mg/kg or higher but could only be detected during the first 2 hr.

Animals↗
PubMed1990

Microassay for the simultaneous determination of cocaine, norcocaine, benzoylecgonine and benzoylnorecgonine by high-performance liquid chromatography.

An improved method for the simultaneous determination of cocaine, norcocaine, benzoylecgonine and benzoylnorecgonine using reversed-phase high-performance liquid chromatography with ultraviolet detection is described. Following solid-phase extraction, chromatography was performed using a column containing an octadecylsilica-coated packing, eluted with 6% acetonitrile in phosphate buffer, pH 2.1, and detected at 233 nm. Using 80-microliters samples, the detection limit is 18 ng/ml for benzoylecgonine and benzoylenorecgonine and 35 ng/ml for cocaine and norcocaine. The coefficients of variation range from 3.5% (benzoylecgonine) to 7.0% (norcocaine). The procedure has been applied to samples of guinea pig plasma, urine and amniotic fluid and human urine.

Amniotic Fluid↗
PubMed1990

Binding of thiopental in neonatal serum.

Protein binding of thiopental was studied in 21 samples of neonatal serum (from placental blood) and compared with protein binding in ten healthy volunteers. These infants ranged between 32 and 43 weeks of gestational age (mean, 37.7 weeks) and the adult age range was from 27 to 54 years (mean, 35.4 years). Because the unbound fraction of the drug is responsible for its pharmacologic effect, a marked difference in the protein binding between neonates and adults may be relevant to the clinician. Blood obtained from freshly delivered placentas or from adult volunteers was allowed to clot and the serum separated from the sample. A portion of the serum was sent for protein and bilirubin analysis and the remainder retained for study. This latter serum was combined with four concentrations of thiopental. These specimens were then ultrafiltered and the amount of thiopental in the ultrafiltrate (unbound) compared with the prefiltered amount (total), as measured by reverse-phase high-performance liquid chromatography. The binding studies were repeated at pH 7.2, 7.4, and 7.6 in both the adult and neonatal serum. Total protein and albumin are significantly less in neonatal serum, whereas bilirubin (total and direct) is significantly higher in neonatal serum than in adult serum (P less than 0.01). Neonatal serum was associated with significantly more unbound thiopental than adult serum at all levels of pH studied (P less than 0.005). Increasing the pH resulted in less free drug in both groups, but this reached statistical significance only in the adult group (P less than 0.025). Drug concentration had no effect on binding in the range examined.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Comparison of chronic morphine and placebo infusion in late gestation fetal lambs: effect upon survival and breathing movements.

A placebo-controlled, randomized study of the effect of a 10-day infusion of morphine (MOR) upon fetal survival and fetal breathing movements was done in late gestation lambs. MOR infusion at a rate of 3 mg.hr-1 did not affect fetal survival or the response of fetal breathing movements to hypercapnia. Chronic exposure to MOR increased the height of the integrated diaphragmatic electromyogram signal (IDIA), respiratory drive and inspiratory effort during periods of eucapnia. Respiratory drive was determined by the product of IDIA height and breathing frequency, and inspiratory effort was the quotient of IDIA height divided by inspiratory time. These effects may be related to accumulation of morphine-3-beta-D-glucuronide. Higher doses of MOR, 10 (n = 3) and 30 (n = 1) mg.hr-1, caused seizures and decreased fetal survival.

Analysis of Variance↗
PubMed1988

Accumulation and clearance of morphine-3-beta-D-glucuronide in fetal lambs.

The time course and extent of morphine-3-beta-D-glucuronide (M3G) production from morphine (MOR) and the clearance of M3G from plasma was studied in the late gestation fetal lamb. MOR was infused at a constant rate into the fetal vena cava and plasma was sampled from the fetus and ewe. Amniotic fluid was also sampled in one animal. M3G was produced in the fetal lamb and accumulated extensively in fetal plasma and amniotic fluid. Seizure activity was observed in two fetal lambs with extremely high plasma concentrations of M3G and MOR. The molar ratio of M3G to MOR in fetal plasma was dependent upon the duration of infusion, reaching a plateau of 60 at about 3 days, but appeared to be independent of the infusion rate over the range studied, 3 to 30 mg hr-1. Maternal plasma MOR and M3G concentrations were substantially less than corresponding fetal plasma concentrations. Using the steady-state plasma concentration of M3G obtained from infusion of MOR and the clearance of M3G derived from single injection of M3G to fetal lambs, the fraction of MOR converted to M3G by the fetus was calculated to be 0.63. Although MOR is conjugated to glucuronic acid in the fetal lamb and excreted into the amniotic fluid it is not readily transferred across the epitheliochorial placenta to the ewe because of restricted permeability.

Algorithms↗
PubMed1984

Fetal breathing movements and the response to carbon dioxide in patients on methadone maintenance.

Fetal breathing movements were monitored on six methadone maintenance patients and ten healthy control patients, studied while breathing room air and while breathing a prepared gas mixture with 5% carbon dioxide, both before and 2 hours after either the usual daily dose of methadone or a diet drink. There was no difference before and after the diet drink in control patients, who showed a significant increase in the incidence of fetal breathing movements from 37.1% +/- 5.9% (SEM) on room air to 69.4% +/- 2.8% while breathing 5% carbon dioxide (p less than 0.01). In the patients studied on room air before receiving methadone, fetal breathing movements were significantly decreased from those of the control group, 4.7% +/- 1.2% (p less than 0.01), with a further decrease when studied after receiving methadone, 1.3% +/- 0.7%. Fetal breathing movements did increase significantly in response to 5% carbon dioxide both before and after receiving methadone; however, in both instances the incidence was significantly less that that of the control group. The findings of the present study on methadone subjects demonstrate that abnormal function of the respiratory control network is evident in utero, which may be predictive of subsequent neonatal respiratory development.

Carbon Dioxide↗
PubMed1983

Cerebral blood flow and metabolism during morphine-induced stimulation of breathing movements in fetal lambs.

Brain blood flow increased in the fetal lamb during morphine-induced stimulation of breathing. The increase in flow was 60% in the cerebral hemispheres and the cerebellum, and 100% in the midbrain plus rhinencephalon, pons, medulla and cervical spinal cord. Oxygen content of arterial blood decreased in all experiments and the arterial carbon dioxide tension increased in all but one of the experiments. The increase in cerebral blood flow observed is predicted by the changes in arterial oxygen content and carbon dioxide tension. Cerebral oxygen consumption and glucose utilization were not changed by morphine treatment. These results suggest that there is no direct effect of morphine upon cerebral blood flow and metabolism in the fetal lamb during morphine-stimulated breathing.

Animals↗
PubMed1982

Ciprofibrate in the therapy of type II hypercholesterolemia. A double-blind trial.

The hypolipidemic efficacy of ciprofibrate was evaluated in patients with type II hypercholesterolemia. Patients were randomized to placebo or ciprofibrate (50 mg or 100 mg/day) and, after a 6-week baseline period, received medication for a period of 12 weeks. Blood samples were analyzed every 2 weeks. Twenty patients completed the study (4 on placebo, 7 on 50 mg/day, and 9 on 100 mg/day ciprofibrate). The drug was well tolerated in all patients. Lipid values in the patients on active drug decreased and attained stable values after 4 weeks of treatment. Compared to baseline values, total and LDL cholesterol decreased 11% and 13% on the 50-mg dose whereas HDL increased 8%. Plasma triglyceride fell by 22%. In patients receiving 100 mg ciprofibrate, total and LDL cholesterol fell by 20% (334 leads to 269 mg/dl) and 24% (262 leads to 198 mg/dl), respectively. HDL increased 9.8% (51 leads to 56 mg/dl) and triglyceride decreased by 30% (102 leads to 69 mg/dl). Values in the placebo group remained stable. We conclude that once daily therapy with 100 mg ciprofibrate, is effective in reducing LDL levels in patients with type II hypercholesterolemia (mainly heterozygous FH) and that this decrease is paralleled by small rises in HDL.

Adult↗
PubMed1982

Altered respiratory control in newborn puppies after chronic prenatal exposure to alpha-1-acetylmethadol (LAAM).

Respiratory studies were conducted on newborn puppies chronically exposed to alpha-l-acetylmethadol . HCl (LAAM) during portions of gestation. Bitches received daily oral doses of LAAM from the second week through the sixth week of pregnancy (LAAM-6) or through the end of a 9-week pregnancy (LAAM-9), but not after parturition. LAAM-9 pups displayed narcotic abstinence signs during the first week after birth, while LAAM-6 pups did not. LAAM-9 pups had increased tidal volume, respiratory frequency, alveolar ventilation and O2-consumption and decreased alveolar CO2-tension during the first week of life compared to placebo-treated controls. The LAAM-9 CO2-response curve was significantly displaced to the left of control. These data are consistent with relative hyperventilation during neonatal withdrawal from LAAM. LAAM-6 pups had decreased tidal volume and alveolar ventilation during 4 of the 6 weeks studied. These changes in ventilation were associated with a decrease in O2 consumption. By 6 weeks after birth CO2-response curves of both LAAM-9 and LAAM-6 pups were shifted to the right of control. These changes in CO2-responsiveness suggest the possibility of prolonged disturbances of respiratory control which may continue beyond the sixth week of life.

Animals↗
PubMed1982

Chloral hydrate and the carbon dioxide chemoreceptor response: a study of puppies and infants.

CO2 chemoreceptor function was assessed during natural sleep and following the administration of 100 mg/kg of chloral hydrate to 26 puppies. With chloral hydrate-induced sleep, there were no significant changes in ventilation or in CO2 chemoreceptor response. The ventilation and CO2 chemoreceptor response of a group of infants in natural sleep were compared with those of a group receiving 50 mg/kg of chloral hydrate. Tidal volume O2 consumption, and CO2 elimination were slightly higher in the group given chloral hydrate. There was no difference in the CO2 chemoreceptor response. The proportion of time spent in rapid eye movement (REM) and non-rapid eye movement (NREM) sleep in chloral hydrate-induced sleep was similar to that occurring in natural sleep. Use of chloral hydrate stabilizes O2 consumption sleep. Use of chloral hydrate stabilizes O2 consumption and CO2 production, and it greatly facilitates the assessment of chemoreceptor function in infants. The CO2 chemoreceptor response appears not to be altered in puppies or infants.

Animals↗
PubMed1981

Respiratory and ventilatory effects of methadone in healthy women.

The effects of oral methadone on respiration, ventilation, pupillary diameter, and plasma concentrations of estrone, estradiol, and progesterone were investigated in healthy nonpregnant women, 21 to 29 yr old. All women were in the follicular phase of the menstrual cycle. The study design was a randomized, double-blind, placebo-controlled trial. Six women received 15 mg methadone . HCl, and six received placebo. Alveolar ventilation and oxygen consumption before treatments correlated with plasma progesterone concentration (r2 = 0.85 and 0.68) but the slope and x-intercept of the ventilatory response to carbon dioxide curve did not. Female sex steroids in plasma were not affected by methadone. Mean elimination half-life of methadone from serum was 19 hr. Methadone-induced respiratory depression and miosis lasted more than 48 hr. The intensity of these changes was a linear function of the logarithm of the serum methadone concentration. Plasma progesterone concentration is an important determinant of resting ventilation and metabolism in the follicular phase of the menstrual cycle but endogenous progesterone does not protect women from the respiratory depressant effects of methadone.

Adult↗
PubMed1980

Respiratory and hemodynamic effects of methadone in pregnant women.

Minute ventilation, end-tidal PCO2, O2 and CO2 concentrations in expired air, pulse rate and arterial blood pressure were measured in the last half of pregnancy in eight women taking methadone daily. Measurements were made with the subjects seated at rest, during the steady state of 50-watt bicycle exercise, and during recovery. Calculations of O2 consumption. CO2 production, alveolar ventilation and oxygen debt were made. Studies were repeated in five subjects postpartum. Methadone diminishes the normal hyperventilation of pregnancy and its effect persists for more than 24 h. When comparisons are made of pregnant and postpartum values, some respiratory stimulation during pregnancy is apparent. Maternal oxygen debt following standard exercise during pregnancy is diminished after the daily dose of methadone and the maternal heart rate response to exercise is diminished concurrently. The maternal hypoventilation induced by methadone and maintained during exercise may be relevant to the low birth weights and high incidence of sudden infant death syndrome observed by others in the offspring of methadone-dependent women.

Blood Pressure↗
PubMed1980

Ventilatory response to carbon dioxide of infants following chronic prenatal methadone exposure.

Nine infants chronically exposed to methadone in utero were studied from birth to 7 weeks of age (66 studies). The maternal dose of methadone/HCl during the third trimester ranged from 14 to 70 mg orally once a day. The mean (range) of serum methadone t 1/2 in the neonates was 53 hours (22 to 113). In the first four days of life the methadone-exposed infants had a significantly (P less than 0.005) decreased sensitivity to carbon dioxide compared to control infants as measured by the slope of the ventilatory response curve. The mean slope +/- SD for the methadone-exposed infants, 10.4 +/- 7.7 ml/minute/kg mm Hg, was one third that of the control group (30.0 +/- 9.9 ml/minute/kg/mm Hg). Total ventilation, respiratory frequency, oxygen consumption, and end-tidal PCO2 were not significantly different in the two groups. The depressed ventilatory response to carbon dioxide persisted for an average of 15 days and lasted as long as 31 days in one infant. The time required to achieve a normal slope was not related to the size of the maternal methadone dose, to neonatal serum methadone t 1/2, or to the severity of and therapy for methadone withdrawal. If this abnormality in sensitivity to carbon dioxide persists beyond the neonatal period in some infants, it may contribute to the increased incidence of the sudden infant death syndrome among infants exposed to methadone in utero. Measurement of the ventilatory response to carbon dioxide may be clinically useful to determine which of these infants are at risk for SIDS.

Carbon Dioxide↗
PubMed1980

Stereospecific radioimmunoassay of alpha-l-acetylmethadol (LAAM).

A sensitive and specific radioimmunoassay has been developed which allows quantitation of picogram amounts of alpha-l-acetylmethadol (LAAM) in biological fluids without prior extraction. Antiserum was obtained from rabbits immunized with antigen prepared by conjugation of alpha-l-methadol hemisuccinate with thyroglobulin. The antiserum was stereospecific, distinguishing LAAM from its three stereoisomers. In addition, there was little cross-reaction in the assay by metabolites of LAAM and no interference with the assay by other narcotic analgesics. The sensitivity of the assay was 50 pg, requiring serum sample sizes as small as 10 microliters. The radioimmunoassay was used to determine serum concentrations of LAAM in five female dogs receiving i.v. injections of 2 mg/kg of LAAM. The decay of LAAM in serum appeared to be multiexponential, with a mean terminal half-life of 35 hr. The dogs were behaviorally depressed for at least 9 hr and hypothermic for at least 24 hr after injection. The persistence of these pharmacological effects was probably due to the slow elimination of LAAM and the presence of major metabolites which are pharmacologically active.

Animals↗