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Biomedical subjects

G D Olsen

Publications and source records attributed to G D Olsen.

At least 19 recordsLinked to original sources
PubMed1992

Noninvasive breathing analysis: repetitive chloral hydrate in neonatal guinea pigs.

A noninvasive method was used to record neonatal breathing, heart rate (HR), and the electroencephalogram (EEG) in guinea pig pups. Neonates were randomly assigned at birth to chloral hydrate (CH) or placebo (PLA) treatment. Treatments were administered 30 min before each study on days 1, 3, 5, 7, 14, and 21 after birth. Animals were studied while they breathed room air followed by air with 5% CO2 and 30% O2. CH decreased breathing frequency (f) and inspiratory minute volume (VI), but not tidal volume (VT) during the first week (P less than 0.05), and reduced the rate of growth throughout the study (P less than 0.01), whereas breathing of CO2 increased f, VT, VI, HR, and the relative power in the delta frequency band of the EEG. The percent change in VI induced by CO2, however, was not affected by drug treatment. There was a significant day of life effect on all breathing parameters and HR. CH has cumulative effects on breathing and growth that should be considered when it is used as a sedative for repeated neonatal studies in guinea pigs.

Animals↗
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↗
PubMed1978

Gentamicin binding to serum and plasma proteins.

Gentamicin binding to serum proteins was studied by equilibrium dialysis at 37 degrees C and pH 7.4 in the presence of both physiologic and adjusted concentrations of ionized calcium and magnesium. The percentage of bound drug was inversely related to the concentration of these two divalent cations, raning from 27% bound with no calcium and magnesium present to 17% bound in the presence of four times physiologic concentrations. No significant difference in the extent of drug-protein binding was noted in a comparison of sera from healthy and uremic subjects. Heparin also was found to affect gentamicin binding. Increasing heparin concentration in serum increased apparent gentamicin-protein binding to 34% in the presence of physiologic amounts of calcium and magnesium. Buffered heparin solutions without plasma proteins bound up to 65% of total drug concentration. Gentamicin-protein binding may have implications regarding pharmacokinetics and renal cortical uptake.

Blood Proteins↗
PubMed1978

Conjugate lateral gaze nystagmus and free phenytoin concentrations in plasma: lack of correlation.

Electrooculographic recordings during left and right conjugate lateral gaze fixation from 10 degrees to 50 degrees were made in 29 patients being treated with phenytoin. At the time of electrooculographic recordings, venous blood samples were drawn for analysis of total and free phenytoin plasma concentrations. Rhythmic horizontal nystagmus occurred in 7 patients, and only at extreme (40 degrees, 50 degrees) later gaze in 6 of these. Measurable free phenytoin levels in the 29 patients ranged from 0.2 to 3.2 mug/ml, and in the 7 patients with nystagmus were 0.6, 0.8, 1.0, 1.0, 1.7, 1.8, and 3.2 mug/ml. Neither the occurrence of nystagmus nor the degree of lateral gaze at onset could be correlated with free phenytoin concentrations in plasma.

Adolescent↗
PubMed1978

Stereospecific antibodies to methadone. II. Synthesis of d- and 1-methadone antigens.

Diastereomeric methadols were prepared by reduction of the methadone enantiomers. Resulting methadols, after purification and characterization by mass spectrometry, were succinylated. The hemisuccinyl derivatives were conjugated with thyroglobulin via carbodiimide condensation. The conjugates of d- and of 1-methadol hemisuccinyl-thyroglobulin were employed as the antigens for immunization of white New Zealand rabbits in order to obtain specific anti d- and anti 1-methadone antisera.

Animals↗
PubMed1978

Methadone-induced respiratory depression in the dog: comparison of steady-state and rebreathing techniques and correlation with serum drug concentration.

The respiratory effect of di-methadone administered subcutaneously was examined in awake, unsedated female Labrador retrievers in which a chronic tracheostomy had been established. Respiratory depression was determined from the change in ventilatory response to carbon dioxide. Two methods for assessing the response were evaluated and compared, namely the classical steady-state and rebreathing techniques. Maximal methadone-induced respiratory depression after administration of 2 mg/kg of dl-methadone occurred by 1 hr as detected by both methods, but the magnitude of the response as detected by the steady-state technique was significantly greater. At 8 hr significant respiratory depression was still detectable by the steady-state but not by the rebreathing technique. At comparable serum drug levels, the rebreathing method consistently detected a smaller degree of drug-induced respiratory depression. Methadone administration produced a decrease in slope of the ventilation-response curve which was significant at 1 and 2 hr for both methods. Slopes of the response curves obtained at pretreatment control measurements were markedly different for the two techniques, being significantly greater for the rebreathing method. Serum dl-methadone concentration was measured by radioimmunoassay. The mean serum half-life of methadone was 4.7 hr. There was excellent correlation between the logarithm of serum drug concentration and drug-induced respiratory depression as measured by either technique.

Animals↗
PubMed1977

New gas chromatogrphic assay for the quantification of methadone. Application in human and animal studies.

A new gas chromatographic assay utilizing 2-dimethylamino-4,4-diphenyl-5-nonanone as the internal standard was developed for the quantification of methadone. The method involved extraction of methadone with 1-chlorobutane from tissue at pH 9.8, re-extraction of an aliquot of the organic solvent with 0.5 M sulphuric acid, alkalinization and final extraction into chloroform. The assay was used to determine the concentration of methadone (i) in whole blood samples from a normal volunteer following a single 9.4-mg oral dose of d-methadone hydrochloride, (ii) in whole blood, saliva and gastric juice from a methadone addict maintained on 90 mg of dimethadone hydrochloride per day, (iii) in mouse liver microsomes incubated with methadone, and (iv) in the perfusate of the isolated perfused rat liver.

Animals↗
PubMed1977

Clinical effects and pharmacokinetics of racemic methadone and its optical isomers.

The respiratory and pupillary effects of oral l-, d-, and d,l-methadone were studied in healthy male volunteers 21 to 35 yr of age. The mean half-life of drug in blood was 22 hr for racemic methadone, 24 hr for l-methadone, and 25 hr for d-methadone. The effects of d-methadone were not significantly different from the placebo response at a 7.5 mg dose, whereas a 50 and 100 mg dose slightly depressed respiration in one subject each. Both 7.5 mg of l-methadone and 15 mg of d,l-methadone induced intense and sustained respiratory depression and miosis. The changes induced by l-methadone were of longer duration than those of d,l-methadone, lasting more than 72 hr in some subjects. Whole blood drug concentration correlated well with respiratory depression and miosis for l- and d,,l-methadone. The potency ratio of l-methadone to d,l-methdone, calculated from blood drug concentration data, was found to be 3.0 for respiratory depression and 2.7 for miosis. The antiduretic effect of 15 mg of d,l-methadone was investigated in three subjects and was found to persist for as long as measurements were taken, namely 11 and 12 hr in two subjects. d,l-Methadone administered frequently for pain may have cumulative effects on respiratory control and ability to excrete a water load.

Adult↗
PubMed1977

Stereospecific antibodies to methadone. I. Radioimmunoassay of d,l-methadone in human serum.

Anti-d,l-methadone antibodies were produced in rabbits immunized with d,l-methadol-hemisuccinate thyroglobulin conjugate. Using the antiserum, a radioimmunoasay (RIA) for determination of d,l-methadone in human serum has been developed and is described. Concentration of d,l-methadone of 1.4 pmol in a native serum sample (volume 0.1 ml or less) could be measured directly by RIA. The antibodies crossreact 100% with d,l-methadone, 50% with d-methadone, 50% with l-methadone and 100% with alpha-d-methadol. No crossreactivity was found with alpha 1-methadol, morphine, meperidine, dextropropoxyphene, 2-ethyl-5-methyl-3,3-diphenyl-l-pyrroline and 2-ethylidene-l, 5-dimethyl-3,3-diphenylpyrrolidene. High sensitivity and small sample requirements make this method suitable for future monitoring of patients on methadone maintenance and for studies where other procedures have lack of sensitivity.

Animals↗
PubMed1976

Iodo-bis(quaternary ammonium) salts. Potential cartilage-selective x-ray contrast agents.

Bis(quaternary ammonium) compounds in which one or both quaternary nitrogens bear iodinated benzyl moieties and the charged centers are separated by 2, 4, 6, or 10 methylene units have been synthesized and evaluted for (a) binding to cartilaginous material, (b) radiocontrast characteristics, and (c) in vitro pharmacological effects. Also prepared was 1,5-diiodo-2,4-bis(beta-trimethylammonioethyl)benzene diiodide, an analogue in which the iodinated aryl group lies between the charged nitrogen centers. Biological studies show that these compounds bind to cartilage but at relatively slow rates and with low persistence, resulting in low and transient levels of radiopacity. In common with simpler bisquaternary compounds, these compounds block synaptic transmission.

Animals↗