Maternal-fetal pharmacokinetics of methanol.

We undertook the present project to elucidate the physiologic factors that govern methanol delivery to the developing conceptus after maternal methanol exposure, and to develop a physiologically based toxicokinetic model to describe methanol disposition in pregnancy. A multi-experimental approach addressed the goals of this project. Initial experiments characterized the systemic disposition of methanol after intravenous or oral administration to nonpregnant female rats.

Methanol inhalation: site and other factors influencing absorption, and an inhalation toxicokinetic model for the rat.

Purpose: This investigation was conducted to identify the site and characteristics of methanol absorption and to develop an inhalation model relating methanol absorption, blood concentration, and elimination.

Methods: Rats were exposed to methanol in chambers that allowed measurement of methanol uptake, ventilation, and blood concentrations; anesthetized rats with a tracheal cannula were examined to determine tracheal concentrations. In separate experiments, methanol exposed rats received an iv methanol bolus to examine the effect of blood methanol on ventilation and absorption; ventilation also was manipulated by CO(2) or pentobarbital to assess the effect of ventilation rate on methanol absorption.

Physiologic pharmacokinetic modeling of gastrointestinal blood flow as a rate-limiting step in the oral absorption of digoxin: implications for patients with congestive heart failure receiving epoprostenol.

A previously validated physiologically based pharmacokinetic model was used to examine whether epoprostenol-induced increases in gastrointestinal blood flow (Qg) could alter digoxin systemic bioavailability to a clinically significant extent in severe congestive heart failure (CHF) patients. A series of simulations was conducted in which the influences of apparent gut tissue-to-plasma partition coefficient (Kg) and Qg on digoxin bioavailability were evaluated. Since epoprostenol also increases blood flow to the liver and kidneys, the effect of concurrent increases in regional blood flow to these organs on digoxin bioavailability also was evaluated.

Phase transitions and the molecular mechanism of contraction.

In this paper, the rotating cross-bridge mechanism for muscle contraction is discussed and much contradictory evidence is put forward. As an alternative, a model is given in which the motor of muscle contraction is placed in the myosin-rod hinge and/or in the actin filament. No definite choice for one of the proposed models can be made yet, although it is clear that some kind of phase transition plays an important role in the mechanism.

Age-related changes in valproic acid binding to rat serum proteins in vitro.

The effect of age on the in vitro binding of valproic acid (VPA) to serum proteins was investigated in rats ranging in age from 14 days (preweaning) to 24 months (senescent). The influence of free fatty acid (FFA) and total protein (TP) concentrations on age-related changes in binding was examined. The protein binding of VPA was altered during development and aging.

Hepatobiliary disposition of valproic acid and valproate glucuronide: use of a pharmacokinetic model to examine the rate-limiting steps and potential sites of drug interactions.

Previous work in this laboratory has suggested that the nonlinear disposition of valproic acid (VPA) in the rat may be due to nonlinear distribution of VPA into the liver. The present study was undertaken to elucidate further the hepatobiliary disposition of VPA. VPA (0.

[The mechanism of muscle contraction: along the path carved by Academician G.M Frank].

On the issue of the mechanism of muscle contraction, the views of the late G.M. Frank, to whom this symposium is dedicated, differed fundamentally from those of the then-current orthodoxy.

Do vertebrate thick filaments contain a core? Observations using ultrathin sectioning and freeze-etching.

Transverse ultrathin sections and the freeze-fracture deep-etch method were used to study the structure of vertebrate thick filaments. We examined intact frog semitendinosus and glycerinated rabbit psoas muscle fibers. In transverse thin sections, using standard staining methods, cores were moderately well revealed.

Comparative toxicokinetics of inhaled methanol in the female CD-1 mouse and Sprague-Dawley rat.

Female CD-1 mice were exposed for 8 hr, both individually and in groups of eight to nine, to 2500, 5000, and 10,000 ppm methanol vapor in a flowthrough exposure chamber. The ventilation of individually exposed mice and the absorption of methanol from the chamber airstream were measured. The extraction of methanol from the airstream and the blood methanol concentration at various time points during and following exposure were determined for the group-exposed mice.

A pharmacokinetic-pharmacodynamic model of tolerance to morphine analgesia during infusion in rats.

A pharmacokinetic-pharmacodynamic (PK-PD) model was constructed to describe the kinetics of tolerance development to morphine-induced antinociception. Tail-flick latencies in response to hot water (50 degrees C) were assessed in male Sprague-Dawley rats exposed to a 12-hr iv infusion of either morphine (1.4 to 3.

Pharmacokinetics and anticonvulsant effect of a new hypnotic, CL 284,846, in rats.

Purpose: CL 284,846 (CL846) is an investigational non-benzodiazepine agent with hypnotic, anxiolytic, myorelaxant and anticonvulsant properties. This study assessed the pharmacokinetics and anticonvulsant action of CL846 in female Sprague-Dawley rats.

Methods: CL846 pharmacokinetics were examined after either an iv bolus dose (2.

Biomechanical characteristics of suture techniques in extensor zone IV.

This study was designed to investigate several biomechanical parameters involved in repair of extensor tendons in Zone IV (over the proximal phalanx). Typical suture techniques over the proximal phalanx did not shorten the tendon significantly nor was there significant loss of flexion at the metacarpophalangeal or proximal interphalangeal joints. The Kleinert modification of the Bunnell technique and modified Kessler technique seemed to be the strongest and provided evidence that dynamic or active range of motion, under controlled conditions and in short arcs, might be physiologically tolerated by repaired tendons.

Comparative toxicokinetics of methanol in the female mouse and rat.

The toxicokinetics of methanol in female CD-1 mice and Sprague-Dawley rats were examined to explore the possibility of species differences in the disposition of the compound. Mice received a single dose of 2.5 g/kg methanol either po (by gavage) or i.

A pharmacokinetic model of inhaled methanol in humans and comparison to methanol disposition in mice and rats.

We estimated kinetic parameters associated with methanol disposition in humans from data reported in the literature. Michaelis-Menten elimination parameters (Vmax = 115 mg/L/hr; Km = 460 mg/L) were selected for input into a semi-physiologic pharmacokinetic model. We used reported literature values for blood or urine methanol concentrations in humans and nonhuman primates after methanol inhalation as input to an inhalation disposition model that evaluated the absorption of methanol, expressed as the fraction of inhaled methanol concentration that was absorbed (phi).

Biliary excretion and enterohepatic recirculation of morphine-3-glucuronide in rats.

Morphine elimination is characterized by a prolonged terminal elimination phase, at least in part because of enterohepatic recirculation (EHR) of morphine as its major metabolite, morphine-3-glucuronide (M3G). This experiment was conducted to characterize M3G disposition after direct administration of the metabolite to intact or bile duct-cannulated (BC) rats, and to develop a pharmacokinetic model of EHR for M3G. Male Sprague-Dawley intact and BC rats (N = 4/group) received a 5 mg/kg iv bolus of M3G, with serum and bile sampled at timed intervals after the dose; urine was collected in toto at the end of the experiment.

Age-dependent intestinal hydrolysis of valproate glucuronide in rat.

1. Age-dependent differences in the intestinal hydrolysis of the glucuronide conjugate of valproic acid were evaluated in the Fisher-344 rat at 14 and 40 days, and 24 months of age. 2.

Age-dependent intestinal absorption of valproic acid in the rat.

The absorption of valproic acid (VPA) across isolated perfused segments of jejunum, ileum and colon was examined in situ in 14-day- to 24-month-old Fischer-344 rats. Within each age group, the intrinsic absorptive clearance (Cla) of VPA at a perfusate concentration of 1 mg/ml was highest in the jejunum, lowest in the colon, and intermediate in the ileum. When intestinal Cla was normalized for the dry weight of the segment, within-group variability decreased.

Persisting in vitro actin motility at nanomolar adenosine triphosphate levels: comparison of skeletal and cardiac myosins.

We have previously demonstrated in vitro actin movement at nanomolar adenosine triphosphate (ATP) levels using heavy meromyosin from skeletal muscle. In the present work we tested whether the motility at nonomolar ATP-concentrations could be supported by cardiac myosin as well. Actomyosin (skeletal actin and bovine ventricular myosin) was pretreated in the in vitro motility assay with 1 mM ATP; subsequently, the ATP level was reduced by multiple rigor-solution washes.

Actin filaments in honeybee-flight muscle move collectively.

To investigate the pattern of actin-filament translation in the intact myofibrillar matrix, we carried out electron micrographic experiments on the "rigor-stretch" model of insect-flight muscle. In this model, thin filaments are mechanically severed from their connections to the Z-line and may then slide freely over the myosin filaments when activated. The model is similar to the in vitro motility assay in that untethered actin filaments slide over myosin, but here the natural filament lattice is retained: sliding takes place through the lattice of thick filaments.

Visualization of the transverse cytoskeletal network in insect-flight muscle by scanning-electron microscopy.

Located at the level of the Z-line, the transverse cytoskeletal network of insect-flight muscle interconnects adjacent myofibrils with one another, and interconnects peripheral myofibrils with the cell membrane. This network has been presumed to keep myofibrils in register, or to distribute tension laterally among myofibrils. In this study, we used scanning-electron microscopy to reveal details of the three-dimensional arrangement of this network.

Birth times of neurons in labellar taste sensilla of the blowfly Phormia regina.

We studied the birth times of neurons of labellar taste sensilla in blowflies using incorporation of the thymidine analogue 5-bromodeoxyuridine (BrdU) as an indicator of birth time. We found that one of the two main sensillum types, the taste papillae, arise according to a clear spatial gradient of birth times, whereas the other sensillum type, taste hairs, arise without any apparent spatial ordering. Within each sensillum type, there was a strong tendency for either all or none of the neurons to have incorporated BrdU.

Passive and active tension in single cardiac myofibrils.

Single myofibrils were isolated from chemically skinned rabbit heart and mounted in an apparatus described previously (Fearn et al., 1993; Linke et al., 1993).