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K W Ward

Publications and source records attributed to K W Ward.

25 records · Page 2Linked to original sources
PubMed1995

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.v. (as a 1-min infusion). Rats received a single oral dose of 2.5 g/kg methanol. As expected, the disposition of methanol was nonlinear in both species. Data obtained after i.v. administration of methanol to mice were well described by a one-compartment model with Michaelis-Menten elimination. Blood methanol concentration--time data after oral administration could be described by a one-compartment (mice) or two-compartment (rats) model with Michaelis-Menten elimination from the central compartment and biphasic absorption from the gastrointestinal tract. Kinetic parameters (Vmax for elimination, apparent volume of the central compartment [Vc], first-order rate constants for intercompartmental transfer [k12 and k21], and first-order absorption rate constants for fast [kAF] and slow [kAS] absorption processes) were compared between species. When normalized for body weight, mice evidenced a higher maximal elimination rate than rats (Vmax = 117 +/- 3 mg/hr/kg vs 60.7 +/- 1.4 mg/hr/kg for rats). The contribution of the fast absorption process to overall methanol absorption also was larger in the mouse than in the rat.

Administration, Oral↗
PubMed1995

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. The similarity of systemic kinetic parameters (volume of distribution; Michaelis-Menten elimination parameters, Vmax and KM) between inhalation exposure and iv and po routes of administration was verified. Total 8-hr ventilation decreased slightly with increasing exposure concentration. The fraction of inhaled methanol absorbed (0.85 +/- 0.14) did not vary statistically with exposure concentration. Measured ventilation, fractional absorption, and systemic kinetic parameters were combined in a semiphysiologic pharmacokinetic model that yielded accurate predictions of blood methanol concentrations during and after an 8-hr exposure. Model predictions for the mouse were compared to a previously developed inhalation toxicokinetic model for the rat. The comparison demonstrated that at similar methanol vapor concentrations, mice evidenced a two- to threefold higher blood methanol concentration than rats, despite the fact that the apparent Vmax for methanol elimination in the mouse is twofold larger than that in the rat. These data may have significant implications in understanding species differences in methanol-induced teratogenic effects.

Absorption↗
PubMedDate not supplied

Dysmorphogenic effects of a specific protein kinase C inhibitor during neurulation.

Protein kinase C (PKC) plays a key role in signal transduction and is an important mediator of events throughout development. However, no information exists regarding the effect of a specific PKC inhibitor on mammalian embryogenesis during neurulation. This investigation was undertaken to examine the effects of a specific inhibitor of PKC, as well as inhibitors of other important kinases, on cultured mouse embryos. CD-1 mouse embryos (3 to 6 somite stage) were exposed to bisindolylmaleimide I (a specific PKC inhibitor) as well as specific inhibitors of PKA, PKG, and MAP kinase kinase for 24 h. The PKC inhibitor was a potent embryotoxicant and elicited malformations at concentrations as low as 0.01 microM. Inhibitors of other kinases also produced malformations but at much higher concentrations than those required to produce similar defects with the PKC inhibitor. These data suggest that PKC plays an important role in mammalian neurulation. Further research is required to clarify the mechanism by which PKC inhibition at this developmental stage produces malformations and the potential effects of environmental toxicants with PKC inhibitory properties on this signal transduction pathway.

Alkaloids↗
PubMedDate not supplied

A randomized, double-blind comparison of sulbactam/ampicillin and clindamycin for the treatment of aerobic and aerobic-anaerobic infections.

In a randomized, prospective, double-blind trial, sulbactam/ampicillin was compared with clindamycin in terms of efficacy and safety for the treatment of bacterial infections. Both sulbactam/ampicillin and clindamycin were given with gentamicin when this course was indicated by clinical or laboratory findings. In five patients the site of infection was pleuropulmonary; in 14, bone; in 11, skin and soft tissue; and in one, intraabdominal. The commonest anaerobes isolated were anaerobic cocci and Bacteroides species; the commonest aerobic and facultative bacteria were Enterobacteriaceae, Pseudomonas aeruginosa, and various gram-positive cocci. All of six assessable patients given sulbactam/ampicillin alone had satisfactory clinical responses, as did seven of nine patients given sulbactam/ampicillin plus gentamicin, all of six patients given clindamycin alone, and six of nine patients given clindamycin plus gentamicin. Pathogens were totally or partially eradicated in four of five, eight of nine, four of five, and three of nine assessable patients given these same regimens. Adverse reactions and laboratory abnormalities were relatively uncommon. Overall, sulbactam/ampicillin was as effective as clindamycin in the treatment of aerobic or mixed aerobic-anaerobic infections; however, the concomitant use of gentamicin was frequently required with both regimens.

Aged↗
PubMedDate not supplied

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). Values of phi for nonexercising subjects typically varied between 0.64 and 0.75; 0.80 was observed to be a reasonable upper boundary for fractional absorption. Absorption efficiency in exercising subjects was lower than that in resting individuals. Incorporation of the kinetic parameters and phi into a pharmacokinetic model of human exposure to methanol, compared to a similar analysis in rodents, indicated that following an 8-hr exposure to 5000 ppm of methanol vapor, blood methanol concentrations in the mouse would be 13- to 18-fold higher than in humans exposed to the same methanol vapor concentration; blood methanol concentrations in the rat under similar conditions would be 5-fold higher than in humans. These results demonstrate the importance in the risk assessment for methanol of basing extrapolations from rodents to humans on actual blood concentrations rather than on methanol vapor exposure concentrations.

Animals↗
PubMedDate not supplied

Vancomycin-intermediate Staphylococcus aureus in a home health-care patient.

In June 2000, vancomycin-intermediate Staphylococcus aureus (VISA) was isolated from a 27-year-old home health-care patient following a complicated cholecystectomy. Two VISA strains were identified with identical MICs to all antimicrobials tested except oxacillin and with closely related pulsed-field gel electrophoresis types. The patient was treated successfully with antimicrobial therapy, biliary drainage, and reconstruction. Standard precautions in the home health setting appear successful in preventing transmission.

Adult↗