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Biomedical subjects

M C Matthews

Publications and source records attributed to M C Matthews.

5 recordsLinked to original sources
PubMed1999

Protection against botulinum toxins provided by passive immunization with botulinum human immune globulin: evaluation using an inhalation model.

Pentavalent botulinum toxoid adsorbed (ABCDE) vaccine is intended to protect military personnel from battlefield exposures to botulinum serotypes A-E. To determine the neutralizing antibody levels in serum that are indicative of protection against aerosolized botulinum toxins, a guinea pig model of passive antibody transfer was developed. Botulinum immune globulin (BIG), derived from plasma of vaccinated volunteers, was administered to guinea pigs by intraperitoneal injection to attain neutralizing antibody levels in serum of ca. 0.25 U ml(-1). Control groups were treated with vaccinia immune globulin (VIG), with dosages normalized to antibody content. Neutralizing antibody levels were determined by a mouse bioassay. Twenty-four hours after BIG treatment, animals were challenged with lethal levels (target of 25 x LCt(50)) of botulinum toxins by an inhalation route. Protection was defined as 80% or greater survival for BIG-treated animals. If protective, additional groups were treated with progressively smaller BIG dosages (75% decreases per iteration) and challenged with 25 x LCt(50) until protection was no longer afforded. Greater than 80% survival was observed at target levels of 0.25 U ml(-1) for all five serotypes. Breakthrough mortality (>20%) was observed at test levels of 0.05, 0. 004, 0.015, 0.014 and 0.003 U ml(-1) for serotypes A-E, respectively. These results, along with neutralizing antibody measurements from clinical trials, can be used to predict human efficacy following vaccination with pentavalent botulinum toxoid adsorbed (ABCDE) vaccine.

Administration, Inhalation↗
PubMed1999

Model for assessing efficacy of topical skin protectants against sulfur mustard vapor using hairless guinea pigs.

Sulfur mustard (HD; 2,2'-dichlorodiethyl sulfide) can produce incapacitating blisters in humans following dermal exposure. Most non-human animal models, however, do not form the large fluid-filled blisters observed in humans. Many models, nevertheless, do produce similar damage at the dermal/epidermal junction when evaluated by histopathology. In this study, it was observed that the hairless guinea pig (HGP) exhibits similar histopathological responses following exposure to HD vapor. Two sets of HGPs were exposed percutaneously for various lengths of time to HD vapor. In one set, the HGPs were sacrificed 24 h after exposure, and skin specimens were collected and processed for histopathology. In the other set, light reflectance was measured at skin test sites 4, 5, 6 and 24 h after exposure, to assess erythema. The Nikolsky's sign test was also performed 24 h after exposure by rotating a metal disk glued to the skin test site and inspecting the skin for loss of epidermis. Probit analysis of data indicated that the exposure durations that produced a 50% incidence of microblisters and Nikolsky's sign were ca. 7.5 and 4.5 min, respectively. Maximum erythema was observed 6 h following a 6 min exposure. Operating parameters for assessing the efficacies of skin protectants have been characterized.

Administration, Topical↗
PubMed1991

Stagewise, adaptive dose allocation for quantal response dose-response studies.

A principal design objective of many dose-response studies is to estimate extreme percentiles of a dose-response distribution, e.g., the ED95 dose for a particular drug therapy, as precisely as feasible using the smallest number of experimental subjects possible. Such a design requirement necessitates that allocation of subjects to drug doses be carried out in a stagewise fashion to maximize the information obtained from each subsequent experimental observation in light of what has previously been determined. This paper describes and illustrates specialized methods and associated computer programs to evaluate, on a stagewise basis, the anticipated relative sensitivities of alternative experimental plans in the case of dichotomous responses. Following each stage of experimentation, the current estimates of the dose-response distribution parameters, as well as the uncertainties in these estimates, are updated and are used to assign subjects to experimental dose levels for the next stage of testing. Competing dose allocations are compared with respect to anticipated improvement in estimation precision. The adoption of such a stagewise dose allocation strategy is illustrated by example.

Animals↗
PubMed1991

Stagewise, group sequential experimental designs for quantal responses. one-sample and two-sample comparisons.

The use of stagewise, group sequential experimental designs with dichotomous responses in toxicity or drug screening programs is discussed. Such designs represent a compromise between the standard, fixed sample size designs and fully sequential designs. Stagewise group sequential designs place specified numbers of animals on test at each stage, up to a maximum number of stages. The greatest increases in sample size efficiency occur with small numbers of stages, particularly when going from one stage to two. Two-stage designs can result in a 15 to 20 percent reduction in average sample size. Five-stage designs can result in a 30 to 40 percent reduction in average sample size, with no appreciable decrease in Type 1 error or power. Examples of the efficiencies that arose in actual screening programs are given. This paper demonstrates that the routine use of stagewise, group sequential designs in standardized screening protocols can result in substantial savings in animal use with virtually no sacrifice of statistical sensitivity.

Animals↗