Physostigmine (PHY) is currently being evaluated as a potential pretreatment against nerve agent challenge. Although it might provide increased protection against nerve agent-induced incapacitation, it is nonetheless behaviorally toxic itself. Addition of a cholinolytic adjunct is expected to significantly reduce this behavioral toxicity. The efficacy of pretreatment regimens (PRG) (composed of PHY in combination with either scopolamine (SCP) or trihexyphenidyl (artane; ART] was evaluated in guinea pigs challenged with soman (98 ug/kg, sc; 3.5 LD50) to determine the dose of PHY and adjunct required for optimal efficacy as well as the better of the two adjuncts. Three different endpoints were measured on each animal: (1) whether or not the animal survived up to 24 hours post challenge, (2) severity of incapacitation, and (3) time to recovery. The survival data revealed no significant differences between the two adjuncts and PHY against soman, but the data suggests that a pretreatment combination of PHY and ART is likely to give a greater therapeutic index than one containing SCP. Furthermore, since ART is less toxic behaviorally, it would most likely be better tolerated as a pretreatment with PHY in non-agent exposed subjects. The findings in this report are not to be construed as an official Department of the Army position unless so designated by other authorized documents. In conducting the work described in this report, the investigators adhered to the "Guide for the Care and Use of Laboratory Animals" as promulgated by the Committee on Revision of the Guide for Laboratory Animal Facilities and Care of the Institute of Laboratory Animal Resources, National Research Council.

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Zero-base budgeting and program evaluation.

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Costs and Cost Analysis↗

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Multiple drug chemotherapy combined with multiple fractions per day (MFD) radiotherapy in an experimental solid tumor model.

A series of multi-drug chemotherapy studies combined with multi fractions per day (MFD) radiotherapy have been carried out in an experimental solid tumor model to provide information on how drugs contribute in combinations, both for effect on tumor and with regard to host toxicity. Twenty-five different combinations of cyclophosphamide (CP) and 5-fluorouracil (FU) were evaluated in this initial study. All tumors received a total dose of 6000 cGy of radiation given in multiple fractions per day for three courses one week after combined chemotherapy. Doses of each drug in the combinations ranged from 25 to 100% of the LD10 (150 mg/kg or .9 mg/m2) of each drug when given as a single agent. Proportional hazards analysis of the survival data yielded optimal doses of 132.8 mg/kg FU and 115.0 mg/kg CP, that is, approximately 3/4 of the LD10 of each drug in the combination. The group close to the optimum combination had a median GD of 295.3 days. Among the 5 rats in this group there were 4 partial responses and 1 cure for a 100% response rate. Excessive toxicity occurred in the group given the highest doses of FU and CP along with the 6000 cGy radiotherapy. These experimental cancer treatment studies in well defined solid tumor models demonstrate how the quantitative inter-relationship between anti-tumor effects and host toxicity to tumor burden and total therapeutic dose chemotherapy (single or multiple combinations) and radiotherapy alone or in combination can be obtained. These major determinants on treatment outcome are difficult or impossible to determine in clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)

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Relationship of tumor regrowth to tumor cell survival, tumor cure rates and host survival in a solid tumor model following combined chemotherapy and radiotherapy.

Endpoints available for comparison of two or more treatment arms in a clinical cancer trial include response rates (complete and partial), time to progression, and patient survival. In experimental systems, similar endpoints are available (tumor cell survival, tumor regrowth, tumor cure rates, and host survival), but there is opportunity for more precise measurements and a wider range for varying the independent variables. Radiotherapy alone was compared with an alternating schedule in which both radiotherapy and cyclophosphamide (CP) were given intermittently for a total of 3 courses of each. Radiotherapy was given as multiple, 250 cGy fractions per day (MFD) in 2-day courses. Cyclophosphamide alone (3 x 150 mg/kg) was equivalent in tumor effect to 3600 cGy of irradiation given with the MFD schedule. The experimental points for the combined modality treatments fell along the lower edge of the zone of additivity. Exprapolation of the plots of log surviving fraction vs. total radiation for the combined treatment predicted a 37% cure rate at 6000 cGy + CP. There was a high probability for long term control and tumor cures only with the highest total doses of radiation (6000, 7000 and 8000 cGy) when combined with CP. The results obtained in well defined experimental tumor models provide quantitative information of the interrelationship of the major determinants on end results of the effectiveness of treatment and acceptable host toxicity of combined chemotherapy and radiotherapy. The quantitative evaluation of these major determinants on treatment outcome in relationship to host toxicity is often difficult or impossible to obtain in clinical host toxicity is often difficult or impossible to obtain in clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)

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