Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent.

The plasma pharmacokinetics of the anti-tumor antibiotic geldanamycin (GM: NSC 122750), a naturally occurring benzoquinoid ansamycin, was characterized in mice and a beagle dog. Concentrations of GM well above 0.1 microgram/ml, which was typically effective against neoplastic cell lines responsive to the drug in vitro, were achieved in the plasma of the mice and the dog treated by i.v. injection. However, the systemic duration of the drug was relatively short. Plasma levels decayed below 0.1 microgram/ml within 3-4 h after administration of the apparent maximum tolerated doses, which were approximately 20 mg/kg for the mice and 4 mg/kg for the dog. The drug exhibited linear pharmacokinetic behavior within the dose ranges studied. However, there were significant interspecies differences in its disposition. Whereas the mean biological half-life of GM was slightly longer in the mice (77.7 min) than in the dog (57.9 min), its mean residence time in the dog (46.6 min) was more than twofold greater than that observed in the mice (20.7 min). Nevertheless, the drug was cleared from plasma much faster by the dog (49.4 ml/min per kg) than by the mice (30.5 ml/min per kg). These apparent anomalies were principally associated with differences in the relative significance of the terminal phase upon overall drug disposition. The liver appeared to be the principal target organ of acute drug toxicity in the dog. Doses of 2.0 and 4.2 mg/kg both produced elevations in serum levels of the transaminases and other indicators of liver function characteristic of acute hepatic necrosis. Additional effects included symptoms of minor gastrointestinal toxicity and alterations in serum chemistry parameters consistent with less severe nephrotoxicity. Drug-related toxicity appeared to be reversible. In consideration of the potential for acute hepatotoxic reactions to GM, as well as to the other benzoquinoid ansamycins based upon structural analogy, additional pharmacological and therapeutic information is required to ascertain whether these compounds are viable candidates for clinical development.

Cost analysis of Hickman catheter insertion at bedside in gynecologic oncology patients.

BACKGROUND: Cost-containment issues are becoming increasingly important in medicine. The current study compares bedside versus operating room insertion of Hickman catheters from a cost and safety standpoint. STUDY DESIGN: A prospective chart review of all patients undergoing Hickman catheter insertion during the study period was performed to determine location of the procedure, rate of successful catheter placement, complications, and cost. RESULTS: Ninety-six patients underwent placement of 108 Hickman catheters during a seven year period. Fifty-three catheters were inserted at bedside while 55 catheters were placed in the operating room. The complication rate was 8 percent for the bedside and 9 percent for the operating room group. Due to anesthesia standby, operating room time, and fluoroscopy, cost analysis revealed a substantial savings of $1,545 per patient if bedside insertion was utilized. CONCLUSIONS: The data indicate that, in select patients, percutaneous insertion of Hickman catheters at bedside is a safe, cost-effective procedure.

Utero-ovarian infection in aged B6C3F1 mice.

An unusually high number of ovarian masses and cysts with purulent material were observed in the B6C3F1 mice on 2 year chemical carcinogenicity studies sponsored by the National Cancer Institute-National Toxicology Program. To determine possible etiology, some of these lesions were cultured for bacteria and a majority yielded Klebsiella sp. Necropsy records of 14,029 female mice in 91 chronic studies necropsied from 1979 to 1983 at six toxicology testing laboratories were reviewed to determine the incidence of lesions and distribution of this disease. Animals for these studies were obtained from barrier production colonies of six suppliers. The incidence of this lesion was low in animals less than 14 months of age, increased with age and reached a peak in 24-26 month old mice. Most animals having this lesion either died or were sacrificed in moribund condition, indicating that this is a life shortening disease of aged B6C3F1 mice. The incidence of lesions ranged from less than 1% to 70% in different chronic studies. There was a marked difference in the incidence in mice from different suppliers and the incidence rate was 2.6 to 15% depending on the source of the animals. The incidence of this lesion in some testing laboratories was several-fold higher than in others and ranged from 0.9 to 20%. The proportion of mice with this lesion was low in some laboratories irrespective of the source of the animals, whereas in other laboratories the incidence was several-fold higher with animals from some, but not all suppliers, indicating testing laboratory-supplier interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

History, survival, and growth patterns of B6C3F1 mice and F344 rats in the National Cancer Institute Carcinogenesis Testing Program.

The history of, and rationale for, the selection of the hybrid B6C3F1 mouse (C57BL/6 female X C3h/He male) and the inbred F344 rat for National Cancer Institute (NCI) bioassays is described. Survival percentages at the end of 2-year tests and weight-gain patterns during the tests of control animals are presented to guide investigators using these same animals in similar long-term experiments. Because information on a large number of animals (9385 mice and 10,023 rats) from a number of laboratories is presented, the conclusions should serve to give general guidance to investigators holding the same animals under a diversity of husbandry conditions. The program experience has been that the B6C3F1 mouse survival at the end of a 24-month study (25.5 months of age) is 80%; the F344 survival for the same period is 75%. This contrasts with the generally held assumption that rats are longer lived than mice. For the period of time from which animal data were collected, there was a progressively slight decrease overall in survival percentage. This observation cannot be explained, and contravenes the expectation that methodological improvements in producing the animals and marked physical improvements in the testing laboratories should have resulted in improving the survival. Weight gain patterns have a distinct and somewhat similar sexual dimorphism for both rat and mouse. The males of each species grow much faster initially and then essentially level off. The female mouse grows slowly and steadily, and by 2 years of age almost equals the male; the female rat shows the same steady gain, but is much lighter than the male at 2 years of age.

Studies of the coagulation system and blood pressure during experimental Bolivian hemorrhagic fever in rhesus monkeys.

Experimental infection of rhesus monkeys (Macaca mulatta) with Machupo virus produced a hemorrhagic disease similar to that of Bolivian hemorrhagic fever in humans. The disease in infected animals was also characterized by the development of hypotension and coagulation abnormalities as indicated by severe thrombocytopenia and prolongation of the activated partial thromboplastin time. Evidence for disseminated intravascular coagulation was inconclusive due to the presence of normal to elevated fibrinogen levels, relatively low levels of circulating fibrin split products, and the lack of widespread fibrin thrombus deposition. The most likely causes of the hemorrhagic tendencies of this disease in infected monkeys were thrombocytopenia and decreased synthesis of coagulation and other plasma proteins due to severe hepatocellular necrosis. Hypotension may also have been due to decreased plasma protein synthesis.

An easily dismantled pig pen for long-term radiation exposure.

A pen to hold individual miniature pigs during long-term radiation exposure studies has been designed and used. Wooden construction results in low cost and minimizes radiation scatter problems associated with higher density materials. An automatic water system is provided.

Susceptibility of laboratory animals to infection by spotted fever group rickettsiae.

An attempt was made to find a suitable animal model for studies of spotted fever group rickettsiae. Inbred and outbred mice, the guinea pig, ferret, gerbil, hamster, wild rabbit, cotton rat, sheep, and miniature swine were tested. Of these, only certain strains of the mouse [Mai:(S) and BALB/cJ] and the guinea pig [Hla:(HA)] exhibited, overtly, the desired characteristics of disease. Other laboratory animals (such as sheep or rabbits) can be used for the production of antiserum against the spotted fever group of rickettsiae; however, these rickettsiae apparently have little or no effect on several other animal species. The lack of overt disease might explain the role of these animals or related genera as reservoirs for the tick-borne spotted fever rickettsiae.

Technique for portal catheterization in rhesus monkeys (Macaca mulatta).

A technique was developed for catheterization of the portal vein in rhesus monkeys (Macaca mulatta). Silicone rubber catheters (0.040 ID by 0.085 inch OD, or 0.030 ID by 0.065 inch OD) were surgically placed into the portal vein via the umbilical, inferior mesenteric, right colic, or ileocolic veins. The right colic and ileocolic veins proved to be the preferred route for catheterization. Both single end-hole and multiple end-hole catheters with 2 side holes were used. Catheter function was dependent upon proper placement within the portal vein and on maintaining patency. Single-hole catheters were successfully maintained by periodic flushing (2-3 times daily) with heparinized saline solution (1.5-4.0 units/ml), and multiple-hole catheters were best maintained by a continuous flow (1-2 ml/hour) of heparinized saline solution (1.5 units/ml). No adverse clinical effects due to the portal catheter were observed in any of the monkeys catheterized. The technique allowed placing the monkey in a restraint chair, thus enabling one to utilize the monkey in a conscious state.

Evaluating new antimalarial drugs against trophozoite induced Plasmodium cynomolgi malaria in rhesus monkeys.

An antimalarial drug testing system is described which utilizes trophozoite induced Plasmodium cynomolgi malaria in rhesus monkeys. The schizonticidal activity of standard antimalarial drugs in this system is reported. The system accurately predicted antimalarial activity in man of 8 of 9 compounds selected for clinical trials.