Anticancer agents and antitrypanosomiasis activity in mice.

Of 303 compounds (66 active against cancer and 237 inactive against cancer) obtained from the Drug Synthesis and Chemistry Branch, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland, 25 were found to be active against Trypanosoma rhodesiense infections of ICR/Ha Swiss mice. Fifteen of these 25 compounds also had anticancer properties. The percentage of anticancer compounds found to have antitrypanosomiasis properties was 22.7. This percentage compares with 6% antitrypanosomiasis compounds among compounds selectecd by other methods.

Alterations in graft--ersus-host reactivity and peripheral leukocytes in mice after erythropoietin treatment.

Treatment of mice on four consecutive days with either erythropoietin (EP) or rabbit antimouse thymocyte serum (ATS) resulted in a significant reduction in antigenic reactivity of spleen cells as measured by the Simonsen assay. In normal animals, treatment with either EP or ATS resulted in lymphopenia and in most instances a neutrophilia and a variable monocytopenia. Similar alterations in these cell types were recorded for polycythemic mice subsequent to treatment with either EP or ATS. These data plus histologic analyses support the idea that there is an inverse relationship between the cells committed to differentiate along the lymphoid cell line and the cells committed to differentiate along myeloid cell lines. Further, the data are consistent with the "carrying capacity" concept regarding the stem cell microenvironment and support the monophyletic theory.

A new chemical series active against African trypanosomes: benzyltriphenylphosphonium salts.

Antitrypanosomal activity for benzyltriphenylphosphonium salts is reported for the first time. Testing was conducted using Trypanosoma rhodesiense infected mice. Of 70 phosphorus-containing compounds tested, 21 were active. Sixteen of these active chemical species were benzyltriphenylphosphonium salts. Four were nonbenzyl triphenyl compounds. The remaining active drug was a benzyldiphenylphosphonium salt.

In search of anti-Trypanosoma cruzi drugs: new leads from a mouse model.

Nine of 25 carefully selected compounds (from a stock of more than 200 000 chemical species amassed principally as a result of testing against other parasitic diseases) were found to have significant suppressive activity against the parasites in the blood of a Trypanosoma cruzi mouse model. Eight of these compounds evaluated in this model had suppressive activity equal to or greater than the reference compound, nifurtimox. For the first time, suppressive activity against T. cruzi is reported for a 7-aminoquinoline, a phosphonium salt, and TAC pamoate; The biological model is believed to be able to serve as a means of identifying other new "leads* in seeking drugs broadly effective against T=ruzi infections in man.

2-acetylpyridine thiosemicarbazones. 13. Derivatives with antifilarial activity.

Several members of a series of 2-acetylpyridine thiosemicarbazones possess in vivo and in vitro macrofilaricidal properties. The most promising of the group tested is N4-(2-aminophenyl)-2-[1-(2-pyridinyl)ethylidene]-hydrazinecarbothioam ide (4), which suppressed 100% of the macrofilariae of Brugia pahangi and 94% of those of Acanthocheilonema viteae in the jird at a dose of 25 mg/kg per day x 5. Compounds 4 and 14 were also shown to inactivate or kill Onchocerca gutturosa and Onchocerca volvulus adult worms as measured by the loss of their motility or the inhibition of the conversion by the worms of the dye MTT to formazan.

The development of a "high volume tissue schizonticidal drug screen" based upon mortality of mice inoculated with sporozoites of Plasmodium berghei.

A biological test system has been developed to assess the prophylactic activity of compounds against sporozoite-induced Plasmodium berghei malaria in mice. The procedure was designed to serve as the foundation of an effort to develop tissue schizonticidal drugs in a manner parallel to that of a previous system employed in the U.S. Arym Antimalarial Drug Development Program to screen compounds for blood schizonticidal activity. In tests with 35 known antimalarial compounds, the new screen was found to be in agreement 93% and 80%, respectively, when assessed compound activity was compared with results obtained in a definitive mouse causal prophylactic test and a rhesus monkey radical curative system.

Biological screening in the U.S. Army antimalarial drug development program.

The methods of testing drugs in the United States Army Antimalarial Drug Development Program are described. To date over two hundred thousand compounds have been screened. For each 3,000 compounds evaluated in the primary screen, only 1 is assessed for efficacy in the final test system. Of those potential antimalarials assessed in this last system, only about half are deemed worthy of preclinical toxicological evaluation.

Screening large numbers of compounds in a model based on mortality of Trypanosoma rhodesiense infected mice.

A test system has been developed to evaluate the trypanosomicidal activity of large numbers of candidate drugs. Based on mortality of mice with blood induced Trypanosoma rhodesiense infections, it serves as a primary screen or as a secondary and confirmatory test for active compounds. Over 5,500 selected compounds have been tested; more than 6% were active.

Activity of anticancer compounds against Trypanosoma cruzi-infected mice.

Chagas' disease, which is caused by Trypanosoma cruzi, remains essentially incurable. Due principally to a lack of profit incentive, the pharmaceutical industry has had limited interest in developing new antichagasic drugs. Thus, a search for agents that exhibit activity against T. cruzi, although medicaments have been developed for the treatment of other diseases, seems justifiable. Responding to evidence that the principal biochemical differences between mammalian cells and African trypanosomes apply equally to T. cruzi, our evaluations were conducted. Previous work showed the effectiveness of anticancer agents against T. rhodesiense. In the present studies, 76 anticancer compounds were assessed for their ability to suppress the trypomastigotes of T. cruzi- infected mice. Five compounds were found to be active. The most effective was cycloheximide, which was more than six times as effective as the standard, nifurtimox.

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.

The antileishmanial activity of lepidines.

A series of lepidines (6-methoxy-4-methyl-8-aminoquinoline derivatives) was studied in a hamster-Leishmania donovani model. Members of this class were found to have activity many-fold that of the standard, meglumine antimoniate (Glucantime). One of them, 8-(6-diethylamino-hexylamino)-6-methoxy-4-methylquinoline, designated WR 6026, when given orally was over 700 times as effective as the standard antimonial drug.

Filariasis testing in a jird model: new drug leads from some old standbys.

A total of 65 compounds, most of which were from chemical classes having members known to be active against one or more parasitic organisms, were evaluated against Brugia pahangi and Acanthocheilonema viteae for macrofilaricidal activity in male Mongolian jirds (Meriones unguiculatus). Sixteen of the 65 compounds tested suppressed the number of parasites. Of these 16, three were suppressive for B. pahangi, 10 for A. viteae, and three for both parasites. The antibiotic nigericin and the antihistaminic isothipendyl were found to be most active.

Antimalarial drugs and reduced incidence of dental plaque.

Known antimalarial compunds from several chemical classes were tested for their ability to inhibit in vitro growth of microorganisms causing dental plaque and to prevent the development of plaque in a hamster model. Approximately a third of the compounds tested inhibited in vitro growth; however, none prevented development of plaque.

Leishmaniasis: in search of new chemotherapeutic agents.

Members of a class of compounds designated lepidines (8-amino-6-methoxy-4-methylquinoline derivatives) were tested in a hamster-Leishmania donovani model and found to have activity many-fold that of a reference drug meglumine antimoniate. One of them, 8-(7-isopropylaminoheptylamino)-6-methoxy-4-methylquinoline, was found to be 138 times as effective as the standard antimonial drug used.

Preparation of veterinary gross anatomy specimens: a method that allows storage at room temperature for four years.

On the basis of methods used to prepare human anatomic specimens, 2 Yucatan miniature pigs were embalmed over 4 years ago. Results obtained suggest that specimens commonly used in the teaching of veterinary gross anatomy may be fixed in this manner. Advantages include no requirement for refrigeration, superior long-term preservation, less offensive odor, and better tissue texture qualities, including less evidence of dehydration.

Support systems at the U.S. government's only medical school, the Uniformed Services University of the Health Sciences.

A brief history and a discussion of general support management employed at the Uniformed Services University of the Health Sciences are given. This includes the "place" of support, leadership philosophy, and guiding principles. Guiding principles advocated by H. Edwards Deming were adopted. Some of the specific management techniques employed in instituting his 14-point plan are emphasized when making personnel selections, "immersing" them in the "culture," and maintaining the environment established.

Henry M. Jackson Foundation for the advancement of military medicine: a brief history.

The Henry M. Jackson Foundation for the Advancement of Military Medicine (HMJFAMM) was created by Congress in 1983. This not-for-profit organization championed by Senator Henry M. Jackson was brought into being to serve as a partner with the Uniformed Services University of the Health Sciences to facilitate the latter's mission execution. In the foundation's 17-year history, which is discussed, it has served multiple functions. A major role has been to manage militarily relevant research. Currently, there are more than 500 research projects, and the HMJFAMM ranks in the top 10% of institutions receiving grants from the National Institutes of Health. More than 500 education funds support more than 200 education programs annually. Each year, hundreds of military physicians and research scientists are assisted in attending outside professional meetings. The Marion B. Sulzberger Chair, a stimulus that gave rise to the foundation, is among almost 50 endowments that now exist under foundation management. This not-for-profit institution currently employs more than 1,100 individuals.

The University Integrated Automated Information System at the Uniformed Services University of the Health Sciences.

The Integrated Automation System put into place at the University Services University of the Health Sciences has been said to be 5 years ahead of those employing the most advanced comparable configurations. This automated data processing creation was accomplished without augmentation of manpower or funding. A brief history of this development and some of its features are presented.

Chagas' disease: a search for treatment and a question--should the disease be of military concern?

If military forces are required to operate in areas that are endemic for Chagas' disease, the occupation should be of critical concern. These areas, located in Central and South America, are many. The matter is of particular importance because no suitable drug exists to treat individuals who contract the disease. We examined 60 compounds of a chemical class, thiosemicarbazones, known to have some activity against the disease. The work was carried out using Trypanosoma cruzi-infected mice. Of the 60 potential drugs evaluated, 12 showed significant suppressive activity. One of these compounds was almost 50% greater than the reference drug used in the test system.

A new class of anti-filariasis compounds: a preliminary look.

Parasitic nematode worms which produce filariasis in humans place approximately one billion people at risk in more than 75 countries. More than 100 million people are infected with these diseases and are recognized as being of significant military importance. During World War II, filariasis was among the leading causes of medical evacuation from the entire South Pacific area. Agents available to treat the diseases exhibit significant toxicity. Better drugs are urgently needed. Data are reported from work using a Mongolian jird animal model on a new class of potential drugs, thiosemicarbazones. These compounds exhibit activity against the parasites which cause both lymphatic filariasis and the "onchocerciasis type" of the disease.