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Biomedical subjects

R A Neal

Publications and source records attributed to R A Neal.

At least 37 records · Page 2Linked to original sources
PubMed1985

Anti-leishmanial effect of allopurinol ribonucleoside and the related compounds, allopurinol, thiopurinol, thiopurinol ribonucleoside, and of formycin B, sinefungin and the lepidine WR6026.

Allopurinol and allopurinol ribonucleoside tested in vitro and in vivo for activity against Leishmania donovani. Activity in vitro was low against the amastigote form of this parasite with ED50 values of the order of 54 and 96 microM and 86 and 213 microM respectively for the two compounds. In vivo inhibition of up to 47% was achieved with allopurinol ribonucleoside given in the drinking water. However, low blood levels were found in the mouse relative to those in man. Low in vivo activity was also seen with allopurinol ribonucleoside against L. major and other species of Leishmania causing cutaneous lesions. The metabolism of allopurinol ribonucleoside in aldehyde oxidase deficient mice (inbred strains DBA/1, DBA/2) resembled that of man, but the antileishmanial activity remained low. Other compounds, formycin B, sinefungin and the lepidine WR6026 were highly active against mice infected with L. donovani or L. major.

Adenosine↗
PubMed1985

Mechanisms of the biological effects of PCBs, polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans in experimental animals.

Polychlorinated biphenyls, certain polychlorinated dibenzo-p-dioxins and certain polychlorinated dibenzofurans cause a variety of biological effects in experimental animals. The mechanism of the induction of certain enzymes is perhaps best understood. That is, there is binding of certain chlorinated biphenyls, dibenzo-p-dioxins and dibenzofurans to a receptor, translocation of the compound-receptor complex into the nucleus followed by an increased activity of a number of enzymes in the cell. Although the concentration of this receptor in various tissues of some mouse strains correlates well with the intensity of some of the biological effects observed in the mouse strains exposed to these compounds, this correlation apparently does not extend across various species. The current evidence suggests that the acute toxic effects of TCDD in various species is in some way associated with binding of TCDD to the receptor. However, biological effects of TCDD in addition to those resulting from binding to the receptor may be required to produce acute toxicity and, perhaps, other effects. The acute toxic effects of TCDD are probably caused by the parent compound rather than metabolites; however, this conclusion must be viewed as tentative. Also, it cannot be excluded at this time that biological effects other than acute toxicity may be caused by metabolites of TCDD. Finally, the acute toxic effects of TCDD appear not to be related, at least not directly, to the rate of metabolism of TCDD in experimental animals nor to the half-life of excretion.

Animals↗
PubMed1984

The vaccine potential of cell surface glycoproteins from Trypanosoma cruzi.

An experimental Trypanosoma cruzi 90 kDa cell surface glycoprotein (GP90) vaccine, previously shown to be protective in mice is similarly effective in marmosets (Callithrix jacchus jacchus). Protection in the mouse is completely dependent on the adjuvant saponin and immunological studies confirm that GP90 is intrisically poorly immunogenic. Both specific antibody and cell mediated immunity are potentiated strongly by saponin and the resulting protective immunity is long lasting (six months). It is effective against the naturally infective, insect-metacyclic, form and a range of heterologous T. cruzi strains including a low mouse passage human isolate. Sterile immunity (that is, complete elimination of parasites) was not however, achieved. Evidence is presented that the levels of tissue damage associated with acute infection, as measured by production of auto anti-tissue immunoglobulins, are significantly reduced in GP90-immunized mice. These and other results are discussed in terms of the desired characteristics for vaccine use of T. cruzi antigens.

Adjuvants, Immunologic↗
PubMed1984

Leishmania major: culture media, mouse strains, and promastigote virulence and infectivity.

Promastigotes of Leishmania major were isolated from an infected mouse in two media, blood agar and Schneider's medium + 30% fetal calf serum, and maintained continuously for over 1 year. Infectivity studies in two strains of mice, outbred CD1 strain and inbred BALB/c strain, showed that promastigotes grown in Schneider's medium maintained infectivity to BALB/c mice throughout the period of cultivation. Infectivity to CD1 strain mice was progressively lost. Promastigotes grown in blood agar medium, however, lost infectivity to both strains of mice at a faster rate than promastigotes grown in Schneider's medium.

Animals↗
PubMed1984

An in-vitro system for determining the activity of compounds against the intracellular amastigote form of Leishmania donovani.

A method has been defined for infecting primary mouse peritoneal macrophages with amastigotes of Leishmania donovani in vitro, and analysing the response of the infected macrophages to treatment with drugs. The growth of intracellular amastigotes was inhibited by all clinically used antileishmanial drugs. Toxic effects on macrophages were observed with some drugs. Other experimental antileishmanial compounds were active in this system. This test is proposed as an initial screening test for the discovery of novel antileishmanial compounds.

Animals↗
PubMed1983

A comparative study of susceptibility of inbred and outbred mouse strains compared with hamsters to infection with New World cutaneous leishmaniases.

One stock of each of Leishmania mexicana mexicana and L. m. amazonensis together with two stocks of L. braziliensis panamensis and L. b. braziliensis were tested for infectivity in inbred mouse strains Balb/c and CBA/H. The infectivity was compared with hamsters and the outbred CD1 mice. Balb/c mice were more susceptible than hamsters to L. mexicana and L. braziliensis panamensis. Balb/c mice were not susceptible to L. b. braziliensis. CBA/H mice showed a low susceptibility to infection while CD1 mice showed an intermediate response.

Animals↗
PubMed1983

Design of carcinogenicity studies, dose selection, route, blood levels, transformation.

The results of subacute toxicity tests are the information most commonly used for setting doses for carcinogenicity studies. However, since diet composition is important in regard to tumor incidence, knowledge of the effect of various doses of the compound on the nutritional composition and quality of the diet of the animals on test is also important. It is also important to determine if any of the doses administered in the study exceed the ability of the species under study to excrete it in a manner which is approximately the same as that seen at lower doses. Similarly, it is important to determine if the higher doses administered lead to the formation of metabolites not seen at lower doses which are more nearly equivalent to those to which humans are or will be exposed. The compound under test should, if possible, be administered by the same route by which human exposure occurs or is anticipated to occur. Because of potential difficulties in the interpretation of the results, gastric intubation is, in general, the least desirable method of administration. In selecting the most appropriate animal species to be used in a carcinogenicity study, consideration should be given to the use of the species and strain of experimental animal that is most biologically and metabolically similar to humans, if such data are available.

Animals↗
PubMed1983

Effectiveness of allopurinol against Leishmania braziliensis panamensis in Aotus trivirgatus.

Orally administered allopurinol at 50 mg/kg for 21 days showed pronounced antileishmanial activity against experimentally induced lesions of Leishmania braziliensis panamensis on the nose of Panamanian Aotus trivirgatus monkeys, with complete healing in 4 of 5, although parasitologic cure was achieved in only 2 of 5. The same total daily dose of drug, given in a divided dose twice daily, resulted in complete healing in all 5, and parasitologic cure in 4 of 5 animals. Standard treatment controls receiving 40 mg/kg of antimony stibogluconate intramuscularly for 15 days showed healing in 4 of 5 monkeys. It is not known if a similar level of effectiveness would result with this dose of allopurinol in humans, since Aotus may have a different pattern of metabolic conversion of the drug to the more active riboside.

Administration, Oral↗
PubMed1983

Biotransformation of phenol to hydroquinone and catechol by rat liver microsomes.

Hepatic microsomal biotransformation of phenol to hydroquinone and catechol has been investigated with special reference to the covalent binding to microsomal protein of reactive metabolites formed during microsomal metabolism of phenol. Incubation of [14C]phenol with microsomes from phenobarbital-treated rat liver in the presence of an NADPH-generating system resulted in the formation of hydroquinone and catechol in the ratio of 20:1. No significant formation of 1,2,4-benzenetriol was observed. The biotransformation of phenol to both hydroquinone and catechol required NADPH and molecular oxygen. NADH was much less effective than NADPH as an electron donor and exhibited no significant synergistic effect when used together with NADPH. The biotransformation was inhibited by typical cytochrome P-450 inhibitors such as carbon monoxide, SKF 525-A, and metyrapone. These results indicated the involvement of cytochrome P-450 in the microsomal hydroxylation of phenol at both the ortho- and para-positions. Covalent binding of radioactivity to microsomal protein was observed when [14C]phenol was incubated with rat liver microsomes in the presence of an NADPH-generating system. The covalent binding was also found to require NADPH and molecular oxygen. Inclusion of cytochrome P-450 inhibitors in the incubation mixture resulted in a decrease in the covalent binding. These results indicated that at least one step in the metabolic activation of phenol to the metabolites responsible for covalent binding to microsomal protein was mediated by cytochrome P-450. Inclusion of N-acetylcysteine in the incubation mixture resulted in the complete inhibition of the covalent binding of radioactivity derived from [14C]phenol to microsomal protein, and there was a concomitant formation of N-acetylcysteine adducts of hydroquinone and catechol. These results indicated that hydroquinone and catechol were both precursors to reactive metabolites responsible for the covalent binding.

Animals↗
PubMed1983

Toxic effects of propylthiouracil in the rat.

Repeated intraperitoneal administration of propylthiouracil (PTU, 0.5-1.5 mmole/Kg) to rats caused a dose related decrease in body weight. A dose dependent increase in liver weight and a decrease in spleen weight were also seen. Leukocyte counts were markedly reduced in all PTU treated animals. Histopathological changes were observed. These consisted of congestion of red pulp of the spleen and vacuolization of the liver.

Animals↗