Plasmodium fragile: efficacy of arteether (alpha/beta) against cerebral malaria model.
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Animals↗
Biomedical subjects
G P Dutta
Publications and source records attributed to G P Dutta.
Sterile protection of monkeys against malaria after administration of interleukin-12.
An estimated 300-500 million new infections and 1.5-2.7 million deaths attributed to malaria occur annually in the developing world, and every year tens of millions of travelers from countries where malaria is not transmitted visit countries with malaria. Because the parasites that cause malaria have developed resistance to many antimalarial drugs, new methods for prevention are required. Intraperitoneal injection into mice of one dose of 150 ng (approximately 7.5 micrograms per kg body weight) recombinant mouse interleukin-12 (rmIL-12) 2 days before challenge with Plasmodium yoelii sporozoites protects 100% of mice against malaria. We report that one subcutaneous injection of 10 micrograms/kg recombinant human IL-12 (rhIL-12) 2 days before challenge with P. cynomolgi sporozoites protected seven of seven rhesus monkeys. Protection was associated with marked increases in plasma levels of interferon-gamma (IFN-gamma), and relative increases of lymphoid cell messenger RNA coding for IFN-gamma and several other cytokines. We speculate that rIL-12 protects monkeys through IFN-gamma-dependent elimination of P. cynomolgi-infected hepatocytes. This first report of rIL-12-induced protection of primates against an infectious agent supports assessment of rhIL-12 for immunoprophylaxis of human malaria.
Animals↗
Poly ICLC enhances the antimalarial activity of chloroquine against multidrug-resistant Plasmodium yoelii nigeriensis in mice.
Swiss mice infected with multidrug-resistant Plasmodium yoelii nigeriensis were treated with polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethyl cellulose (Poly ICLC), a potent interferon (IFN) inducer and immune enhancer, in combination with chloroquine (CQ), which completely eliminated the malaria parasite from these animals. The enhancement of the antimalarial activity of poly ICLC was found to be completely reversed by the cytochrome P-450 inducer, phenobarbitone. No effect of Nw nitro-L-arginine (NLA), an inhibitor of nitric oxide, was seen on the enhancement of the antimalarial activity of CQ by Poly ICLC. These results suggest the possible involvement of cytochrome P-450 enzyme-mediated mechanism in the enhancement of the antimalarial activity of CQ by Poly ICLC.
Animals↗
Crisis in health care for the people.
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Delivery of Health Care↗
Sodium beta-artelinate--a new potential gametocytocide.
The water-soluble artemisinin analogue sodium beta-artelinate, a fast-acting blood schizontocide, was evaluated for gametocytocidal action against simian malaria Plasmodium cynomolgi B, and a single dose of the compound has been found to be an effective gametocytocide by both oral and intravenous routes. The compound was able to sterilize the circulating gametocytes in rhesus monkey, resulting in loss of mosquito infectivity and oocyst development in the Anopheles stephensi. However, no sporontocidal action has been observed with this compound.
Administration, Oral↗
Killing of Leishmania donovani amastigotes by poly ICLC in hamsters.
In vitro as well as in vivo studies suggest that cytokine-induced synthesis of nitric oxide (NO) from L-arginine is a major effector mechanism against intracellular pathogens. In this study, we demonstrate that golden hamsters infected with Leishmania donovani amastigotes upon treatment with polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly ICLC), a potent interferon inducer and immune enhancer, in combination with L-arginine, develop the capacity to eliminate intracellular pathogens. This antileishmanial activity of poly ICLC was suppressed by N w nitro-L-arginine (N w NLA), an inhibitor of inducible NO synthase. Furthermore, prolonged treatment of infected animals with L-arginine alone for 5 days more after 5 day treatment with poly ICLC plus L-arginine increased the antileishmanial activity compared with 5 day treatment with poly ICLC plus L-arginine, suggesting that inducible NO synthase, once activated, produces NO for 5 days more. Our results suggest that an L-arginine-dependent, NO-mediated mechanism is probably responsible for the antileishmanial action of poly ICLC.
Animals↗
Poly ICLC inhibits Plasmodium cynomolgi B malaria infection in rhesus monkeys.
Prophylatic treatment with a single dose of 1.0 or 2.0 mg/kg (body weight) of polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (Poly ICLC), a potent interferon (IFN) inducer and immune enhancer, 18 h before intravenous inoculation of sporozoites (1.04 x 10(5)-0.70 x 10(6) sporozoites) of Plasmodium cynomolgi B in the rhesus monkey, completely abolished the infectivity of sporozoites. The inhibitory effect of Poly ICLC is dose dependent in monkeys infected with P. cynomolgi B sporozoites. Treatment with lower doses of Poly ICLC (0.5 mg/kg) provided significant protection, but the lowest dose of Poly ICLC used (0.1 mg/kg) failed to provide any protection. Prophylactic treatment with Poly ICLC, however, had no protective effect against trophozoite-induced infection.
Animals↗
Gametocytocidal activity of alpha/beta arteether by the oral route of administration.
Arteether (alpha/beta) (a mixture of alpha and beta enantioners) has been reported to possess gametocytocidal activity against Plasmodium cynomolgi B when the drug is given by the intramuscular route, but it would be preferable to use oral route therapy for gametocyte carriers. This is a report of a study of the gametocytocidal action of arteether administered by the oral route. The results indicate high levels of activity at 10 mg/kg in a single dose or in two divided doses when given orally.
Administration, Oral↗
Histochemical changes in host tissues from Plasmodium cynomolgi B infected rhesus monkey (Macaca mulatta).
Plasmodium cynomolgi B has been used to infect the rhesus monkey to study the histochemical changes (lipid infiltration, glycogen, protein, DNA and RNA) in liver, kidney and spleen during early (exoerythrocytic) and late (chronic) stages of malarial infection. Infected liver showed significant lipid infiltration during exoerythrocytic and erythrocytic (acute phase) stage of infection. Kidney showed lipid deposition during acute phase of infection while spleen sections were negative for lipid depositions. As a result of malarial infection there was significant depletion of glycogen in liver during exoerythrocytic stage of infection. Glycogen content increased in liver and kidney during erythrocytic stage of infection. The spleen which is the main target of immunopathology in malaria showed no change in glycogen content. During exoerythrocytic phase host tissue organs showed no change in protein and nucleic acids while erythrocytic phase showed slightly increased proteins in liver and kidney. Nucleic acids became decreased in liver and spleen during erythrocytic phase of infection. The parasite used in this study has a defined prepatent period, can be cyclically passaged with ease and non fatal in nature.
Animals↗
In-vitro cultivation of exoerythrocytic stages of Plasmodium cynomolgi in hepatocytes of Macaca radiata.
Hepatocytes from bonet monkey (Macaca radiata) obtained by perfusion of a liver biopsy were infected in-vitro with Plasmodium cynomolgi bastianellii sporozoites raised in Anopheles stephensi. The development of exoerythrocytic (EE) stages was seen under phase contrast microscope and by Giemsa staining. Multinucleated EE-stages were seen in the cultured hepatocytes on day 7-8 post-sporozoite inoculation.
Animals↗
In vivo study of artemisinin and its derivatives against primary amebic meningoencephalitis caused by Naegleria fowleri.
Artemisinin and its derivatives, beta-arteether and sodium artesunic acid, have been evaluated for activity against experimental primary amebic meningoencephalitis and the efficacy of these compounds has been compared with that of the standard drug amphotericin B. In vivo experiments in Swiss mice have shown that amphotericin B at a dose of 2.5 mg/kg for 5 days produced 100% protection in the mice infected intranasally with Naegleria fowleri. Artemisinin, beta-arteether, and sodium artesunic acid, even when tested at high doses (60-180 mg/kg x 5 days), were not curative and showed only slight protection as indicated by extension of mean survival time.
Amebiasis↗
Immunomodulation by morphine in Plasmodium berghei-infected mice.
The effect of morphine on immunomodulation and host defense have been investigated during Plasmodium berghei infection in BALB/c mice. A single low (5.0 mg/kg) subcutaneous dose of morphine strongly suppressed (sometimes completely eliminated) the parasitaemia, whereas a high dose (80.0 mg/kg) exerted mild potentiating effect. Mice treated with the low dose showed a significant (p < 0.05) increase in the total number of circulating leukocytes, the number (pool-size) of peritoneal macrophages, and the phagocytic activity of peritoneal macrophages, in vitro. Conversely, in mice treated with the high dose, all these parameters were diminished. Silica (3.0 mg/mouse), administered intravenously, abrogated the morphine-induced protective effects but did not affect its potentiation of the infection. Naloxone pretreatment (4.0 mg/kg) completely blocked the protective effects of morphine, suggesting the mediation via naloxone-sensitive opiate-receptors; paradoxically, it did not affect the potentiating effects. These observations indicate that morphine exerted a dose-dependent, biphasic effect on the course of P. berghei infection in mice, apparently by modulating the macrophage-mediated protective mechanisms.
Adjuvants, Immunologic↗
Role of fatty infiltration during malaria in rhesus monkey.
P. cynomolgi B-rhesus monkey model of malarial infection has been used to study lipid infiltration in host tissues in early (exoerythrocytic) and late (chronic) stages of malaria infection. Histochemically we could demonstrate significant infiltration of neutral & total lipids in liver during the exoerythrocytic stage and in liver and kidney in the erythrocytic stage. The parasite used in the study closely resembles the human parasite P. vivax. It has a defined prepatent period, can be cyclically passaged with ease and non fatal in nature.
Animals↗
Ethics in medical profession.
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Developing Countries↗
Problems of research in developing countries.
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Developing Countries↗
Presbytis entellus, a new experimental host for Plasmodium fragile.
The course of blood-induced Plasmodium fragile infection in 3 simian hosts, Macaca radiata (bonnet monkey), Macaca mulatta (rhesus monkey), and Presbytis entellus (Indian langur), was studied. The infection in 8 bonnet monkeys was very mild and nonfatal. In M. mulatta, P. fragile produced acute initial infection followed by anemia and death in 3 of 6 monkeys. The parasite has a relatively high level of virulence for P. entellus, a new experimental host for P. fragile, in which peak parasitemia ranging between 15 and 75% was recorded, and the infection was uniformly fatal. Plasmodium fragile infection in P. entellus can serve as an ideal biological counterpart to human Plasmodium falciparum.
Animals↗
Effect of the antimalarial agents primaquine and (N'-3-acetyl-4-5-dihydro-2-furanyl)-N4-(6-methoxy-8-quinolinyl)1,4-pent ane-diamine on oxidative stress and antioxidant defences in mice.
The effects of the newly developed antimalarial compound, CDRI 80/53 [(N'-3-acetyl-4-5-dihydro-2-furanyl)-N4-(6-methoxy-8-quinolinyl)1,4- pentane-diamine], and primaquine (PQ) on the antioxidant system of mice were determined at equi-effective antimalarial doses on enzyme systems responsible for protection against oxygen, i.e. hepatic superoxide dismutase and catalase. While PQ significantly inhibited these enzyme activities CDRI 80/53 did not. However, both compound 80/53 and PQ increased the level of superoxide anion and lipid peroxidation. It is concluded that compound 80/53 has less effect on antioxidant defence enzymes than PQ.
Animals↗