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Primaquine (PQ) is the only drug used to prevent relapse of malaria due to P. vivax and P. ovale, by eradicating the dormant liver form of the parasite (hypnozoites). The side-effects associated with PQ limits is uses in treatment of malaria. To overcome the premature oxidative deamination and to increase the life span of drug in the biological system, the novel glyco-conjugates of PQ were synthesized by coupling of primaquine with hexoses in phosphate buffer. The saccharide part of the hybrid molecules thought to direct the drug to the liver, where hypnozoites resides. All the synthesized compounds were fully characterized and evaluated for their radical curative activities. The three compounds viz glucoside (15a), galactoside (15b) and mannoside (15c) with high activity were tested for their activity in rhesus monkeys where the most active compound 15b showed twofold activity (100% radical curative activity at 1.92 mmol/kg) than the standard drug PQ diphosphate (3.861 mmol/kg). It is proposed that results from these studies may be advantageous to develop a new potent tissue schizonticide antimalarial compound., (© 2017 John Wiley & Sons A/S.)

Blood schizontocidal activity of 10 selected cis-fused cyclopenteno-1,2,4-trioxanes (namely Fenozan compound nos 6, 7, 11, 27, 32, 39, 44, 45, 48 and 51) have been re-investigated to establish their curative doses against the multidrug-resistant Plasmodium yoelii nigeriensis strain, which is lethal in Swiss mice. Freshly prepared formulations of these compounds prepared either in neutral groundnut (peanut) oil or in dimethyl sulfoxide (DMSO)-Tween-water, were compared for their antimalarial activity. Only 2 compounds, namely Fenozan derivatives 11 and 45, formulated in neutral groundnut oil for oral administration, showed highest activity with 100% cure rate in MDR P. yoelii nigeriensis-infected mice, while the DMSO-Tween-water formulations were inactive. Fenozan-48 produced 72.2% cure, when administered orally in groundnut oil (formulation) while its DMSO-Tween formulation was inactive. In the case of Fenozan 7, the oil and DMSO-Tween formulations produced 92.3 and 76.0% cures respectively. Fenozan derivatives nos 6, 27, 32, 39, 44 and 51 were not protective either in groundnut oil or DMSO-Tween oral formulations. The present study has applied more rigorous criteria for selection of active compounds, and has identified the 3,3-spirocyclopentane derivative Fenozan 11, and the 3,3-spirohydropyran derivative Fenozan 45, as potential blood schizontocides which can completely eliminate multidrug-resistant malaria infection in mice. Both these compounds are candidates for pre-clinical development. The present study advocates the preferred use of an oil vehicle for oral evaluation of potential antimalarial trioxanes/fenozans instead of the DMSO formulation, which gives inferior curative efficacy.

The gametocytocidal action of a new enamine analogue of primaquine, elubaquine (compound CDRI 80/53, bulaquine), has been evaluated against Plasmodium cynomolgi B in rhesus monkeys. Colony bred Anopheles stephensi mosquitoes were fed on gametocyte carrying rhesus monkeys prior to and at varying intervals after oral administration of a single dose of elubaquine at doses ranging between 0.63 and 5.00 mg/kg. Complete loss of oocyst development and mosquito infectivity was observed within 24 h after administering a single 1.25 mg/kg dose, while higher dose of 3.75 mg/kg inhibited oocyst development within 5 h, indicating gametocytocidal action of the compound. Elubaquine did not show any action against developing oocysts in the vector.

Many different drug-resistant lines of rodent malaria are available as screening models. It is obligatory to screen new compounds for antimalarial activity against a series of resistant lines in order to identify a compound with potential for the treatment of multi-drug resistant (MDR) malaria infections. Instead of using a battery of resistant lines, a single MDR Plasmodium yoelii nigeriensis strain that shows a wide spectrum of drug resistance to high doses of chloroquine, mepacrine, amodiaquine, mefloquine, quinine, quinidine, halofantrine as well as tetracyclines, fluoroquinolines and erythromycin, was used to assess the blood schizontocidal efficacy of a new macrolide azithromycin and other antibiotics. The present study shows that only azithromycin has the potential to control an MDR P. y. nigeriensis infection in Swiss mice, provided the treatment with a dose of 50-100 mg/kg/day by oral route is continued for a period of 7 days. Tetracycline, oxytetracycline, doxycyline, erythromycin, ciprofloxacin and norfloxacin, although active in vitro, failed to protect the mice. Tetracycline, ciprofloxacin and norfloxacin combinations with chloroquine did not control the infection. Additionally, the antimalarial efficacy of azithromycin can be potentiated with the addition of arteether, which is an ethyl ether derivative of artemisinin. A total (100%) curative effect has been obtained with a shorter regimen of 4 days only.

Plasmodium knowlesi (W1) shows a high level of innate resistance to mefloquine as shown by recrudescence of blood-induced infection in rhesus monkeys, following oral mefloquine treatment with up to 80-160 mg/kg total dose over 3-4 days. Ketoconazole, at a dose of 75 mg/kg/day x 10 days given orally to P. knowlesi-infected rhesus monkeys, exerted a suppressive antimalarial effect in 1 of the 2 monkeys as evidenced by a delayed recrudescence (on day 30) and curative action in case of the other monkey, whereas a lower dose of ketoconazole (25 mg/kg/day x 10 days) failed to suppress infection effectively. When ketoconazole at a low dose (25 mg/kg/day x 10 days) treatment was combined with mefloquine (20 mg/kg/ day x 4), 1 of the 2 infected monkeys was cured, while the combination of a higher dose of ketoconazole (75 mg/kg/day x 10 days) with mefloquine (20 mg/kg/day x 4), had a complete curative effect on P. knowlesi infection in all the treated monkeys (7/7). Besides exerting direct antimalarial action against a mefloquine-resistant P. knowlesi, ketoconazole also acts as an inhibitor of hepatic microsomal CYP4503A, which regulates and slows down mefloquine biotransformation to carboxymefloquine, resulting in a possible elevation of the effective plasma drug level, which seems to be responsible for elimination of the resistant P. knowlesi. The study shows a resistance reversal effect of a ketoconazole - mefloquine combination that could be exploited for the control of mefloquine-resistant malaria infection. The study shows that ketoconazole can reverse mefloquine resistance of P. knowlesi. These findings can also be applied to reverse mefloquine resistance of P.falciparum in areas where mefloquine resistance is already established. The precise role of parasite CYP450 in mefloquine resistance and its possible role, if any, in expelling the intracellular mefloquine from the resistant plasmodia still remains to be elucidated.

Ketoconazole at 200 mg/kg dose has been found to exert marginal antimalarial action against multidrug resistant (MDR) Plasmodium yoelii nigeriensis (P. yoelii nigeriensis) in Swiss mice with 25% protection (2/8 mice) while at lower Ketoconazole dose i.e., 75-100 mg/kg, 14.28% mice were protected. Mefloquine (MFQ) (at 8 and 16 mg/kg) exerted suppressive action against MDR P. yoelii nigeriensis resulting in 25 and 14.28% protection of mice respectively. Combined treatment with Ketoconazole and mefloquine resulted in protection of 5/6 mice (83.33%) at MFQ 4 mg/kg + Ketoconazole 100 mg/kg dose, 7/8 (87.5%) mice at MFQ 8 mg/kg + Ketoconazole 20 mg/kg dose and 5/7 (71.42%) mice at MFQ 16 mg/kg + Ketoconazole 25 mg/kg dose and 5/6 (83.33%) mice at MFQ 16 mg/kg + Ketoconazole 100 mg/kg dose. Ketoconazole has been found to enhance the protective effect of mefloquine against MFQ resistant P. yoelii nigeriensis resulting in 66-88% protection of the mice treated with the appropriate combinations. The combination also increased suppression of parasitaemia at different times. The Ketoconazole combination with MFQ significantly increased the mean survival time of the treated mice compared to individual drugs alone. The study shows that Ketoconazole when administered with MFQ exerts bio-enhancing action against mefloquine resistance of MDR P. yoelii nigeriensis.

A new 8-aminoquinoline antimalarial WR 238605 (Tafenoquine), developed initially as a primaquine alternative for prevention of Plasmodium vivax relapses was evaluated for blood schizontocidal activity against two simian malaria infections namely Plasmodium cynomolgi B and Plasmodium fragile in rhesus monkeys. Treatment with WR 238605 at a dose of 3.16 mg(base)/kg/day x 7 days cured established trophozoite induced infections in monkeys with both these parasites. The lower dose of 1.00 mg/kg/day cured 9 out of 12 monkeys infected with P. cynomolgi B and 10 out of 11 monkeys infected with P. fragile. Primaquine was only partially curative at 10.0 mg(base)/kg/day x 7 dose regimen against both these infections. The potent blood schizontocidal activity of tafenoquine adds to the armoury of antimalarial drugs.

An antihistaminic drug, cyproheptadine (20-25mg/kg x 4 days), showed significant schizontocidal activity in the blood against a lethal multidrug-resistant (MDR) strain of Plasmodium yoelii nigeriensis (highly resistant to chloroquine, mefloquine, and quinine); the protection of mice ranged between 75 and 100%. A combination of cyproheptadine (15 mg/kg) and chloroquine improved antimalarial activity compared to treatment with either drug alone, whereas a combination of cyproheptadine with quinine or mefloquine did not improve its antimalarial activity. Chloroquine and cyproheptadine inhibited haem polymerization activity in cell-free extracts and in in vivo experiments with MDR P. yoelii, but the combination did not cause a more significant inhibition than found with either drug alone. Cyproheptadine has been shown to produce dose-dependent inhibition of haem polymerization activity both in vitro and in vivo. The mechanism of the antimalarial action of cyproheptadine and its enhanced antimalarial activity with chloroquine could be due, in part, to their inhibitory effect on haem polymerization.

Background: Plasmodium yoelii nigeriensis (P. y. nigeriensis) produces lethal malaria infection in Swiss albino mice. Tumor necrosis factor (TNF) has been implicated in the pathogenesis of malaria by production of reactive oxygen species. Chloroquine is a traditionally used antimalarial and has been postulated to inhibit TNF secretion during malaria infection., Objective: The study the comparative effect of chloroquine and TNF treatment on hepatic oxidative stress and antioxidant defense indices in normal and P. y. nigeriensis-infected mice., Materials and Methods: The mice were divided into six groups, each consisting of four to six animals. They were normal mice, normal mice treated with chloroquine, normal mice treated with TNF-alpha, P. y. nigeriensis-infected mice, P. y. nigeriensis-infected mice treated with chloroquine and P. y. nigeriensis-infected mice treated with TNF-alpha., Results: Chloroquine treatment of the normal mice caused no significant alterations in hepatic oxidative stress and antioxidant defense indices while TNF treatment of normal mice caused a significant decrease in hepatic superoxide dismutase. Chloroquine treatment of P. y. nigeriensis-infected mice caused a decrease in blood parasitemia which was accompanied by restoration of altered indices to near normal levels. However, TNF treatment of P. y. nigeriensis-infected mice had no effect on blood parasitemia but caused a significant increase of hepatic xanthine oxidase and lipid peroxidation and a decrease in the activity of hepatic superoxide dismutase., Conclusion: Exogenous TNF acts synergistically with P. y. nigeriensis infection to generate oxidative stress in the host and also causes an impairment of the antioxidant defense enzyme SOD, while chloroquine treatment reduces the severity of malaria infection by decreasing the blood parasitemia and also perhaps by inhibiting the TNF release.

Pyronaridine, administered intramuscularly (im) to Swiss mice infected with the lethal multidrug-resistant Plasmodium yoelii nigeriensis, was found to exert high blood schizontocidal activity. The efficacy of doses of pyronaridine ranging from 0.625 to 30 mg (base/kg) was evaluated using a 4 day treatment schedule (drug was administered at 0, 24, 48 and 72 hrs). It was found that doses of 2.5mg/ kg and higher protected animals completely from the lethal effects of the parasite. The same degree of protection was found when the treatment duration was reduced to 3 days. This study shows that pyronaridine is a potentially useful antimalarial drug that could be exploited for the control of multidrug-resistant malaria infection.

A multidrug-resistant strain of Plasmodium yoelii nigeriensis (MDR) showing a wide spectrum of resistance to chloroquine, amodiaquine, mepacrine, mefloquine, halofantrine, quinine, and quinidine was used in this study for in vivo evaluation of the blood schizontocidal activity of pyronaridine, a topoisomerase II inhibitor, in Swiss mice. The parasite produces 100% lethal infection in mice. The drug was administered orally once a day from day 0 onward. The initial studies showed that low doses of pyronaridine (0.625 to 5.0 mg base/kg x9 days) did not completely control blood-induced P. yoelii nigeriensis infection. Finally a series of doses of pyronaridine ranging from 1.25 to 30.0 mg/kg administered orally for 7 consecutive days were evaluated and in spite of high level of resistance to standard antimalarials, the parasite P. yoelii nigeriensis has shown complete susceptibility to pyronaridine (15 mg/kg dose x7 days). The present paper also compares the merits of a single MDR strain vs a battery of different resistant lines for quick antimalarials screening., (Copyright 2000 Academic Press.)

The present communication deals with drug-resistant Plasmodium falciparum malaria complicating hematologic malignancies (leukemias, n = 24, and lymphomas, n = 7) in children. Of 50 cases of hematologic malignancies, 31 patients were microscopically diagnosed as having P. falciparum infection (MP +). Initially, all the patients were treated with chloroquine. The results of primary treatment showed chloroquine resistance in 16 (51. 62%) cases. Of these 16 chloroquine-resistant cases, 13 were secondarily treated with a combination of pyrimethamine plus sulfamethopyrazine. The results of secondary treatment also revealed resistance to pyrimethamine plus sulfamethopyrazine in 6 of 13 (46. 10%) cases. The 6 pyrimethamine plus sulfamethopyrazine-resistant P. falciparum cases were finally cured by quinine therapy, against which no resistance was encountered. Conversely, in the control group comprising 38 cases of P. falciparum without malignancy, the incidence of chloroquine resistance was found in only 9 cases, which is rather low (23.70%). Of these 7 chloroquine-resistant cases, 5 were found to be sensitive to pyrimethamine plus sulfamethopyrazine treatment, while the 2 nonresponders were finally cured with quinine. The overall results of this study show a high prevalence of chloroquine resistance among clinical cases of falciparum malaria (25/69; 30.6%). Among the nonresponders (n = 20) 40% of cases were also resistant to the pyrimethamine plus sulfamethopyrazine combination. There was no resistance to quinine., (Copyright 1999 Academic Press.)

Reactive oxygen species are important mediators of tissue injury during malaria infection. The status of hepatic oxidative stress and antioxidant defence indices were studied during Plasmodium yoelii nigeriensis (P. y. nigeriensis) infection and chloroquine/ polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose (poly ICLC) treatment of infected mice. P. y. nigeriensis infection resulted in a significant increase in oxidative stress indices viz., xanthine oxidase and rate of lipid peroxidation (LPO). This was accompanied by a highly significant increase in antioxidant defence indices viz., reduced glutathione (GSH) and glutathione reductase while superoxide dismutase (SOD) and catalase showed a highly significant decrease with respect to normal mice. Chloroquine treatment of infected mice caused a decrease in parasitaemia which was associated with restoration of indices altered during infection towards normalization. Poly ICLC treatment of infected mice caused no change in blood parasitaemia but resulted in a significant increase in GSH, glutathione reductase, SOD and catalase with respect to infected mice. Combination therapy of chloroquine and poly ICLC resulted in clearance of parasitaemia and restoration of all oxidative stress and antioxidant defence indices to normal levels.

Artemisinin and its derivative alpha, beta-arteether have been evaluated for activity against experimental primary amoebic meningoencephalitis. In vivo experiments have shown that amphotericin B at dose of 2.5 mg/kg for 5 days produced 100% protection. Artemisinin and alpha, beta-arteether, even when tested at a high doses (60-120 mg/kg x 5 days and 90-180 mg/x 5 days) respectively, were not curative and showed only slight protection as indicated by extension of mean survival time.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Purified human C-reactive protein(CRP: 0.5-50.0 micrograms/kg) given intravenously to monkeys (Macaca mulatta) induced serum colony-stimulating activity (CSF); maximum induction occurred at 10.0 micrograms/kg. In vitro also, purified human CRP (0.1-50.0 micrograms/ml) stimulated monkey blood monocyte-derived macrophages to release CSF in to the medium (CM); 5.0 micrograms/ml CRP appeared optimal. Both in vivo and in vitro, the kinetics of the production of CSF were similar with maximal response occurring 6 h after stimulation and return to background levels by 48 h. Rabbit anti-CRP antibody completely abrogated the production of CSFs in vitro, suggesting a specific interaction between CRP and macrophages. A neutralizing concentration of rabbit anti-human interleukin-1 (IL-1) polyclonal antibody had no effect on CRP induction of CSF-activity, indicating it to be IL-1 independent. CRP-induced CSFs, both in the serum and CM, were functionally similar as they supported the formation of granulocyte (G), macrophage (M) and GM colonies, in similar proportions. The macrophage production of CSFs appeared to be lipopolysaccharide-independent as polymyxin B (25.0 micrograms/ml) had no inhibitory effect. Heat-treated (80 degrees C, 1 h, pH 7.0) CRP did not stimulate the macrophages to produce CSFs. The CSF release was dependent on protein synthesis as it was completely inhibited by cycloheximide (50.0 micrograms/ml). This study demonstrates that purified human CRP can induce the production of serum CSF activity in monkeys, and can stimulate monkey macrophages to produce CSFs in vitro.

Methionine-enkephalin (ME) and its synthetic congener Tyr-D-Ala-Gly-Me-Phe-Gly-NH.C3H7-iso (82/205), in a concentration-dependent biphasic manner modulated the concanavalin A (Con A)-stimulated phagocytosis-promoting (PP)-activity elaboration in the culture supernatants of mouse splenocytes in vitro. Both these peptides at 1 x 10(-5) and 1 x 10(-6) M inhibited the production of PP activity; conversely, at 1 x 10(-7)-1 x 10(-9) M they augmented it. Peptide 82/205 was nearly 1.2-fold more inhibitory and approximately 1.8-fold more potent in augmenting the PP activity elaboration. The PP activity appeared to be due to lymphokines (LK) gamma interferon and interleukin-4 as the neutralizing concentrations of monoclonal antibodies against these LK significantly (p < 0.05) inhibited it. Cycloheximide (50.0 micrograms/ml) completely inhibited the production of LK indicating their de novo synthesis. The peptides appeared to exert their inhibitory and augmenting effects via delta- and mu-opioid receptors, respectively, as pretreatment of splenocytes with 100-fold higher (1 x 10(-3) M) concentration of naloxone was required to block their inhibitory effect; the augmenting effect was blocked by 1 x 10(-5) M only. None of the peptides or naloxone could directly stimulate the splenocytes for PP-LK elaboration.

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.

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.

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.

Hepatic heme-oxygenase and heme levels were monitored during Plasmodium berghei infection and chloroquine treatment in Swiss albino mice. A progressive increase in heme-oxygenase and heme levels was noticed with the rise in parasitemia. Further, chloroquine treatment did not result in any change towards normal heme-oxygenase and heme content, when they were assayed a week after cessation of drug treatment. Chloroquine treatment of non-parasitized and parasitized mice resulted in significant loss of the enzyme activity after about 6 weeks.

Ammonia, lactate and glutamate levels and the activities of glutamine synthetase (GS), glutamate dehydrogenase (GDH), glutaminase (GLN), aspartate transaminase (AST), phosphofructokinase (PFK) and monoamine oxidase (MAO) were compared in the brain tissue of normal and P. yoelii infected mice. The brain lactate increased by 96% at peak parasitaemia. Cerebral ammonia also exhibited an increase in infected mice which was parasitaemia dependent, while glutamate remained almost unchanged. The brain glutamine synthetase registered an increase of 35% (P < 0.001) in post-mitochondrial fractions, this effect being perceptible even at low parasitaemia, but attained constancy at parasitaemia levels higher than 20%. The activity of monoamine oxidase and phosphofructokinase increased by 105% (P < 0.02) and 41% (P < 0.05) respectively while glutamate dehydrogenase decreased by 15% (P < 0.001). Glutaminase and aspartate transaminase were not significantly influenced by infection (tested only at high parasitaemia levels). It has been postulated that cerebral hypoxia and aberrations in ammonia metabolism may both contribute towards malaria induced cerebral complications.

alpha-Artelinic acid [8], a potent, stable, and water-soluble antimalarial agent, has been synthesized from artemisinin [1], the sesquiterpene lactone endoperoxide isolated from Artemisia annua. The blood schizontocidal antimalarial activity of alpha-artelinic acid evaluated against Plasmodium knowlesi is also reported.

Plasmodium yoelii nigeriensis infection in mice caused an increase in uptake of 125I-labeled bovine serum albumin, 51Cr-labeled erythrocytes and Evans blue dye from peripheral circulation into the brain. Isolated cerebral microvessels which were characterized in terms of their morphology under scanning electron microscope and enhancement of the specific activities of biochemical markers, viz. alkaline phosphatase, gamma-glutamyl transpeptidase, and monoamine oxidase, showed significant decrease in these activities due to P. yoelii nigeriensis infection. On the other hand, relatively minor (statistically insignificant) changes occurred in the first two enzyme specific activities in the cerebral cortex and monoamine oxidase registered an increase in this tissue due to infection. Histological examination of the cerebral tissue of infected animals by light and electron microscopy showed broken blood vessel walls and leakage of erythrocytes into extravascular space, some of which contained intraerythrocytic malarial parasite in a state of cell division.

Plasmodium cynomolgi total antigens soluble in culture medium (P.c.SA), and noninfective P. cynomolgi-infected monkey erythrocytes (P.c.IE) were compared for their potential to induce colony-stimulating factors (CSFs). When injected intravenously in monkeys, both preparations induced an increase in the serum CSFs levels; P.c.IE appeared to be 1.6-fold more potent than the P.c.SA. In vitro P.c.IE induced 1.8-fold more CSF by monkey blood monocyte-derived macrophages than P.c. However, both in vivo and in vitro, the peak CSFs levels induced by P.c.SA were attained apparently 8 h earlier. CSF generated by P.c.SA and P.c.IE induced the formation of macrophage, granulocyte and granulocyte-macrophage colonies, in vitro; P.c.IE-generated CSF induced the formation of significantly (P < 0.01) higher numbers of granulocyte-macrophage colonies, indicating that the CSF induced by them stimulated different biological responses. The CSF induction appeared to be LPS-independent.

Almost all of the important enzymes of glycolytic sequence were studied in isolated schizonts of Plasmodium knowlesi as well as in normal and P. knowlesi parasitized rhesus red blood cells. Significant activities of all the glycolytic enzymes assayed were observed in cell-free schizonts and the levels of all were found to be considerably elevated in infected host erythrocytes, confirming that the consumption of glucose is dramatically increased in host red cells, consequent to malaria infection.