Gaur RL et al. (2007) Parasitology "Anti-filarial activity of novel formulations of albendazole against experimental brugian filariasis."

Khanna M, Singh S, Murthy PK, Gaur RL, Dixit S, Sahoo MK

[Parasitology, 2007]

The study was aimed at developing better orally active albendazole (ALB) formulations. Six formulations (ALB-1 to ALB-6) were prepared and tested against Brugia malayi in Mastomys coucha and jird (Meriones unguiculatus) at 200 mg/kg, orally, for 5 consecutive days. The anti-filarial efficacy was assessed against microfilariae (mf), adult worms and female reproductive potential. Three of the 6 ALB formulations showed greatly improved female worm sterilizing potential (ALB-1: 90%; ALB-3: 63%; ALB-4: 77% of untreated control) in B. malayi - M. coucha model. Sterilization efficacy of ALB-1 was also better than that shown by pure-ALB (P<0.001) or its marketed tablet formulation, Zentel (P<0.01), while that of ALB-4 was better than pure-ALB (P<0.05). The activity of ALB-3, pure-ALB and Zentel was, however, comparable. ALB-1 also showed late microfilaricidal activity with a maximum of 78% fall in microfilarial count. In contrast, neither the pure ALB nor Zentel showed any microfilaricidal activity. In the jird - B. malayi model, ALB-1 and ALB-4 showed marginal sterilizing efficacy whereas pure ALB or Zentel were ineffective. In conclusion the anti-filarial efficacy of ALB-1 was found to be superior to pure-ALB or Zentel.

Gaur RL et al. (2008) Indian J Med Res "Antifilarial activity of Caesalpinia bonducella against experimental filarial infections."

Kulshreshtha DK, Gaur RL, Sahoo MK, Rastogi S, Murthy PK, Dixit S, Fatma N, Chatterjee RK

[Indian J Med Res, 2008]

BACKGROUND & OBJECTIVE: Lymphatic filariasis is a disabling disease that continues to cripple population in tropical countries. Currently available antifilarial drugs are not able to control the disease. Therefore, a better antifilarial is urgently required for proper management of the disease. We undertook this study to assess the antifilarial activity of Caesalpinia bonducella-seed kernel against rodent filarial parasite in experimental model. METHODS: Microfilaraemic cotton rats and Mastomys coucha harbouring Litomosoides sigmodontis and Brugia malayi respectively, were treated with crude extract or fractions of the seed kernel C. bonducella through oral route for 5 consecutive days. Microfilaricidal, macrofilaricidal and female worm sterilizing efficacy was assessed. RESULTS: Crude extract showed gradual fall in microfilariae (mf) count in L. sigmodontis-cotton rat model from day 8 post-treatment attaining more than 95 per cent fall by the end of observation period. It also exhibited 96 per cent macrofilaricidal and 100 per cent female sterilizing efficacy. The butanol fraction F018 caused 73.7 per cent reduction in mf count and 82.5 per cent mortality in adult worms with 100 per cent female sterilization. The aqueous fraction F019 exerted more than 90 per cent microfilaricidal activity and 100 per cent worm sterilization. Two chromatographic fractions, F024 and F025 of hexane soluble fraction exhibited 64 and 95 per cent macrofilaricidal activity, respectively. Both the fractions caused gradual fall in microfilaraemia and 100 per cent worm sterilization. In B. malayi-M. coucha model F025 showed gradual reduction in microfilaraemia and caused 80 per cent sterilization of female parasites INTERPRETATION & CONCLUSION: In conclusion, C. bonducella- seed kernel extract and fractions showed microfilaricidal, macrofilaricidal and female-sterilizing efficacy against L. sigmodontis and microfilaricidal and female-sterilizing efficacy against B. malayi in animal models, indicating the potential of this plant in providing a lead for new antifilarial drug development.

Dixit S et al. (2006) Vaccine "Protection against L3 induced Brugia malayi infection in Mastomys coucha pre-immunized with BmAFII fraction of the filarial adult worm."

Gaur RL, Dixit S, Murthy PK, Murthy PS, Sahoo MK, Joseph SK

[Vaccine, 2006]

The present study was aimed at investigating protective efficacy of BmAFII (Sephadex G-200 eluted fraction of Brugia malayi adult worm extract) against establishment of infective larvae (L3)-induced B. malayi infection in Mastomys coucha and to delineate immunological responses induced in the host. Healthy male M. coucha were immunized with BmAFII and subsequently inoculated with B. malayi L3. Specific IgG and cell mediated immune responses (cellular proliferation) including release of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), transforming growth factor-beta (TGF-beta) and nitric oxide (NO) from host's cells stimulated with BmAFII or lipopolysaccharide (LPS)/concanavalin A (Con A) in vitro were determined. Immunization with BmAFII reduced the adult worm recovery by 85.7% (P<0.001) and microfilaraemia by 77-95% of unimmunized controls (P<0.05-0.01). Immunization alone resulted in downregulation of responses of cellular proliferation, IFN-gamma, TNF-alpha and NO production (P<0.01) but increased TGF-beta release (P<0.001) whereas the converse was seen after L3 inoculation in these animals. In unimmunized+L3 inoculated animals all the above parameters were found downregulated (P<0.01-0.001). The cell proliferative response of BmAFII immunized+L3 challenged animals was larger for Con A (P<0.001) but not for BmAFII. Specific IgG levels were higher in immunized, immunized+L3 inoculated and unimmunized+L3 inoculated groups (P<0.001) compared to unimmunized animals, the highest level being shown by immunized+L3 inoculated group. In conclusion, immunization with BmAFII suppresses establishment of L3-induced infection in M. coucha by stimulating proinflammatory responses to L3.

Khan MA et al. (2004) Ann Trop Med Parasitol "Responses of Mastomys coucha, that have been infected with Brugia malayi and treated with diethylcarbamazine or albendazole, to re-exposure to infection."

Saleemuddin M, Gaur RL, Dixit S, Khan MA, Murthy PK

[Ann Trop Med Parasitol, 2004]

The responses of Mastomys coucha to re-exposure to infection with homologous infective larvae (L(3)) of Brugia malayi were investigated, after initial infections with the nematode had been treated subcutaneously for 5 days with diethylcarbamazine (DEC; 150 mg citrate/kg. day) or albendazole (ALB; 50 mg/kg. day). The parasite burdens, serum concentrations of IgG reacting with a soluble somatic extract of adult B. malayi (BmAS), and cytokine and lymphocyte-proliferative responses to filarial antigen (BmAS) or mitogen (concanavilin A or lipopolysaccharide) were studied. The results demonstrated, for the first time, that re-infection with L(3) was only successful in the DEC-treated animals, not the ALB-treated ones. When the ALB-treated animals were re-exposed, interferon-gamma production decreased, lymphocyte-proliferative responses either remained the same (with concanavilin A) or decreased (with BmAS), and concentrations of specific IgG decreased. When the DEC-treated animals were re-exposed, microfilaraemias re-appeared and, although production of interferon-gamma decreased, there were no detectable lymphocyte proliferative responses, and concentrations of specific IgG remained unchanged. Taken together, the results indicate that, at least in the M. coucha model of human filariasis, ALB but not DEC treatment may help to prevent the development of re-infections.

Singh BK et al. (2008) Eur J Med Chem "Synthesis of 2-sulfanyl-6-methyl-1,4-dihydropyrimidines as a new class of antifilarial agents."

Maulik PR, Yadav GP, Saxena N, Singh BK, Sahoo MK, Mishra M, Tripathi RP, Gaur RL, Murthy PK

[Eur J Med Chem, 2008]

A series of 2-sulfanyl-6-methyl-1,4-dihydropyrimidines (8-21) were synthesized in good yields by alkylation of 5-methyl-6-phenyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid ethyl esters (2-7) with different alkyl or aralkyl halides in the presence of a combination of anhydrous K(2)CO(3) and catalytic amount of tetrabutyl ammonium bromide. The title compounds were evaluated for their antifilarial activity against adult parasites of human lymphatic filarial parasite Brugia malayi (sub-periodic strain) in vitro and in vivo at various concentrations. One of the compounds (18) showed promising antifilarial activity.

Murthy PK et al. (2008) Acta Trop "Influence of Brugia malayi life stages and BmAFII fraction on experimental Leishmania donovani infection in hamsters."

Gaur RL, Joseph SK, Sahoo MK, Dixit S, Shakya N, Palne S, Kumar R, Gupta S, Murthy PK

[Acta Trop, 2008]

The influence of live Brugia malayi parasites and a Sephadex G-200 fraction of the adult parasite extract (BmAFII) on the progression of Leishmania donovani infection was studied. Inbred hamsters were first infected with B. malayi infective 3rd stage larvae (L3), adult worms or microfilariae (mf), and then with L. donovani amastigotes (Ld), or vice versa or received both the infections simultaneously; a group of animals were first immunized with BmAFII and then infected with Ld. L. donovani parasite burden was determined between 17 and 19 days post amastigote challenge (p.a.c.) and, in case of immunized animals, between 32 and 35 days p.a.c also. Nitric oxide (NO) release from peritoneal macrophages and cellular proliferative responses of lymphnode cells were assessed in BmAFII-immunized animals given leishmania infection or no infection. Leishmanial parasite burden was significantly reduced in animals exposed to filarial L3 before amastigote inoculation and in animals given filarial adult worms after or together with amastigotes. Prior immunization of leishmania-infected animals with BmAFII also reduced the leishmanial parasite burden (17-19 days p.a.c.: >90%; 32-35 days p.a.c.: 60%). These animals showed upregulation of NO release and cellular proliferative responses to promastigote antigen or BmAFII stimulation in vitro. The findings show, for the first time, that B. malayi L3/adult worms or immunization with BmAFII inhibits progression of L. donovani infection in hamsters and this is associated with upregulation of NO and lymphocyte proliferative responses indicating that Th1 response might be responsible for this.