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Physiological Chemistry and Physics and... 2000A well known glucose antimetabolite, 2-deoxy glucose (2DG) widely used in chemotherapy of cancer along with radiation, was evaluated as an antifilarial agent by nuclear... (Comparative Study)
Comparative Study
A well known glucose antimetabolite, 2-deoxy glucose (2DG) widely used in chemotherapy of cancer along with radiation, was evaluated as an antifilarial agent by nuclear magnetic resonance. The uptake and metabolism of 2DG in the experimental filarial infection Acanthocheilonema viteae was studied by in vivo multinuclear NMR. An unusually long retention time of 2DG6P within these parasites was observed on continuous 31P NMR monitoring, along with a decrease in ATP levels. These results led to therapeutic investigation in A. viteae infected host Mastomys coucha. 2DG showed a remarkable adulticidal activity (73.6%) with 50% sterilization of surviving female worms at a dose of 250 mg/kg x 5, p.o. NMR observations and activity profile substantiate the findings of one another, directed towards the hitting of bioenergetic machinery of A. viteae by macrofilaricidal agent (2DG).
Topics: Administration, Oral; Animals; Antimetabolites; Deoxyglucose; Dipetalonema; Dipetalonema Infections; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Energy Metabolism; Filaricides; Host-Parasite Interactions; Lactates; Magnetic Resonance Spectroscopy; Mice; Treatment Outcome
PubMed: 10970042
DOI: No ID Found -
Journal of Helminthology Sep 2000Investigations were undertaken to determine whether the tick Ornithodoros moubata moubata mounted a detectable immune response to primary and secondary infections with...
Investigations were undertaken to determine whether the tick Ornithodoros moubata moubata mounted a detectable immune response to primary and secondary infections with Acanthocheilonema viteae. Uninfected control tick survival rate was 70%, but only 45% in the primary infection group. Post-secondary infection survival rate (82%) was comparable to controls, indicating that these selected ticks had some protective advantage. Mean A. viteae infective larvae recovery from ticks with secondary infections was 31.4% lower than expected, suggesting the development of immunity. SDS-PAGE of haemolymph for proteins induced post-primary infection yielded a stronger signal at 45 kDa than controls, which was further elevated post-secondary infection. Proteins at 48, 22 and 16 to 18 kDa were detected in haemolymph from infected ticks but not seen from controls. The direct effect of haemolymph on microfilarial viability was examined using a novel in vitro assay; in these preliminary trials no differences were observed in parasite viability when exposed to haemolymph from infected or uninfected groups of ticks.
Topics: Animals; Dipetalonema Infections; Electrophoresis, Polyacrylamide Gel; Hemolymph; Ticks
PubMed: 10953223
DOI: No ID Found -
Acta Tropica Sep 2000Six synthetic 2H-1-benzopyran-2-one (cournarin) derivatives (CDRI compounds # 1, 2, 3, 4, 5 and 6) were evaluated for filaricidal activity against Litomosoides carinii...
Six synthetic 2H-1-benzopyran-2-one (cournarin) derivatives (CDRI compounds # 1, 2, 3, 4, 5 and 6) were evaluated for filaricidal activity against Litomosoides carinii and Acanthocheilonema viteae infections in cotton rats (Sigmodon hispidus) and Mastomys coucha respectively. Significant effects on macrofilariae (>80% death/sterilisation) were detected with compounds #2, 3 and 6 against L. carinii and/or A. viteae. Thus detection of filaricidal activity in benzopyrones, which are so far known for anti-inflammatory activity, provides a new lead for development of better filaricidal agents for combating filariasis.
Topics: Administration, Oral; Animals; Anticoagulants; Coumarins; Dipetalonema; Dipetalonema Infections; Female; Filariasis; Filarioidea; Humans; Injections, Intravenous; Male; Microfilariae; Ticks
PubMed: 10936568
DOI: 10.1016/s0001-706x(00)00070-x -
Bioorganic & Medicinal Chemistry Letters Jul 2000The syntheses of 7-chloro-4-(substituted amino) quinolines (2-22) and their antifilarial activities are delineated. Some of the screened compounds have shown promising...
The syntheses of 7-chloro-4-(substituted amino) quinolines (2-22) and their antifilarial activities are delineated. Some of the screened compounds have shown promising filarial response and sterilization effect on female Acanthocheilonema viteae in rodents.
Topics: Aminoquinolines; Animals; Chemistry, Pharmaceutical; Dipetalonema; Dipetalonema Infections; Drug Evaluation, Preclinical; Female; Filaricides; Molecular Structure; Muridae
PubMed: 10888320
DOI: 10.1016/s0960-894x(00)00255-9 -
Meditsinskaia Parazitologiia I... 1999Fauna of pathogen's met in the organism of the primary tick-borne disease vectors--Ixodes persulcatus Schulze and Ixodes ricinus (L.) was observed. Prevalence of...
Fauna of pathogen's met in the organism of the primary tick-borne disease vectors--Ixodes persulcatus Schulze and Ixodes ricinus (L.) was observed. Prevalence of Borrelia mono- and poly-infection in the I. persulcatus ticks within a season of the vector activity was analyzed and increase of the number of the dual infected specimens during the season was demonstrated. The first determination of Ehrlichia infected I. ricinus and I. persulcatus collected in the Baltic region of Russia was stated. The triple infection of Ixodes ticks in was proved: infection by the two species of Borrelia and Ehrlichia; infection by the three species of Borrelia and infection by the tick-borne encephalitis virus and two species of Borrelia. The first determination of the tick-borne encephalitis virus in I. ricinus in the recreational zone of Kaliningrad Province (Courland [correction of Curonian] Spit) was described. Dipetalonema sp. was detected in the St. Petersburg population of I. persulcatus. The prevalence of poly-infection among I. persulcatus ticks was stated.
Topics: Animals; Arachnid Vectors; Ecosystem; Humans; Ixodes; Russia; Seasons; Tick-Borne Diseases
PubMed: 10703200
DOI: No ID Found -
Molecular and Cellular Probes Dec 1999The mosquito-borne filarial worm, Dirofilaria immitis, causes heartworm disease in dogs. Detection of this parasite in its mosquito intermediate host currently involves...
The mosquito-borne filarial worm, Dirofilaria immitis, causes heartworm disease in dogs. Detection of this parasite in its mosquito intermediate host currently involves dissection and microscopic examination for larval stages. Although this method is used commonly as a screening tool for epidemiological surveys, it lacks both sensitivity and specificity. In this study, a more efficient PCR- and probe-based diagnostic assay was developed. The target selected for this assay is a segment of the 16 S rRNA gene. The assay specifically detects as little as 10 pg of D. immitis genomic DNA, equivalent to DNA derived from one third stage larva (L(3)), but does not detect 100 ng (10 000-fold excess) of the purified DNA from several other filarial nematodes, including Dirofilaria striata, Dirofilaria tenuis, Dipetalonema reconditum, Wuchereria bancroftii, Brugia pahangi, B. malayi, Onchocerca volvulus or Loa loa. This assay also detects one L(3)of D. immitis, the minimal biological unit of infection, in a pool of 200 mosquito heads. This assay can serve as a highly specific and sensitive tool for efficiently screening the large numbers of mosquitoes to determine, with statistical validity the seasonal transmission pattern of D. immitis in a locality prior to designing a rational preventive medication program for that parasite.
Topics: Animals; Base Sequence; Cloning, Molecular; Culicidae; DNA Probes; DNA, Helminth; Dirofilaria immitis; Dirofilariasis; Dog Diseases; Dogs; Genes, Helminth; Host-Parasite Interactions; Molecular Sequence Data; Polymerase Chain Reaction; RNA, Helminth; RNA, Ribosomal, 16S; Sensitivity and Specificity
PubMed: 10657147
DOI: 10.1006/mcpr.1999.0270 -
International Journal For Parasitology Sep 1999The gene encoding the cytoplasmic copper/zinc superoxide dismutase (AVSOD1) from the filarial parasite Acanthocheilonema viteae was isolated from a genomic DNA library...
Up-regulation of extracellular copper/zinc superoxide dismutase mRNA after transmission of the filarial parasite Acanthocheilonema viteae in the vertebrate host Meriones unguiculatus.
The gene encoding the cytoplasmic copper/zinc superoxide dismutase (AVSOD1) from the filarial parasite Acanthocheilonema viteae was isolated from a genomic DNA library using a degenerate oligonucleotide probe. Additionally, cDNAs of the AVSOD1 and the secreted extracellular SOD (AVSOD2) were both cloned by RT-PCR, and the AVSOD2 was expressed at high levels in E. coli. The amino acid sequence of the AVSOD1 is 89.5 and 87.5% identical to that of the corresponding enzymes of Brugia pahangi and Onchocerca volvulus, respectively. In contrast, the AVSOD2 shows a lower degree of identity to the other filarial SODs and is extensively glycosylated. RT-PCR studies demonstrate the expression of both SOD subtypes in all developmental stages of A. viteae and indicate up-regulation of the AVSOD2 expression after transmission from the vector to the definitive host. This suggests an enhanced requirement for SOD activity in post-infective larval stages and adults of A. viteae. ELISAs performed with purified recombinant AVSOD2 show that the AVSOD2 is not a major target for the immune system in naturally infected jirds.
Topics: Amino Acid Sequence; Animals; Dipetalonema Infections; Gene Expression Regulation, Enzymologic; Gerbillinae; Molecular Sequence Data; RNA, Helminth; RNA, Messenger; Reactive Oxygen Species; Rodent Diseases; Sequence Homology, Amino Acid; Superoxide Dismutase; Up-Regulation
PubMed: 10579430
DOI: 10.1016/s0020-7519(99)00073-9 -
Memorias Do Instituto Oswaldo Cruz 1999Six hundred and eleven random-source dogs (338 male, 273 female) one year of age or older, from six sections of the city of Recife, Pernambuco, were examined antemortem...
Six hundred and eleven random-source dogs (338 male, 273 female) one year of age or older, from six sections of the city of Recife, Pernambuco, were examined antemortem for circulating microfilariae Dirofilaria immitis and Dipetalonema reconditum adult heartworm (D. immitis) antigen, and examined postmortem for adult heartworms. The prevalence of heartworm infection was 2.3% (14/611), as determined by necropsy for adult worms, and 1% (6/611) had circulating microfilariae of D. immitis; thus, 57.1% of the heartworm-infected dogs had occult infections. The results of serological testing indicated that 1.3% (8/611) of the dogs were positive for adult heartworm antigen. A total of 42 (6.9%) of the dogs had microfilariae of D. reconditum; 40 of these had only D. reconditum and two additional dogs had microfilariae of both species, D. immitis and D. reconditum.
Topics: Animals; Brazil; Dirofilaria immitis; Dirofilariasis; Dog Diseases; Dogs; Female; Male; Prevalence
PubMed: 10464398
DOI: 10.1590/s0074-02761999000500004 -
Potent 1,3-disubstituted-9H-pyrido[3,4-b]indoles as new lead compounds in antifilarial chemotherapy.Bioorganic & Medicinal Chemistry Jun 1999Substituted 9H-pyrido[3,4-b]indoles (beta-carbolines) identified in our laboratory as potential pharmacophore for designing macrofilaricidal agents, have been explored...
Substituted 9H-pyrido[3,4-b]indoles (beta-carbolines) identified in our laboratory as potential pharmacophore for designing macrofilaricidal agents, have been explored further for identifying the pharmacophore responsible for high order of adulticidal activity. This has led to syntheses and macrofilaricidal evaluations of a number of 1-aryl-9H-pyrido[3,4-b]indole-3-carboxylate derivatives (3-7). The macrofilarical activity was initially evaluated in vivo against Acanthoeilonema viteae. Amongst all the synthesized compounds, only twelve compounds namely 3a, 3c, 3d, 3f, 4c, 4d, 4f, 5a, 6f, 6h, 6i and 7h have exhibited either > 90% micro- or macrofilaricidal activity or sterilization of female worms. These compounds have also been screened against Litomosoides carinii and of these only 3f and 5a have also been found to be active. Finally these two compounds have been evaluated against Brugia malayi. The structure activity relationship (SAR) associated with position-1 and 3 substituents in beta-carbolines have been discussed. It has been observed that the presence of carbomethoxy at position-3 and an aryl substituent at position- in beta-carbolines effectively enhance antifilarial activity particularly against A. viteae. Amongst the various compounds screened, methyl 1-(4-methylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (4c) has shown highest adulticidal activity and methyl 1-(4-chlorophenyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole-3-carboxyla te (3a) has shown highest microfilaricidal action against A. viteae at 50 mg/ kg x 5 days (i.p.). Another derivative of this compound namely 1-(4-chlorophenyl)-3-hydroxymethyl-9H-pyrido[3,4-b]indole (5a) exhibited highest activity against L. carinii at 30 mg/kg x 5 days (i.p.) and against B. malayi at 50 mg/kg x 5 days (i.p.) or at 200 mg/kg x 5 days (p.o.).
Topics: Animals; Brugia malayi; Carbolines; Dipetalonema; Dipetalonema Infections; Disease Models, Animal; Filariasis; Filaricides; Filarioidea; Lead; Male; Rats; Structure-Activity Relationship
PubMed: 10428395
DOI: 10.1016/s0968-0896(99)00050-4 -
Potent 1,3-disubstituted-9H-pyrido[3,4-b]indoles as new lead compounds in antifilarial chemotherapy.Journal of Medicinal Chemistry May 1999Substituted 9H-pyrido[3,4-b]indoles (beta-carbolines), identified in our laboratory as potential pharmacophores for designing macrofilaricidal agents, have been explored...
Substituted 9H-pyrido[3,4-b]indoles (beta-carbolines), identified in our laboratory as potential pharmacophores for designing macrofilaricidal agents, have been explored further for identifying the pharmacophore responsible for the high order of adulticidal activity. This has led to syntheses and macrofilaricidal evaluations of a number of 1-aryl-9H-pyrido[3,4-b]indole-3-carboxylate derivatives (3-7). The macrofilaricidal activity was initially evaluated in vivo against Acanthoeilonema viteae. Among all the synthesized compounds, only 12 compounds, namely 3a, 3c, 3d, 3f, 4c, 4d, 4f, 5a, 6f, 6h, 6i, and 7h, have exhibited either >90% micro- or macrofilaricidal activity or sterlization of female worms. These compounds have also been screened against Litomosoides carinii, and of these only 3f and 5a have also been found to be active. Finally these two compounds have been evaluated against Brugia malayi. The structure-activity relationship (SAR) associated with position 1 and 3 substituents in beta-carbolines has been discussed. It has been observed that the presence of a carbomethoxy at position 3 and an aryl substituent at position 1 in beta-carbolines effectively enhances antifilarial activity particularly against A. viteae. Among the various compounds screened, methyl 1-(4-methylphenyl)-9H-pyrido[3,4-b]indole-3-carboxylate (4c) has shown the highest adulticidal activity and methyl 1-(4-chlorophenyl)-1,2,3,4-tetrahydro-9H-pyrido[3, 4-b]indole-3-carboxylate (3a) has shown the highest microfilaricidal action against A. viteae at 50 mg/kg x 5 days (ip). Another derivative of this compound, namely 1-(4-chlorophenyl)-3-(hydroxymethyl)-9H-pyrido[3,4-b]indole (5a), exhibited the highest activity against L. carinii at 30 mg/kg x 5 days (ip) and against B. malayiat 50 mg/kg x 5 days (ip) or at 200 mg/kg x 5 days (po).
Topics: Animals; Brugia malayi; Dipetalonema Infections; Female; Filariasis; Filaricides; Filarioidea; Indoles; Male; Muridae; Sigmodontinae; Structure-Activity Relationship
PubMed: 10229635
DOI: 10.1021/jm9800705