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Sent on Wednesday, 2009 Mar 18Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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| PubMed Results |
- 1: Pharmacogenomics. 2009 Mar;10(3):451-61.
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Cutaneous leishmaniasis: disease susceptibility and pharmacogenetic implications.
St John's Institute of Dermatology, St Thomas'Hospital, Lambeth Palace Road, London SE17EH, UK. mahreenameen@hotmail.com
Cutaneous leishmaniasis is a major tropical infection of public health importance caused by a number of vector-borne Leishmania protozoa species. Evidence supports a highly complex etiology. Environmental, parasite and host factors determine pathogenesis, and result in a diverse clinical spectrum of disease. Disease susceptibility, clinical course, prognosis and therapy response are highly variable, suggesting a genetic basis. Epidemiological studies have demonstrated familial aggregation, and family and association studies have identified HLA and non-HLA gene associations. Further progress in susceptibility gene identification for leishmaniasis would require genome-wide scans and candidate gene-association studies in large cohorts. Correlation between host genotype and therapy response has important pharmacogenetic implications, especially as current therapies for leishmaniasis are inadequate and progress in new drug development has been poor.
PMID: 19290793 [PubMed - in process]
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- ReviewImmunogenetics of leishmanial and mycobacterial infections: the Belem Family Study. [Philos Trans R Soc Lond B Biol Sci. 1997]
- Genetics of host resistance and susceptibility to intramacrophage pathogens: a study of multicase families of tuberculosis, leprosy and leishmaniasis in north-eastern Brazil. [Int J Parasitol. 1998]
- Cutaneous leishmaniasis: therapeutic strategies and future directions. [Expert Opin Pharmacother. 2007]
- ReviewDoes the Leishmania major paradigm of pathogenesis and protection hold for New World cutaneous leishmaniases or the visceral disease? [Immunol Rev. 2004]
- [Interpretation of laboratory data during cryptic leishmaniasis in dog] [Parassitologia. 2004]
- 2: Antimicrob Agents Chemother. 2009 Mar 16. [Epub ahead of print]
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Novel S-adenosylmethionine Decarboxylase Inhibitors for the Treatment of Human African Trypanosomiasis.
Genzyme Corporation, 153 Second Avenue, Waltham MA USA 02451; University of Texas Southwestern Medical Center, Department of Pharmacology, 6001 Forest Park Road, Dallas, TX 75390-9041, USA; Swiss Tropical Institute, Parasite Chemotherapy, Socinstrasse 57 P.O. Box CH-4002, Basel, Switzerland; Pace University, Haskins Laboratory, Dept of Biological and Health Sciences, Dept of Chemistry and Physical Sciences, 41 Park Row, New York, NY 10038.
Trypanosomiasis remains a significant disease across the sub-Saharan African continent, with a prevalence of 50-70,000. Utility of current therapies is limited by issues of toxicity and the need to administer compounds intravenously. We have begun a program to pursue lead optimization around MDL 73811, an irreversible inhibitor of S-adenosylmethionine decarboxylase (AdoMetDC). This compound is potent, but in previous studies cleared rapidly from the blood of rats (Byers et al, 1991 Biochem J 274:527-533). One of the analogs synthesized (Genz-644131) was shown to be highly active against Trypanosoma brucei rhodesiense, in vitro (IC50 = 400 pg/ml). Enzyme kinetic studies showed Genz-644131 to be approximately 5-fold more potent than MDL 73811 against the T. b. brucei AdoMetDC-prozyme complex. This compound was stable in vitro in rat and human liver microsomal and hepatocyte assays, was stable in rat whole blood assays, did not significantly inhibit human cytochrome P450 (CYP) enzymes, had no measurable efflux in CaCo-2 cells and was only 41% bound by serum proteins. Pharmacokinetic studies in mice following intraperitoneal dosing showed that the half-life of Genz-644131 was 3-fold greater than that of MDL 73811 (7.4 hr vs. 2.5 hr). Furthermore, brain penetration of Genz-644131 was 4.3-fold higher than that of MDL 73811. Finally, in vivo efficacy studies in T. b. brucei strain STIB 795-infected mice showed that Genz-644131 significantly extended survival (from 6.75 days for controls to >30 days for treated animals) and cured animals infected with T. b. brucei strain LAB 110 EATRO. Taken together, the data strengthen validation of AdoMetDC as an important parasite target and these studies have shown that analogs of MDL 73811 can be synthesized with improved potency and brain penetration.
PMID: 19289530 [PubMed - as supplied by publisher]
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- Antitrypanosomal effects of polyamine biosynthesis inhibitors correlate with increases in Trypanosoma brucei brucei S-adenosyl-L-methionine. [Biochem J. 1991]
- Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase. [Antimicrob Agents Chemother. 1990]
- Uptake of the antitrypanosomal drug 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL 73811) by the purine transport system of Trypanosoma brucei brucei. [Biochem J. 1992]
- ReviewDevelopment of drug resistance in Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Treatment of human African trypanosomiasis with natural products (Review). [Int J Mol Med. 2008]
- ReviewPreclinical pharmacokinetics: an approach towards safer and efficacious drugs. [Curr Drug Metab. 2006]
- 3: Infect Immun. 2009 Mar 16. [Epub ahead of print]
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Designing therapies against experimental visceral leishmaniasis by modulating the membrane fluidity of antigen presenting cells.
Indian Institute of Chemical Biology, Council of Scientific & Industrial Research, 4, Raja S.C. Mullick Road, Kolkata - 700032, India; Rajendra Memorial Research Institute of Medical Sciences, Indian Council of Medical Research, Patna- 800007, India.
The membrane fluidity of APCs has a significant bearing on the T-cell stimulating ability and is dependent on the cholesterol content of the membrane. The relationship, if any, between the membrane fluidity and the defective cell mediated immunity (CMI) in visceral leishmaniasis has been investigated. Systemic administration of cholesterol by liposome delivery (Cholesterol-liposome) in Leishmania donovani (LD) infected hamsters was found to cure the infection. Splenic macrophages as a prototype of APCs of infected hamsters showed decreased membrane cholesterol and inability to drive T-cells, which was corrected by cholesterol-liposome treatment. The effect was cholesterol specific because liposomes made up of analogue 4-cholesten-3-one showed hardly any protection. Infection led to increase in IL-10, TGF-beta and IL-4 with concomitant decrease in IFN-gamma, TNF-alpha and iNOS signals, which was reverted upon cholesterol-liposome treatment. The antileishmanial T-cell repertoire, whose expansion appeared to be associated with protection, was presumably of Th1 type as evident from enhanced IFN-gamma signals and predominance of IgG2 isotype. The protected group produced significantly higher ROS and NO compared to the infected groups, culminating in the killing of LD parasites. Therefore cholesterol-liposome treatment promises to be yet another simple strategy to enhance CMI response in LD infection. To our knowledge this is the first report on the therapeutic role of cholesterol-liposome in any form of the diseases.
PMID: 19289510 [PubMed - as supplied by publisher]
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- Kinetoplastid membrane protein-11 DNA vaccination induces complete protection against both pentavalent antimonial-sensitive and -resistant strains of Leishmania donovani that correlates with inducible nitric oxide synthase activity and IL-4 generation: evidence for mixed Th1- and Th2-like responses in visceral leishmaniasis. [J Immunol. 2005]
- Hybrid cell vaccination resolves Leishmania donovani infection by eliciting a strong CD8+ cytotoxic T-lymphocyte response with concomitant suppression of interleukin-10 (IL-10) but not IL-4 or IL-13. [Infect Immun. 2007]
- The capacity to produce IFN-gamma rather than the presence of interleukin-4 determines the resistance and the degree of susceptibility to Leishmania donovani infection in mice. [J Interferon Cytokine Res. 2000]
- ReviewInterferon-gamma: biologic functions and HCV therapy (type I/II) (1 of 2 parts). [Clin Ter. 2006]
- ReviewImmunity and immunosuppression in experimental visceral leishmaniasis. [Braz J Med Biol Res. 2004]
- 4: Epidemiol Infect. 2009 Mar 17:1-5. [Epub ahead of print]
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New reports of Australian cutaneous leishmaniasis in Northern Australian macropods.
Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
SUMMARYCutaneous leishmaniasis caused by various species of Leishmania is a significant zoonotic disease in many parts of the world. We describe the first cases of Australian cutaneous leishmaniasis in eight northern wallaroos, one black wallaroo and two agile wallabies from the Northern Territory of Australia. Diagnosis was made through a combination of gross appearance of lesions, cytology, histology, direct culture, serology and a species-specific real-time PCR. The causative organism was found to be the same unique species of Leishmania previously identified in red kangaroos. These clinical findings provide further evidence for the continuous transmission of the Australian Leishmania species and its presence highlights the importance of continued monitoring and research into the life-cycle of this parasite.
PMID: 19288959 [PubMed - as supplied by publisher]
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- PCR detection and sequencing of parasite ITS-rDNA gene from reservoirs host of zoonotic cutaneous leishmaniasis in central Iran. [Parasitol Res. 2008]
- Mediterranean leishmaniasis in HIV-infected patients: epidemiological, clinical, and diagnostic features of 22 cases. [Infection. 1998]
- [Interpretation of laboratory data during cryptic leishmaniasis in dog] [Parassitologia. 2004]
- Review[Feline leishmaniasis: what's the epidemiological role of the cat?] [Parassitologia. 2004]
- Review[Parasite identification in the surveillance of imported leishmaniasis cases in Italy] [Parassitologia. 2004]
- 5: Zhongguo Ji Sheng Chong Xue Yu Ji Sheng Chong Bing Za Zhi. 2008 Dec 30;26(6):485.
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[A case of peripheral T cell lymphoma complicated with visceral leishmaniasis]
[Article in Chinese]PMID: 19288932 [PubMed - in process]
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- CD10 expression in peripheral T-cell lymphomas complicated by a proliferation of large B-cells. [Mod Pathol. 2006]
- [Visceral leishmaniasis complicated by herpes zoster. An unusual case in the pediatric age] [Minerva Pediatr. 1992]
- CT findings in visceral leishmaniasis mimicking lymphoma. [Comput Med Imaging Graph. 1988]
- ReviewImmunity and immunosuppression in experimental visceral leishmaniasis. [Braz J Med Biol Res. 2004]
- ReviewClinical use of polymerase chain reaction performed on peripheral blood and bone marrow samples for the diagnosis and monitoring of visceral leishmaniasis in HIV-infected and HIV-uninfected patients: a single-center, 8-year experience in Italy and review of the literature. [Clin Infect Dis. 2007]
- 6: Parasite. 2008 Dec;15(4):595-8.
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Suitability of a rapid DNA isolation and amplification for detection of Trypanosoma cruzi in Triatoma infestans dry fecal spots collected on filter paper.
LIM 36, Laboratório de Investigação Médica, Pediatria Clínica, Departamento de Pediatria, Faculdade de Medicina da Universidade de São Paulo, Brasil. lmabraz@usp.br
A rapid DNA extraction was used for T. cruzi detection in triatomines dry fecal spots collected on filter paper and analyzed by PCR. Fifty T. infestans were fed on experimentally infected Balb/C mice with high T. cruzi parasitemia and divided into five groups of ten triatomines, and 100 triatomines were infected with lower parasitemia and divided into five groups of 20 triatomines. One dry fecal spot was analyzed per group on days 1, 2, 3, 4 and 5 post feeding. Amplification targeted T. cruzi TCZ sequence and resulted positive from day 4 after bugs feeding in the two models (high and lower parasitemial. The rapid DNA isolation and PCR proposed are suitable for detection of T. cruzi DNA in filter paper and should be considered in field research.
PMID: 19202767 [PubMed - indexed for MEDLINE]
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- ReviewUse of polymerase chain reaction to diagnose the fifth reported US case of autochthonous transmission of Trypanosoma cruzi, in Tennessee, 1998. [J Infect Dis. 2000]
- Review[Detection of molecular heterogeneity of Trypanosoma cruzi] [Rev Soc Bras Med Trop. 2005]
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