Relative Insensitivity of a Kenyan Strain of Leishmania donovani to Pentavalent Antimony Therapy in Hamsters

1983 ◽  
Vol 69 (2) ◽  
pp. 446 ◽  
Author(s):  
William L. Hanson ◽  
Virginia B. Waits ◽  
Larry D. Hendricks ◽  
W. T. Hockmeyer ◽  
David E. Davidson ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Pentavalent Antimony ◽  
Kenyan Strain

scholarly journals Heat shock protein 70 (HSP70) expression in antimony susceptible/resistant clinical isolates of Leishmania donovani

2015 ◽  
Vol 3 (1) ◽  
pp. 22-28 ◽  
Author(s):  
Mahendra Maharjan ◽  
Rentala Madhubala
Keyword(s):  
Leishmania Donovani ◽  
Gene Copy Number ◽  
Clinical Isolates ◽  
Gene Copy ◽  
Hsp70 Expression ◽  
First Line ◽  
Over Expression ◽  
Hsp70 Protein ◽  
Pentavalent Antimony ◽  
Different Parts

Pentavalent antimonials have long been the first line of defence against leishmaniasis, but resistance has been reported in different parts of the world. Pentavalent antimony is reduced into trivalent form in the cells and is a potential inducer of HSP70 in L. donovani. Expression profile of HSP70 in antimony susceptible and resistant L. donovani isolates were characterized by Southern blot, Northern blot and western blot analysis. HSP70 gene copy number, gene expression and HSP70 protein expression was found uniform in both antimony sensitive and resistant clinical isolates. In laboratory condition, Leishmania cells respond to antimonial drug stress by three fold over expression of the HSP70 protein. The observed results indicated that HSP70 play important role in stress tolerance against antimonial drug without differential expression in antimony sensitive and resistance clinical isolates of L. donovani.Nepal Journal of Biotechnology. Dec. 2015 Vol. 3, No. 1: 22-28

scholarly journals Resistance of Leishmania donovani to Sodium Stibogluconate Is Related to the Expression of Host and Parasite γ-Glutamylcysteine Synthetase

2006 ◽  
Vol 50 (1) ◽  
pp. 88-95 ◽  
Author(s):  
K. C. Carter ◽  
S. Hutchison ◽  
F. L. Henriquez ◽  
D. Légaré ◽  
M. Ouellette ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Sodium Stibogluconate ◽  
Surfactant Vesicles ◽  
Pentavalent Antimony ◽  
Regulated Expression ◽  
Nonionic Surfactant Vesicles ◽  
Sequencing Studies ◽  
Glutamylcysteine Synthetase ◽  
Strain Dependent

ABSTRACT Sequencing studies showed that the γ-glutamylcysteine synthetase (γ-GCS) heavy chain genes from sodium stibogluconate (SSG)-resistant (SSG-R) and SSG-susceptible (SSG-S) Leishmania donovani strains were identical, indicating that SSG resistance was related to quantitative differences in γ-GCS expression rather than gene interstrain polymorphisms. In vitro infection of murine macrophages with the SSG-R strain, but not the SSG-S strain, down regulated expression of host γ-GCS, which would result in a reduction in intramacrophage glutathione (GSH) levels and promote an oxidative intramacrophage environment. This would inhibit, or minimize, the reduction of SSG pentavalent antimony to its more toxic trivalent form. Macrophage studies showed that the SSG-R strain expressed higher levels of γ-GCS compared to the SSG-S strain, which would result in higher GSH levels, giving increased protection against oxidative stress and facilitating SSG efflux. However a similar differential effect on host and parasite γ-GCS expression was not obtained when using tissues from infected mice. In this case γ-GCS expression was organ and strain dependent for both the host and the parasite, indicating that environmental conditions have a profound effect on γ-GCS expression. Consistent with the proposed mechanism from in vitro studies, increasing tissue GSH levels in the presence of SSG by cotreatment of L. donovani-infected mice with SSG solution and GSH incorporated into nonionic surfactant vesicles was more effective in reducing liver, spleen, and bone marrow parasite burdens than monotherapy with SSG. Together, these results indicate that SSG resistance is associated with manipulation of both host and parasite GSH levels by L. donovani.

scholarly journals Stage-Specific Activity of Pentavalent Antimony against Leishmania donovani Axenic Amastigotes

1999 ◽  
Vol 43 (2) ◽  
pp. 278-282 ◽  
Author(s):  
Moshe Ephros ◽  
Ari Bitnun ◽  
Pninit Shaked ◽  
Ella Waldman ◽  
Dan Zilberstein
Keyword(s):  
Leishmania Donovani ◽  
Developmental Stages ◽  
Specific Activity ◽  
Cross Resistance ◽  
Sodium Stibogluconate ◽  
Meglumine Antimoniate ◽  
Human Visceral Leishmaniasis ◽  
Axenic Amastigotes ◽  
Pentavalent Antimony

ABSTRACT The standard treatment of human visceral leishmaniasis involves the use of pentavalent antimony (SbV) compounds. In recent years increasing numbers of clinical failures of treatment with SbV have been reported, probably due to the development of parasite resistance to this compound. The mode of action and mechanisms of resistance to SbV have not been fully elucidated. In the present study an axenic amastigote culture was used to study the in vitro responses of Leishmania donovani to SbV. Susceptibility to both sodium stibogluconate and meglumine antimoniate was found to be stage specific. Amastigotes were 73 to 271 times more susceptible to SbV than were promastigotes. As opposed to SbV, trivalent antimony (SbIII) was similarly toxic to both developmental stages. When promastigotes were transformed to amastigotes, susceptibility to meglumine antimoniate developed after 4 to 5 days, upon the completion of differentiation. In contrast, with transformation from amastigotes to promastigotes, resistance to meglumine antimoniate was acquired rapidly, within 24 h, before the completion of differentiation. The culture of promastigotes at an acidic pH (5.5) or at an elevated temperature (37°C) alone did not lead to the appearance of SbV susceptibility, emphasizing the requirement of both these environmental factors for the development of SbV susceptibility. A previously isolated sodium stibogluconate (Pentostam)-resistant L. donovani mutant (Ld1S.20) is also resistant to meglumine antimoniate, indicating cross-resistance to SbV-containing compounds. In contrast, no cross-resistance was found with SbIII, suggesting a mechanism of SbV resistance different from that described in Leishmania tarentolae. These data show that L. donovani susceptibility to SbV is parasite intrinsic, stage specific, and macrophage independent.

scholarly journals In Vitro Sensitivity Testing of Leishmania Clinical Field Isolates: Preconditioning of Promastigotes Enhances Infectivity for Macrophage Host Cells

2009 ◽  
Vol 53 (12) ◽  
pp. 5197-5203 ◽  
Author(s):  
Raquel Inocêncio da Luz ◽  
Marieke Vermeersch ◽  
Jean-Claude Dujardin ◽  
Paul Cos ◽  
Louis Maes
Keyword(s):  
Leishmania Donovani ◽  
Host Cells ◽  
Laboratory Model ◽  
Macrophage Infection ◽  
Sensitivity Testing ◽  
Field Isolates ◽  
Pentavalent Antimony ◽  
Experimental Drug ◽  
Mouse Macrophages

ABSTRACT Diagnostic material from patients with leishmaniasis is generally available as promastigotes, and proper testing for susceptibility to first-line drugs by the intracellular amastigote assay is frequently hampered by the poor infectivity of the promastigotes for the macrophage host cell. Several conditions for optimization of the in vitro metacyclogenesis and cell infectivity of Leishmania donovani, L. guyanensis, and L. braziliensis field strains obtained from patients receiving standard antimony medication were investigated. Triggering log-phase promastigotes to become amastigote-like by increasing the temperature or acidifying the culture medium was not successful. Adequate metacyclogenesis and the highest levels of macrophage infection were obtained after 5-day-old late-log-phase promastigote cultures were preconditioned at 25°C to pH 5.4 for 24 h in Schneider's medium prior to infection. The susceptibility assay with primary peritoneal mouse macrophages included pentavalent antimony (SbV; sodium stibogluconate), trivalent antimony (SbIII; potassium antimonyl tartrate), miltefosine, and the experimental drug PX-6518. All strains were sensitive to miltefosine (50% inhibitory concentration [IC50] < 10 μM) and PX-6518 (IC50 < 2 μg/ml) but showed distinct susceptibility to SbV and/or SbIII, depending on whether they were derived from cured, relapse, or nonresponder patients. Within the available set of Leishmania species and strains, simultaneous SbV-SbIII resistance was clearly associated with treatment failure; however, a larger set of isolates is still needed to judge the predictive value of SbV-SbIII susceptibility profiling on treatment outcome. In conclusion, the proposed conditioning protocol further contributes toward a more standardized laboratory model for evaluation of the drug sensitivities of field isolates.

Increased metacyclogenesis of antimony-resistant Leishmania donovani clinical lines

Parasitology ◽  
2011 ◽  
Vol 138 (11) ◽  
pp. 1392-1399 ◽  
Author(s):  
M. OUAKAD ◽  
M. VANAERSCHOT ◽  
S. RIJAL ◽  
S. SUNDAR ◽  
N. SPEYBROECK ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Drug Resistant ◽  
Pentavalent Antimony ◽  
Sensitive Isolate ◽  
Potential Risks ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Complement Lysis ◽  
Chemotherapeutic Interventions

SUMMARYMathematical models predict that the future of epidemics of drug-resistant pathogens depends in part on the competitive fitness of drug-resistant strains. Considering metacyclogenesis (differentiation process essential for infectivity) as a major contributor to the fitness of Leishmania donovani, we tested its relationship with pentavalent antimony (SbV) resistance in clinical lines. Different methods for the assessment of metacyclogenesis were cross-validated: gene expression profiling (META1 and SHERP), morphometry (microscopy and FACS), in vitro infectivity to macrophages and resistance to complement lysis. This was done on a model constituted by 2 pairs of reference strains cloned from a SbV-resistant and -sensitive isolate. We selected the most adequate parameter and extended the analysis of metacyclogenesis diversity to a sample of 20 clinical lines with different in vitro susceptibility to the drug. The capacity of metacyclogenesis, as measured by the complement lysis test, was shown to be significantly higher in SbV-resistant clinical lines of L. donovani than in SbV-sensitive lines. Together with other lines of evidence, it is concluded that L. donovani constitutes a unique example and model of drug-resistant pathogens with traits of increased fitness. These findings raise a fundamental question about the potential risks of selecting more virulent pathogens through massive chemotherapeutic interventions.

scholarly journals Antagonizing Deactivating Cytokines To Enhance Host Defense and Chemotherapy in Experimental Visceral Leishmaniasis

2005 ◽  
Vol 73 (7) ◽  
pp. 3903-3911 ◽  
Author(s):  
Henry W. Murray ◽  
Kathleen C. Flanders ◽  
Debra D. Donaldson ◽  
Joseph P. Sypek ◽  
Philip J. Gotwals ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Th1 Cell ◽  
Pentavalent Antimony ◽  
Ifn Γ ◽  
Liver Infection

ABSTRACT In experimental visceral leishmaniasis, inhibition of interleukin 10 (IL-10) signaling enhances Th1-cell-associated responses, promoting gamma interferon (IFN-γ) secretion, granuloma assembly, macrophage activation with substantial liver parasite killing, and synergy with pentavalent antimony (Sb) chemotherapy. To determine if inhibiting other suppressive cytokines has similar therapeutic potential, Leishmania donovani-infected BALB/c mice were injected with anti-IL-4 monoclonal antibody or receptor fusion antagonists of IL-13 or transforming growth factor β (TGF-β). Targeting IL-13 or TGF-β enabled inhibition of L. donovani replication but little parasite killing; anti-IL-4 had no effect. None of the three antagonists promoted IFN-γ production, granuloma maturation, or Sb efficacy. Excess IL-13 and TGF-β exacerbated liver infection; however, effects were transient. Among IL-10, IL-4, IL-13, and TGF-β, cytokines capable of disabling Th1-cell mechanisms (including those which support chemotherapy), IL-10 appears to be the appropriate target for therapeutic inhibition in visceral L. donovani infection.

scholarly journals Activity of oral atovaquone alone and in combination with antimony in experimental visceral leishmaniasis.

1996 ◽  
Vol 40 (3) ◽  
pp. 586-587 ◽  
Author(s):  
H W Murray ◽  
J Hariprashad
Keyword(s):  
Body Weight ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Potential Role ◽  
Oral Agent ◽  
Pentavalent Antimony ◽  
Suboptimal Dose ◽  
Parasite Replication ◽  
Visceral Infection

BALB/c mice with established visceral infection caused by the intracellular protozoan Leishmania donovani were treated with oral atovaquone for 7 days. Treatment with 100 mg/kg of body weight per day was optimal and halted parasite replication in the liver. In mice treated with atovaquone, the effect of a suboptimal dose of pentavalent antimony was converted from partially leishmanistatic to leishmanicidal. These results demonstrate the in vivo antileishmanial effect of atovaquone and suggest a potential role for this oral agent in visceral leishmaniasis as an adjunct to conventional antimony treatment.

scholarly journals The Treatment of Visceral Leishmaniasis: Safety and Efficacy

2013 ◽  
Vol 52 (192) ◽  
Author(s):  
Rajesh Kumar Jha ◽  
Ajit Kumar Sah ◽  
Dev Kumar Shah ◽  
Phoolgen Sah
Keyword(s):  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Leishmania Donovani ◽  
Adverse Drug Events ◽  
Serological Tests ◽  
Socioeconomic Condition ◽  
First Line Therapy ◽  
Line Therapy ◽  
Pentavalent Antimony ◽  
Almost All

Visceral leishmaniasis is the disease of poor; however availability of only expensive treatment of this disease impinges the socioeconomic condition of those affected. If untreated, almost all cases of visceral leishmaniasis are fatal. The demonstration of the leishmania donovani bodies from the tissue aspirates or serological tests confirms the diagnosis of the disease. Pentavalent antimony, amphotericin B, paromomycin, diamine pentamidine, miltefosine, sitamaquine and some new combinations are integrated in the limited therapeutic armoury for treatment of visceral leishmaniasis. The recommended first and second line therapy in the Indian sub-continent is miltefosine and amphotericin B respectively.Pentavalent antimonial, preceding first line therapy, has been replaced by miltefosine due to former increasing failure rate and toxicity.The problem of drug resistance, some of the serious drug toxicities along with high-priced drugs extends challenges equally to pharmaceutical companies and medical practitioners.More research on adverse drug events for the existing drugs and efforts to develop safer and effective drugs to counter resistance outbreaks for the successful management of visceral leishmaniasis are needed.  Keywords: amphotericin; miltefosine; pentavalent antimony; paromomycin.    

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