scholarly journals Efficacy of Combined Therapy with Liposome-Encapsulated Meglumine Antimoniate and Allopurinol in Treatment of Canine Visceral Leishmaniasis

2012 ◽  
Vol 56 (6) ◽  
pp. 2858-2867 ◽  
Author(s):  
Sydnei M. da Silva ◽  
Izabela F. G. Amorim ◽  
Raul R. Ribeiro ◽  
Erly G. Azevedo ◽  
Cynthia Demicheli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Visceral Leishmaniasis ◽  
Drug Combination ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Parasite Load ◽  
The Other ◽  
Sand Flies ◽  
Content Type ◽  
Meglumine Antimoniate

ABSTRACTAn innovative liposomal formulation of meglumine antimoniate (LMA) was recently reported to promote both long-term parasite suppression and reduction of infectivity to sand flies in dogs with visceral leishmaniasis. However, 5 months after treatment, parasites were still found in the bone marrow of all treated dogs. In order to improve treatment with LMA, the present study aimed to evaluate its efficacy in combination with allopurinol. Mongrel dogs naturally infected withLeishmania infantumwere treated with six doses of LMA (6.5 mg Sb/kg of body weight/dose) given at 4-day intervals, plus allopurinol (20 mg/kg/24 hper os) for 140 days. Comparison was made with groups treated with LMA, allopurinol, empty liposomes plus allopurinol, empty liposomes, and saline. Dogs remained without treatment from day 140 to 200 after the start of treatment. The drug combination promoted both clinical improvement of dogs and significant reduction in the parasitic load in bone marrow and spleen on days 140 and 200 compared to these parameters in the pretreatment period. This is in contrast with the other protocols, which did not result in significant reduction of the bone marrow parasite load on day 200. Strikingly, the combined treatment, in contrast to the other regimens, induced negative quantitative PCR (qPCR) results in the liver of 100% of the dogs. Both xenodiagnosis and skin parasite determination by qPCR indicated that the drug combination was effective in blocking the transmission of skin parasites to sand flies. Based on all of the parasitological tests performed on day 200, 50% of the animals that received the combined treatment were considered cured.

scholarly journals Reduced Tissue Parasitic Load and Infectivity to Sand Flies in Dogs Naturally Infected by Leishmania (Leishmania) chagasi following Treatment with a Liposome Formulation of Meglumine Antimoniate

2008 ◽  
Vol 52 (7) ◽  
pp. 2564-2572 ◽  
Author(s):  
Raul R. Ribeiro ◽  
Eliane P. Moura ◽  
Vitor M. Pimentel ◽  
Weverton M. Sampaio ◽  
Sydnei M. Silva ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lymph Nodes ◽  
The Other ◽  
Sand Fly ◽  
Lutzomyia Longipalpis ◽  
Sand Flies ◽  
Cervical Lymph Nodes ◽  
Meglumine Antimoniate ◽  
Liposome Formulation ◽  
Group I

ABSTRACT The toxicity and antileishmanial effectiveness of a novel liposome formulation of meglumine antimoniate in mongrel dogs with visceral leishmaniasis (VL) obtained from a region where VL is endemic in Brazil have been investigated. Groups of 12 animals received by the intravenous route four doses (with 4-day intervals) of either liposomal meglumine antimoniate (group I [GI], 6.5 mg Sb/kg of body weight/dose), empty liposomes (GII), or isotonic saline (GIII). Evaluation of markers of hematopoietic, hepatic, and renal functions before and just after treatment showed no significant change. On the other hand, transitory adverse reactions, including prostration, defecation, tachypnea, and sialorrhea, were observed during the first 15 min after injections in GI and GII. Parasitological evaluation of sternal bone marrow 4 days after the last dose showed a significant reduction of parasite burden in GI, compared to the other groups. Immunocytochemical evaluations of the skin, bone marrow, cervical lymph nodes, livers, and spleens of dogs for parasites, 150 days after treatment, indicated significant parasite suppression (higher than 95.7%) in the lymph nodes, livers, and spleens of GI, compared to control groups. Feeding of Lutzomyia longipalpis phlebotomines on dogs from GI, 150 days after treatment, resulted in a significant reduction of sand fly infection efficiency, compared to feeding on animals from GII and GIII. This is the first report of both long-term parasite suppression and reduction of infectivity to sand flies in naturally infected dogs following treatment with a liposome-encapsulated drug. Importantly, this was achieved using a 20-fold-lower cumulative dose of Sb than is used for conventional antimonial treatment.

scholarly journals Experimental Evaluation of Second-Line Oral Treatments of Visceral Leishmaniasis Caused by Leishmania infantum

1999 ◽  
Vol 43 (1) ◽  
pp. 172-174 ◽  
Author(s):  
Jean-Pierre Gangneux ◽  
Michael Dullin ◽  
Annie Sulahian ◽  
Yves Jean-Francois Garin ◽  
Francis Derouin
Keyword(s):  
Visceral Leishmaniasis ◽  
Murine Model ◽  
Experimental Evaluation ◽  
Leishmania Infantum ◽  
Parasite Load ◽  
Second Line ◽  
Meglumine Antimoniate ◽  
Marked Activity

ABSTRACT In a murine model of Leishmania infantum visceral leishmaniasis, metronidazole, ketoconazole, fluconazole, itraconazole, and terbinafine were less effective than antimonial agents in reducing hepatic parasite load. Ketoconazole potentiated the effect of meglumine antimoniate reference therapy through its marked activity against spleen infection.

scholarly journals T cell suppression in the bone marrow of visceral leishmaniasis patients: impact of parasite load

2017 ◽  
Vol 191 (3) ◽  
pp. 318-327 ◽  
Author(s):  
P. Kumar ◽  
P. Misra ◽  
C. P. Thakur ◽  
A. Saurabh ◽  
N. Rishi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Visceral Leishmaniasis ◽  
Parasite Load ◽  
T Cell Suppression ◽  
Cell Suppression

scholarly journals Morphological Changes in the Bone Marrow of the Dogs with Visceral Leishmaniasis

2014 ◽  
Vol 2014 ◽  
pp. 1-5 ◽  
Author(s):  
Claudia Momo ◽  
Ana Paula Prudente Jacintho ◽  
Pamela Rodrigues Reina Moreira ◽  
Danísio Prado Munari ◽  
Gisele Fabrino Machado ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Visceral Leishmaniasis ◽  
Morphological Changes ◽  
Clinical Signs ◽  
Parasite Load ◽  
Systemic Circulation ◽  
Clinical Group ◽  
Leishmania Chagasi ◽  
Control Center ◽  
A Site

The aim of this study was to evaluate the most frequent lesions in the bone marrow of dogs naturally infected byLeishmania (Leishmania) chagasi.Thirty-three dogs sacrificed at the Zoonosis Control Center of Araçatuba, a municipality endemic for visceral leishmaniasis (VL), were used. The animals were classified as asymptomatic, oligosymptomatic, and symptomatic groups. At the necropsy, bone marrow samples were collected from the femur, fixed, processed, and stained with hematoxylin and eosin. The lesion intensity was classified as mild, moderate, or severe. The parasite load was determined using immunohistochemistry. The most important lesions consisted of multifocal to diffuse granulomas, megakaryocytic dysplasia, and medullary aplasia. There were no statistical differences between the three clinical groups regarding parasite load and lesion intensity. Asymptomatic dogs also presented high parasitism in the bone marrow as dogs with clinical signs of VL. It was concluded that, regardless of clinical group, the bone marrow is a site for multiplication ofLeishmania chagasi. Possibly, the bone marrow dysplasia may arise from the presence of many parasitized and activated macrophages in this organ. Consequently, it affects the profile of hematopoietic cells in the bone marrow and systemic circulation.

scholarly journals Newly regenerated axons via scaffolds promote sub-lesional reorganization and motor recovery with epidural electrical stimulation

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ahad M. Siddiqui ◽  
Riazul Islam ◽  
Carlos A. Cuellar ◽  
Jodi L. Silvernail ◽  
Bruce Knudsen ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Schwann Cell ◽  
Motor Function ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Motor Recovery ◽  
The Other ◽  
Functional Improvement ◽  
Motor Training ◽  
Spinal Circuitry

AbstractHere, we report the effect of newly regenerated axons via scaffolds on reorganization of spinal circuitry and restoration of motor functions with epidural electrical stimulation (EES). Motor recovery was evaluated for 7 weeks after spinal transection and following implantation with scaffolds seeded with neurotrophin producing Schwann cell and with rapamycin microspheres. Combined treatment with scaffolds and EES-enabled stepping led to functional improvement compared to groups with scaffold or EES, although, the number of axons across scaffolds was not different between groups. Re-transection through the scaffold at week 6 reduced EES-enabled stepping, still demonstrating better performance compared to the other groups. Greater synaptic reorganization in the presence of regenerated axons was found in group with combined therapy. These findings suggest that newly regenerated axons through cell-containing scaffolds with EES-enabled motor training reorganize the sub-lesional circuitry improving motor recovery, demonstrating that neuroregenerative and neuromodulatory therapies cumulatively enhancing motor function after complete SCI.

scholarly journals Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Valter Viana Andrade-Neto ◽  
Juliana da Silva Pacheco ◽  
Job Domingos Inácio ◽  
Elmo Eduardo Almeida-Amaral ◽  
Eduardo Caio Torres-Santos ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Cutaneous Lesion ◽  
Parasite Burden ◽  
Parasite Load ◽  
New Drugs ◽  
Drug Candidate ◽  
Success Rates ◽  
Meglumine Antimoniate ◽  
Future Possibility

Translational studies involving the reuse and association of drugs are approaches that can result in higher success rates in the discovery and development of drugs for serious public health problems, including leishmaniasis. If we consider the number of pathogenic species in relation to therapeutic options, this arsenal is still small, and each drug possesses a disadvantage in terms of toxicity, efficacy, price, or treatment regimen. In the search for new drugs, we performed a drug screening of L. amazonensis promastigotes and intracellular amastigotes of fifty available drugs belonging to several classes according to their pharmacophoric group. Spironolactone, a potassium-sparing diuretic, proved to be the most promising drug candidate. After demonstrating the in vitro antileishmanial activity, we evaluated the efficacy on a murine experimental model with L. amazonensis and L. infantum. The treatment controlled the cutaneous lesion and reduced the parasite burden of L. amazonensis significantly, as effectively as meglumine antimoniate. The treatment of experimental visceral leishmaniasis was effective in reducing the parasite load on the main affected organs (spleen and liver) via high doses of spironolactone. The association between spironolactone and meglumine antimoniate promoted better control of the parasite load in the spleen and liver compared to the group treated with meglumine antimoniate alone. These results reveal a possible benefit of the concomitant use of spironolactone and meglumine antimoniate that should be studied more in depth for the future possibility of repositioning for leishmaniasis co-therapy.

scholarly journals Therapy with a Combination of Low Doses of Interleukin 12 and Chloroquine Completely Cures Blood-Stage Malaria, Prevents Severe Anemia, and Induces Immunity to Reinfection

1999 ◽  
Vol 67 (2) ◽  
pp. 513-519 ◽  
Author(s):  
Karkada Mohan ◽  
Hakeem Sam ◽  
Mary M. Stevenson
Keyword(s):  
Mrna Expression ◽  
Combined Therapy ◽  
Combined Treatment ◽  
Parasite Load ◽  
Blood Stage ◽  
Erythroid Cell ◽  
Interleukin 12 ◽  
Severe Anemia ◽  
Low Doses ◽  
Ifn Γ

ABSTRACT The immunoregulatory cytokine interleukin 12 (IL-12) induces host resistance against experimental malaria. In this study, we tested the feasibility of using IL-12 in combination with chloroquine (CQ) to rescue susceptible A/J mice from lethal blood-stage Plasmodium chabaudi AS infection. Combined treatment with low doses of CQ and IL-12 resulted in a >15-fold reduction in the parasite load and 100% survival of A/J mice with established infections. Compared to control mice, which succumbed to severe anemia, CQ-plus-IL-12-treated mice had significantly higher early- and late-stage erythroid-cell progenitors in the bone marrow and spleen, resulting in significantly higher hematocrits, erythrocyte counts, and percentages of reticulocytes. Production of parasite-specific gamma interferon (IFN-γ) by splenocytes from these mice was upregulated >20-fold relative to controls in parallel with enhanced IFN-γ mRNA expression. Further, enhanced responsiveness to IL-12 and increased downstream IFN-γ production in CQ-plus-IL-12-treated mice was evident from increased mRNA expression for the β1 and β2 subunits of IL-12 receptor in the splenocytes. Moreover, this combined therapy induced higher levels of anti-malaria antibodies than did CQ alone as well as sterile immunity against reinfection. Because IL-12 can be used at low doses and is effective even in established infections, it may be feasible to use this immunochemotherapeutic approach in human malaria.

scholarly journals Therapeutic Efficacy of a Mixed Formulation of Conventional and PEGylated Liposomes Containing Meglumine Antimoniate, Combined with Allopurinol, in Dogs Naturally Infected with Leishmania infantum

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Cristiano C. P. dos Santos ◽  
Guilherme S. Ramos ◽  
Renata C. De Paula ◽  
Karen F. Faria ◽  
Paulo O. L. Moreira ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Leishmania Infantum ◽  
Parasite Burden ◽  
Mononuclear Phagocyte ◽  
Clinical Staging ◽  
Control Group ◽  
Content Type ◽  
Meglumine Antimoniate ◽  
Pegylated Liposomes ◽  
Pretreatment Period

ABSTRACT The treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote a marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP plus Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg of body weight/dose) at 4-day intervals plus allopurinol at 30 mg/kg/12 h per os (p.o.) during 130 days (LCP+Allop); LC plus Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) plus allopurinol during 130 days (LC+Allop); Allop, treated with allopurinol only; and a nontreated control. Parasite loads were evaluated by quantitative PCR in liver, spleen, and bone marrow tissue and by immunohistochemistry in the ear skin, before treatment, just after treatment, and 4 months later. The LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen, and bone marrow 4 months after treatment compared to the pretreatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin in comparison to the control group. On the basis of clinical staging and parasitological evaluations, the LCP formulation exhibited a more favorable therapeutic profile than the LC one, being therefore promising for the treatment of canine visceral leishmaniasis.

Diverse liver morphology in two cases of visceral leishmaniasis: Same face, different expressions

2021 ◽  
pp. 004947552110381
Author(s):  
Shashi Dhawan ◽  
Satyender S Dharamdesani
Keyword(s):  
Bone Marrow ◽  
Visceral Leishmaniasis ◽  
Bone Marrow Examination ◽  
The Other ◽  
Endemic Region ◽  
Travel History ◽  
Liver Morphology ◽  
Liver Biopsies

Two cases of visceral leishmaniasis are presented; one patient was from an endemic region and visceral leishmaniasis was suspected clinically, while the other was from a non-endemic region and it was not suspected clinically. Bone marrow examination was negative in both cases and both showed different morphological pictures in the liver biopsies. These are discussed. Importance of travel history is also highlighted even if it is in distant past.

scholarly journals Benefits of Ascorbic Acid in Association with Low-Dose Benznidazole in Treatment of Chagas Disease

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Maiara Voltarelli Providello ◽  
Zumira Aparecida Carneiro ◽  
Gisele Bulhões Portapilla ◽  
Gabriel Tavares do Vale ◽  
Ricardo Souza Camargo ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Chagas Disease ◽  
Low Dose ◽  
Cardiac Tissue ◽  
Combined Therapy ◽  
Combined Treatment ◽  
New Drugs ◽  
Tissue Destruction ◽  
Content Type

ABSTRACT The acute phase of Chagas disease (CD) is characterized by high parasitic proliferation and intense inflammation, exacerbating the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). These reactive molecules are also increased by the metabolism of the nitroheterocyclic compounds benznidazole (BZ) and nifurtimox, the only drugs available for the treatment of CD. This oxidative environment, associated with the intracellular multiplication of Trypanosoma cruzi, leads to tissue destruction, triggering the pathogenic process. Both drugs have limited efficacy and serious side effects, which demonstrates the need to seek alternative therapies. Due to the difficulty in developing new drugs, reviewing therapeutic regimens appears advantageous, and the use of BZ in low doses associated with antioxidants, such as ascorbic acid (AA), would be a valid alternative to attenuate oxidative stress. In our in vivo studies, mice receiving the combination of 7.14 mg/kg of body weight/day AA and 10 mg/kg/day BZ10 (AA+BZ10) showed a reduction in parasitemia that was more effective than that with those receiving BZ or AA alone. The combined treatment was effective in decreasing intracellular ROS and lipid peroxidation in cardiac tissue. Histological and PCR analyzes showed that AA also reduced the cardiac parasitism. However, the greatest benefit was seen in AA+BZ10 group, since cardiac inflammation was significantly reduced. In addition, the combined therapy prevented the hepatic damage induced by the infection. Our findings suggest that AA combined with a low dose of BZ may improve the trypanocidal activity and attenuate the toxic effects of BZ. The decrease in oxidative damage and inflammation observed in mice treated with AA+BZ10 could result in increased cardioprotection.

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