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1.
Eur J Pharm Sci ; 145: 105256, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32032778

RESUMO

The present study evaluates the efficacy of sodium stibogluconate (SSG) co-loaded with ketoconazole (KTZ) in nano-elastic liposomes (NELs) for the topical treatment of cutaneous leishmaniasis (CL). SSG-KTZ co-loaded NELs were developed and assessed for various physicochemical properties and anti-leishmanial potential. The optimized nano-vesicles have an average size of 212.8 ± 3.1 nm and entrapment efficiency of 61.2 ± 2.9%. SSG-KTZ co-loaded NELs displayed 5.37-fold higher skin permeation of SSG as compared to drug solution. SSG and KTZ displayed a synergistic interaction and flow cytometry revealed enhanced killing of DsRed Leishmania mexicana in infected macrophages. In-vitro and in-vivo anti-leishmanial studies indicated a 10.67-fold lower IC50 value and a 35.33-fold reduced parasitic burden as compared with plain SSG solution, respectively. SSG-KTZ co-loaded NELs were found to be a promising approach for the topical treatment of CL.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Elasticidade , Cetoconazol/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Nanopartículas/administração & dosagem , Administração Tópica , Animais , Gluconato de Antimônio e Sódio/metabolismo , Antiprotozoários/metabolismo , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/metabolismo , Feminino , Cetoconazol/metabolismo , Leishmaniose Cutânea/metabolismo , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/metabolismo , Técnicas de Cultura de Órgãos , Distribuição Aleatória , Pele/efeitos dos fármacos , Pele/metabolismo
2.
Exp Parasitol ; 204: 107728, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31348915

RESUMO

BACKGROUND: Co-infection with Leishmania major and Schistosoma mansoni may have significant consequences for disease progression, severity and subsequent transmission dynamics. Pentavalent antimonials and Praziquantel (PZQ) are used as first line of treatment for Leishmania and Schistosoma infections respectively. However, there is limited insight on how combined therapy with the standard drugs impacts the host in comorbidity. The study aimed to determine the efficacy of combined chemotherapy using Pentostam (P) and PZQ in murine model co-infected with L. major and S. mansoni. METHODS: A 3 × 4 factorial design with three parasite infection groups (Lm, Sm, Lm + Sm to represent L. major, S. mansoni and L. major + S. mansoni respectively) and four treatment regimens [P, PZQ, P + PZQ, and PBS designating Pentostam (GlaxoSmithKline UK), Praziquantel (Biltricide®, Bayer Ag. Leverkusen, Germany), Pentostam + Praziquantel and Phosphate buffered saline] as factors was applied. RESULTS: Significant changes were observed in the serum Interferon gamma (IFN-γ), and Macrophage inflammatory protein-one alpha (MIP-1α) levels among various treatment groups between week 8 and week 10 (p < 0.05). There was increased IFN-γ in the L. major infected mice subjected to PZQ and PBS, and in L. major + S. mansoni infected BALB/c mice treated with P + PZQ. Subsequently, MIP-1α levels increased significantly in both the L. major infected mice under PZQ and PBS and in L. major + S. mansoni infected BALB/c mice undergoing concurrent chemotherapy with P + PZQ between 8 and 10 weeks (p < 0.05). In the comorbidity, simultaneous chemotherapy resulted in less severe histopathological effects in the liver. CONCLUSION: It was evident, combined first line of treatment is a more effective strategy in managing co-infection of L. major and S. mansoni. The findings denote simultaneous chemotherapy compliments immunomodulation in the helminth-protozoa comorbidity hence, less severe pathological effects following the parasites infection. Recent cases of increased incidences of polyparasitism in vertebrates call for better ways to manage co-infections. The findings presented necessitate intrinsic biological interest on examining optimal combined chemotherapeutic agents strategies in helminth-protozoa concomitance and the related infections abatement trends vis-a-vis host-parasite relationships.


Assuntos
Anti-Helmínticos/uso terapêutico , Antiprotozoários/uso terapêutico , Comorbidade , Leishmania major/patogenicidade , Leishmaniose Cutânea/complicações , Esquistossomose mansoni/complicações , Análise de Variância , Animais , Anti-Helmínticos/administração & dosagem , Gluconato de Antimônio e Sódio/administração & dosagem , Gluconato de Antimônio e Sódio/uso terapêutico , Antiprotozoários/administração & dosagem , Quimiocina CCL3/sangue , Modelos Animais de Doenças , Quimioterapia Combinada , Interferon gama/sangue , Leishmania major/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/patologia , Fígado/parasitologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Praziquantel/administração & dosagem , Praziquantel/uso terapêutico , Schistosoma mansoni/efeitos dos fármacos , Schistosoma mansoni/patogenicidade , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/imunologia , Esquistossomose mansoni/patologia
4.
Acta Derm Venereol ; 99(1): 53-57, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30281141

RESUMO

Conventional treatment of cutaneous leishmaniasis often leaves permanent scars with frequent psychosocial sequelae. The aim of this study was to compare the efficacy, safety, associated pain and final cosmetic outcome of fractional carbon dioxide (CO2) laser followed by topical application of sodium stibogluconate vs. sodium stibogluconate injections for the treatment of cutaneous leishmaniasis. A total of 181 lesions (20 patients) were randomly assigned to receive intralesional injections of sodium stibogluconate (control group) or fractional CO2 laser treatment followed by topical application of sodium stibogluconate (study group). The visual analogue scale (VAS) score of the control group was much higher than that of the study group (6.85 vs. 3.5, respectively, p<0.001). Both the patients and 2 blinded dermatologists found the final cosmetic outcome to be superior for laser-treated lesions (p = 0.001 vs. p =0.008 for controls). Fractional CO2 laser treatment followed by topical application of sodium stibogluconate is less painful and leads to a better final cosmetic outcome compared with intralesional injections of sodium stibogluconate.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Terapia a Laser/instrumentação , Lasers de Gás/uso terapêutico , Leishmaniose Cutânea/terapia , Pele/efeitos dos fármacos , Pele/efeitos da radiação , Administração Cutânea , Adulto , Gluconato de Antimônio e Sódio/efeitos adversos , Antiprotozoários/efeitos adversos , Terapia Combinada , Feminino , Humanos , Injeções Intralesionais , Israel , Terapia a Laser/efeitos adversos , Lasers de Gás/efeitos adversos , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/parasitologia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Satisfação do Paciente , Estudos Prospectivos , Pele/parasitologia , Pele/patologia , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
5.
J Dermatolog Treat ; 30(1): 87-91, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29764246

RESUMO

OBJECTIVES: The aim of our study was to assess the efficacy of intralesional metronidazole on Leishmania donovani cutaneous leishmaniasis (CL). MATERIAL AND METHODS: A total of 188 patients with CL were randomly allocated to intralesional sodium stibogluconate (SSG) and intralesional metronidazole. Cure was assessed after 1-10 injections. Cure rates were assessed for statistical significance using chi-square test at p = .05 level (SLCTR/2014/028). RESULTS: When the treatment cutoff was taken at 100%, the rate of cure for SSG (n = 64, 65.6%) was higher than that of metronidazole (n = 45, 48.9%): statistically significant at p < .05 level (Yates corrected chi-square 5.37, df = 1, p < .5). When the treatment cutoff was taken at >80%, the rate of cure for SSG (n = 75, 77.1%) was also higher than that of metronidazole (n = 58, 63.0%): statistically significant at p < .05 level (Yates corrected chi-square 4.46, df = 1, p < .5). Since it is based on a smaller sample, we estimated the statistical power of the test at a cutoff of 100% [above 80%] results identified a risk ratio of 1.4 [1.3], and a statistical power based on normal approximation at 74.8% [70.0%], respectively. CONCLUSION: This study showed that intralesional SSG has the best response against CL, while intralesional metronidazole was an effective alternative treatment.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Metronidazol/administração & dosagem , Adulto , Método Duplo-Cego , Feminino , Humanos , Injeções Intralesionais , Leishmania donovani , Masculino , Metronidazol/uso terapêutico , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
6.
Drug Deliv ; 25(1): 1595-1606, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30105918

RESUMO

Topical drug delivery against cutaneous leishmaniasis (CL) signifies an effective alternate for improving the availability and reducing the toxicity associated with the parenteral administration of conventional sodium stibogluconate (SSG) injection. The basic aim of the study was to develop nano-deformable liposomes (NDLs) for the dermal delivery of SSG against CL. NDLs were formulated by a modified thin film hydration method and optimized via Box-Behnken statistical design. The physicochemical properties of SSG-NDLs were established in terms of vesicle size (195.1 nm), polydispersity index (0.158), zeta potential (-32.8 mV), and entrapment efficiency (35.26%). Moreover, deformability index, in vitro release, and macrophage uptake studies were also accomplished. SSG-NDLs were entrapped within Carbopol gel network for the ease of skin application. The ex vivo skin permeation study revealed that SSG-NDLs gel provided 10-fold higher skin retention towards the deeper skin layers, attained without use of classical permeation enhancers. Moreover, in vivo skin irritation and histopathological studies verified safety of the topically applied formulation. Interestingly, the cytotoxic potential of SSG-NDLs (1.3 mg/ml) was higher than plain SSG (1.65 mg/ml). The anti-leishmanial activity on intramacrophage amastigote model of Leishmania tropica showed that IC50 value of the SSG-NDLs was ∼ fourfold lower than the plain drug solution with marked increase in the selectivity index. The in vivo results displayed higher anti-leishmanial activity by efficiently healing lesion and successfully reducing parasite burden. Concisely, the outcomes indicated that the targeted delivery of SSG could be accomplished by using topically applied NDLs for the effective treatment of CL.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Leishmaniose/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Nanopartículas/administração & dosagem , Administração Tópica , Animais , Gluconato de Antimônio e Sódio/metabolismo , Antiprotozoários/metabolismo , Relação Dose-Resposta a Droga , Feminino , Leishmaniose/metabolismo , Lipossomos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/metabolismo , Técnicas de Cultura de Órgãos , Ratos , Absorção Cutânea/efeitos dos fármacos , Absorção Cutânea/fisiologia , Resultado do Tratamento
7.
Int J Infect Dis ; 74: 109-116, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30017946

RESUMO

OBJECTIVES: This study sought to determine the endemic Leishmania species, the clinical features of cutaneous leishmaniasis (CL) in the Central Rift Valley in Kenya and to give an account on unresponsiveness to treatment in the region. METHODS: Participants were clinically identified and grouped into untreated, classical and recidivate based on clinical manifestation and clinical data. Leishmaniasis recidivans lesions were scaly hyperemic papules that appeared before the classic lesion had healed or after healing. The demographics and socio-economic data were recorded and lesion scraping samples screened through microscopy and Internal Transcribed Spacer 1-PCR. Leishmania species were identified using Restriction Fragment Length Polymorphism. RESULTS: A total of 52 participants were sampled, of which, 44.2% of the cases were recidivate and L. tropica the only species identified. All patients had been treated using sodium stibogluconate (SSG) which is the recommended first-line drug in Kenya. 60% of the patients experienced prolonged exposure to the drug (>30 days). CONCLUSION: L. tropica is the endemic Leishmania species for CL leading to classical and leishmaniasis recidivans. Treatment of CL in the area is not effective hence, alternative measures/therapy should be considered to cope with the unresponsiveness.


Assuntos
Leishmania tropica/isolamento & purificação , Leishmaniose Cutânea/parasitologia , Adolescente , Adulto , Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Criança , Feminino , Humanos , Quênia/epidemiologia , Leishmania tropica/genética , Leishmania tropica/fisiologia , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/epidemiologia , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Pele/parasitologia , Adulto Jovem
8.
Pediatr Dermatol ; 35(3): 366-369, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29574997

RESUMO

BACKGROUND: Leishmaniasis is a protozoan zoonotic parasitic infection with cutaneous, mucocutaneous, and visceral manifestations. Israel is endemic for cutaneous leishmaniasis, which is a self-limited disease but is associated with scarring, which is often a source of psychological and social burden for patients. Scars can be especially devastating for children and teenagers. A wide range of physical and medical approaches is used to treat cutaneous leishmaniasis, among which intralesional injections of sodium stibogluconate rank among the most frequently used. Unfortunately, despite being effective, this therapeutic modality can be very painful. Fractional ablative laser creates a controlled mesh-like pattern of tissue ablation in the skin that promotes dermal remodeling and collagen production while at the same time facilitating enhanced delivery of topically applied medications. METHODS: Patients were treated with fractional ablative carbon dioxide laser followed by immediate topical application of sodium stibogluconate. All children were diagnosed with cutaneous leishmaniasis prior to treatment initiation.. RESULTS: Ten children were treated. One leishmania tropica-positive girl failed to respond. The other nine patients achieved clinical cure and demonstrated good to excellent final cosmesis. Self-rated patient satisfaction and tolerance were high No adverse effects were observed or reported during treatment. CONCLUSION: Fractional ablative carbon dioxide laser followed by topical sodium stibogluconate application appears to be a safe and promising treatment for cutaneous leishmaniasis infection in children. Future controlled studies are required to validate these findings and compare this technique with traditional approaches.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Lasers de Gás/uso terapêutico , Leishmania/efeitos dos fármacos , Leishmaniose Cutânea/terapia , Administração Cutânea , Adolescente , Gluconato de Antimônio e Sódio/efeitos adversos , Antiprotozoários/efeitos adversos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Doenças Negligenciadas/terapia , Satisfação do Paciente/estatística & dados numéricos , Estudos Retrospectivos , Resultado do Tratamento
9.
Pathog Glob Health ; 111(6): 317-326, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28820339

RESUMO

BACKGROUND: Sri Lanka is a new focus of human cutaneous leishmaniasis caused by a genetic variant of usually visceralizing parasite Leishmania donovani. Over 3000 cases have been reported to our institution alone, during the past two decades. Recent emergence of visceral leishmaniasis is of concern. METHODS: Patients suspected of having visceral leishmaniasis (n = 120) fulfilling at least two of six criteria (fever > 2 weeks, weight loss, tiredness affecting daily functions, splenomegaly, hepatomegaly and anemia) were studied using clinic-epidemiological, immunological and haematological parameters. Seven cases (four progressive, treated (group A) and 3 non- progressive, potentially asymptomatic and observed (group B) were identified. Clinical cases were treated with systemic sodium stibogluconate or amphotericin B and all were followed up at the leishmaniasis clinic of University of Colombo for 3 years with one case followed up for 9 years. RESULTS: All treated cases responded well to anti leishmanial treatment. Relapses were not noticed. Clinical features subsided in all non-progressive cases and did not develop suggestive clinical features or change of laboratory parameters. Visceral leishmaniasis cases have been originated from different districts within the country. Majority had a travel history to identified local foci of cutaneous leishmaniasis. CONCLUSION: Visceral leishmaniasis is recognized as an emerging health threat in Sri Lanka. At least a proportion of locally identified strains of L. donovani possess the ability to visceralize. Apparent anti leishmanial sensitivity is encouraging. Timely efforts in disease containment will be important in which accurate understanding of transmission characteristics, increased professional and community awareness, improved diagnostics and availability of appropriate treatment regimens.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Doenças Transmissíveis Emergentes/epidemiologia , Leishmania donovani/isolamento & purificação , Leishmaniose Visceral/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anfotericina B/administração & dosagem , Antiprotozoários/administração & dosagem , Criança , Pré-Escolar , Doenças Transmissíveis Emergentes/diagnóstico , Doenças Transmissíveis Emergentes/tratamento farmacológico , Feminino , Humanos , Lactente , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Sri Lanka/epidemiologia , Adulto Jovem
10.
Am J Trop Med Hyg ; 97(4): 1120-1126, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28820681

RESUMO

Leishmania donovani causes cutaneous leishmaniasis (CL) in Sri Lanka. Standard treatment is multiple, painful doses of intralesional sodium stibogluconate (IL-SSG). Treatment failures are increasingly reported, hence the need to investigate alternatives. Efficacy, safety, and cost-effectiveness of thermotherapy were assessed for the first time for L. donovani CL. A single blinded noninferiority randomized controlled trial was conducted on new laboratory-confirmed CL patients with single lesions (N = 213). Selected patients were randomly assigned to 1) test group (N = 98; single session of radiofrequency-induced heat therapy (RFHT) given at 50°C for 30 seconds) and 2) control group (N = 115; 1-3 mL IL-SSG given weekly, until cure/10 doses). Patients were followed-up fortnightly for 12 weeks to assess clinical cure. Cost of treatment was assessed using scenario building technique. Cure rates by 8, 10, and 12 weeks in RFHT group were 46.5%, 56.5%, and 65.9% as opposed to 28%, 40.8%, and 59.4% in IL-SSG group, with no major adverse events. Cure rate by RFHT was significantly higher at 8 weeks (P = 0.009, odds ratio [OR]: 2.236, confidence interval [CI]: 1.217-4.108) and 10 weeks (P = 0.035, OR: 1.881, CI: 1.044-3.388), but comparable thereafter. Cost of RFHT was 7 times less (USD = 1.54/patient) than IL-SSG (USD = 11.09/patient). A single application of RFHT is safe, cost-effective, and convenient, compared with multiple doses of IL-SSG in the treatment of L. donovani CL. Therefore, RFHT would be considered noninferior as per trial outcome when compared with standard IL-SSG therapy with multiple benefits for the patient and the national health care system.


Assuntos
Hipertermia Induzida , Leishmania donovani , Leishmaniose Cutânea/terapia , Leishmaniose Visceral/terapia , Adolescente , Adulto , Gluconato de Antimônio e Sódio/administração & dosagem , Gluconato de Antimônio e Sódio/uso terapêutico , Criança , Feminino , Humanos , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Leishmaniose Visceral/parasitologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
PLoS Negl Trop Dis ; 11(2): e0005391, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28187202

RESUMO

Asymptomatic leishmaniasis may drive the epidemic and an important challenge to reach the goal of joint Visceral Leishmaniasis (VL) elimination initiative taken by three Asian countries. The role of these asymptomatic carriers in disease transmission, prognosis at individual level and rate of transformation to symptomatic VL/Post Kala-azar Dermal Leishmaniasis (PKDL) needs to be evaluated. Asymptomatic cases were diagnosed by active mass survey in eight tribal villages by detecting antileishmanial antibody using rK39 based rapid diagnostic kits and followed up for three years to observe the pattern of sero-conversion and disease transformation. Out of 2890 total population, 2603 were screened. Antileishmanial antibody was detected in 185 individuals of them 96 had a history of VL/PKDL and 89 without such history. Seventy nine such individuals were classified as asymptomatic leishmaniasis and ten as active VL with a ratio of 7.9:1. Out of 79 asymptomatic cases 2 were lost to follow up as they moved to other places. Amongst asymptomatically infected persons, disease transformation in 8/77 (10.39%) and sero-conversion in 62/77 (80.52%) cases were noted. Seven (9.09%) remained sero-positive even after three years. Progression to clinical disease among asymptomatic individuals was taking place at any time up to three years after the baseline survey. If there are no VL /PKDL cases for two or more years, it does not mean that the area is free from leishmaniasis as symptomatic VL or PKDL may appear even after three years, if there are such asymptomatic cases. So, asymptomatic infected individuals need much attention for VL elimination programme that has been initiated by three adjoining endemic countries.


Assuntos
Leishmaniose Visceral/epidemiologia , Adolescente , Adulto , Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Doenças Assintomáticas , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Índia/epidemiologia , Lactente , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Masculino , Adulto Jovem
12.
Clin Drug Investig ; 37(3): 259-272, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28066878

RESUMO

INTRODUCTION: In 2010, WHO recommended a new first-line treatment for visceral leishmaniasis (VL) in Eastern Africa. The new treatment, a combination of intravenous (IV) or intramuscular (IM) sodium stibogluconate (SSG) and IM paromomycin (PM) was an improvement over SSG monotherapy, the previous first-line VL treatment in the region. To monitor the new treatment's safety and effectiveness in routine clinical practice a pharmacovigilance (PV) programme was developed. METHODS: A prospective PV cohort was developed. Regulatory approval was obtained in Sudan, Kenya, Uganda and Ethiopia. Twelve sentinel sites sponsored by the Ministries of Health, Médecins Sans Frontières (MSF) and Drugs for Neglected Diseases initiative (DNDi) participated. VL patients treated using the new treatment were consented and included in a common registry that collected demographics, baseline clinical characteristics, adverse events, serious adverse events and treatment outcomes. Six-monthly periodic safety update reports (PSUR) were prepared and reviewed by a PV steering committee. RESULTS: Overall 3126 patients were enrolled: 1962 (62.7%) from Sudan, 652 (20.9%) from Kenya, 322 (10.3%) from Ethiopia and 190 (6.1%) from Uganda. Patients were mostly male children (68.1%, median age 11 years) with primary VL (97.8%). SSG-PM initial cure rate was 95.1%; no geographical differences were noted. HIV/VL co-infected patients and patients older than 50 years had initial cure rates of 56 and 81.4%, respectively, while 1063 (34%) patients had at least one adverse event (AE) during treatment and 1.92% (n = 60) had a serious adverse event (SAE) with a mortality of 1.0% (n = 32). There were no serious unexpected adverse drug reactions. CONCLUSIONS: This first regional PV programme in VL supports SSG-PM combination as first-line treatment for primary VL in Eastern Africa. SSG-PM was effective and safe except in HIV/VL co-infected or older patients. Active PV surveillance of targeted safety, effectiveness and key VL outcomes such us VL relapse, PKDL and HIV/VL co-infection should continue and PV data integrated to national and WHO PV databases.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Visceral/tratamento farmacológico , Paromomicina/administração & dosagem , Administração Intravenosa , Adolescente , Adulto , África Oriental , Criança , Pré-Escolar , Coinfecção , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Farmacovigilância , Estudos Prospectivos , Recidiva , Resultado do Tratamento , Adulto Jovem
13.
Cytokine ; 91: 6-9, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27940090

RESUMO

BACKGROUND: In Ethiopia, visceral leishmaniasis (VL) is a growing public health threat. Among the key challenges in VL control in Ethiopia is lack of an effective test of cure. The recommended test of cure is parasite detection. As sterile cure is not expected with the current widely used drugs, the value of parasite detection as test of cure is questionable. Moreover, the sampling is invasive, requires a well-equipped facility and highly skilled personnel, which are all hardly found in endemic set-ups. OBJECTIVE: Our aim was to assess the value of sCD40L, MMP9 and IL-10 serum levels as signature biomarkers of clinical cure in VL cases from Ethiopia. METHODS: A total of 45 VL cases before and after treatment and 30 endemic healthy controls were included in the study. Sandwich ELISA was used to measure serum levels of sCD40L, MMP9 and IL-10. RESULT: The mean sCD40L, MMP9 and IL-10 serum levels changed significantly at clinical cure. At individual case level sCD40L and MMP9 showed an increasing trend. Yet, the degree of increase in serum level of MMP9 seems to be affected by nutritional status of the individual VL case. The mean IL-10 serum level was significantly reduced at clinical cure. As seen on case by case basis, all demonstrated a declining trend except that two VL cases had a high IL10 level at clinical cure. CONCLUSION: Our result is suggestive of the possibility of developing a signature biomarker to monitor VL treatment in Ethiopia using one or a combination of parameters.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Ligante de CD40/sangue , Interleucina-10/sangue , Leishmaniose Visceral , Metaloproteinase 9 da Matriz/sangue , Adulto , Etiópia , Feminino , Humanos , Leishmaniose Visceral/sangue , Leishmaniose Visceral/tratamento farmacológico , Masculino
14.
PLoS Negl Trop Dis ; 10(9): e0004880, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27627654

RESUMO

BACKGROUND: SSG&PM over 17 days is recommended as first line treatment for visceral leishmaniasis in eastern Africa, but is painful and requires hospitalization. Combination regimens including AmBisome and miltefosine are safe and effective in India, but there are no published data from trials of combination therapies including these drugs from Africa. METHODS: A phase II open-label, non-comparative randomized trial was conducted in Sudan and Kenya to evaluate the efficacy and safety of three treatment regimens: 10 mg/kg single dose AmBisome plus 10 days of SSG (20 mg/kg/day), 10 mg/kg single dose AmBisome plus 10 days of miltefosine (2.5mg/kg/day) and miltefosine alone (2.5 mg/kg/day for 28 days). The primary endpoint was initial parasitological cure at Day 28, and secondary endpoints included definitive cure at Day 210, and pharmacokinetic (miltefosine) and pharmacodynamic assessments. RESULTS: In sequential analyses with 49-51 patients per arm, initial cure was 85% (95% CI: 73-92) in all arms. At D210, definitive cure was 87% (95% CI: 77-97) for AmBisome + SSG, 77% (95% CI 64-90) for AmBisome + miltefosine and 72% (95% CI 60-85) for miltefosine alone, with lower efficacy in younger patients, who weigh less. Miltefosine pharmacokinetic data indicated under-exposure in children compared to adults. CONCLUSION: No major safety concerns were identified, but point estimates of definitive cure were less than 90% for each regimen so none will be evaluated in Phase III trials in their current form. Allometric dosing of miltefosine in children needs to be evaluated. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov, number NCT01067443.


Assuntos
Anfotericina B/administração & dosagem , Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Adolescente , Adulto , Anfotericina B/efeitos adversos , Gluconato de Antimônio e Sódio/efeitos adversos , Antiprotozoários/farmacocinética , Criança , Quimioterapia Combinada , Feminino , Humanos , Quênia , Leishmania donovani , Masculino , Pessoa de Meia-Idade , Carga Parasitária , Fosforilcolina/administração & dosagem , Fosforilcolina/efeitos adversos , Fosforilcolina/farmacocinética , Sudão , Resultado do Tratamento , Adulto Jovem
15.
Ethiop Med J ; 54(1): 33-6, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27191028

RESUMO

Visceral leishmaniasis (VL) is a ftial and growing public health problem in Ethiopia. VL is recently reported outside the major endemic foci, the lowlands in the northwest and the Omo and Abaroba-plain, Segen and Woito valleys in the southwest. Here, we report a visceral leishmaniasis case from Benishangul-Gumuz Regional state near the Guba area. The patient had no history of travel to known VL endemic areas. The patient is a temporary farm laborer from West Go'jam Zone, Wanbermna District in Amhara Regional State. While in Benishangul-Gumuz, the patient was diagnosed with prolonged and intermittentfever, epistaxis, splenomegaly, skin pallor, diarrhea, cough and oedema. Laboratory diagnosis results showed that he had marked leucopenia, thrombocytopenia and anemia. The patient was suspected of having VL and checked with rK39 immunochromnatography and direct agglutination tests which were positive for anti leishmanial antibodies. After getting full dose of sodium stibogluconate as per the national visceral leishmaniasis treatment guideline, was clinically cured. As the area in Benshangul-Gumuz where this patient contracted visceral leishmaniasis is under social and ecological transformation with large scale projects attracting huge influx of temporary laborers and settlers, due attention is needed with respect to introduction or emergence of VL transmission.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Leishmania donovani/imunologia , Leishmaniose Visceral , Antiprotozoários/administração & dosagem , Etiópia/epidemiologia , Humanos , Leishmaniose Visceral/diagnóstico , Leishmaniose Visceral/tratamento farmacológico , Leishmaniose Visceral/epidemiologia , Leishmaniose Visceral/etiologia , Leishmaniose Visceral/fisiopatologia , Masculino , Testes Sorológicos , Resultado do Tratamento , Adulto Jovem
16.
Artigo em Inglês | MEDLINE | ID: mdl-26924403

RESUMO

BACKGROUND: Cutaneous leishmaniasis in India is mainly confined to the deserts of Rajasthan; some cases have been reported from the dry north-western half of the Indo-Gangetic plain, including Punjab, Himachal Pradesh, Delhi and Varanasi. AIMS: To highlight a new focus of cutaneous leishmaniasis in the Jammu division of Jammu and Kashmir State, previously a non-endemic area. This report presents the clinico-epidemiological and investigative results of 120 new cases of cutaneous leishmaniasis detected between November 2012 and October 2013. METHODS: The clinical diagnosis of cutaneous leishmaniasis was made using criteria proposed by Bari and Rahman. It was further confirmed by the demonstration of Leishman-Donovan bodies in Leishman stained slit skin smears and skin biopsy specimens, and/or by a satisfactory response to intra-lesional sodium stibogluconate given weekly for 4 weeks. Serial clinical photographs were taken before giving injections and at the end of the 6 th week. RESULTS: There were 67 females and 53 males with an age range of 8 months to 80 years. The most frequently affected site was the face. Lesions were most commonly of the nodulo-ulcerative type. The number of lesions ranged from 1 to 4. Farmers (28.1%), homemakers (27.2%) and students (27.2%) were significantly over-represented among the occupations (P < 0.001). Skin smears and biopsies were positive for Leishman-Donovan bodies in 50.8% and 44.2% cases, respectively. CONCLUSIONS: There is a new focus of cutaneous leishmaniasis in Jammu division which deserves urgent attention from the public health angle. Further epidemiological studies are warranted to establish the identity of the vector and the strain of Leishmania involved.


Assuntos
Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Criança , Pré-Escolar , Feminino , Humanos , Índia/epidemiologia , Lactente , Injeções Intralesionais , Leishmaniose Cutânea/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Am J Trop Med Hyg ; 94(1): 107-13, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26483122

RESUMO

Mucosal leishmaniasis (ML) is a disfiguring manifestation of Leishmania (Viannia) infection. We evaluated parasite load (PL) over time as a potential biomarker of treatment outcome in ML. PL was assessed with kinetoplast DNA quantitative real-time polymerase chain reaction (kDNA-qPCR) at enrollment, days 14 and 21-28 of therapy and 3, 6, 12-18, and 18-24 months after treatment of ML and correlated to demographic, clinical, and parasitologic factors. Forty-four patients were enrolled: 30 men and 14 women. Enrollment PL differed significantly by causative species (P < 0.001), and was higher in patients with severe ML (nasal and laryngeal involvement) compared with those with only isolated nasal involvement (median = 1,285 versus 51.5 parasites/µg tissue DNA; P = 0.005). Two patterns of PL emerged: pattern 1 (N = 23) was characterized by a sequential decline in PL during and after therapy until kDNA was undetectable. Pattern 2 (N = 18) was characterized by clearance of detectable kDNA during treatment, followed by an increased PL thereafter. All patients who failed treatment (N = 4) demonstrated pattern 1. Leishmania (Viannia) braziliensis was overrepresented among those with pattern 2 (P = 0.019). PL can be quantified by cytology brush qPCR during and after treatment in ML. We demonstrate that treatment failure was associated with undetectable PL, and L. (V.) braziliensis infection was overrepresented in those with rebounding PL.


Assuntos
Anfotericina B/uso terapêutico , Gluconato de Antimônio e Sódio/uso terapêutico , DNA de Cinetoplasto/genética , Leishmaniose Mucocutânea/parasitologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anfotericina B/administração & dosagem , Gluconato de Antimônio e Sódio/administração & dosagem , Biomarcadores , Criança , DNA de Protozoário/genética , DNA de Protozoário/isolamento & purificação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Reação em Cadeia da Polimerase em Tempo Real , Resultado do Tratamento , Adulto Jovem
18.
PLoS Negl Trop Dis ; 9(10): e0004138, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26485704

RESUMO

Post Kala-azar Dermal Leishmaniasis (PKDL) is a chronic but not life-threatening disease; patients generally do not demand treatment, deserve much more attention because PKDL is highly relevant in the context of Visceral Leishmaniasis (VL) elimination. There is no standard guideline for diagnosis and treatment for PKDL. A species-specific PCR on slit skin smear demonstrated a sensitivity of 93.8%, but it has not been applied for routine diagnostic purpose. The study was conducted to determine the actual disease burden in an endemic area of Malda district, West Bengal, comparison of the three diagnostic tools for PKDL case detection and pattern of lesion regression after treatment. The prevalence of PKDL was determined by active surveillance and confirmed by PCR based diagnosis. Patients were treated with either sodium stibogluconate (SSG) or oral miltefosine and followed up for two years to observe lesion regression period. Twenty six PKDL cases were detected with a prevalence rate of 27.5% among the antileishmanial antibody positive cases. Among three diagnostic methods used, PCR is highly sensitive (88.46%) for case confirmation. In majority of the cases skin lesions persisted after treatment completion which gradually disappeared during 6-12 months post treatment period. Reappearance of lesions noted in two cases after 1.5 years of miltefosine treatment. A significant number of PKDL patients would remain undiagnosed without active mass surveys. Such surveys are required in other endemic areas to attain the ultimate goal of eliminating Kala-azar. PCR-based method is helpful in confirming diagnosis of PKDL, referral laboratory at district or state level can achieve it. So a well-designed study with higher number of samples is essential to establish when/whether PKDL patients are free from parasite after treatment and to determine which PKDL patients need treatment for longer period.


Assuntos
Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/epidemiologia , Leishmaniose Visceral/complicações , Administração Oral , Adolescente , Adulto , Animais , Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Criança , Pré-Escolar , Transmissão de Doença Infecciosa , Monitoramento Epidemiológico , Feminino , Humanos , Índia/epidemiologia , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/transmissão , Masculino , Fosforilcolina/administração & dosagem , Fosforilcolina/análogos & derivados , Reação em Cadeia da Polimerase , Prevalência , Recidiva , População Rural , Adulto Jovem
19.
Int J Antimicrob Agents ; 45(3): 268-77, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25600891

RESUMO

Since there are very few affordable antileishmanial drugs available, antimonial resistance has crippled antileishmanial therapy, thereby emphasising the need for development of novel therapeutic strategies. This study aimed to evaluate the antileishmanial role of combined therapy with sodium antimony gluconate (SAG) and the triterpenoid glycyrrhizic acid (GA) against infection with SAG-resistant Leishmania (GE1F8R). Combination therapy with GA and SAG successfully limited infection with SAG-resistant Leishmania in a synergistic manner (fractional inhibitory concentration index <1.0). At the same time, mice infected with SAG-resistant Leishmania and co-treated with GA and SAG exhibited a significant reduction in hepatic and splenic parasite burden. In probing the mechanism, it was observed that GA treatment suppressed the expression and efflux activity of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1), two host ABC transporters responsible for antimony efflux from host cells infected with SAG-resistant parasites. This suppression correlated with greater intracellular antimony retention during SAG therapy both in vitro and in vivo, which was reflected in the reduced parasite load. Furthermore, co-administration of GA and SAG induced a shift in the cytokine balance towards a Th1 phenotype by augmenting pro-inflammatory cytokines (such as IL-12, IFNγ and TNFα) and inducing nitric oxide generation in GE1F8R-infected macrophages as well as GE1F8R-infected mice. This study aims to provide an affordable leishmanicidal alternative to expensive antileishmanial drugs such as miltefosine and amphotericin B. Furthermore, this report explores the role of GA as a resistance modulator in MRP1- and P-gp-overexpressing conditions.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Resistência a Medicamentos , Ácido Glicirrízico/administração & dosagem , Leishmania/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Animais , Gluconato de Antimônio e Sódio/farmacologia , Antiprotozoários/farmacologia , Transporte Biológico Ativo/efeitos dos fármacos , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacologia , Ácido Glicirrízico/farmacologia , Leishmania/isolamento & purificação , Leishmaniose Visceral/parasitologia , Fígado/parasitologia , Camundongos Endogâmicos BALB C , Carga Parasitária , Baço/parasitologia , Resultado do Tratamento
20.
Int J Dermatol ; 54(5): 555-63, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25600472

RESUMO

BACKGROUND: Intralesional 7% hypertonic saline (HS) has been shown to be effective and safe against Leishmania donovani and Leishmania major cutaneous leishmaniasis (CL), with cure rates of 92% and 96%, respectively. This study was designed to assess the efficacy and safety of 10% and 15% HS in CL. METHODS: A total of 444 patients (643 lesions) were randomly allocated to sodium stibogluconate (SSG), 10% HS and 15% HS at a ratio of 2 : 2 : 1, taking into consideration any unwanted side effects that might arise with 15% HS. The follow-up period was 18 months. Survival analysis using Cox proportional hazard regression was performed to assess the effectiveness of the three treatment modalities. The clinical trial was registered at the Sri Lanka Clinical Trial Registry (SLCTR/2013/024). RESULTS: Treatment with SSG resulted in a cure rate of 96.3% within one to seven injections (mean: 3.6 injections); the mean (median) duration of treatment was six weeks (6 weeks) per lesion. Treatment with 10% HS showed a cure rate of 93.0% within one to 10 injections (mean: 5.28 injections); the mean (median) duration of treatment was 9.3 weeks (9 weeks) per lesion. Treatment with 15% HS showed a cure rate of 93.6% within two to 10 injections (mean: 5.3 injections); the mean (median) duration of treatment was 11.3 weeks (10.0 weeks) per lesion. Treatment with 10% HS and 15% HS caused cutaneous necrosis in 3.1% and 30.6% of lesions, respectively. Despite continuous data collection for 14 months, we were unable to recruit a sample of sufficient size. Seventeen (3.8%) patients were lost to follow-up, and 24 (5.4%) were partial or non-responders. CONCLUSIONS: This study found 10% HS to be an effective and safe alternative to SSG. Treatment with HS at concentrations of 15% or above was not safe as a result of cutaneous necrosis. Safety was not studied for concentrations of 11-14%, and these concentrations should be avoided pending further evidence. Hypertonic saline is very cheap (< US$1 per 100 ml, whereas SSG is priced at US$160 per 100 ml), is prepared locally and has no systemic side effects and minimal local side effects.


Assuntos
Gluconato de Antimônio e Sódio/administração & dosagem , Antiprotozoários/administração & dosagem , Leishmania donovani , Leishmaniose Cutânea/tratamento farmacológico , Solução Salina Hipertônica/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Lactente , Injeções Intralesionais , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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