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Sodium stibogluconate loaded nano-deformable liposomes for topical treatment of leishmaniasis: macrophage as a target cell.

ABSTRACT: 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.

SUBMITTER: Dar MJ

PROVIDER: S-EPMC6095017 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Sodium stibogluconate loaded nano-deformable liposomes for topical treatment of leishmaniasis: macrophage as a target cell.

Dar M Junaid MJ Din Fakhar Ud FU Khan Gul Majid GM

Drug delivery 20181101 1

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 ...[more]

PMID: 30105918

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Project description:BackgroundPatients with New World cutaneous leishmaniasis (NWCL) caused by Leishmania Viannia are treated with parenteral sodium stibogluconate (SbV) to reduce the risk of development of mucocutanous leishmaniasis. Our centre manages patients with NWCL on an outpatient-basis. This study was conducted to assess the safety and efficacy of this approach.MethodologyWe reviewed records of 67 consecutive NWCL patients, aged 17-61 years, treated as day-cases with 20 mg/kg/day SbV for up to 28 days at our UK centre. Data had been collected in a standardised format at the time of treatment using a care-record tool. Patients reported adverse-effects daily using a structured questionnaire. Blood tests and electrocardiograms were performed twice weekly to monitor for toxicity.Principal findingsParenteral SbV treatment was associated with an early, significant suppression of mean lymphocyte and platelet counts. By day four of treatment, lymphocytes reduced by 0.53×10(9)/L (CI 0.29×10(9)/L to 0.76×10(9)/L, p<0.001), and platelets by 31,000/µL (CI 16,000/µL to 46,000/µL, p<0.001). SbV was further associated with significant elevation of serum alanine transaminase concentrations, with a mean peak rise of 107 iu/L by day 13 (CI 52 iu/L to 161 iu/L, p<0.001). These disturbances were temporary and did not result in adverse clinical events. Patient-described symptoms were cumulative and at three weeks of treatment, 59.6% of patients experienced myalgia and 29.8% malaise. Treatment adherence and clinical outcomes were comparable to inpatient treatment studies. A total of 1407 individual doses of SbV resulted in only 26 nights' hospital admission, a saving of 1381 bed-days compared to inpatient treatment.Conclusions/significanceIn specialist centres, NWCL patients aged below 65 years and without co-morbidities can be safely and effectively treated without hospital admission. This reduces the cost of treatment, and is much preferred by patients. Twice weekly blood and electrocardiographic monitoring may be surplus to requirement in clinically well, low-risk patients.

Project description: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.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.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.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.

Dataset Information

Sodium stibogluconate loaded nano-deformable liposomes for topical treatment of leishmaniasis: macrophage as a target cell.

Publications

Sodium stibogluconate loaded nano-deformable liposomes for topical treatment of leishmaniasis: macrophage as a target cell.

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