Browsing by Author "Neha Agrawal"

Now showing 1 - 8 of 8

Amphotericin B Deoxycholate Treatment of Post–Kala-Azar Dermal Leishmaniasis in India
(American Society of Tropical Medicine and Hygiene, 2024) Shyam Sundar; Jaya Chakravarty; Jitendra Singh; Deepak Verma; Neha Agrawal; Anju Dinkar
Post–kala-azar dermal leishmaniasis (PKDL) is widely prevalent in the endemic regions of India, but its treatment remains unsatisfactory. The WHO recommends a 12-week treatment with oral miltefosine, but its ocular toxicities are a serious concern. The late 1980s and early 1990s saw the use of sodium stibogluconate and amphotericin B (AmB) for a brief period. Both drugs had frequent adverse events and were expensive, and the duration of treatments was unacceptably long. This retrospective study evaluated, analyzed, and reported the outcomes of PKDL patients treated with a shorter course of AmB, the most effective antileishmanial drug. The hospital records of PKDL patients treated with AmB by 30 alternate-day infusions over 60 days (instead of conventional 60–80 infusions over 100–120 days) between September 2010 and August 2016 were reviewed. Only patients with confirmed parasitological diagnosis were included. Their records were studied for treatment-related adverse events, end-of-treatment parasitological status, and 12-month follow-up results. One hundred two patients were eligible for this study between September 2010 and August 2016. After therapy, 92/102 (90.2%) patients improved; 3 (2.9%) had to cease treatment owing to severe adverse effects, and one died of severe diarrhea unrelated to AmB. Six (5.9%) patients withdrew consent before the treatment was complete. At the 12-month evaluation, 89/102 (87.3%) patients attained a final cure. A 30-infusion regimen of AmB remains highly effective in PKDL. Without a shorter, safer, and more economical regimen for the treatment of PKDL, it should be used until a better regimen is available. Copyright © 2024 American Society of Tropical Medicine and Hygiene.
Current and emerging therapies for the treatment of leishmaniasis
(Taylor and Francis Ltd., 2024) Shyam Sundar; Jitendra Singh; Vishal Kumar Singh; Neha Agrawal; Rajiv Kumar
Introduction: Leishmaniasis, a neglected protozoan illness caused by kinetoplastid pathogens encompasses three major clinical subtypes: visceral, cutaneous and mucocutaneous leishmaniasis. Pentavalent antimonials (SbV) have long been the preferred treatment worldwide but increased drug resistance, and significant side effects, including cardiotoxicity have limited their use, particularly in visceral leishmaniasis in India. Similarly, other approved alternatives have concerns such as teratogenicity, high cost, and drug resistance. Areas covered: This review aims to provide an overview of emerging therapy for leishmaniasis, highlighting the latest advancements in the field and discuss their potential impact on the treatment and prevention of this neglected tropical disease. It also discusses the limitation of current treatments and need for novel approaches to address them effectively. Expert opinion: For almost eight decades, treatment for all forms of leishmaniasis was solely dependent on SbV, despite several drawbacks like long treatment regimens, cardiotoxicity, and drug resistance. In the past 20 years, three drugs with antileishmanial activity were developed for human disease, but their distribution to endemic regions and accessibility for patients remain neglected. We sorely need new antileishmanial drugs, and we present here the emerging targets for developing new antileishmanial compounds that could be brought into the clinics. © 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Development of a multiplexed assay for detection of leishmania donovani and leishmania infantum protein biomarkers in urine samples of patients with visceral leishmaniasis
(American Society for Microbiology, 2019) Claudia Abeijon; Fabiana Alves; Severine Monnerat; Monique Wasunna; Jane Mbui; Agostinho G. Viana; Lilian L. Bueno; Williane F. Siqueira; Silvio G. Carvalho; Neha Agrawal; Ricardo Fujiwara; Shyam Sundar; Antonio Campos-Neto
Visceral leishmaniasis (VL) is a serious and fatal disease caused by the parasites Leishmania infantum and Leishmania donovani. The gold standard diagnostic test for VL is the demonstration of parasites or their DNA in spleen, lymph node, or bone marrow aspirates. Serological tests exist but cannot distinguish active VL from either prior exposure to the parasites or previously treated VL disease. Using mass spectroscopy, we have previously identified three L. infantum protein biomarkers (Li-isd1, Li-txn1, and Li-ntf2) in the urine of VL patients and developed a sensitive and specific urine-based antigen detection assay for the diagnosis of VL that occurs in Brazil (where VL is caused by L. infantum). However, unpublished observations from our laboratory at DetectoGen showed that these biomarkers were detected in only 55% to 60% of VL patients from India and Kenya, where the disease is caused by L. donovani. Here, we report the discovery and characterization of two new biomarkers of L. donovani (Ld-mao1 and Ld-ppi1) present in the urine of VL patients from these two countries. Capture enzyme-linked immunosorbent assays using specific rabbit IgG and chicken IgY were developed, and the assays had sensitivities of 44.4% and 28.8% for the detection of Ld-mao1 and Ld-ppi1, respectively. In contrast, a multiplexed assay designed to simultaneously detect all five leishmanial biomarkers markedly increased the assay sensitivity to 82.2%. These results validate the utility of leishmanial protein biomarkers found in the urine of VL patients as powerful tools for the development of an accurate diagnostic test for this disease. Copyright © 2019 American Society for Microbiology. All Rights Reserved.
Effectiveness of single-dose liposomal amphotericin b in visceral leishmaniasis in Bihar
(American Society of Tropical Medicine and Hygiene, 2019) Shyam Sundar; Anup Singh; Neha Agrawal; Jaya Chakravarty
Liposomal amphotericin B (LAmB) is recommended for treatment of Indian visceral leishmaniasis (VL), with a cure rate of more than 95% in the Indian subcontinent. A prospective observational study of 1,143 subjects was performed with a longer follow-up than prior studies (12 months) to evaluate the long-term effectiveness and safety of LAmB for the treatment of VL. Patients received a single dose of 10 mg/kg LAmB and were evaluated for initial cure at day 30 and final cure at 6 and 12 months to see the response to the therapy. Furthermore, predictors of relapse were also calculated. At day 30, the initial cure rate was 100%; however, at 6 months and 12 months, cure rates were 97.0% and 94.2% by per-protocol analysis and 96.9% and 93.9% by intension-to-treat analysis, respectively. Fever was the most common adverse event (AE). There were no deaths and serious AEs. Male gender, weight less than 30 kg, and spleen size more than 4 cmat the start of the treatment were significant risk factors of relapse. Liposomal amphotericinBwas found to be very effective and safe in the treatment of VL. A longer follow-up period of 12 months is recommended to pick up late relapses. © 2019 by The American Society of Tropical Medicine and Hygiene.
Exploiting knowledge on pharmacodynamics-pharmacokinetics for accelerated anti-leishmanial drug discovery/development
(Taylor and Francis Ltd, 2019) Shyam Sundar; Neha Agrawal; Bhawana Singh
Introduction: Being on the top list of neglected tropical diseases, leishmaniasis has been marked for elimination by 2020. In the light of small armamentarium of drugs and their associated drawbacks, the understanding of pharmacodynamics and/or pharmacokinetics becomes a priority to achieve and sustain disease elimination. Areas covered: The authors have looked into pharmacological aspects of existing and emerging drugs for treatment of leishmaniasis. An in-depth understanding of pharmacodynamics and pharmacokinetics (PKPD) provides a rationale for drug designing and optimizing the treatment strategies. It forms a key to prevent drug resistance and avoid drug-associated adverse effects. The authors have compiled the researches on the PKPD of different anti-leishmanial formulations that have the potential for improved and/or effective disease intervention. Expert opinion: Understanding the pharmacological aspects of drugs forms the basis for the clinical application of novel drugs. Tailoring drug dosage and individualized treatment can avoid the adverse events and bridge gap between the in vitro models and their clinical application. An integrated approach, with pragmatic use of technological advances can improve phenotypic screening and physiochemical properties of novel drugs. Concomitantly, this can serve to improve clinical efficacies, reduce the incidence of relapse and accelerate the drug discovery/development process for leishmaniasis elimination. © 2019, © 2019 Informa UK Limited, trading as Taylor & Francis Group.
Investigational new drugs for the treatment of leishmaniasis
(Taylor and Francis Ltd., 2024) Shyam Sundar; Vishal Kumar Singh; Neha Agrawal; Om Prakash Singh; Rajiv Kumar
Introduction: Over the past 20 years, significant progress has been made in anti-leishmanial therapy. Three new drugs/formulations are available for the treatment of various forms of leishmaniasis, namely oral miltefosine, paromomycin and liposomal amphotericin B. However, these advances in drug development have added considerable complexity for clinicians including toxicity, emergence of resistance and decreased sensitivity of available drugs. The development of newer drugs with less toxicity and more efficacy is urgently needed. Areas covered: This review comprehensively examines the latest developments and current status of antileishmanial drugs for the treatment of leishmaniasis across the world. Several new investigational drugs that showed anti-leishmanial activity under in vitro or in vivo conditions and either underwent the phase-I/II clinical trials or are on the verge of entering the trials were reviewed. We also delve into the challenges of drug resistance and discuss the emergence of new and effective antileishmanial compounds. Expert opinion: The available treatments for leishmaniasis are limited in number, toxic, expensive, and demand extensive healthcare resources. Every available antileishmanial drug is associated with several disadvantages, such as drug resistance and toxicity or high cost. Miltefosine is potentially teratogenic. New antileishmanial drugs/treatment modalities are sorely needed for expanding future treatment options. © 2024 Informa UK Limited, trading as Taylor & Francis Group.
Safety and Effectiveness of Miltefosine in Post-Kala-Azar Dermal Leishmaniasis: An Observational Study
(Oxford University Press, 2023) Shyam Sundar; Jitendra Singh; Anju Dinkar; Neha Agrawal
Background: Post-kala-azar dermal leishmaniasis (PKDL) is a dermal complication of visceral leishmaniasis. Oral miltefosine (MF) is the first-line treatment for PKDL patients in South Asia. This study assessed the safety and effectiveness of MF therapy after 12 months of follow-up to explore more precise data. Methods: In this observational study, 300 confirmed PKDL patients were enrolled. MF with the usual dose was administered to all patients for 12 weeks and followed up for 1 year. Clinical evolution was recorded systematically by photographs at screening and at 12 weeks, 6 months, and 12 months after treatment onset. Definitive cure consisted of disappearance of skin lesions with a negative PCR at 12 weeks or with >70% of lesions, disappearing or fading at 12-month follow-up. Patients with reappearing clinical features and any positive diagnostics of PKDL during the follow-up were considered as nonresponsive. Results: Among 300 patients, 286 (95.3%) completed 12 weeks of treatment. The per-protocol cure rate at 12 months was 97%, but 7 patients relapsed and 51 (17%) were lost to 12-month follow-up, resulting in a final cure rate of only 76%. Eye-related adverse events were noted in 11 (3.7%) patients and resolved in most (72.7%) within 12 months. Unfortunately, 3 patients had persistent partial vision loss. Mild to moderate gastrointestinal side effects were seen in 28% patients. Conclusions: Moderate effectiveness of MF was observed in the present study. A significant number of patients developed ocular complications, and thus MF for treatment for PKDL should be suspended and replaced with a safer alternative regimen. © 2023 The Author(s). Published by Oxford University Press on behalf of Infectious Diseases Society of America.
Short-course paromomycin treatment of visceral leishmaniasis in India: 14-Day vs 21-day treatment
(2009) Shyam Sundar; Neha Agrawal; Rakesh Arora; Dipti Agarwal; Madhukar Rai; Jaya Chakravarty
Background. Treatment of visceral leishmaniasis (VL) is far from satisfactory. There is an urgent need for a therapy that is efficacious, safe, affordable, and of short duration. Methods. A randomized open-label study was conducted to assess the efficacy and safety of 2 regimens of paromomycin administered intramuscularly. Group A received 11 mg/kg/day for 14 days [n = 217) and group B received 11 mg/kg/day for 21 days (n = 112) for the treatment of VL in India. Results. Mild grade injection site pain was the most common adverse event. There was no nephrotoxicity, but 4 patients in group A had to discontinue treatment because of grade 3 elevation of hepatic enzymes. Initial cure was observed in 91.2% and 96.4% of patients in group A and group B, respectively. Definitive cure at 6 months of follow up was seen in 82% of patients in group A and 92% of patients in group B by intention-to-treat analysis and in 84.3% of patients in group A and 92.8% of patients in group B by per protocol analysis. Conclusions. Although the cure rate in the group of patients who received the 14-day regimen was not optimal, the results with respect to initial cure were encouraging. Further studies that combine a short course of paromomycin with treatment with another antileishmanial agent are warranted. (ClinicalTrials.gov identifier: NCT00629031). © 2009 by the Infectious Diseases Society of America. All rights reserved.