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The treatment of visceral leishmaniasis (kala-azar) often requires prolonged therapy. In this open-label, randomized study involving more than 400 patients in Bihar, India, a single infusion of liposomal amphotericin B was noninferior to a regimen of 15 alternate-day infusions of conventional amphotericin B deoxycholate. In patients in Bihar, India, a single infusion of liposomal amphotericin B was noninferior to a regimen of 15 alternate-day infusions of conventional amphotericin B deoxycholate. Some 90% of patients with visceral leishmaniasis (kala-azar) in India and nearly 50% of patients worldwide live in the northeastern Indian state of Bihar. 1 In Bihar, treatment with liposomal amphotericin B is effective in regimens as brief as 5 days, 1 – 3 offering a remedy for the principal drawback of all other antileishmanial agents: a prolonged duration of treatment. 1 , 4 However, when such a regimen of liposomal amphotericin B was abbreviated still further, to a single infusion of 5 or 7.5 mg per kilogram of body weight, the efficacy of the drug (90 to 91% 4 – 6 ) did not reach the . . .

In Southeast Asia, treatment is recommended for all patients with post-kala-azar dermal leishmaniasis (PKDL). Adherence to the first-line regimen, twelve weeks of miltefosine (MF), is low and ocular toxicity has been observed with this exposure period. We assessed the safety and efficacy of two shorter-course treatments: liposomal amphotericin B (LAmB) alone and combined with MF. An open-label, phase II, randomized, parallel-arm, non-comparative trial was conducted in patients with parasitologically confirmed PKDL, 6 to ≤60 years. Patients were assigned to 20 mg/kg LAmB (total dose, in five injections over 15 days) alone or combined with allometric MF (3 weeks). The primary endpoint was definitive cure at 12 months, defined as complete resolution of papular and nodular lesions and >80% re-pigmentation of macular lesions. Definitive cure at 24 months was a secondary efficacy endpoint. 118/126 patients completed the trial. Definitive cure at 12 months was observed in 29% (18/63) patients receiving LAmB and 30% (19/63) receiving LAmB/MF (mITT), increasing to 58% and 66%, respectively, at 24 months. Most lesions had resolved/improved at 12 and 24 months for patients receiving LAmB (90%, 83%) and LAmB/MF (85%, 88%) by qualitative assessment. One death, unrelated to study drugs, was reported; no study drug-related serious adverse events were observed. The most frequent adverse drug reactions were MF-related vomiting and nausea, and LAmB-related hypokalaemia and infusion reactions. Most adverse events were mild; no ocular adverse events occurred. Both regimens are suitably safe and efficacious alternatives to long-course MF for PKDL in South Asia. CTRI/2017/04/008421.

Background. The treatment of cutaneous leishmaniasis (CL) caused by leishmania braziliensis in Brazil with pentavalent antimony (Sb) is associated with a high rate of failure, up to 45% of cases. In addition, Sb can only administered parenterally and has important toxic effect. An effective, safe, and oral treatment for CL is required. Methods. A randomized controlled clinical trial was conducted to compare the efficacy and safety of high-dosage oral fluconazole (6.5–8.0 mg/kg/d for 28 days) versus a standard Sb protocol (20 mg/kg/d for 20 days) for the treatment of CL in Bahia, Brazil. Results. A total of 53 subjects were included in the trial; 26 were treated with Sb, and 27 with fluconazole. Intention-to-treat analysis showed initial cure rates (2 months after treatment) of 22.2% (6 of 27) in the fluconazole and 53.8% (14 of 26) in the Sb group (P = .04). Six months after treatment, the final cure rate remained the same in both groups, without any replaces. The frequencies of adverse effects in the Sb and fluconazole groups were similar, 34.6% versus 37% respectively. One patient treated with fluconazole discontinued treatment owing to malaise, headache, and moderate dizziness (Common Terminology Criteria for Adverse Events grade 2). Conclusions. Oral fluconazole at a dosage of 6.5–8 mg/kg/d for 28 days should not be considered an effective treatment for CL caused by L. braziliensis. Clinical Trials Registration. NCT01953744.

Visceral leishmaniasis (kala-azar) disproportionately affects the rural poor, with approximately 500,000 cases worldwide. Treatment options are limited, especially in resource-poor settings. In this open label, comparator-controlled trial, intramuscular paromomycin was found to be noninferior to intravenous amphotericin B in the treatment of visceral leishmaniasis, with cure rates of 94.6% and 98.8%, respectively. Intramuscular paromomycin was found to be noninferior to intravenous amphotericin B in the treatment of visceral leishmaniasis, with cure rates of 94.6% and 98.8%, respectively. Visceral leishmaniasis (kala-azar) is primarily a fatal vectorborne parasitic disease characterized by fever, hepatosplenomegaly, and pancytopenia. Most of the approximately 500,000 cases of visceral leishmaniasis reported worldwide affect the rural poor in India, Nepal, Bangladesh, Sudan, and Brazil. 1 Treatment options for visceral leishmaniasis are limited. Sodium stibogluconate, a historically effective and affordable pentavalent antimonial compound, is associated with fatal toxic effects, 2 – 4 and in some regions its use has led to the development of resistant strains of Leishmania donovani, 5 with the result that fewer than 50% of treated patients are cured. 2 , 6 – 8 In regions where antimony resistance is prevalent, . . .

causes fatal and debilitating brain and eye diseases. Medicines that are currently used to treat toxoplasmosis commonly have toxic side effects and require prolonged courses that range from weeks to more than a year. The need for long treatment durations and the risk of relapsing disease are in part due to the lack of efficacy against tissue cysts. The challenges for developing a more effective treatment for toxoplasmosis include decreasing toxicity, achieving therapeutic concentrations in the brain and eye, shortening duration, eliminating tissue cysts from the host, safety in pregnancy, and creating a formulation that is inexpensive and practical for use in resource-poor areas of the world. Over the last decade, significant progress has been made in identifying and developing new compounds for the treatment of toxoplasmosis. Unlike clinically used medicines that were repurposed for toxoplasmosis, these compounds have been optimized for efficacy against toxoplasmosis during preclinical development. Medicines with enhanced efficacy as well as features that address the unique aspects of toxoplasmosis have the potential to greatly improve toxoplasmosis therapy. This review discusses the facets of toxoplasmosis that are pertinent to drug design and the advances, challenges, and current status of preclinical drug research for toxoplasmosis.

Improved treatment approaches are needed for visceral leishmaniasis. We assessed the efficacy and safety of three potential short-course combination treatments compared with the standard monotherapy in India. Standard treatment (1 mg/kg amphotericin B infusion on alternate days for 30 days, total dose 15 mg/kg) was compared with three drug combinations (single injection of 5 mg/kg liposomal amphotericin B and 7-day 50 mg oral miltefosine or single 10-day 11 mg/kg intramuscular paromomycin; or 10 days each of miltefosine and paromomycin) in an open-label, parallel-group, non-inferiority, randomised controlled trial in two hospital sites in Bihar, India. Patients aged 5–60 years with parasitologically confirmed visceral leishmaniasis were randomly assigned one of the four treatments by the trial statistician by use of a computer-generated list. Clinical assessments were done at the end of treatment (15 days on combination treatment; 31 days for standard treatment) and after 45 days and 6 months. The primary endpoint was definitive cure (defined as no sign or symptom of visceral leishmaniasis and parasitologically cured to the last follow-up). Analyses were done both by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00696969. Between June, 2008, and July, 2009, 634 patients were assigned amphotericin B (n=157), liposomal amphotericin B with miltefosine (n=160) or paromomycin (n=158), or miltefosine and paromomycin (n=159). 618 patients were in the per-protocol population. There were two relapses in each group. The numbers with definitive cure at 6 months for the intention-to-treat population were 146 (cure rate 93·0%; CI 87·5–96·3) for amphotericin B, 156 (97·5%; 93·3–99·2) for liposomal amphotericin B and miltefosine, 154 (97·5%; 93·24–99·2) for liposomal amphotericin B and paromomycin, and 157 (98·7%; 95·1–99·8) for miltefosine and paromomycin. All combinations were non-inferior to the standard treatment, in both the intention-to-treat and per-protocol populations. Patients in the combination groups had fewer adverse events than did those assigned standard treatment. Combination treatments for visceral leishmaniasis are efficacious and safe, and decrease the duration of therapy, thereby encouraging adherence and reducing emergence of drug-resistant parasites. Drugs for Neglected Diseases initiative and the Indian Council of Medical Research.

Cutaneous leishmaniasis (CL) is caused by Leishmania parasites and affects 1.2 million cases annually, mainly in the Americas and the Eastern Mediterranean region. The standard treatment with pentavalent antimonials is often limited by its toxicity, prompting the search for alternative therapies. Arnica montana L. (Asteraceae) is a well-known phytotherapeutic plant with anti-inflammatory properties, traditionally used to treat bruises, sprains, distortions, and inflammation caused by insect bites. In our previous work, Arnica tincture (AT) obtained from the flowers showed excellent in vitro activity against Leishmania and in vivo activity in a golden hamster model of CL. It also demonstrated high skin permeability and retention in the epidermis without systemic circulation, making it a promising option for topical treatment of CL. We conducted a randomized, open-label, phase Ib-II clinical trial. Adults with parasitologically confirmed uncomplicated CL were randomly assigned to receive AT topically, 3 times daily, for either 30 or 45 days. We assessed therapeutic response and monitored safety by recording adverse events at each follow-up visit. All adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. Sixteen subjects were enrolled, with eight assigned to each treatment regimen. Twelve participants completed the 180-day follow-up, all achieved complete lesion healing (100% cure rate). Four participants withdrew their informed consent before or during treatment. The most common adverse events were mild and included erythema, pain, edema, and a burning sensation at the application site. No severe adverse effects were reported. AT showed promising results in treating CL and had a favorable safety profile. Due to the small sample size and lack of comparison with standard therapies, further studies with more robust methodologies are needed to confirm these findings. NCT05094908.

Treatment of Visceral Leishmaniasis (VL), a neglected tropical disease, is very challenging with few treatment options. Long duration of treatment and drug toxicity further limit the target of achieving VL elimination. Chemotherapy remains the treatment of choice. Single dose of liposomal amphotericin B (LAmB) and multidrug therapy (LAmB + miltefosine, LAmB + paromomycin (PM), or miltefosine + PM) are recommended treatment regimen for treatment of VL in Indian sub-continent. Combination therapy of pentavalent antimonials (Sbv) and PM in East Africa and LAmB in the Mediterranean region/South America remains the treatment of choice. Various drugs having anti-leishmania properties are in preclinical phase and need further development. An effective treatment and secondary prophylaxis of HIV-VL co-infection should be developed to decrease treatment failure and drug resistance.

Human protozoan diseases represent a serious health problem worldwide, affecting mainly people in social and economic vulnerability. These diseases have attracted little investment in drug discovery, which is reflected in the limited available therapeutic arsenal. Authorized drugs present problems such as low efficacy in some stages of the disease or toxicity, which result in undesirable side effects and treatment abandonment. Moreover, the emergence of drug-resistant parasite strains makes necessary an even greater effort to develop safe and effective antiparasitic agents. Among the chemotypes investigated for parasitic diseases, the indole nucleus has emerged as a privileged molecular scaffold for the generation of new drug candidates. In this review, the authors provide an overview of the indole-based compounds developed against important parasitic diseases, namely malaria, trypanosomiasis and leishmaniasis, by focusing on the design, optimization and synthesis of the most relevant synthetic indole scaffolds recently reported.

Background Cryptosporidium infection and diarrhea (cryptosporidiosis) is a life-threatening infection in persons with HIV and also in children of 6–18 months of age in the developing world. To date, only nitazoxanide is licensed for treatment of cryptosporidiosis, and only in persons after the first year of life and with healthy immune systems. Clofazimine (CFZ: Lamprene®), an established drug that has been used for leprosy for more than 50 years, recently has been described as effective against Cryptosporidium in vitro and in mouse infections. The efficacy and pharmacokinetics of CFZ in vivo , in HIV-infected patients with cryptosporidial diarrhea are not known. Methods CRYPTOFAZ includes a randomized, double-blind, placebo-controlled study of the safety, tolerability and Cryptosporidium inhibitory activity of orally administered CFZ in subjects with HIV infection and chronic diarrhea with Cryptosporidium. An additional open label aspect of the study will compare the pharmacokinetics (PK) of orally administered CFZ in HIV-infected individuals with and without Cryptosporidium-associated diarrhea. The study will recruit a total of 66 subjects. Study participants will be given either CFZ or a placebo for 5 days while in hospital and will be followed up after discharge. Cryptosporidium will be diagnosed by quantitative PCR as the definitive test and by stool ELISA, which will also be used to quantify the shedding of Cryptosporidium in stool. PK will be studied on plasma and stool samples. Primary endpoints include reduction in the number of Cryptosporidium shed in stools over a 5-day period and compared to placebo recipients and the PK of CFZ in plasma assessed by area under the curve, peak plasma concentration, and half-life (T ½) determined after the last dose. Discussion This study provides an opportunity to explore a possible treatment option for HIV-infected patients with cryptosporidial diarrhea, who, as of now in Malawi and most of sub-Saharan Africa, do not have a definitive treatment apart from supportive care. The strength of this study lies in it being a randomized, double-blind, placebo-controlled trial. If shown to be effective and safe, the findings will also lay a foundation for a future study of the use of CFZ in children 6–18 months of age. Trial registration ClinicalTrials.gov, NCT03341767 . Registered on 14 November 2017.