Antischistosomal, antionchocercal and antitrypanosomal potentials of some Ghanaian traditional medicines and their constituents.

BACKGROUND: Ghana is endemic for some neglected tropical diseases (NTDs) including schistosomiasis, onchocerciasis and lymphatic filariasis. The major intervention for these diseases is mass drug administration of a few repeatedly recycled drugs which is a cause for major concern due to reduced efficacy of the drugs and the emergence of drug resistance. Evidently, new treatments are needed urgently. Medicinal plants, on the other hand, have a reputable history as important sources of potent therapeutic agents in the treatment of various diseases among African populations, Ghana inclusively, and provide very useful starting points for the discovery of much-needed new or alternative drugs. METHODOLOGY/PRINCIPAL FINDINGS: In this study, extracts of fifteen traditional medicines used for treating various NTDs in local communities were screened in vitro for efficacy against schistosomiasis, onchocerciasis and African trypanosomiasis. Two extracts, NTD-B4-DCM and NTD-B7-DCM, prepared from traditional medicines used to treat schistosomiasis, displayed the highest activity (IC50 = 30.5 µg/mL and 30.8 µg/mL, respectively) against Schistosoma mansoni adult worms. NTD-B2-DCM, also obtained from an antischistosomal remedy, was the most active against female and male adult Onchocera ochengi worms (IC50 = 76.2 µg/mL and 76.7 µg/mL, respectively). Antitrypanosomal assay of the extracts against Trypanosoma brucei brucei gave the most promising results (IC50 = 5.63 µg/mL to 18.71 µg/mL). Incidentally, NTD-B4-DCM and NTD-B2-DCM, also exhibited the greatest antitrypanosomal activities (IC50 = 5.63 µg/mL and 7.12 µg/mL, respectively). Following the favourable outcome of the antitrypanosomal screening, this assay was selected for bioactivity-guided fractionation. NTD-B4-DCM, the most active extract, was fractionated and subsequent isolation of bioactive constituents led to an eupatoriochromene-rich oil (42.6%) which was 1.3-fold (IC50 <0.0977 µg/mL) more active than the standard antitrypanosomal drug, diminazene aceturate (IC50 = 0.13 µg/mL). CONCLUSION/SIGNIFICANCE: These findings justify the use of traditional medicines and demonstrate their prospects towards NTDs drug discovery.

Leishmanicidal activity of Piper marginatum Jacq. from Santarém-PA against Leishmania amazonensis.

Leishmaniasis is an infectious disease that has high endemicity and is among the six parasitic diseases of higher occurrence in the world. The current treatments are limited due to their toxicity, treatment resistance and high cost which have increased the search for new substances of natural origin for its therapy. Based on this, an in vitro biological and chemical investigation was carried out to evaluate the potential of Piper marginatum against Leishmania amazonesis. P. marginatum leaves were collected to obtain the essential oil (EO) and the ethanolic extract (CE). The chemical profile of the CE and fractions was obtained by 1H NMR. The analysis of the EO chemical composition was performed by GC-MS. EO, CE and fractions were submitted to antileishmanial and cytotoxicity assays against macrophages. The chromatographic profiles of EO, CE and fractions showed the presence of phenolic compounds and terpenoids, having 3,4-Methylenedioxypropiophenone as a major compound. All P. marginatum samples showed low toxicity to macrophages. The CE and the methanolic, hexane and ethyl acetate fractions had low cytotoxicity when compared to Pentamidine. All tested samples inhibited growth of L. amazonensis promastigotes. The antileishmanial activity of EO, CE and fractions were evaluated in macrophages infected with L. (L.) amazonensis and treated with the concentrations 1, 10 and 100 µg/mL for 48 h. All samples were active, but EO and CE showed superior activity against amastigote forms when compared to the promastigote forms of L. amazonensis. This work describes for the first time the antileishmanial activity of the species P. marginatum and its cytotoxicity against macrophages, suggesting that it can be an alternative source of natural products in the phytotherapeutic treatment of leishmaniasis.

A semi-synthetic neolignan derivative from dihydrodieugenol B selectively affects the bioenergetic system of Leishmania infantum and inhibits cell division.

Leishmaniasis is a neglected disease that affects more than 12 million people, with a limited therapy. Plant-derived natural products represent a useful source of anti-protozoan prototypes. In this work, four derivatives were prepared from neolignans isolated from the Brazilian plant Nectandra leucantha, and their effects against intracellular amastigotes of Leishmania (L.) infantum evaluated in vitro. IC50 values between 6 and 35 µM were observed and in silico predictions suggested good oral bioavailability, no PAINS similarities, and ADMET risks typical of lipophilic compounds. The most selective (SI > 32) compound was chosen for lethal action and immunomodulatory studies. This compound caused a transient depolarization of the plasma membrane potential and induced an imbalance of intracellular Ca2+, possibly resulting in a mitochondrial impairment and leading to a strong depolarization of the membrane potential and decrease of ATP levels. The derivative also interfered with the cell cycle of Leishmania, inducing a programmed cell death-like mechanism and affecting DNA replication. Further immunomodulatory studies demonstrated that the compound eliminates amastigotes via an independent activation of the host cell, with decrease levels of IL-10, TNF and MCP-1. Additionally, this derivative caused no hemolytic effects in murine erythrocytes and could be considered promising for future lead studies.

Strongyloidiasis: A Neglected Tropical Disease.

Most of the 30 to 100 million people infected with Strongyloides stercoralis have subclinical (or asymptomatic) infections. These infections are commonly chronic and longstanding. A change in immune status can increase parasite numbers, leading to hyperinfection syndrome, dissemination, and death if unrecognized. The use of corticosteroids and HTLV-1 infection are most commonly associated with the hyperinfection syndrome. Strongyloides adult parasites reside in the small intestine and induce immune responses that are like other nematodes. Definitive diagnosis of S stercoralis infection is based on stool examinations for larvae. S stercoralis remains largely neglected.

In vitro Anti-Trypanosomal Activities of Indanone-Based Chalcones.

Human African trypanosomiasis is a neglected infectious disease that affects mostly people living in the rural areas of Africa. Current treatment options are limited to just four drugs that have been in use of four to nine decades. The life-threatening toxic side-effects associated with the use of these drugs are disconcerting. Poor efficacy, low oral bioavailability, and high cost are other shortcomings of current HAT treatments. Evaluating the potentials of known hits for other therapeutic areas may be a fast and convenient method to discover new hit compounds against alternative targets. A library of 34 known indanone based chalcones was screened against T.b. brucei and nine potent hits, having IC50 values between 0.5-8.9 µM, were found. The SAR studies of this series could provide useful information in guiding future exploration of this class of compounds in search of more potent, safe, and low cost anti-trypanosomal agents. Graphical Abstract.

Fragment-based drug discovery as alternative strategy to the drug development for neglected diseases.

Neglected diseases (NDs) affect large populations and almost whole continents, representing 12% of the global health burden. In contrast, the treatment available today is limited and sometimes ineffective. Under this scenery, the Fragment-Based Drug Discovery emerged as one of the most promising alternatives to the traditional methods of drug development. This method allows achieving new lead compounds with smaller size of fragment libraries. Even with the wide Fragment-Based Drug Discovery success resulting in new effective therapeutic agents against different diseases, until this moment few studies have been applied this approach for NDs area. In this article, we discuss the basic Fragment-Based Drug Discovery process, brief successful ideas of general applications and show a landscape of its use in NDs, encouraging the implementation of this strategy as an interesting way to optimize the development of new drugs to NDs.

Integrating Neglected Tropical Disease and Immunization Programs: The Experiences of the Tanzanian Ministry of Health.

Global health practitioners are increasingly advocating for the integration of community-based health-care platforms as a strategy for increasing the coverage of programs, encouraging program efficiency, and promoting universal health-care goals. To leverage the strengths of compatible programs and avoid geographic and temporal duplications in efforts, the Tanzanian Ministry of Health and Social Welfare coordinated immunization and neglected tropical disease programs for the first time in 2014. Specifically, a measles and rubella supplementary vaccine campaign, mass drug administration (MDA) of ivermectin and albendazole, and Vitamin A were provisionally integrated into a shared community-based delivery platform. Over 21 million people were targeted by the integrated campaign, with the immunization program and MDA program reaching 97% and 93% of targeted individuals, respectively. The purpose of this short report is to share the Tanzanian experience of launching and managing this integrated campaign with key stakeholders.

Search for Antiprotozoal Activity in Herbal Medicinal Preparations; New Natural Leads against Neglected Tropical Diseases.

Sleeping sickness, Chagas disease, Leishmaniasis, and Malaria are infectious diseases caused by unicellular eukaryotic parasites ("protozoans"). The three first mentioned are classified as Neglected Tropical Diseases (NTDs) by the World Health Organization and together threaten more than one billion lives worldwide. Due to the lack of research interest and the high increase of resistance against the existing treatments, the search for effective and safe new therapies is urgently required. In view of the large tradition of natural products as sources against infectious diseases [1,2], the aim of the present study is to investigate the potential of legally approved and marketed herbal medicinal products (HMPs) as antiprotozoal agents. Fifty-eight extracts from 53 HMPs on the German market were tested by a Multiple-Target-Screening (MTS) against parasites of the genera Leishmania, Trypanosoma, and Plasmodium. Sixteen HMPs showed in vitro activity against at least one of the pathogens (IC50 < 10 µg/mL). Six extracts from preparations of Salvia, Valeriana, Hypericum, Silybum, Arnica, and Curcuma exhibited high activity (IC50 < 2.5 µg/mL). They were analytically characterized by UHPLC/ESI-QqTOF-MSMS and the activity-guided fractionation of the extracts with the aim to isolate and identify the active compounds is in progress.

Preventive chemotherapy and the fight against neglected tropical diseases.

Preventive chemotherapy is the public health strategy recommended by the WHO against a set of neglected tropical diseases that includes four groups of helminth infections (lymphatic filariasis, onchocerciasis, schistosomiasis and soil-transmitted helminthiasis) and one chlamydial (trachoma) infection. This article presents the characteristics of preventive chemotherapy interventions directed against each disease targeted by this strategy and provides an update on the status of their implementation worldwide.

Development of novel drugs for human African trypanosomiasis.

Human African trypanosomiasis (HAT) or 'sleeping sickness' is a neglected tropical disease caused by the parasite Trypanosoma brucei. Novel models for funding pharmaceutical development against HAT are beginning to yield results. The Drugs for Neglected Diseases initiative (DNDi) rediscovered a nitroimidazole, fexinidazole, which is currently in Phase I clinical trials. Novel benzoxaboroles, discovered by Anacor, Scynexis and DNDi, have good pharmacokinetic properties in plasma and in the brain and are curative in a murine model of stage two HAT with brain infection. The Consortium for Parasitic Drug Development (CPDD) has identified a series of dicationic compounds that can cure a monkey model of stage two HAT. With other screening programs yielding hits, the pipeline for new HAT drugs might finally begin to fill.