scholarly journals Onchocerciasis drug development: from preclinical models to humans

2021 ◽  
Author(s):  
Adela Ngwewondo ◽  
Ivan Scandale ◽  
Sabine Specht
Keyword(s):  
Drug Development ◽  
Neglected Tropical Diseases ◽  
Clinical Stage ◽  
Safety Margin ◽  
New Drugs ◽  
World Health ◽  
Program Goal ◽  
Medical Needs ◽  
Disease Elimination ◽  
Development Pipeline

Abstract Twenty diseases are recognized as neglected tropical diseases (NTDs) by World Health Assembly resolutions, including human filarial diseases. The end of NTDs is embedded within the Sustainable Development Goals for 2030, under target 3.3. Onchocerciasis afflicts approximately 20.9 million people worldwide with > 90% of those infected residing in Africa. Control programs have made tremendous efforts in the management of onchocerciasis by mass drug administration and aerial larviciding; however, disease elimination is not yet achieved. In the new WHO roadmap, it is recognized that new drugs or drug regimens that kill or permanently sterilize adult filarial worms would significantly improve elimination timelines and accelerate the achievement of the program goal of disease elimination. Drug development is, however, handicapped by high attrition rates, and many promising molecules fail in preclinical development or in subsequent toxicological, safety and efficacy testing; thus, research and development (R&D) costs are, in aggregate, very high. Drug discovery and development for NTDs is largely driven by unmet medical needs put forward by the global health community; the area is underfunded and since no high return on investment is possible, there is no dedicated drug development pipeline for human filariasis. Repurposing existing drugs is one approach to filling the drug development pipeline for human filariasis. The high cost and slow pace of discovery and development of new drugs has led to the repurposing of “old” drugs, as this is more cost-effective and allows development timelines to be shortened. However, even if a drug is marketed for a human or veterinary indication, the safety margin and dosing regimen will need to be re-evaluated to determine the risk in humans. Drug repurposing is a promising approach to enlarging the pool of active molecules in the drug development pipeline. Another consideration when providing new treatment options is the use of combinations, which is not addressed in this review. We here summarize recent advances in the late preclinical or early clinical stage in the search for a potent macrofilaricide, including drugs against the nematode and against its endosymbiont, Wolbachia pipientis.

scholarly journals Neglected tropical diseases in Brazil

2009 ◽  
Vol 51 (5) ◽  
pp. 247-253 ◽  
Author(s):  
José Angelo L. Lindoso ◽  
Ana Angélica B.P. Lindoso
Keyword(s):  
Neglected Tropical Diseases ◽  
Clinical Manifestations ◽  
Northern Region ◽  
New Drugs ◽  
World Health ◽  
Tropical Diseases ◽  
The North ◽  
The World ◽  
The Status ◽  
Health Organization

Poverty is intrinsically related to the incidence of Neglected Tropical Diseases (NTDs). The main countries that have the lowest human development indices (HDI) and the highest burdens of NTDs are located in tropical and subtropical regions of the world. Among these countries is Brazil, which is ranked 70th in HDI. Nine out of the ten NTDs established by the World Health Organization (WHO) are present in Brazil. Leishmaniasis, tuberculosis, dengue fever and leprosy are present over almost the entire Brazilian territory. More than 90% of malaria cases occur in the Northern region of the country, and lymphatic filariasis and onchocerciasis occur in outbreaks in a particular region. The North and Northeast regions of Brazil have the lowest HDIs and the highest rates of NTDs. These diseases are considered neglected because there is not important investment in projects for the development of new drugs and vaccines and existing programs to control these diseases are not sufficient. Another problem related to NTDs is co-infection with HIV, which favors the occurrence of severe clinical manifestations and therapeutic failure. In this article, we describe the status of the main NTDs currently occurring in Brazil and relate them to the HDI and poverty.

scholarly journals Development of emodepside as a possible adulticidal treatment for human onchocerciasis—The fruit of a successful industrial–academic collaboration

2021 ◽  
Vol 17 (7) ◽  
pp. e1009682
Author(s):  
Jürgen Krücken ◽  
Lindy Holden-Dye ◽  
Jennifer Keiser ◽  
Roger K. Prichard ◽  
Simon Townson ◽  
...  
Keyword(s):  
Drug Development ◽  
Broad Spectrum ◽  
Neglected Tropical Diseases ◽  
Current Knowledge ◽  
Animal Health ◽  
World Health ◽  
Parasitic Nematodes ◽  
Term Therapy ◽  
Neglected Diseases ◽  
Phase I Clinical Trials

Current mass drug administration (MDA) programs for the treatment of human river blindness (onchocerciasis) caused by the filarial worm Onchocerca volvulus rely on ivermectin, an anthelmintic originally developed for animal health. These treatments are primarily directed against migrating microfilariae and also suppress fecundity for several months, but fail to eliminate adult O. volvulus. Therefore, elimination programs need time frames of decades, well exceeding the life span of adult worms. The situation is worsened by decreased ivermectin efficacy after long-term therapy. To improve treatment options against onchocerciasis, a drug development candidate should ideally kill or irreversibly sterilize adult worms. Emodepside is a broad-spectrum anthelmintic used for the treatment of parasitic nematodes in cats and dogs (Profender and Procox). Our current knowledge of the pharmacology of emodepside is the result of more than 2 decades of intensive collaborative research between academia and the pharmaceutical industry. Emodepside has a novel mode of action with a broad spectrum of activity, including against extraintestinal nematode stages such as migrating larvae or macrofilariae. Therefore, emodepside is considered to be among the most promising candidates for evaluation as an adulticide treatment against onchocerciasis. Consequently, in 2014, Bayer and the Drugs for Neglected Diseases initiative (DNDi) started a collaboration to develop emodepside for the treatment of patients suffering from the disease. Macrofilaricidal activity has been demonstrated in various models, including Onchocerca ochengi in cattle, the parasite most closely related to O. volvulus. Emodepside has now successfully passed Phase I clinical trials, and a Phase II study is planned. This Bayer–DNDi partnership is an outstanding example of “One World Health,” in which experience gained in veterinary science and drug development is translated to human health and leads to improved tools to combat neglected tropical diseases (NTDs) and shorten development pathways and timelines in an otherwise neglected area.

scholarly journals Drug Resistance in Visceral Leishmaniasis

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Helena C. Maltezou
Keyword(s):  
Visceral Leishmaniasis ◽  
Neglected Tropical Diseases ◽  
Public Health Problem ◽  
New Drugs ◽  
World Health ◽  
Oral Agent ◽  
Molecular Surveillance ◽  
Health Organization ◽  
Combination Regimens ◽  
Emergence Of Resistance

Visceral leishmaniasis remains a public health problem worldwide. This illness was included by the World Health Organization in the list of neglected tropical diseases targeted for elimination by 2015. The widespread emergence of resistance to pentavalent antimonials in India where half cases occur globally and the unavailability of a vaccine in clinical use constitute major obstacles in achieving this goal. The last decade new antileishmanials became available, including the oral agent miltefosine. However, in poor endemic countries their wide use was curtailed because of the high costs, and also due to concerns of toxicity and emergence of resistance. Various mechanisms of antileishmanial resistance were identified recently in field isolates. Their elucidation will boost the design of new drugs and the molecular surveillance of resistance. Combination regimens should be evaluated in large trials. Overall, the development of antileishmanials has been generally slow; new drugs are needed. In order to control visceral leishmaniasis worldwide, treatment advances should become affordable in the poorest countries, where they are needed most.

scholarly journals NTD Diagnostics for Disease Elimination: A Review

Diagnostics ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 375
Author(s):  
Emma Michelle Taylor
Keyword(s):  
Neglected Tropical Diseases ◽  
Point Of Care ◽  
Multiple Roles ◽  
Tropical Diseases ◽  
Point Of Care Testing ◽  
Disease Elimination ◽  
Attack Phase ◽  
Development Pipeline ◽  
Diagnostic Technologies ◽  
The Ideal

Neglected Tropical Diseases (NTDs) marked out for disease elimination provide a lens through which to explore the changing status of diagnosis in global health. This paper reports on the findings of a scoping review, which set out to explore the main debates around diagnosis for the elimination of NTDs, including the multiple roles diagnostic technologies are being ascribed and the ideal characteristics of tests. It also attempts to summarise the state of diagnosis for three NTDs with elimination goals. The review places special emphasis on point-of-care testing in acknowledgement of the remote and underserved areas where NTDs proliferate. Early NTD campaigns were largely focused on attack phase planning, whereby a similar set of interventions could be transplanted anywhere. Now, with elimination goals in sight, strategies must be tailored to local settings if they are to attain and sustain success. Diagnostic data helps with local adaptation and is increasingly used for programmatic decision-making. The review finds that elimination goals reframe whom diagnosis is for and the myriad roles diagnostics can play. The exigencies of elimination also serve to highlight deficiencies in the current diagnostic arsenal and development pipeline for many NTDs. Moving forward, a guiding framework is needed to drive research and stimulate investment in diagnosis to support NTD goals.

The Effect of Price on Pharmaceutical R&D

2009 ◽  
Vol 9 (1) ◽  
Author(s):  
Abdulkadir Civan ◽  
Michael T. Maloney
Keyword(s):  
United States ◽  
Drug Development ◽  
Price Elasticity ◽  
The United States ◽  
Mortality Rates ◽  
New Drugs ◽  
New Drug ◽  
Development Pipeline ◽  
New Drug Development

Abstract This work extends prior research that finds drug development is driven by demand factors such as mortality rates of the diseases new drugs are aimed at. Here we find that the number of drugs in the development pipeline is strongly positively related to the price of existing drugs treating those diseases. This gives us a direct price elasticity measure from which we can draw some inference about the effect on new drug development that might occur if the pricing regime in the United States were to change.

scholarly journals Supporting drug development for neglected tropical diseases using mathematical modelling

2021 ◽  
Author(s):  
Martin Walker ◽  
Jonathan I D Hamley ◽  
Philip Milton ◽  
Frédéric Monnot ◽  
Sally Kinrade ◽  
...  
Keyword(s):  
Drug Development ◽  
Mathematical Modelling ◽  
Neglected Tropical Diseases ◽  
Public Health Problem ◽  
World Health ◽  
Tropical Diseases ◽  
Resource Saving ◽  
Preventive Chemotherapy ◽  
Health Organization ◽  
Chemotherapy Strategy

Abstract Drug-based interventions are at the heart of global efforts to reach elimination as a public health problem (trachoma, soil-transmitted helminthiases, schistosomiasis, lymphatic filariasis) or elimination of transmission (onchocerciasis) for five of the most prevalent neglected tropical diseases tackled via the World Health Organization preventive chemotherapy strategy. While for some of these diseases there is optimism that currently available drugs will be sufficient to achieve the proposed elimination goals, for others—particularly onchocerciasis—there is a growing consensus that novel therapeutic options will be needed. Since in this area no high return of investment is possible, minimizing wasted money and resources is essential. Here, we use illustrative results to show how mathematical modelling can guide the drug development pathway, yielding resource-saving and efficiency payoffs, from the refinement of target product profiles and intended context of use, to the design of clinical trials.

scholarly journals Screening Marine Natural Products for New Drug Leads against Trypanosomatids and Malaria

Marine Drugs ◽  
2020 ◽  
Vol 18 (4) ◽  
pp. 187 ◽  
Author(s):  
María Álvarez-Bardón ◽  
Yolanda Pérez-Pertejo ◽  
César Ordóñez ◽  
Daniel Sepúlveda-Crespo ◽  
Nestor M. Carballeira ◽  
...  
Keyword(s):  
Natural Products ◽  
High Throughput Screening ◽  
High Performance ◽  
Social Issues ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
World Health ◽  
World Population ◽  
The World ◽  
Health Organization

Neglected Tropical Diseases (NTD) represent a serious threat to humans, especially for those living in poor or developing countries. Almost one-sixth of the world population is at risk of suffering from these diseases and many thousands die because of NTDs, to which we should add the sanitary, labor and social issues that hinder the economic development of these countries. Protozoan-borne diseases are responsible for more than one million deaths every year. Visceral leishmaniasis, Chagas disease or sleeping sickness are among the most lethal NTDs. Despite not being considered an NTD by the World Health Organization (WHO), malaria must be added to this sinister group. Malaria, caused by the apicomplexan parasite Plasmodium falciparum, is responsible for thousands of deaths each year. The treatment of this disease has been losing effectiveness year after year. Many of the medicines currently in use are obsolete due to their gradual loss of efficacy, their intrinsic toxicity and the emergence of drug resistance or a lack of adherence to treatment. Therefore, there is an urgent and global need for new drugs. Despite this, the scant interest shown by most of the stakeholders involved in the pharmaceutical industry makes our present therapeutic arsenal scarce, and until recently, the search for new drugs has not been seriously addressed. The sources of new drugs for these and other pathologies include natural products, synthetic molecules or repurposing drugs. The most frequent sources of natural products are microorganisms, e.g., bacteria, fungi, yeasts, algae and plants, which are able to synthesize many drugs that are currently in use (e.g. antimicrobials, antitumor, immunosuppressants, etc.). The marine environment is another well-established source of bioactive natural products, with recent applications against parasites, bacteria and other pathogens which affect humans and animals. Drug discovery techniques have rapidly advanced since the beginning of the millennium. The combination of novel techniques that include the genetic modification of pathogens, bioimaging and robotics has given rise to the standardization of High-Performance Screening platforms in the discovery of drugs. These advancements have accelerated the discovery of new chemical entities with antiparasitic effects. This review presents critical updates regarding the use of High-Throughput Screening (HTS) in the discovery of drugs for NTDs transmitted by protozoa, including malaria, and its application in the discovery of new drugs of marine origin.

scholarly journals Anthelmintic drug discovery: target identification, screening methods and the role of open science

2020 ◽  
Vol 16 ◽  
pp. 1203-1224 ◽  
Author(s):  
Frederick A Partridge ◽  
Ruth Forman ◽  
Carole J R Bataille ◽  
Graham M Wynne ◽  
Marina Nick ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Neglected Tropical Diseases ◽  
Open Science ◽  
New Drugs ◽  
World Health ◽  
Neglected Diseases ◽  
Screening Methods ◽  
Screening Programs ◽  
Anthelmintic Drug ◽  
Compound Screening

Helminths, including cestodes, nematodes and trematodes, are a huge global health burden, infecting hundreds of millions of people. In many cases, existing drugs such as benzimidazoles, diethylcarbamazine, ivermectin and praziquantel are insufficiently efficacious, contraindicated in some populations, or at risk of the development of resistance, thereby impeding progress towards World Health Organization goals to control or eliminate these neglected tropical diseases. However, there has been limited recent progress in developing new drugs for these diseases due to lack of commercial attractiveness, leading to the introduction of novel, more efficient models for drug innovation that attempt to reduce the cost of research and development. Open science aims to achieve this by encouraging collaboration and the sharing of data and resources between organisations. In this review we discuss how open science has been applied to anthelmintic drug discovery. Open resources, including genomic information from many parasites, are enabling the identification of targets for new antiparasitic agents. Phenotypic screening remains important, and there has been much progress in open-source systems for compound screening with parasites, including motility assays but also high content assays with more detailed investigation of helminth physiology. Distributed open science compound screening programs, such as the Medicines for Malaria Venture Pathogen Box, have been successful at facilitating screening in diverse assays against many different parasite pathogens and models. Of the compounds identified so far in these screens, tolfenpyrad, a repurposed insecticide, shows significant promise and there has been much progress in creating more potent and selective derivatives. This work exemplifies how open science approaches can catalyse drug discovery against neglected diseases.

scholarly journals Collaborative Use Repurposing Engine (CURE): FDA-NCATS/NIH Effort to Capture the Global Clinical Experience of Drug Repurposing to Facilitate Development of New Treatments for Neglected and Emerging Infectious Diseases

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S12-S12 ◽  
Author(s):  
Heather Stone ◽  
Leonard Sacks ◽  
Rosemary Tiernan ◽  
Mili Duggal ◽  
Timothy Sheils ◽  
...  
Keyword(s):  
Clinical Experience ◽  
Health Care Providers ◽  
Neglected Tropical Diseases ◽  
Mobile App ◽  
New Drugs ◽  
Global Network ◽  
Case Report Form ◽  
Tropical Diseases ◽  
Care Providers ◽  
Medical Needs

Abstract Background Repurposing approved products has proven a critical strategy to serve unmet medical needs. Historically, 40% of drugs approved for treatment of tropical diseases were repurposed, including albendazole for echinococcosis and neurocysticercosis, and azithromycin for trachoma. Advantages of repurposing include that approved drugs are well characterized, do not require expensive development programs needed for new drugs, and are frequently active against multiple diseases. Owing to the limited number of drugs approved to treat neglected tropical diseases (NTDs) and emerging or drug-resistant infections, healthcare practitioners use existing drugs in novel ways to treat patients with these conditions. This clinical experience, regardless of whether the outcomes are positive or negative, often is not reported or shared, and the knowledge is therefore lost. Methods FDA and NCATS/NIH have built a pilot program called Collaborative Use Repurposing Engine (CURE) to capture and centralize the global experience of new uses of approved medical products to treat emerging threats, NTDs, and multidrug-resistant organisms. CURE includes a website (https://cure.ncats.io/) and a mobile app (download “PROJECT CURE” at Google Play Store). CURE provides a simple case report form for health care providers to report their experiences, and a collection of cases that have already been reported (including successful and unsuccessful treatments) which they can browse. Healthcare providers who register can also participate in a Treatment Discussion Forum, allowing for engagement with fellow clinicians. CURE could be a global network connecting major treatment centers, academics, private practitioners, government facilities, and other clinicians serving as a means of rapid communication of treatment outcomes between providers treating patients with these conditions. Results See attached screen shots. Conclusion Although this evidence may be insufficient to establish the safety or effectiveness of a new use for an existing product, this clinical experience may provide signals and generate hypotheses for future clinical study. It may allow for rapid identification of promising treatment approaches in urgent situations such as during outbreaks of emerging infectious threats. Disclosures All authors: No reported disclosures.

Insights into newly approved drugs from a medicinal chemistry perspective

2021 ◽  
Vol 21 ◽  
Author(s):  
Elys Juliane Cardoso Lima ◽  
Renan Augusto Gomes ◽  
Evelin Fornari ◽  
Flavio da Silva Emery ◽  
Gustavo Henrique Goulart Trossini
Keyword(s):  
Drug Design ◽  
Drug Development ◽  
Drug Administration ◽  
Medicinal Chemistry ◽  
Food And Drug Administration ◽  
New Drugs ◽  
Design And Optimization ◽  
Continuous Evolution ◽  
Development Pipeline ◽  
Approved Drugs

: The development of new drugs is becoming notably harder each decade. To overcome the present pitfalls in the drug development pipeline, such as those related to potency, selectivity, or absorption, distribution, metabolism, excretion and toxicity properties, medicinal chemistry strategies need to be in continuous evolution and need to become even more multidisciplinary. In this review, we present how structure-based, ligand-based, and fragment-based drug design (SBDD, LBDD, and FBDD, respectively) and their respective techniques were used for the design and optimization of successful cases of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA).

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