DOCSLIB.ORG

(12) Patent Application Publication (10) Pub. No.: US 2014/0213624 A1 Pollmeier Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) Patent Application Publication (10) Pub. No.: US 2014/0213624 A1 Pollmeier Et Al US 20140213624A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0213624 A1 Pollmeier et al. (43) Pub. Date: Jul. 31, 2014 (54) METHOD FOR TREATING AND CURING Publication Classification LESHMANIOSIS USING FEXINIDAZOLE (51) Int. Cl. (71) Applicant: Merial Limited, Duluth, GA (US) A613 L/4164 (2006.01) (52) U.S. Cl. (72) Inventors: Matthias Pollmeier, Francheville (FR): CPC .................................. A61K 31/4164 (2013.01) Jeffrey Lynn Blair, Lyon (FR) USPC .......................................................... S14/398 (73) Assignee: Merial Limited, Duluth, GA (US) (21) Appl. No.: 14/169,713 (57) ABSTRACT (22) Filed: Jan. 31, 2014 Related U.S. Application Data The present invention encompasses methods of using fex (60) Provisional application No. 61/758,918, filed on Jan. inidazole to treat and eliminate and/or cure L. infantum infec 31, 2013. tions in canines. US 2014/0213624 A1 Jul. 31, 2014 METHOD FOR TREATING AND CURING Articular involvement is also fairly common and may present LESHMANIOSIS USING FEXINIDAZOLE as lameness with Swollen joints or simply as a stiff gait. Less common findings include ocular lesions (<5%), chronic diar INCORPORATION BY REFERENCE rhea (30%) and long, deformed brittle nails (20%) referred to 0001. This application claims priority to provisional appli as onychogryphosis (Lindsay DS et al., Slappendel RJet al.). cation U.S. Ser. No. 61/758,918, filed on Jan. 31, 2013, which 0005. Currently there are three drugs specifically is incorporated by reference herein in its entirety. All docu approved for the treatment of canine leishmaniosis in Europe: ments cited or referenced herein (“herein cited documents”), N-methyl-glucamine (meglumine) antimoniate (GLUCAN and all documents cited or referenced in herein cited docu TIMER), Merial), miltefosine (MILTEFORANR, Virbac), ments, together with any manufacturers instructions, and domperidone (LEISHGUARDR, Esteve, Spain). The descriptions, product specifications, and product sheets for most commonly recommended treatment protocols for dogs any products mentioned herein or in any document incorpo with clinical leishmaniosis by European Veterinary groups rated by reference herein, are hereby incorporated herein by are meglumine antimoniate or miltefosine in combination reference, and may be employed in the practice of the inven with allopurinol, a xanthine oxidase inhibitor with anti-leish tion. mania properties (Oliva G et al., Solano-Gallego L et al.). Domperidone is an antidopaminergic compound that has FIELD OF THE INVENTION been demonstrated to enhance the cell mediated immune response to leishmania infection in dogs. Even in combina 0002 The present invention relates to formulations for tion with allopurinol, both meglumine antimoniate and milte combating Leishmania infections in animals. Specifically, the fosine do not result in a parasitologic cure 100% of the time, present invention provides pharmaceutical compositions of and relapse of disease is common (Mana Let al., Mateo M. et fexinidazole and methods of treating, controlling, and com al., Solano-Gallego L et al., Oliva G et al.) Domperidone is pletely eradicating or curing leishmaniosis. indicated for the prevention or treatment of mild to moderate cases of canine leishmaniosis and its use in combination BACKGROUND OF THE INVENTION therapies is under investigation (Solano-Gallego L et al.). In 0003 Leishmania is a genus of Trypanosomatid protozoa, addition to the inability to produce a parasitologic cure, all of and is the parasite responsible for the disease leishmaniosis the recommended treatment protocols are associated with which is a major and severe parasitic disease that affects significant side effects: meglumine antimoniate is associated humans, canines, and to a lesser degree, felines. Leishmania with nephrotoxicity and cellulitis at the injection site, milte species are spread through Sandflies of the genus Phleboto fosine is associated with Vomiting and diarrhea, and allopu mus in the Old World and of the genus Lutzomyia in the New rinol can induce Xanthine urolithiasis (Solano-Gallego L et World. In humans, there are several forms of the disease al.). named by their clinical presentation including cutaneous, 0006 Mass detection of seropositive dogs followed by mucocutaneous or visceral leishmaniosis caused by a variety culling and/or drug treatment or the mass application of del of species of Leishmania. The predominant cause of canine tamethrin-impregnated collars were shown to have an impact leishmaniosis is L. infantum (sometimes referred to as L. in reducing human and canine leishmaniosis prevalence in chagasi in New World) which causes both visceral and cuta endemic areas of Southern Europe, Africa, and Asia (Maroli neous forms in dogs and the clinical distinction of the form of et al., 2001; Mazloumi Gavgani A. S. et al., 2002), although disease is less important. L. infantum is a cause for all forms the efficacy of eliminating Seropositive canines has been of disease in humans and dogs serve as the primary reservoir debated(Dietze Ret al., 1997: Moreira Jr. et al., 2004). These for human infections caused by this species (Baneth Get al). control measures are either considered unacceptable, expen L. infantum is widely distributed in temperate and subtropical sive or not effective (Gradoni L. et al., 2005). Encouragingly, countries of Southern Europe, Africa, Asia, South America Susan Wyllie (SciTransl. Med 4, 119, 2012) recently reported and Central America, and the incidence of L. infantum is fexinidazole was able to Suppress infection due to L. donovani expanding geographically (Dantas-Torres F et al., 2012, infection (leishmania species affecting humans). However, it Baneth Get al., Peterson CA et a? 0.2009, Ready PD et al., is not known whether the drug will work against the predomi Miro Get al. 2010). nantly canine leishmania Strain, L. infantum, nor is it known 0004 Canine leishmaniosis is a slowly progressive dis whether complete elimination (also referred to herein as “cur ease that can take years to become clinically apparent (McCo ing') of canine leishmaniosis infection is possible. "Elimina nkey S E et al., 2002). Signs are frequently non-specific and tion” or “curing is deemed to be “substantially complete” if diagnosis in non-endemic regions is often overlooked. Some the leishmaniosis clinical symptoms do not return after drug dogs appear naturally resistant to this parasite and can act as treatment (post-drug treatment re-exposure to the parasites asymptomatic reservoir hosts (Grosjean NL et al., 2003). notwithstanding). Moreover, the mouse model does not faith Approximately 10% of dogs residing in endemic areas actu fully recapitulate canine Leishmania infection. For example, ally develop clinical disease (Lindsay D S et al., 2002). Some mice show no clinical signs and do not die from parasite, of the more frequently reported clinical signs of leishmani whereas dogs do. Thus, a skilled person cannot, with any osis include skin lesions, listlessness, fatigue and exercise certainty, expect that a treatment method capable of reducing intolerance coupled with anorexia and weight loss that even the number of L. donovani parasites in mice, will also prevent tually culminate as wasting disease with chronic renal failure clinical signs and death—caused by L. infantum—in a dog. as the main cause of mortality (McConkey S E et al.; Solano Adding to the uncertainty is that Leishmania parasites are Gallego Letal). These signs may or may not be accompanied notoriously resistant to drug treatment, and many drugs use by fever, local or generalized lymphadenopathy, and ful in combating other diseases (including diseases caused by hepatosplenomegaly (Grosjean NL et al., 2003; Lindsay DS related protozoans) are not efficacious against Leishmania. et al., McConkey S E et al.; Martinez-Subiela Set al., 2002). For example, Leishmania parasites are well-known to reduce US 2014/0213624 A1 Jul. 31, 2014 drug concentration by both decreasing drug uptake and by SUMMARY OF THE INVENTION increasing drug efflux/sequestration (Haldar, 2011). Finally, anti-leishmaniosis drugs are extremely toxic, and thus poorly 0027. The present invention demonstrated for the first time tolerated by humans and non-human animals alike. that fexinidazole treatment can Substantially or completely 0007 Thus, there remains a need for effective and efficient eliminate or cure L. infantum infection in canines. No relapse methods of eradicating or curing leishmania infections. was observed 180 days after treatment initiation. Methods of the invention include methods for treating animals with fex REFERENCES inidazole to eliminate or cure, Substantially or completely, infections caused by Leishmania parasites. As used herein, 0008 Baneth, Get al. “Canine leishmaniosis—new con the terms "eliminate” and "eradicate' should be considered to cepts and insights on an expanding Zoonosis: part one.” have synonymous meanings. Trends in Parasitology Vol. 24, No. 7, pgs 324-30. 0028 Veterinary compositions of the invention may be in 0009 Dantas-Torres, Fetal. “Canine leishmaniosis in the the form of soft chewable formulations that are palatable for Old and New Worlds: unveiled similarities and differences. animals, or any other Suitable dosage form. For example, the Trends in Parasitology December 2012, Vol. 28, No. 12, formulation may be a tablet, a paste, a feed premix, a powder, pgs 531-38. oragel. In other embodiments, the compositions of the inven 0010 Gradoni L. et al., 2005,
Load more

Recommended publications
  • Fexinidazole – New Orphan Drug Approval
    Fexinidazole – New orphan drug approval • On July 19, 2021, Sanofi announced the FDA approval of fexinidazole, for the treatment of both the first-stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis (HAT) due to Trypanosoma brucei gambiense (T. brucei gambiense) in patients 6 years of age and older and weighing at least 20 kg. — Due to the decreased efficacy observed in patients with severe second stage HAT (cerebrospinal fluid white blood cell count > 100 cells/µL) due to T. brucei gambiense disease, fexinidazole should only be used in these patients if there are no other available treatment options. • Sleeping sickness is a parasitic disease transmitted by the bite of an infected tse-tse fly. It affects mostly populations living in remote rural areas of sub-Saharan Africa. Left untreated, sleeping sickness is almost always fatal. — According to the CDC, less than 100 cases of sleeping sickness have been reported annually to the World Health Organization. Infection of international travelers is rare, but it occasionally occurs and most cases of sleeping sickness imported into the U.S. have been in travelers who were on safari in East Africa. • The efficacy of fexinidazole was established in a randomized, comparative open-label trial in 394 adult patients with late second-stage HAT due to T. brucei gambiense. Patients were randomized to a 10-day treatment regimen of either fexinidazole or nifurtimox-eflornithine combination therapy (NECT). The outcome at 18 months was considered a success if patients were classified as a cure or probable cure. — Success at 18 months was achieved in 91.2% of patients treated with fexinidazole vs.
    [Show full text]
  • Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis
    ORIGINAL RESEARCH published: 13 April 2021 doi: 10.3389/fphar.2021.636265 Efficacy of Spironolactone Treatment in Murine Models of Cutaneous and Visceral Leishmaniasis Valter Viana Andrade-Neto 1, Juliana da Silva Pacheco 1,2, Job Domingos Inácio 1, Elmo Eduardo Almeida-Amaral 1, Eduardo Caio Torres-Santos 1* and Edezio Ferreira Cunha-Junior 1,3* 1Laboratorio de Bioquímica de Tripanosomatídeos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil, 2Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee, United Kingdom, 3Laboratório de Imunoparasitologia, Unidade Integrada de Pesquisa em Produtos Bioativos e Biociencias,ˆ Universidade Federal do Rio de Janeiro, Campus UFRJ-Macaé, Macaé, Brazil Translational studies involving the reuse and association of drugs are approaches that can result in higher success rates in the discovery and development of drugs for serious public health problems, including leishmaniasis. If we consider the number of pathogenic species in relation to therapeutic options, this arsenal is still small, and Edited by: each drug possesses a disadvantage in terms of toxicity, efficacy, price, or treatment Paula Gomes, regimen. In the search for new drugs, we performed a drug screening of L. University of Porto, Portugal amazonensis promastigotes and intracellular amastigotes of fifty available drugs Reviewed by: Manoj Kumar Singh, belonging to several classes according to their pharmacophoric group. Adamas University, India Spironolactone, a potassium-sparing diuretic, proved to be the most promising Adnan Ahmed Bekhit, Alexandria University, Egypt drug candidate. After demonstrating the in vitro antileishmanial activity, we fi *Correspondence: evaluated the ef cacy on a murine experimental model with L.
    [Show full text]
  • Rediscovery of Fexinidazole
    New Drugs against Trypanosomatid Parasites: Rediscovery of Fexinidazole INAUGURALDISSERTATION zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Marcel Kaiser aus Obermumpf, Aargau Basel, 2014 Originaldokument gespeichert auf dem Dokumentenserver der Universität Basel edoc.unibas.ch Dieses Werk ist unter dem Vertrag „Creative Commons Namensnennung-Keine kommerzielle Nutzung-Keine Bearbeitung 3.0 Schweiz“ (CC BY-NC-ND 3.0 CH) lizenziert. Die vollständige Lizenz kann unter creativecommons.org/licenses/by-nc-nd/3.0/ch/ eingesehen werden. 1 Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel auf Antrag von Prof. Reto Brun, Prof. Simon Croft Basel, den 10. Dezember 2013 Prof. Dr. Jörg Schibler, Dekan 2 3 Table of Contents Acknowledgement .............................................................................................. 5 Summary ............................................................................................................ 6 Zusammenfassung .............................................................................................. 8 CHAPTER 1: General introduction ................................................................. 10 CHAPTER 2: Fexinidazole - A New Oral Nitroimidazole Drug Candidate Entering Clinical Development for the Treatment of Sleeping Sickness ........ 26 CHAPTER 3: Anti-trypanosomal activity of Fexinidazole – A New Oral Nitroimidazole Drug Candidate for the Treatment
    [Show full text]
  • Nitroaromatic Antibiotics As Nitrogen Oxide Sources
    Review biomolecules Nitroaromatic Antibiotics as Nitrogen Oxide Sources Review Allison M. Rice, Yueming Long and S. Bruce King * Nitroaromatic Antibiotics as Nitrogen Oxide Sources Department of Chemistry and Biochemistry, Wake Forest University, Winston-Salem, NC 27101, USA; Allison M. Rice , Yueming [email protected] and S. Bruce (A.M.R.); King [email protected] * (Y.L.) * Correspondence: [email protected]; Tel.: +1-336-702-1954 Department of Chemistry and Biochemistry, Wake Forest University, Winston-Salem, NC 27101, USA; [email protected]: Nitroaromatic (A.M.R.); [email protected] antibiotics (Y.L.) show activity against anaerobic bacteria and parasites, finding * Correspondence: [email protected]; Tel.: +1-336-702-1954 use in the treatment of Heliobacter pylori infections, tuberculosis, trichomoniasis, human African trypanosomiasis, Chagas disease and leishmaniasis. Despite this activity and a clear need for the Abstract: Nitroaromatic antibiotics show activity against anaerobic bacteria and parasites, finding usedevelopment in the treatment of new of Heliobacter treatments pylori forinfections, these conditio tuberculosis,ns, the trichomoniasis, associated toxicity human Africanand lack of clear trypanosomiasis,mechanisms of action Chagas have disease limited and their leishmaniasis. therapeutic Despite development. this activity Nitroaro and a clearmatic need antibiotics for require thereductive development bioactivation of new treatments for activity for theseand this conditions, reductive the associatedmetabolism toxicity can convert
    [Show full text]
  • Repurposing As a Strategy for the Discovery of New Anti-Leishmanials: The-State-Of-The-Art
    SPECIAL ISSUE REVIEW 219 Repurposing as a strategy for the discovery of new anti-leishmanials: the-state-of-the-art REBECCA L. CHARLTON1,2, BARTIRA ROSSI-BERGMANN2, PAUL W. DENNY3 and PATRICK G. STEEL1* 1 Department of Chemistry, University Science Laboratories, South Road, Durham DH1 3LE, UK 2 Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Ilha do Fundão, CEP 21·949-900 Rio de Janeiro, RJ, Brazil 3 Department of Biosciences, University Science Laboratories, South Road, Durham DH1 3LE, UK (Received 28 February 2017; revised 23 May 2017; accepted 25 May 2017; first published online 14 August 2017) SUMMARY Leishmaniasis is a vector-borne neglected tropical disease caused by protozoan parasites of the genus Leishmania for which there is a paucity of effective viable non-toxic drugs. There are 1·3 million new cases each year causing considerable socio- economic hardship, best measured in 2·4 million disability adjusted life years, with greatest impact on the poorest com- munities, which means that desperately needed new antileishmanial treatments have to be both affordable and accessible. Established medicines with cheaper and faster development times may hold the cure for this neglected tropical disease. This concept of using old drugs for new diseases may not be novel but, with the ambitious target of controlling or eradi- cating tropical diseases by 2020, this strategy is still an important one. In this review, we will explore the current state-of- the-art of drug repurposing strategies in the search for new treatments for leishmaniasis. Key words: leishmaniasis, repurposing, repositioning, drug discovery.
    [Show full text]
  • Fexinidazole: a New Oral Drug for the Treatment of Human African
    FEXINIDAZOLE A NEW ORAL DRUG FOR THE TREATMENT OF HUMAN AFRICAN TRYPANOSOMIASIS S. Chang Research and Development, Drugs for Neglected Diseases initiative, Geneva, Switzerland Fexinidazole, currently in phase I clinical study for human African trypanosomiasis (HAT, also known as sleeping sickness), is the first success of DNDi's compound mining efforts for nitroimidazoles initiated in 2005. The project aimed to identify promising drug candidates among new and old nitroheterocycles, a class known to have broad spectrum of anti-infective activities against many pathogens including trypanosomes. By the end of 2006, over 500 nitroheterocycle compounds, from more than15 different sources in both academia and the pharmaceutical industry, were identified, collected, and evaluated in vitro. Fexinidazole (Hoe 239), a 2- substituted 5-nitroimidazole, was rediscovered. Fexinidazole has been shown to be moderately active in vitro against African trypanosomes, and oral administration of fexinidazole cures mice with both acute and chronic infection, the latter a model for the advanced and fatal form of the disease when parasites have disseminated into the brain. In laboratory animals, fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. Furthermore, fexinidazole is rapidly metabolized in vivo to at least two biologically active metabolites that are likely to account for a significant portion of the therapeutic effect. Toxicology studies (including safety pharmacology and 4-week repeated-dose toxicokinetics in rat and dog) have shown that fexinidazole is well tolerated, with no issues of concern identified. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo.
    [Show full text]
  • Neglected Tropical Diseases
    SANOFI GLOBAL HEALTH IMPROVING ACCESS NEGLECTED TO HEALTHCARE BURDEN OF NEGLECTED TROPICAL DISEASES MAINLY FOR THE MOST VULNERABLE TROPICAL DISEASES IMPACTS UNDERSERVED POPULATIONS Our Global Health entity is committed to improving access to healthcare for the most vulnerable people living in low- and middle- Neglected Tropical Diseases (NTDs) are a group of Over income countries. Working hand in hand with partners we provide 20 bacterial, parasitic, viral, and fungal infections sustainable solutions for unmet medical needs with a focus on infectious identified by the World Health Organization (WHO) 1.7 billion diseases like malaria, tuberculosis and neglected tropical diseases, and that are prevalent in many of the tropical and people are impacted (2) non-communicable diseases such as diabetes, cardiovascular diseases sub-tropical low and middle-income countries, and mental disorders. impacting more than 1.7 billion people. These diseases can lead to lifelong disabilities, profound pain and suffering, stigma, isolation and in some cases death. In addition to their impact on health, NTDs contribute to an immense social and economic burden which perpetuates the cycle of poverty by preventing individuals from leading productive lives, and by adversely affecting families, communities, and countries as a whole. Although many of these diseases can be prevented and/or treated successfully, and efforts are done to provide appropriate coverage, Himarkley_Getty Images. Himarkley_Getty many people affected by NTDs do not receive © the basic care they need. There is still a gap to be filled between the existing programs and the real needs to achieve their control or elimination. This has been identified in the Sustainable Development Goals (SDGs) establishing an objective of ending among others the epidemic of Neglected Tropical Diseases by 2030.
    [Show full text]
  • Efficacy and Toxicity of Fexinidazole and Nifurtimox Plus Eflornithine in the Treatment of African Trypanosomiasis: a Systematic Review
    Open Access Review Article DOI: 10.7759/cureus.16881 Efficacy and Toxicity of Fexinidazole and Nifurtimox Plus Eflornithine in the Treatment of African Trypanosomiasis: A Systematic Review Jessica Hidalgo 1 , Juan Fernando Ortiz 2 , Stephanie P. Fabara 3 , Ahmed Eissa-Garcés 4 , Dinesh Reddy 5 , Kristina D. Collins 6 , Raghavendra Tirupathi 7 1. Internal Medicine, San Francisco de Quito University, Quito, ECU 2. Neurology, Larkin Community Hospital, Miami, USA 3. Internal Medicine, Santiago de Guayaquil Catholic University, Guayaquil, ECU 4. Neurology, San Francisco de Quito University, Quito, ECU 5. Neurology, Mysore Medical College, Mysore, IND 6. Internal Medicine, University of the West Indies, Kingston, JAM 7. Internal Medicine, Keystone Health, Chambersburg, USA Corresponding author: Juan Fernando Ortiz, [email protected] Abstract Human African trypanosomiasis (HAT), or sleeping sickness disease, is an infection caused mainly by Trypanosoma brucei gambiense-human African trypanosomiasis (g-HAT) and is transmitted by tsetse flies. The disease goes through two stages: hemolymphatic and meningo-encephalic phases. The treatment for the second stage has changed from melarsoprol or eflornithine to nifurtimox-eflornithine combination therapy (NECT) and fexinidazole. We aimed to systematically review the literature on the efficacy and toxicity of fexinidazole and NECT. We used PubMed advanced strategy and Google Scholar databases, including clinical trials and observational studies on humans in the last 20 years in the English literature. Applying the inclusion/exclusion criteria, we reviewed eight studies. We used Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocol. For assessing bias, we used the Cochrane Collaboration’s tool for risk assessment of the clinical trials and the Robins-I tool for the observational studies.
    [Show full text]
  • Fexinidazole Tablets Occurs in a Concentration-Dependent Manner
    HIGHLIGHTS OF PRESCRIBING INFORMATION • QT Interval Prolongation: Prolongation of the QT interval due to These highlights do not include all the information needed to use Fexinidazole Tablets occurs in a concentration-dependent manner. Avoid FEXINIDAZOLE TABLETS safely and effectively. See full prescribing use in patients with known prolongation, proarrhythmic conditions, and information for FEXINIDAZOLE TABLETS. concomitant use with drugs that prolong the QT interval, those that block cardiac potassium channels, and/or those that induce bradycardia, or are FEXINIDAZOLE tablets, for oral use inducers of hepatic CYP450. (5.2, 7.1, 7.2, 12.2) Initial U.S. Approval: 2021 • Neuropsychiatric Adverse Reactions: Adverse reactions such as agitation, ----------------------------INDICATIONS AND USAGE--------------------------- anxiety, abnormal behavior, depression, suicidal ideation, nightmares, Fexinidazole Tablets is a nitroimidazole antimicrobial, indicated for the hallucination, and personality change have been observed during therapy. treatment of both first-stage (hemolymphatic) and second-stage Inform patients and their caregivers of the risk. Consider alternative (meningoencephalitic) human African trypanosomiasis (HAT) due to therapy or increased monitoring of the patient, including hospitalization in Trypanosoma brucei gambiense in patients 6 years of age and older and patients with psychiatric disorders, or if these adverse reactions occur. (5.3) weighing at least 20 kg. (1) • Neutropenia: Avoid concomitant use of drugs which may cause Limitations of Use neutropenia and monitor leukocyte count periodically. Monitor patients Due to the decreased efficacy observed in patients with severe second stage with neutropenia for symptoms or signs of infection. (5.4, 6.1) HAT (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/µL) • Potential for Hepatotoxicity: Evaluate liver-related laboratory tests at the due to T.
    [Show full text]
  • FEXINIDAZOLE and VL-2098 SHYAM SUNDAR Target Product Profile for a NCE
    SMe N O N CH O 2 N 2 Me NITROIMIDAZOLES FOR VISCERAL LEISHMANIASIS – FEXINIDAZOLE AND VL-2098 SHYAM SUNDAR Target Product Profile for a NCE Optimal Target Profile Minimal Target Profile Target Label VL and PKDL VL Spp All species L. donavani Distribution All areas Either India or Africa Target Population Immunocompetent and Immunocompetent immunosuppressed Clinical Efficacy > 95% > 90% Resistance Active against resistant strains Safety and No AEs requiring monitoring 1 monitoring visit in mid/end - point Tolerability Contraindications None Pregnancy/lactation Interactions None - Compatible for None for malaria, TB, and HIV combination therapy concomitant therapies Formulation Oral / im depot Oral / im depot Treatment Regimen 1/day for 10 days po/ 3 shots bid for <10 days po; or >3 shots over 10 days* over 10 days Stability 3 yrs in zone 4 Stable under conditions that can be reasonably achieved in the target region (> 2 yr) Cost < $10 / course <$80 / course Fexinidazole • Discovery : 1970 HOE 239, discontinued 1980 • Chemical Name: 1H-imidazole,1-methyl-2-[[4- methylthio) phenoxy] methyl] 5-nitro-imidazole SMe • Metabolism N O N CH O 2 N 2 Me N CYP N N CH O SCH O2N 2 3 O N CH O SOCH3 O N CH O SO CH N 2 N 2 2 N 2 2 3 Me FMO Me Me Fexinidazole Fexinidazole sulfoxide (M1) Fexinidazole sulfone (M2) • PM FEXI = 279 g/mol • PM M1 = 295g/mol • PM M2 = 311g/mol In vitro data of fexinidazole and metabolites on L donovani In vivo data in mice infected with L donovani PK summary § Bioavailability Fexi : rapidly absorbed: median Tmx: 3 – 4 H; mean
    [Show full text]
  • The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History
    Tropical Medicine and Infectious Disease Review The Drugs of Sleeping Sickness: Their Mechanisms of Action and Resistance, and a Brief History Harry P. De Koning Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8TA, UK; [email protected]; Tel.: +44-141-3303753 Received: 19 December 2019; Accepted: 16 January 2020; Published: 19 January 2020 Abstract: With the incidence of sleeping sickness in decline and genuine progress being made towards the WHO goal of eliminating sleeping sickness as a major public health concern, this is a good moment to evaluate the drugs that ‘got the job done’: their development, their limitations and the resistance that the parasites developed against them. This retrospective looks back on the remarkable story of chemotherapy against trypanosomiasis, a story that goes back to the very origins and conception of chemotherapy in the first years of the 20 century and is still not finished today. Keywords: sleeping sickness; human African trypanosomiasis; trypanosoma brucei; drugs; drug resistance; history 1. Introduction The first clue towards understanding drug sensitivity and, conversely, resistance, in human African trypanosomiasis (HAT) is that most drugs are very old and quite simply toxic to any cell—if they can enter it. That places the mechanisms of uptake at the centre of selectivity, toxicity and resistance issues for all the older trypanocides such as diamidines (e.g., pentamidine, pafuramidine, diminazene), suramin and the melaminophenyl arsenicals. Significantly, none of these drug classes, dating from the 1910s to the 1940s, were designed for a specific intracellular target and even today identification of their targets has defied all attempts with advanced postgenomic, proteomic and metabolomic techniques—in short, they are examples of polypharmacology, where the active agent acts on multiple cellular targets.
    [Show full text]
  • Visceral Leishmaniasis Strategy
    Visceral Leishmaniasis Strategy Kampala, 03rd October 2018 Leishmaniasis: unmet medical needs VL • Disease of poverty • Multiple manifestations • Inadequate treatments • Targeted by WHO and SDGs Visceral Leishmaniasis (VL) • 50,000 − 90,000 cases/year • > 50% are children • 82 countries worldwide • 20,000 - 30,000 deaths/year CL • 556 million at risk in high burden countries Cutaneous Leishmaniasis (CL) • 900,000 −1,200,000 cases/year • 91 countries worldwide • 399 million at risk in high burden countries • Social stigmatization Three epidemiological hot-spots for VL WHO country profile, 2004-2008 WHO report, high-burden countries, 2014 Region Cases reported/year Estimated annual Cases reported/year Estimated annual Latin America 3,661 5,000 to 7,000 3,571 not informed Eastern Africa 8,569 30,000 to 40,000 16,413 24,157 to 41,813 Indian subcontinent 42,619 160,000 to 320,000 10,311 12,373 to 13,015 Alvar et all, 2012; PLOS One 7(5): e35671 WHO WER (38) 2017, 92: 557-572 Current drugs for leishmaniasis • Variable efficacy, serious toxicities, only one is oral & rest are painful iv/im • Urgent need for new effective, safe, and convenient treatments • painful • painful • rigor & chills • painful • teratogenic injections injections • nephrotoxicity injections • gastrointestinal • cardiotoxicity • cardiotoxicity • hypokalemia • nephrotoxicity toxicity • hepatotoxicity • hepatotoxicity • Anaphylaxis • hepatotoxicity • hepatotoxicity • Pancreatitis • Pancreatitis • Ototoxicity Current treatments/region Efficacy at 6 months post-treatment is indicated
    [Show full text]