History of malaria and sleeping sickness Treatment development ›Hematozoa ›many species were discovered in various hosts and classified ›mammals ~ 50 species; birds ~ 40 species; reptiles ~ 60 species ›five species that regularly infect human ›P. vivax, P. falciparum, P. malariae, P. ovale, and P. knowlesi Plasmodium SouvisejÃcà obrázek Výsledek obrázku pro samec symbol SouvisejÃcà obrázek ›Malaria ›249 millions cases worldwide (2022) ›608 000 deaths (80% of being five and under) ›Mainly in sub-Saharan Africa ›Every minute a child dies ›Associated with poverty ›Negative effect on economic development ›12 billions USD loss Plasmodium SouvisejÃcà obrázek Výsledek obrázku pro samec symbol SouvisejÃcà obrázek ›Malaria ›249 millions cases worldwide (2022) ›608 000 deaths (80% of being five and under) ›Mainly in sub-Saharan Africa ›Every minute a child dies ›Associated with poverty ›Negative effect on economic development ›12 billions USD loss ›Hematozoa ›many species were discovered in various hosts and classified ›mammals ~ 50 species; birds ~ 40 species; reptiles ~ 60 species ›five species that regularly infect human ›P. vivax, P. falciparum, P. malariae, P. ovale, and P. knowlesi ›P. falciparum – very ancient human parasites, co-evolved with humans (host cospecication) ›The others parasites species transferred to humans from primates › ›Sickle cell anemia (srpkovitá) ›Point mutation in beta-globing chain ›Hetezygotes children – 10 times less likely to dies from malaria › › › › › › › › › › ›Thalassemias ›Anemia, loss of alpha- or beta globin chains ›Binds less oxygen ›50 less chance to get infected History of malaria History of malaria ›Huge effect on human population ›Barrier to social and economic development (detrimental and mental effects of repeated malarial infections) › ›First effective treatment for malaria, South America ›17th century ›Jesuit´s bark ›Powdered bark of cinchona tree (tropical Andes) contains chinin ›trade, variable content, religious reasons (Oliver Cromwell) › ›Only for wealthy (alternatives failed – willow bark) › ›19st century – isolation of quinine (Caventou and Pelletier) ›Procedure not patented ›Rapid establishment of factories (modern pharmaceutical industry) ›1826 – Pelletier produced 3600 kg annually ›Huge pressure on import of cinchona tree ›European plant hunters ›Finally smuggled – plantations in Brittish and Dutch colonies in Asia ›Cinchona ledgeriana – plantations in Java (Dutch) 13% of quinine content, 97% world`s supply (monopoly until 1942) ›Resistance to quinine reported in 1910 • Cinchona Trees: How to Grow and Maintain Tips undefined Peru in danger of losing its national cinchona tree Discovery of the parasite Mosquito-malaria hypothesis ›Sir Ronald Ross (1857 – 1932) ›Brittish medical doctor ›1894 - search for malaria transmission in Secunderabad, he examinated wrong mosquitoes! ›Finally in 1897 he looked at different mosquito (dapple-winged) that fed on the malaria patient and described a stage in the mosquito gut ›Transferred to Calcutta (no malaria), upon Manson advice he studied bird malaria ›Life cycle of P. relictum ›1899 –sent to Sierra Leone and implied first measures to control transmission (draining puddles, rivers straightened) › ›1902 – Nobel prize for his work on the transmission of malaria ›Battista Grassi (infections of healthy volunteers) ›Patrick Manson (1844 – 1922) ›Scottish physician ›Filariosis is transmitted by mosquitoes › ›Suggested that malaria can be also transmitted with mosquitoes ›Maintain fruitful collaboration with Ross ›Introduced preventive measures to reduce exposure to mosquitoes Malaria control - The Case of Panama Canal ›1882 – 1889 – bankruptcy of the French company (F. de Lesseps) ›Mosquitoes did not recognize as a problem ›30 000 deaths › ›1904 – major William Gorgas appointed as a advisor (experienced from Cuba) ›1914 – funds to control malaria in US ›1939 – DDT (Nobel prize in 1948) ›1951 – USA malaria free QUININE and its derivates The curious antiprion activity of antimalarial quinolines ›derivatives are some of the oldest drugs around ›all stem ultimately from quinine ›a natural product isolated from the bark of the Andean cinchona tree ›the first antimalarial drug by the early 1800s MALARIA TREATMENT ›types of drugs and the length of treatment will vary, depending on: ›species of malaria parasite ›the severity of symptoms ›age of patient ›pregnancy ›mefloquine (prophylaxis) ›results of a huge effort Walter Reed Inst (Vietnam war), screen of 250 thousands compounds ›trials in prison populations › › › Mefloquine hydrochloride (Mefloquin hydrochloride) | Parasite Inhibitor | MedChemExpress ›chloroquine phosphate = the preferred treatment for any malaria parasite ›in many parts of the world the parasites are resistant to chloroquine › ›combination of atovaquone and proguanil (Malarone) › ›quinine sulfate (Qualaquin) with doxycycline (Vibramycin, Monodox, others) › › › › › › ›artemisinin-based combination therapies (ACTs) = the first line treatment demonstrated resistance to nearly all of the available antimalarial drugs › CHLOROQUINE ›1950s ›primarily used to prevent and treat malaria (Korean war) ›inhibit parasite's ability to digest haemoglobin ›the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes ›caps hemozoin molecules to prevent biocrystallization of heme (hemozoin) ›binds to heme (or ferriprotoporphyrin‐IX, FP) to form the FP-chloroquine complex ›this complex is highly toxic to the cell and disrupts membrane function › PRIMAQUINE ›1952 ›to treat and prevent malaria and to treat Pneumocystis pneumonia ›to prevent relapse of malaria → eliminates hypnozoites, the dormant liver form ›the exact mechanism of action is not fully understood ›oxidative damage to the cell interfering with the electron transport ›effective against the gametocytes → prevents spread to the mosquito Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: Current state of the art - ScienceDirect resistance Figure 1. The Effect of Chloroquine on Heme Detoxification in the Lysosome of a Chloroquine-Sensitive Plasmodium falciparum Malaria Parasite (Panel A) and a Chloroquine-Resistant Malaria Parasite (Panel B).In Panel A, in the lysosome of a chloroquine-sensitive parasite, hydrogen ions enter through the proton pump, acidifying the lyso-somal environment (pH 5.5). This process is probably regulated by the Pgh1 protein, which releases anions into the lysosome tooptimize the difference in the transmembrane charge. During the digestion of hemoglobin (Hb), protonated basic amino acids(AAH+) are released together with toxic ferriprotoporphyrin IX (Fp9). Ferriprotoporphyrin IX is detoxified by polymerization to crys-talline hemozoin. The weak base chloroquine, present in the cytoplasm (pH 7.4), dissolves in the lysosomal membrane and entersthe acidic environment, undergoing protonation to a form (CQH+) that is insoluble in the membrane and that quickly becomes con-centrated. CQH+ binds to ferriprotoporphyrin IX and thus inhibits its polymerization, which leads to the accumulation of ferripro-toporphyrin IX, causing membrane damage. The protonated basic amino acids exit the lysosome by means of the transmembraneprotein PfCRT. The PfCRT protein probably has a limited affinity for CQH+ and exports some of the drug from chloroquine-sensitiveparasites.Panel B shows the lysosome of a parasite with mutations in pfcrt and pfmdr 1 related to chloroquine resistance. The mutant PfCRTprobably has an increased affinity for CQH+ and exports large amounts of the drug, enabling the polymerization of ferriprotopor-phyrin IX to proceed normally. Concomitantly, the mutant PfCRT would have a reduced affinity for AAH+, which may reduce theefficiency of the export of AAH+ and, in the absence of chloroquine, result in the accumulation of more protons (H+) in the lyso-some. The presence of mutant Pgh1 may partially prevent this accumulation of protons, increasing the fitness of parasites withpfcrt and pfmdr 1 mutations. The mutation in pfmdr 1 also increases the sensitivity of the parasite to mefloquine and artemisinin,probably as a result of the partial inactivation of the ability of mutant Pgh1 to export these drugs (3) (PDF) A Molecular Marker for Chloroquine-Resistant Falciparum Malaria. Available from: https://www.researchgate.net/publication/12158530_A_Molecular_Marker_for_Chloroquine-Resistant_Falc iparum_Malaria [accessed Apr 24 2024]. Atovaquone ›broad-spectrum activity against Plasmodium, Babesia, Toxoplasma and Pneumocystis ›collapse of the mitochondrial membrane potential › ›structurally similar to the inner mitochondrial protein ubiquinone (ubiquinol) = coenzyme Q ›an integral component of electron flow in aerobic respiration ›ubiquinone accepts electrons from dehydrogenase enzymes and passes them to electron transport cytochromes → electrons from ubiquinone to cytochrome bc1 (complex III) requires binding of coenzyme Q-complex III at the Qo cytochrome domain ›this step which is inhibited by atovaquone › ›the structure of the Qo cytochrome binding site has been defined and explains the selective toxicity of atovaquone to parasitic mitochondria › ›collapse of the mitochondrial membrane potential › ›inhibition of dihydroorotate dehydrogenase that is required in the biosynthesis of pyrimidines ›inhibition of ATP production „competitive inhibitor of ubiquinol“ Atovaquone - Wikipedia Inhibitors of the Plasmodium Mitochondrial Electron Transport Chain. Schematic diagram of the enzymes involved in electron transport across the inner mitochondrial membrane in Plasmodium. Atovaquone, the only mitochondrial electron transport chain inhibitor in clinical use, specifically inhibit cytB. Abbreviations: cytB, cytochrome b; DHODH, dihydroorotate dehydrogenase; NDH2, type II NADH:ubiquinone oxidoreductase; Q, ubiquinone; QH2, ubiquinol; Qi , ubiquinol reductase site of cytochrome b; Qo, ubiquinone oxidase site of cytochrome b; sadh, flavoprotein subunit of succinyl dehydrogenase. Artemisia annua Artemisinin Artemisinin.svg Artemisinin ART reacts with accessible heme and as a result, generate ROS, which is a potentially damaging agent. A portion of ART gets into mitochondria, where mitochondrial dysfunctions occur. Artesunate ← the most widely used derivate of artemisinin, hydrophylic ATS simultaneously interferes with ① redox homeostasis, ② lipid metabolism, and ③ protein synthesis in P. falciparum to exert antimalarial effects by targeting several essential proteins. DV: digestive vacuole; HZ: hemozoin; Mito: mitochondrion Digestion of hemoglobin (Hb) releases ferriprotoporphyrin‐IX (FP). Normally FP polymerizes to hemozoin but some unpolymerized FP can react with O2 to form ROS, superoxide radical that can be reduced to H2O2 by superoxide dismutase (SOD) in the cytosol. Artemisinins react with the FP iron (FP‐Fe2+) to form activated drugs and ROS that then attack hemoglobin digesting proteases, mitochondrial transport chain, and the mitochondrial membrane, and many cytosolic targets including the cysteine‐containing redox system of the parasite destroying them and exacerbating ROS formation and eventually death of the parasite. PLOS Medicine: The Activities of Current Antimalarial Drugs on the Life Cycle Stages of Plasmodium: A Comparative Study with Human and Rodent Parasites Malaria treatment VACCINE AGAINST MALARIA ›the only approved vaccine as of 2015 is RTS,S (trade name Mosquirix) ›requires four injections, and has a relatively low efficacy ›consists of the P. falciparum circumsporozoite protein (CSP) › › › › › › › › › › › › › › ›PfSPZ Vaccine is a candidate malaria vaccine ›non-replicating irradiated whole sporozoites ›PfSPZ is the acronym: Plasmodium falciparum (Pf) and sporozoites (SPZ) VACCINE AGAINST MALARIA ›transmission-blocking vaccine ›anti-infection vaccine ›(RTS,S and pfSPZ) ›anti-disease vaccine › SouvisejÃcà obrázek Výsledek obrázku pro bed nets malaria Treating bed nets with antimalarial compound blocks parasite from developing in mosquitoes (atovaquone) + treatment with insecticides Anopheles gambiae African Trypanosomes Adapted from Lukeš et al., 2022. Trends in Parasitol. Trypanosoma brucei (T. b. brucei, T. b. gambiense, T. b. rhodesiense, T. b. evansi, T. b. equiperdum) T. congolense, T. vivax - -Human African Trypanosomiasis (HAT) -36 African states -50 millions in affected areas -Always lethal if untreated - -Animal African Trypanosomiasis (AAT) -Direct loos of livestock products -Loss of crop productivity due to loss of the anmals draught power Text Description automatically generated with low confidence PARTITION INSTITUTE OF PARASITOLOGY First accounts of sleeping sickness Winterbottom syndrom Colonization of Africa Slave trade THE SLEEPING SICKNESS: Cutting a continent out from under him. - political cartoon made by Gordon Ross (''Puck'' magazine), United States, October 1911 HE SLEEPING SICKNESS: Cutting a continent out from under him'' - political cartoon made by Gordon Ross (''Puck'' magazine), United States, October 1911 Trypanosomes are very ancient parasites that emerged 380 millions years ago, they are ubiquitous, some salivarian forms began to transmit to mammalas when tsetse flies emerged some 35 millions years ago The relative late arrival of humans may explain why African game animals are tolearnt towards most species of trypanosomes , btu humans and domestic animals are more susceptible HAT beamce very impactful when slaves traders emerged and later colonial forces arrived to Africa First accounts of sleeping sickness came from ship doctors who worked for slave-trade companies 1775 – first accurate medica report on HAR by English naval surgeion John Atkins - only the second stage Thomas Winterbottom in 1803 - report on a characteristics swolled lymph nodes PARTITION INSTITUTE OF PARASITOLOGY First accounts of sleeping sickness Winterbottom syndrom Colonization of Africa Slave trade 1st epidemic killed 250,000 Ugandans ILLUSTRATIONS BY IVAN SENYONJO HE SLEEPING SICKNESS: Cutting a continent out from under him'' - political cartoon made by Gordon Ross (''Puck'' magazine), United States, October 1911 Trypanosomes are very ancient parasites that emerged 380 millions years ago, they are ubiquitous, some salivarian forms began to transmit to mammalas when tsetse flies emerged some 35 millions years ago The relative late arrival of humans may explain why African game animals are tolearnt towards most species of trypanosomes , btu humans and domestic animals are more susceptible HAT beamce very impactful when slaves traders emerged and later colonial forces arrived to Africa First accounts of sleeping sickness came from ship doctors who worked for slave-trade companies 1775 – first accurate medica report on HAR by English naval surgeion John Atkins - only the second stage Thomas Winterbottom in 1803 - report on a characteristics swolled lymph nodes Female symbol - Free signaling icons Male symbol - Free signs icons INSTITUTE OF PARASITOLOGY The discovery of Trypanosoma brucei David and Mary Bruce (1855 – 1931] -Scottish pathologist and microbiologist -1894 – sent to Zululand to investigate an outbreak of nagana (the fly disease) Michaël Smorowski on Twitter: "From my collection, two Zululand QV #stamps. #Zululand (see map) has a complex and rich history. 1887: British defeated the Zulus and annexed Zululand => creation of a T. b. brucei - Human African trypanosomiases HAT is a disease with a truly historic dimensions Its maximum possible distribution corresponds to the rande of tsetse flies, which covers an area of 8 km2 1895 – David Bruce reported that the tsetse fly was linked to cattle trypanosomiases Dutton in 1902 – West Africa – t gambiense Castellani I 1903 – east Africa t rhodesiense –trypanosomes in cerebrospinal fluid 1852 – Scottish missionary and explorer Livingstone – magana is transmitted by tsetse 1895 – scottish microbiologist and pathologist David brucediscovered Tb as the cause of cattle trypanosomiases The first observation of trypanosomes in human blood was made bh brittish colonial surgeon Robert Michael Forde in 1901 – he though it was a worm (steamboat captain in Gambia) But Everette Dutton identified them as trypnaosomes and proposed the name Gambiense 1902 – Bruce provided comclusive evidence that HAT s transmitted by stsetse fly, but he thought ot was mechanical, German mlitary surgeon Friedrich Karl Kleine who showed cyclical transmission in tsetse flies Bruce then described the full life cycle T. congo and T. vivax doscivered in 1904 and 1905 INSTITUTE OF PARASITOLOGY The discovery of Trypanosoma brucei INSTITUTE OF PARASITOLOGY Two species, two diseases Brun et al., Lancet 2010, 375:148-159 Tbg is responsible for chronic form of HAT in West and cetrnal Africa Tbr give rise to acute form in East and Southers Africa There are two distinctstages also known as heamolymphatic pahse is defined bt the restrictions of trypanosomes to the blood and lymph system, the sympotoms are fever, headches, joiny pains, itchign The second late phase also known as a neurologival phase is characterized by the presence of trpanosomes in the cerebrospinal fluid, typical signs: confusion, disturbed sleep pattern, sensory disturbances, extreme lethargy, poor conditions, seizrues, comaco Paul Ehrlich (1854 – 1915) http://t1.gstatic.com/images?q=tbn:ANd9GcRlQFE2fsi1tZDxEFBLVtM44MhKjybAL1mtqO8tm1-3aEepjDE&t=1&usg= __-ejt7sPh7U5-5ayRpbpmMuOfxao= Ø the so-called father of the modern chemotherapy Ø original proponent of the “magic bullet” Ø 1900s - first synthetic drug Ø1905 – Atoxyl (toxic side effects – blindness) Ø1922 – Suramin (1st stage, T.b. rhodesiense, IV) Ø1937 – Pentamidine (1st stage, T. b. gambiense, IM) Ø1949 – Melarsoprol (2nd stage of the disease, highly toxic, IV) Ø Ø Ø Ø Ø Ø Ø Ø Ø Ø Nobel prize for medicine 1908 File:Salvarsan-montage.png INSTITUTE OF PARASITOLOGY Drug discovery for treating sleeping sickness The detection of the causative agent the mode of transmisison and the first documnted major epidemics coincided with the advent of moder pharmacology – there was a interest in finding drugs 1908 colonial powers geva drug debelopmed the highest priority Paul Erlich - Atoxyl – arsenic based compund – toxic , damaging a optic nerve, active only againts the 1 stage INSTITUTE OF PARASITOLOGY Epidemics and control of the disease Anglophone colonies T. rhodesiense Wild and domestic animals are reservoir Approach: •vector control (spraying, traps) •bush clearing •game destruction •chemopreventive use of veterinary drugs Francophone colonies T. gambiense Humans are only reservoir Approach: •focused on medical problems •mobile team (E. Jamot) • •1926 – atoxylisation •1950s – pentaminidiasation (2 mill. people) C.B. Marcondes (ed.), Arthropod Borne Diseases, DOI 10.1007/978-3-319-13884-8_18 HAT had a tremendous impact on population HAT hampered the colonization , all invaders in africa were challenged by logistics sicne horses were very suscptionel to trypanosomes It is not difficult to understand the manifold early attenpts to control the disease The finding of trypanosomes coincide with the first hhuge epidemics - Kenya and Uganda - left 500 thousands peope dead (most like Tbr) Belgian congo The colonial powers were horrifed by the speed at which their working force was dying The response of Anglophone and Francophone colonial powers differed signicinatly Francophone – chose to concetrate directly on modeical problems, introduction of mobile teams actively searching and screenign populations, systematic case detection and treatment with the aim of elimination of the patrasite reservoir . atoxysilation and pentamidization prevalce of HAT decreased from as high as 60% in 1919 to 0.2 - 4.1 % in 1930, Beligian Congo . massive adminitartion of penatmidine to 2 mil people in 1950 Anglophone - Tbr, they were confronted with more widepsread proble of ideases in domectis animals, which also presneted a reservoir for humans. Their approach included tsetse traps, spraying bush cclearing, and game destrction and later chempreventive ise of veterinary drugs INSTITUTE OF PARASITOLOGY First turning point and a colloisal failure Suramin – Bayer – arsenic based compound 1st stage Melarsoprol – 2nd stage, - 10% patienst diy from encelopathy (50% dead), 35 days treatments Eflronithine, Nifurtimox – drawbakcs – potential for resistance Another line of reaseach – diamidines (1930), discover ny serendepity pentamidine, ver effective, 1st stage, Lumbar puncture – painful - to determine the stage and decide treatment, source of distressm stigma and technical difficutires The drugs available were commercilized during the first half of 20th century, the pharmaceutical industry had no financial motivationto seek new products fir a dusease with a market representing a few ten thousands of cases per year, living I rural and impoverished regions of central Africa. Eflornithine was developed as a potnetial anti-cancer drug, The control measures were very succesful, progresively controlled disease, reaching a very low generailied transmisison by mid 1960 with w minimum of 4000 cases decalred in Africa in 1964 INSTITUTE OF PARASITOLOGY DNDi - Drugs for Neglected Diseases Initiative MISSION: •Developing drugs on a not-to-profit bases •Needs-driven portfolio •Raises awareness about lack of R&D for NTDs •Strengthen R&D activities in endemic countries With the colonial powers withdrawing, between 1960 – 1975 - new era began. The young countries created national institutons to continue to fight HAT, but decreaseing funds, different health priorities, expenditures for HAT was reduced, awarness and survaillence decreased, no mobility teams, social instability, conflicts, insecuiruty – significant resurgence of Tbg in 1980 and 1990 mainly affectign Angola, COngo, Sudan and Uganda, situation again was reminisncet to that in 1920 Melarsoprol still the only opiton to the 2nd stage, Drug develpoment was dormant for 50 years Commitment of Sanofi 20 years ago – the company decided to provide the exisiting trypanocides free of charge (melarsoprol, eflornithne, pentamidine)) Supplied financial assisatnce to national cotrnol programes, Bayer provided Suramin and nifurtimox, Bill and amelinda Gates gace millions of dollars And Drugs for negelected diseases initiative coordinated clinical testing of new candidates Eflornithine as a failed anti-cancer drug was shown to be active for 2md stage NECT – reduced the number of eflortnithine infusion from 56 to 14, amount of eflo by half and hospitalization by 1/3 Fexinidazole Acoziborole (oral, long half life, good penetration to CNS) Extraoridnary achievement Interuption of transmission soon DNDI initiataed a major compoudn minign effort in 2005 to explore old and new nitroimidazoles as drug leads againts HAT Out of 830 drugs, fexinidazole proved to be orally active against Tbg and Tbr, had an excellent safety profile 2018 – approved Has limitations - its absorption depends on food intake, lowered efficacy for patinets with advanced symptoms Hence the search for magic bullet still on Treatment The recommended drugs in the treatment of trypanosomiasis. Chemical... | Download Scientific Diagram the first line treatment: Pentamidine (1941) resistance, ineffective against late stage Suramin (1921) – severe side effects Melarsoprol (1949) arsenic anti-freeze, sometimes fatal, only in severe cases the second line treatment: eflornithine nifurtimox-eflornithine combination treatment (NECT) Suramin drug gets 'dramatic' results treating autism in children after just one dose 100 years after it was developed CDC - African Trypanosomiasis DNDi, Swiss tropical Insitute, MSF 56 slow dripping infusion every six houra INSTITUTE OF PARASITOLOGY Second turning point – the change for a better New treatment: •NECT – combinatory therapy, IV • •Fexinidazole – 10 tables, orally, active for the 2nd stage • •Acoziboroles – 1 tablet - Click to enlarge http://www.cid.ed.ac.uk/images/Added%20Images/New%20Initiatives/Page%201.jpg LEGIDEON NEWS NOW // - Togo Becomes First African Country to be Validated Sleeping Sickness-free Symptoms, transmission, and current treatments for sleeping sickness | DNDi Putting sleeping sickness to sleep forever Diagnostics Surveillance Treatment Vector control Pentamidine and Melarsoprol Pentamidine Injection (Pentam) - Dosage, Uses, Side effects | Antimicrobial drugs -cross resistance Pentamidine •Diamidines, accumulate in mt •Binds DNA •Pleiotrophic effect on various cell fce Melarsoprol •Generates a toxic adduct with trypanothione (MelT) Melarsoprol - Wikipedia Pentamidine (MP-601205) | Antimicrobial Agent | MedChemExpress Injekce do svalu, 7 dnu Pentamidin puvodne protoze snizuje glukozu v krvi – vyhladoveni trypek Accumulate in the mit. mM concentration DK cells sensitive Antitrypanosomal aktivita – vysledek akumulace vedouci k multiple deleterious effetxts Melarsoprol – IV Figure 2. Schematic model of melarsoprol and pentamidine transport in Trypanosoma brucei. The schematic shows known and putative mechanisms. Both drugs are thought to enter trypanosomes via the P2 and AQP2 transporters; the weight of the arrows reflects their relative contributions to uptake. The presence of the AQP2 gene appears to correlate with HAPT1 activity but it is not yet certain that AQP2 codes for this activity. The P-type H+ ATPases (HA1–3) may provide a proton motive force that drives pentamidine uptake. Melarsen oxide forms a toxic adduct with trypanothione (TSH/TS), known as Mel T, which inhibits TSH synthesis and is also removed from the cell via the ABC transporter, MRPA. An additional low-affinity pentamidine transport activity (not shown) may contribute to transport of pentamidine at concentrations above 0.1, 10 days Eflornithine Nifurtimox-eflornithine combination treatment (NECT) Nifurtimox ›Originally for T. cruzi ›forms a nitro-anion radical metabolite ›causing significant breakdown of DNA ›mechanism is similar to action of metronidazole Eflornithine ›Failed cancer drug ›polyamine synthesis disruption ›irreversibly binding to ornithine decarboxylase ›preventing the natural substrate ornithine from accessing the active site Frontiers | New Approaches to Overcome Transport Related Drug Resistance in Trypanosomatid Parasites | Pharmacology ODC is the key enzyme in the cellular production of polyamines (spermine, spermidine, putrescine), which are essential for cell division and as such eflornithine was developed to inhibit cancer cell proliferation ODC in mammals – 20 minutes ODC in tryps 18 hours NECT - The overall conclusions were that the combination is non-inferior to eflornithine monotherapy and has considerable advantages such as protection against resistance, lower cost, easier and shorter administration as well as a reduction in adverse eects by 50% INSTITUTE OF PARASITOLOGY WHO bold targets Elimination of transmission of gambiense HAT Elimination as a public health problem of rhodesiense HAT by 2030 •https://doi.org/10.1371/journal.pntd.0010047 Acoziboroles – combines all three desired qualities - well abosped, oral, penetration to CNS, long half life Migth be a ley to interruption of transmission Positive serology negative parasitological tests Fewer than 1000 cases I Africa The very eand of eradication process areextremelu challenging, contr Cotrnol measuers will have to be maintained, for a long time obver a vast teritory Sustained funding despite of low incidents Screening activities enagenment of local populations The political isntabiity is worrying The animal reservoir is another problem, Wild animals are vector, reservoies that can sustained human infections Acoziboroles for anmimals, HAT can be a first disease to be eradciated thanks to tretment and not vaccine , Lets dream a little Towards elimination of dreadful comeback Several challenges still have to be overcome WHO set the goal fpr the elimination of HAT asued vby Tbg as aoublic heath problem for 2020 and for the total interruption of transmission tohumasn by 2030. First of all – donor fatigue must be avoided HAT is stigmatized, linked to many spirits and believes Doctor will recognize it? Tbr . Zoonotic! We celebrate several marvellous achievements – toole were improved, patienst bńumber down, but tor each the set goals The goal must now be maintain tge momentum and even bigger effrot of the research sicentists field workers developments agenices companies will fail if they are no parraleled by achievemnts in the political filed bringing piece, stability and minimal standard fo living people in remote regions most affected. https://www.youtube.com/watch?v=J2eqP7sMoAY