Update on New Anti - Malarials

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An Update on New Anti – Malarials:

An Update on New Anti – Malarials 1 6/2/2012

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Current scenario in Anti - Malarials 2 6/2/2012

Currently used Anti - Malarials:

3 6/2/2012 Drug Target of action Mode of action Adverse effects Clinical uses Chloroquine Blood-stage schizonticides Direct heme binding, Inhibit heme Fe(II)FPIX Polymerase. GI upset, itching, dizziness, psoriasis etc. Treatment and chemoprophylaxis of sensitive parasites Quinine Erythrocyte schizonticides Same as CQ Tinnitus, vertigo, syncope, headache etc. Treatment of CQ-resistant P. falciparum Mefloquine Blood-stage schizonticides Formation of toxic substance, Swelling of food vacuole Vomiting, headache, insomnia etc. Chemoprophylaxix and treatment of P. falciparum Currently used Anti - M alarials

Currently used Anti - Malarials:

4 6/2/2012 Drug Target of action Mode of action Adverse effects Clinical uses Primaquine Tissue-stage schizonticides & gametocytocides Generation of toxic metabolites, Oxygen radicals in Plasmodial mitochondria GI upset, anorexia, elevated methemoglobinaemia Radical cure and terminal prophylaxis of P. Vivax & P. Ovale Halofantrine/ Pyronaridine Erythrocytic schizonticides Inhibit heme polymerase, Inhibit vacuolar degradation GI upset, cardiac arrest Treatment of CQ-resistant P. falciparum Atovaquone Blood-stage schizonticides Inhibit mitochondrial electron transport GI upset, stomatitis Treatment and chemoprophylaxis of P. falciparum, in combination with Proguanil Currently used Anti - M alarials

Currently used Anti - Malarials:

5 6/2/2012 Drug Target of action Mode of action Adverse effects Clinical uses Pyrimethamine/ Sulfadoxine Blood-stage schizonticides Inhibitor of dhfr- ts /dhps, thereby, inhibit parasitic DNA Headache. SJS, Skin rash Headache. SJS, Skin rash Treatment of CQ-resistant P. falciparum (in combination as SP) Proguanil Erythrocytic schizonticides Inhibit dhfr and stops pyrimidine biosynthesis GI upset, nausea, Vomiting Chemoprophylaxis (with CQ) Artemisinin and its derivatives Erythrocytic schizonticides & gametocytocides Formation of iron catalysed free radical, Alkylation of heme, Membrane damage by free radical Neurotoxicity, anorexia, dizziness Treatment of multidrug- resistant P. falciparum Currently used Anti - M alarials

Currently used Anti - Malarials:

6 6/2/2012 Drug Target of action Mode of action Adverse effects Clinical uses Tetracycline/Doxycycline Blood-stage schizonticides Inhibit mitochondrial protein synthesis, block nucleic acid synthesis Nausea, vomiting, diarrhoea Treatment and chemoprophylaxis of P. falciparum Note: dhfr- ts : Dihydrofolate reductase- thymidylate synthase, dhps : Dihydrofolate pteroate synthase, SJS: Steven’s Johnson Syndrome. ****** Currently used Anti - M alarials

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New Drugs…Are they required??? 7 6/2/2012

Need of new Anti - Malarials:

Need of new Anti - M alarials 8 6/2/2012 Increasing Resistance against ACTs Less treatment options in malaria Demand - Supply imbalance of Artemisinin Multiple doses of current therapy – Non compliance FDC available in only some ACTs Sulfa reactions, SJS observed with Sulfadoxine Fat dependent bioavailability of Lumefantrine New Molecules are Warranted Potential Vaccines in 2025

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9 6/2/2012 Treatment failure rates artemether – lumefantrine in the Greater Mekong subregion (2001–2009)

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10 6/2/2012

Treatment failure rates with artesunate –sulfadoxine –pyrimethamine in selected countries (2001–2008):

11 6/2/2012 Treatment failure rates with artesunate – sulfadoxine – pyrimethamine in selected countries (2001–2008)

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12 6/2/2012

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13 6/2/2012 (1.) National Medicines Policy and (2.) Procurement and Forecast of ACTs Millions of ACT treatment courses Cumulative No. of countries adopting ACT as 1st-line Rx Cumulative number of countries adopting ACTs as 1st-line treatment Cumulative number of countries deploying ACT s Forecast: 124 Million

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14 6/2/2012

Some of the New Drug Targets:

Some of the New Drug Targets Dihydroorotate dehydrogenase ( DHODH): The parasite and mammalian forms differ considerably. Potent and selective compounds have been developed 2) A denosine deaminase inhibitors: 3) Inhibitors designed to be active against the transition state of purine nucleoside phosphorylase have been shown to be active against P. falciparum . Compounds are safe and ready to test on humans 4) Apicoplast – an organelle selectively present in Plasmodium Metabolic pathways in apicoplast are potential targets e .g. Fosmidomycin targeting 1-deoxy-d-xylulose 5-phosphate pathway. In Phase – II 15 6/2/2012

Some of the New Drug Targets:

Some of the New Drug Targets 5) Protease targets: Are potential but selective parasite selectivity is an issue e.g. cysteine proteases - falcipain57 and the serine protease inhibitors - PfSUB1 were difficult to develop as drug candidates because of selectivity issues . 6) Choline channel blocker - A lbitiazolium bromide. Important because IV/IM possible and hence can be useful against severe malaria. In Phase II 7) Imidazolopiperazine : In Nov 2011, new class discovered active against both liver and blood stages of parasite - Hence, useful to prevent and treat malaria 16 6/2/2012

Some of the New Drug Targets:

Some of the New Drug Targets

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Drugs in Phase – III or completed Phase - III 18 6/2/2012

Arterolane + Piperaquine:

Arterolane + Piperaquine 19 6/2/2012 Endoperoxide Pharmacophore Arterolane Artesunate H ence, availability never a problem!!!! W ith efficacy against P. falciparum Synthetic

Arterolane + Piperaquine:

Arterolane + Piperaquine First New Chemical Entity (NCE) of India ( Arterolane ) Phase – III trials completed for uncomplicated P. falciparum while that for P. vivax are on - going Developed in line with WHOs recommendation of Anti – Malarial drugs Fixed Dose Combination (FDC) with only 3 tablets (1 OD *3 days) Regimen No fat dependent bioavailability issues life Lumefantrine Will be launched soon in India by Ranbaxy Laboratories Ltd. 20 6/2/2012

Dihydroartemisinin + Piperaquine:

Dihydroartemisinin + Piperaquine Dihydroartemisinin is derived from natural source Combined with long acting drug Piperaquine Has been u sed extensively in China and Cambodia Approved by EMA recently and WHO recommended FDC Approved by 21 countries world wide Trials are still on - going in Indian Population 21 6/2/2012 Dihydroartemisinin Piperaquine

Artesunate + Pyronaridine:

Artesunate + Pyronaridine Developed by Korean company Shin Poong and MMV jointly Completed Phase III trials and proved to be non inferior to Artemether + Lumefatrine FDC with only 3 tablets (1 OD *3 days) regimen like Arterolane + Piperaquine For approval with EMA 22 6/2/2012 Artesunate Pyronaridine

Azithromycin + Chloroquine:

Azithromycin + Chloroquine Safe and well tolerated in pregnant women: hence a potential combination for use in early pregnancy Passing the WHO approved criteria of 95%efficacy with respect to patient being free of parasite recrudescence on day 28 FDC for prophylactic use during pregnancy for which 4 tablets are to be taken Clinical signs of synergy between two molecules seen Most advanced non ACT based regimen currently in pipeline 23 6/2/2012 Azithromycin Chloroquine

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- Drugs in Phase – I or Phase - II 24 6/2/2012

Drugs in Phase I of II Clinical Trials:

Drugs in Phase I of II Clinical Trials 7 in Phase II and 8 in Phase I Focus is not no efficacy at these stages but how novel or useful the molecule is going to be? Should be able to be used by varied population Dramatic life saving response 25 6/2/2012

Artemisone (Artemifone):

26 Artemisone ( Artemifone ) 6/2/2012 Semisynthetic derivative of Artemisinin with additional thiomorpholino group in 10 – position Proved effective in Phase –II Project was dropped as there was no dramatic advantage compared to parent drug. However…

Artemisone (Artemifone):

Artemisone ( Artemifone ) 27 6/2/2012 In Nov 2009, NEJM reported the first clinical trial confirming Artemisinin resistance in Thai – Cambodia region Median Parasite Clearance Time (PCT) increased to 84h compared to 48h Artemisone was hence thought of if it had continue to show PCT <48h, as it is structurally different than artemisinin Proof of concept study has been planned to see this advantage in artemisinin resistant area

Novel 4 - Aminoquinolines:

28 Novel 4 - A minoquinolines 6/2/2012 Ferroquine N – ter – butyl - isoquine AQ - 13 Can be advantageous if… Cross resistance is less Dose is reduced than currently used 4 – aminoquinolines Better safety profile than current drugs in the class Commonly used 4 – aminoquinolines are Chloroquine 2) Amodiaquine Basic Ring Newer 4 – aminoquinolines in development are

Ferroquine:

29 Ferroquine 6/2/2012 Developed at University of Lille Has a Ferrocene moiety (Iron sandwiched between two organic rings) which contributes to the physico - chemical properties of Ferroquine { Artesunate + Ferroquine } is in Phase – II trial Dose ranging study comparing it with Artesunate + Amodiaquine was conducted in 2008 Ferrocene moiety

Isoquine & AQ - 13:

30 Isoquine & AQ - 13 6/2/2012 Mechanism of Amodiaquine toxicity Isoquine do not generate quinine – imine that are suspected to cause side effects of amodiaquine when used repeatedly for prophylaxis At Phase – I stage of drug development AQ – 13 is simplified 4 – amino quinoline with advantage of less dose , hence less bio-burden and cost. Phase – I study completed

(+) Mefloquine:

31 (+) Mefloquine 6/2/2012 One of the diasterioisomer is responsible for commonly seen CNS side effects and Gastrointestinal intolerance of Mefloquine (+) erythro Mefloquine is under trial and can be potential to reduce the side effects associated with Mefloquine Also the cost of production is similar to that of Mefloquine racemic mixture Mefloquine

Ozonides:

32 Ozonides 6/2/2012 Three (3) ozonide are there under development 1) CDRI 97/98 a simple trioxolane developed by Central Drug Research Institute, India (Phase – I started) 2) OZ439 next generation ozonide by University of Nebraska, Phase – I started in April 09 3) Trioxaquine – fusion between 4 – aminoquinoline and a trioxane developed by Sanofi - A ventis

Fosmidomycin and 4 - Pyridone :

33 Fosmidomycin and 4 - Pyridone 6/2/2012 Pyruvate and glyceraldehyde 3-phosphate 1-Deoxy-D-xylulose 5-phosphate DOXP synthase In combination with Clindamycin it has shown good action against Plasmodium falciparum Project is in Phase – II of drug development Fosmidomycin Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III ) Effective against A tovoquone resistant strains Phase – I completed

Methylene Blue (MB):

34 Methylene Blue (MB) 6/2/2012 Activity of dyes against malarial parasite seen >80 years ago Phase – II studies of MB + Chloroquine are published but failed to meet the WHO criteria of 95%efficacy Disadvantage: a) It interacts with large number of various targets in body b) Blue coloration of urine However, MB + Amodiaquine / Artesunate trials is under recruitment phase

Tafenoquine:

35 Tafenoquine 6/2/2012 A Novel 8-aminoquinoline Since last 60 yrs primaquine is the most commonly used drug of this class for radical cure in P. vivax Disadvantage of primaquine is that it is 14 day long therapy and hence compliance is always an issue Tafenoquine was produced in 1980s However, Tafenoquine might be developed as shorter course of therapy and has a better therapeutic window But, it also showed signs of haemolysis due to G6PD deficiency Tafenoquine

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36 6/2/2012 This project is aimed at development of Human monoclonal antibodies as tools for malaria research and therapy and was started in 1 st January 2007. Overall objective : To generate human monoclonal antibodies (HumAbs) with specificity for P. falciparum antigens of importance in acquired protection to P. f alciparum-induced malaria. Specific objective : To generate HumAbs with specificity for antigens exposed on the surface of infected erythrocytes To generate HumAbs with specificity for variants of the PfMSP1 antigen To test the reactivity and specificity of the developed HumAbs with respect to P. Falciparum isolates obtained from infected individuals HUMALMAB

Other drug classes for radical cure:

37 Other drug classes for radical cure 6/2/2012 Tinidazole – a nitroimidazole Is metabolized in liver and has shown some effect against dormant hypnozoites in primate model Clinical trials are going in Thailand 2) Mirincamycin Efficacy shown in pre – clinical studies Showed activity against hypnozoites in primate models Tinidazole Mirincamycin

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Malaria Vaccine 38 6/2/2012

Malaria Vaccine – Urgent need:

39 Malaria Vaccine – Urgent need 6/2/2012 A safe , effective, and affordable malaria vaccine would create a powerful public health benefit by closing the gap left by other interventions like insecticide bed nets etc Challenges: scientific unknowns, inadequate funding, too little cooperation among scientists and among funding agencies, limited private-sector involvement, mixed levels of interest from developing countries, and as yet uncertain mechanisms for procuring and distributing a successful vaccine To meet these challenges the global malaria vaccine community came together to establish a shared vision and goals and to identify the activities that could address some of the above-mentioned challenges in Aug 2006 Result was: Malaria Vaccine Technology Roadmap Strategic Goal By 2025, develop and license a malaria vaccine that has a protective efficacy of more than 80 % against clinical disease 3 and lasts longer than four years Landmark By 2015, develop and license a first-generation malaria vaccine that has a protective efficacy of more than 50% against severe disease and death and lasts longer than one year.

Closest Vaccine - RTS,S/AS01:

40 Closest Vaccine - RTS,S/AS01 6/2/2012 Name : GlaxoSmithKline Biologicals (GSK) RTS,S AS01/AS02 Development stage : Phase 3 trial Main partner : GlaxoSmithKline Biologicals Additional partners : Malaria Clinical Trials Alliance; 11 African clinical trial sites Platform : The RTS,S antigen, produced in S. cerevisiae , consists of the two proteins RTS and S that intracellularly and spontaneously assemble into mixed polymeric particulate structures that are each estimated to contain, on average, 100 polypeptides Antigen : RTS,S consists of sequences of the circumsporozoite protein and the hepatitis B surface antigen ( HBsAg ) Adjuvant : AS02D/AS01E 1) AS02 : proprietary oil-in-water emulsion formulated with MPL® and Stimulon ® QS21 immunostimulants 2)AS01 : liposome formulation with MPL® and QS21 immunostimulants

First Result published in NEJM:

41 First Result published in NEJM 6/2/2012

References:

42 References 6/2/2012 World Health Organization. World Malaria Report 2008. <http://malaria.who. int /wmr2008/malaria2008.pdf> (2008 ). Bassat , Q. et al . Dihydroartemisinin-piperaquine versus artemether lumefantrine for treating non complicated malaria in African children: a randomized open label phase III non inferiority trial in five African countries. PLoS Med . Ramharter , M. et al . Fixed-dose pyronaridine-artesunate combination for treatment of uncomplicated falciparum malaria in pediatric patients in Gabon . J. Infect. Dis . 198, 911–919 (2008). Dunne , M.W. et al . A multicenter study of azithromycin, alone and in combination with chloroquine , for the treatment of acute uncomplicated Plasmodium falciparum malaria in India. J. Infect. Dis . 191, 1582–1588 (2005 ). Haynes , R.K. et al . Artemisone —a highly active antimalarial drug of the artemisinin class. Angew . Chem. Int. Ed. Engl . 45, 2082–2088 (2006 ). Biot , C., Glorian , G., Maciejewski , L.A. & Brocard , J.S. Synthesis and antimalarial activity in vitro and in vivo of a new ferrocene-chloroquine analogue. J. Med. Chem . 40, 3715–3718 (1997). O’Neill , P.M. et al . Isoquine and related amodiaquine analogues: a new generation of improved 4-aminoquinoline antimalarials . J. Med. Chem . 46, 4933–4945 (2003). Mzayek , F. et al . Randomized dose-ranging controlled trial of AQ-13, a candidate antimalarial, and chloroquine in healthy volunteers. PLoS Clin . Trials 2 , e6 (2007 ). Wiesner , J., Borrmann , S. & Jomaa , H. Fosmidomycin for the treatment of malaria . Parasitol. Res . 90 (suppl. 2), S71–S76 (2003 ). Zoungrana , A. et al . Safety and efficacy of methylene blue combined with artesunate or amodiaquine for uncomplicated falciparum malaria: a randomized controlled trial from Burkina Faso. PLoS One 3, e1630 (2008 ). Yeates , C.L. et al . Synthesis and structure–activity relationships of 4-pyridones as potential antimalarials . J. Med. Chem . 51, 2845–2852 (2008 ). Walsh , D.S. et al . Randomized dose-ranging study of the safety and efficacy of WR 238605 ( Tafenoquine ) in the prevention of relapse of Plasmodium vivax malaria in Thailand. J. Infect. Dis . 180, 1282–1287 (1999 ). Timothy N. C. Wells*, Pedro L. Alonso‡ and Winston E. Gutteridge , New medicines to improve control and contribute to the eradication of malaria. Natures review drug discovery, Nov 09, Vol:8 http://www.sciencemag.org/content/334/6061/1372.abstract

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43 6/2/2012 Thank You Fight against Malaria Continues…

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