PHARMACOTHERAPY & RECENT ADVANCES OF

CHLOROQUINE RESISTANT MALARIA

BY- Dr. NITIN SHINDE•Resident Dept. of Pharmacology

• LOKMANYA TILAK MUNICIPAL MEDICAL COLLEGE & GENERAL HOSPITAL.

•SION, MUMBAI– 400022.• DATE – 12-09-2015. 1

Overview-Pharmacotherapy  Introduction with Global & Indian Scenario chloroquine resistant

malaria. Definition of Chloroquine resistant malaria. Mechanism of Chloroquine resistant malaria. Diagnosis of Chloroquine resistant malaria. Pharmacotherapy of uncomplicated P.Falciparum Chloroquine

resistant malaria Pharmacotherapy of complicated Chloroquine resistant malaria Pharmacotherapy of P.Vivax Chloroquine resistant malaria Pharmacotherapy of Chloroquine resistant malaria in pregnancy Guidelines for the management of chloroquine resistant malaria Chemoprophylaxis of chloroquine resistant malaria

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Overview-Recent Advances

Newer combinations. EXISTING TARGETS- NEW DRUGS. New targets- New Drugs- Fosmidomycin,TES, OZ439. Drugs reversing Chloroquine Resistance New chemosensitizing agents- Tricyclic acridone

molecules. Newer Drug Targets- Apicoplast and others. Antimalarial Vaccine- Pre-erythrocytic, Erythrocytic and

Transmission Blocking Vaccines. Role of genome sequencing. Natural Agents. Conclusion.

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Introduction:

Malaria kills 1.5 to 2.7 m people world wide every year

95% are due to P.falciparum

In India P. falciparum up to 34%

Case fatality rate is up to 9%

Chloroquine resistance is major concern

Multi drug resistance emerged in India

Global Scenario….P. falciparum resistance Chloroquine resistant strains are found now in

nearly all areas of chloroquine use including South America, Central America, east of the Panama Canal, the Western Pacific, East Asia

P. vivax resistance Recent reports from Indonesia (Irian Jaya, Sumatra)

and Papua, New Guinea Papua, New Guinea indicate high levels of P. vivax schizonts resistant to chloroquine.

P. ovale and P. malariae resistance P. ovale and P. malariae forms have not shown

resistance to chloroquine

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Indian Scenario… NMCP(1953-58)- Incidance of malaria declined from 75

million cases & 8 Lakh deaths to about 1-2 million cases and zero death till 1958.

NMEP(1963)- More than 120 million cases and 20 Lakh deaths in next two years.

The first confirmed report of chloroquine resistance in P. falciparum was reported in Diphu Diphu area of Karbianglong Karbianglong district of Assam in 1973.district of Assam in 1973.

Incidence being 5% to full dose chloroquine Resurgence of P. falciparum resistant to chloroquine has

been noticed in several regions of India, more in North Eastern parts of the country

NMCP- National Malaria Control ProgrammeNMEP- National Malaria Eradication Programme

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BURDEN OF DRUG RESISTANTMALARIA

Recurrent infections More malaria –More deaths Epidemics Work/school, productivity, Anaemia, Pregnancy complications Greater financial costs - (Health service,community, individual)

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DefinitionThe ability of a parasite strain to survive or multiply despite the

administration and absorption of a drug given in doses equal to or higher than those usually recommended but within the

tolerance of the subject (WHO, 1986). provided that the drug gained access to the parasite or the infected red cell for the

duration of time necessary for its action. (Bruce-Chwatt et al,).

Another definition:

It is the ability of a parasite strain to multiply or to survive in the presence of concentrations of a drug that normally destroy parasites of the same species or prevent their

multiplication.

Mechanism Of Resistance Resistant strains are able to

efflux the drug by an active pump mechanism.

pfcrt gene encodes a transporter in the membrane of acidic digestive vacuole causing efflux of chloroquine from the food vacuole

:K76T Mutation There is an increase in the

surface area of the resistant parasites, permitting more efficient pinocytosis.

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Diagnosis of Chloroquine resistant malaria Clinical Diagnosis Malaria Blood Smear Fluorescent microscopy (RDT)Rapid Diagnostic Tests: Serological test

with PF-HRP-2. It should be noted that Pf HRP-2 based kits may

show positive result up to three weeks after successful treatment and parasite clearance.

In these cases, results should be correlated with microscopic diagnosis.

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Pharmacotherapy of uncomplicated P.Falciparum Chloroquine resistant malaria with Artemisinine Combination Therapy.

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What are Artemisinins ?

Artemisinin derivatives

Methyl Ether

Hemisuccinate

Ethyl Ether

Arteether Artemether

Artesunate

Dihydroartemisin

Qinghaosu ("ching-how-soo")

Artesunate Artemether Arteethersolubility Water soluble Lipid soluble Lipid soluble

Route oral, IM, IV oral, IM IM

Metabolite DHA DHA DHA

t1/2 2-4 hrs 3-10 hrs 23 hrs

Side effects

Drug fever,rashCardio toxicity,Raised liver enzymes,

Cardio toxicity,Blood changes,Raised liverEnzymes,Neurotoxicity.

NeurotoxicityNausea,Dizziness,Depressed GIT activity

WHY ACT FOR CHLOROQUINE RESISTANT MALARIA?

• The artemisinins produce rapid clearance of parasitaemia and rapid resolution of symptoms

• Combination therapy prevents resistance.• Shorter T ½ so only problem is Recrudescence.

The partner medicine :• Have different mechanisms of action ,• longer half-lives• and must independently be sufficiently

efficacious in treating malaria.

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ARTEMISININ BASED COMBINATION THERAPY (ACT)

WHO Recommends following Artemisinin based

combination regimes for the management of

Chloroquine resistant P.Falciparum malaria.

1. Artesunate-sulfadoxine + Pyrimethamine(AS-S/P)

2.Artemether-Lumefantrine(AS/LF)

3.Artesunate/Mefloquine(AS/MQ)

4. Artesunate-Amodiaquine(AS/AQ)

5. Dihydroartemisinin(DHA)-Piperaquine

WHO

NVBDCP

ACT regimen Comment

Artesunate-Sulfadoxine/PyrimethamineAS 100mg BD X 3d + S 1500mg (25mg/kg) + P 75mg (1.25mg/kg) single dose

1st line drug for falciparum under NVBDCP, India. > 96% cure rateNon effective against MDR strain for S/P(north-east India)

Artemether/Lumefantrine (1:6) AM 80mg BD + Lf 480mg BD X 3d (adult dose) >35kg = adult dose, 25-35kg= 3/4th dose, 15-25kg= ½ dose, 5-15kg = 1/4th dose

FDC approved.Preferred in (north-east India).African countries.Lf Given with fatty food, t/2 -- 2-3d, highly effective. 95-99% cure rateBoth can raise QT int. c/i in 1st Trimester of pregnancy and lactation.

Artesunate/Mefloquine

AS -100mg BD (4mg/kg/day) X 3d +MQ -750mg (15mg/kg) on day2 & 500mg (10mg/kg) on day3

FDC approved . Highly effective, well tolerated. Extensive use in Thailand & Myanmar, MQ-Resistance prevented

DHA/ piperaquine (1:8)DHA 120mg (2mg/kg) + piperaquine 960mg (16mg/kg) X 3d

Efficacy comparable to AM/LF, children- well tolerated> 98% cure rate

ACT regimen Comment

Artesunate-AmodiaquineArtesunate 200mg(4 mg/kg/day) + Amodiaquine600mg (10mg/kg) per day X 3days.

Early results encouraging, Low costAQ –short t/2, active metabolite, t/2 = 10-18d.Reduced Agranulocytosis and hepatotoxicity.Recently Approved in India.

Artorolane/piperaquineArtorolane150mg + piperaquine750mg per day X 3days.

Arterolane synthetic analogue, developed in India, low cost & well tolerated.Not FDA Approved.

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Artesunate + mefloquine VsArtemether + lumefantrine

RCT - A total of 470 (235 in each arm) patients were enrolled

The unadjusted 28-day cure rate was higher in artesunate-mefloquine arm than in the artemether-lumefantrine arm (79.7% versus 67.8%; P < 0.004)

After correction for reinfection, the 28-day cure rates were similar in the two groups (96.04% versus 96.93%)

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Pharmacotherapy of Chloroquine resistant Severe P.falciparum malaria

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(Complicated)Severe falciparum malaria

cerebral malaria- Coma, convulsions Renal Impairment Noncardiogenic pulmonary edema Liver Dysfunction Hypoglycemia Metabolic acidosis. Hematological abnormality like hemoglobinuria, Normocytic anemia, bleeding, DIC Other complications : jaundice, extreme weakness,

impaired consciousness. Hypotension/shock

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Management Of Severe Malaria Rapid clinical assessment and confirmation of the

diagnosis full doses of parenteral antimalarial treatment should be started without delay.

1. Artesunate 2.4 mg/kg i.v. or i.m. given on admission (time = 0), then repeat the dose at 12 h and 24 h, then once a day for 7d.

2. Artemether 3.2 mg/kg i.m. given on admission then 1.6 mg/kg per day for next 7 days.

*Recommended by NVBDCP

3. Arteether 3.2 mg/kg i.m. given on admission then 1.6 mg/kg per day for next 4 days.

Switch to oral 3 day ACT whenever pt can take oral medicines.

QUININE IV INFUSION- (7 days course)

Loading dose : 20mg/kg i.v over 4hrs diluted in 5% dextrose to prevent hypoglycemia Followed by -Maintenance Dose: 10mg/kg over 4hr in adults or 2hr in children every 8hrly till patients condition improves.Then switch over to oral Quinine 600 mg (10mg/kg) TDS to complete the 7 day course.Doxycycline 100 mg OD can also be given with quinine

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Parental Artemisinin are fast ,more effective, better tolerated and now preferred over Quinine for severe malaria

Adverse effects of Quinine

Higher doses : Affects hearing & vision,Cardio depressant , hemoglobinuria.

QT prolongation during i.v On rapid i.v it causes hypotension. Cinchonism :Reversible Ringing in ears, nausea, vomiting, headache, mental

confusion, vertigo, difficulty in hearing & visual disturbance, diarrhoea ,flushing & marked perspiration .

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Pharmacotherapy of Chloroquine resistant

P. Vivax malaria

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CHLOROQUINE RESISTANT P. VIVAX

Recent development.

Gravity of the threat posed by vivax malaria to public health has been poorly appreciated

Resistance in P. vivax is more serious as hypnozoites will cause relapse of resistant parasites.

Reported in focal areas of India, Burma, Indonesia, Papua ,New Guinea, Brazil, Guyana, Colombia and Solomon Islands

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CHLOROQUINE RESISTANT P. VIVAX

Quinine 600 mg (10 mg/kg every 8 h. with Doxycycline 100 mg once a day are administered for 7 days.

This is followed by Primaquine 15 mg (0.25 mg/kg ) once a day for 14 days.

NVNVBDCP: : 7 day quinine 600mg 8hrly+ Doxycycline 100mg daily/clindamycin 600mg 12hrly is second line treatment in chloroquine resistance to falciparum & vivax malaria plus Primaquine for 30 Days.

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Treatment of Malaria in Pregnancy• P. falciparum:

• 1st Trimester: Quinine 600mg TDS for 7 days

2nd & 3rd Trimester: ACT– Any ACT combination or– Artesunate + Clindamycin 7 days or– Quinine + Clindamycin 7 days

• P vivax: Clindamycin 10 mg/kg. • Note: Primaquine is contraindicated in

pregnancy.

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Guidelines for treatment of Malaria -2014

Grading of Resistance:Sensitive (S):Clearance of parasitaemia within 7 days

without recrudescence

Low Grade Resistance (R1): Clearance of parasitaemia followed by recrudescence ( 28 Days after the last dose)

High Grade ( RII): Greater than 75% but less than 100% of parasites cleared within 7 days

High Grade ( RIII) : Parasite count does not fall by more than 75%

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Recommended ACT in national drug policy is fixed dose combination (FDC) of Artemether-lumefantrine (AL).

Not recommended during the first trimester of pregnancy and for children weighing <5 kg.

Lumefantrine(Aminoalcohol)

Tissue Stage

Blood Stage

Gametocidal

Pf

Pv

Po

Pm

As combination, in Treatment of of Multidrug resistant P.f malaria

• Structurally similar to Structurally similar to Mefloquine .Mefloquine .

• Oral BA- variable, better Oral BA- variable, better with fatty foodswith fatty foods

• Elimination t1/2 - 3 daysElimination t1/2 - 3 days

• Well tolerated as Well tolerated as compared to compared to halofantrinehalofantrine

• Nausea, abdominal Nausea, abdominal discomfort, headache discomfort, headache and dizzinessand dizziness

• Prolongation of QT Prolongation of QT interval.(less than interval.(less than halofentrine )halofentrine )

• C/I in Pregnancy and C/I in Pregnancy and lactation.lactation.

Chemoprophylaxis Non immune travellers Army units Migrant workers

Chemoprophylaxis

Short-term chemoprophylaxis (less than 6 weeks) Doxycycline: 100 mg daily in adults 1.5 mg/kg for children> 8 years old The drug should be started 2 days before travel and

continued till 4 weeks after returning from endemic area of chloroquine resistant malaria.

Long-term chemoprophylaxis (more than 6 weeks) Mefloquine: 250 mg or 5 mg/kg started 1-2 weeks

before taken weekly till 4 weeks after return from endemic area.

administered two weeks before, during and four weeks after leaving the area.

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Mefloquine

Spectrum- Blood schizontocide No activity against hepatic stages & gametocytes

Pharmacokinetics Well absorbed orally Parenteral preparations cause severe local reactions Widely distributed Highly bound (~98%) to plasma proteins Terminal t ½ of ~20 days

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Contd…

Prophylaxis and chemotherapy of drug-resistant P. falciparum and P. vivax malaria

Adverse effects- Nausea, vomiting, dizziness, and neuropsychiatric

reactions

C/I - patients with a history of seizures Should not be given with halofantrine

Approved for pregnancy (after first trimester)

Atovaquone- Proguanil(Malarone)DRUG ADULT DOSE PEDIATRIC

DOSE COMMENTS

Atovaquone/Proguanil(MALARONE)

Adult tablets contain250 mg atovaquoneand 100 mg proguanilhydrochloride. 1 adulttablet orally, daily

Pediatric tablets (62.5 mgatovaquone/25 mg proguanil HCl).5-8 kg: 1/2 ped tab/day>8-10 kg: 3/4 ped tab/day>10-20 kg: 1 ped tab/day>20-30 kg: 2 ped tab/day>30-40 kg: 3 ped tab/day>40 kg: 1 adult tablet daily

Begin 1-2 days before travel to endemic areas. Take daily and for 7 daysafter leaving such areas. Not recommended for prophylaxis for children <5 kg, pregnantwomen, and women breast-feeding infants weighing <5 kg.

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Contd…

Prophylaxis and treatment of malaria

Fixed dose combination 250 mg atovaquone and 100 mg proguanil

hydrochloride

FDC - Treating drug-resistant P. falciparum malaria Chemoprophylaxis of malaria

NOT USED IN INDIA

Atovaquone(Napthaquione)

Tissue Stage

Blood Stage

Gametocidal

Pf

Pv

Po

Pm

As combination, Chemoprophylaxis of P.f malaria & Therapy of Multidrug resistant malaria

• Inhibits ETC in mitochondria Inhibits electron transport and collapses the mitochondrial membrane

• BA ↑ with fatty meals

• 99% of plasma protein bound

• Elimination t1/2 from plasma of 2-3 days in adults and 1-2 days in children

• Mild- abdominal pain, nausea, vomiting, diarrhea, headache, rash warranting cesation

• Not recommended in children <11 kg, pregnant women, and lactating mothers

Proguanil(Buguanides)

Tissue Stage

Blood Stage

Gametocidal

Pf

Pv

Po

Pm

As combination, Chemoprophylaxis of P.f malaria & Therapy of Multidrug resistant malaria

• Acts on Pre erthrocytic stages but not on Hypnozoites

• Metabolized by CYP2C19 to cycloguanil

• Slow blood schizontocides

• In pregnancy, with folate supplements

• Vomiting, abdominal pain• Cast nephropathy.

• Hematological changes (megaloblastic anemia and pancytopenia) - in severe renal impairment

• Rapid resistence if used as monotherapy

Recent Advances

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1.NEW COMBINATION THERAPY

More Promising than monotherapy Moe efficacious & retards the resistant strains.

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Arterolane Trioxalane congener of artmisinine . Rapidly acting high efficacy erythrocytic

schizonticide but duration of action is short. Sensitive against resistant plasmodium species. Each tablet of FDC consists of arterolane (150 mg)

and piperaquine (750 mg) OD for 3 days. Status: Ranbaxy Laboratories Limited has received

the regulatory approval for.. Synriam (arterolane maleate 150 mg +piperaquine

phosphate 750 mg drug) in seven African countries- April 2014.

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PIPERAQUINE

Synthetic Bisquinoline compound belonging to 4-amioquinoline group .

Piperaquine has a slow and longer schizontocidal activity against erythrocytic stages of both P. vivax andP. falciparum  chloroquine-resistant strains.

Activity against chloroquine-resistant strains may be attributed to bulky bisquinoline structure itself, which possibly also contributes to inhibition of chloroquine efflux transporters from the parasite food vacuole

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PYRONARIDINE

Newer drug derived from mepacrine developed in china.

MOA: Similar to chloroquine. Highly effective erythrocytic schizonticide. Effective against both chloroquine sensitive and

resistant strains. At high doses analgesic and antipyretic action is

also seen. S/E – Mild abd. Pain , Headache, vomiting. Artesunate(200mg) + Pyronaridine (600mg) for 3

days in phase III Clinical trials.(Approved in china).48

2.EXISTING TARGETS- NEW DRUGS

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CHLORPROGUANIL

Chloro derivative of proguanil. MOA: Similar to proguanil. Combined with Dapsone (Lapdap)

Side effect profile and other features similar to Proguanil.

Withdrawn due to hematologic complications in G-6PD Patients

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5-FLUOROOROTATE Orotic acid, an intermediate of pyrimidine

biosynthesis. 5-fluoroorotate, a cytotoxic derivative of orotic acid,

may be a potent and selective antimalarial agent. In vitro, 5-fluoroorotate caused 50% inhibition of the

growth of Plasmodium falciparum at a concentration of 6.0 nM. In contrast to 5-fluorouracil.

Chloroquine-susceptible and chloroquine-resistant clones of P. falciparum were equally susceptible to 5-fluoroorotate.

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Existing targets- New Drugs

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G-25 Promising lead compound. Phosphatidylcholine synthesis inhibitor. In vivo activity against P. falciparum: P. falciparum

infection in Aotus monkeys was cleared 4 days after treatment with G25 dosages as low as 0.03 mg/kg administered twice daily for 8 days.

The researchers comment that G25 was as effective as quinine and pyrimethamine/sulfadoxine.

Indicate that G25 fulfills essential criteria for the development of a new class of antimalarials.

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Existing targets- New Drugs

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TAFENOQUINE

Primaquine analogue with a long elimination–half-life (14–28 days for tafenoquine,versus 4–6 hours for primaquine) .

It has activity against the blood and liver stages of malaria .

In vitro and in vivo animal models have shown that tafenoquine is more potent and less toxic than primaquine

Status: Preclinical.

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ArtemisoneArms InterventionExperimental: Artemisone/Mefloquine (AmiM3)

Drug: Artemisone/Mefloquine (AmiM3)Artemisone 4 mg/kg/day for 3 days plus mefloquine 15mg/kg on day 3 and 10mg/kg on day 4

Active Comparator: Artesunate/Mefloquine (MAS3)

Drug: ArtesunateArtesunate 4mg/kg/day for 3 days plus mefloquine 15mg/kg on day 3 and 10mg/kg on day 4

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Shown promising efficacy for the treatment of uncomplicated falciparum malaria in phase III trials in Thailand and seems to be at least as efficacious as artesunate. No significant toxicity has been reported for artemisone and it is very well tolerated.Status – Phase III.

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3.New targets- New Drugs

Apicoplast targets:Chloroplast-like organelle

Maintains specific functions including fatty acid, heme & amino acid metabolism

Fosmidomycin & TE3 are such drug acting on apicoplast.

Fosmidomycin  MOA: inhibits the 1-desoxy-D-xylulose-5-

phosphate reductoisomerase in the mevalonate-independent pathway of isoprenoid synthesis in apicoplast.

Fosmidomycin was initially developed as an antibacterial drug, but has shown efficacy in combination with clindamycin or azithromycin against P. falciparum malaria.

In combination with clindamycin . Discontinued - Phase-II for Malaria (In children) in

Mozambique due to unfavourable results. (NCT01464138) .

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TE3 TE3, a prodrug of a bis-ammonium compound Acts on phospholipid metabolism through the

inhibition of de novo phosphatidylcholine synthesis in apicoplast

combined with a putative activity on heme detoxification.

This new class of compounds has shown potent in vivo antimalarial activity in the primate model Aotus

No cross resistance in vitro with known antimalarials.

Status: Preclinical.

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Ozonide OZ439

• Synthetic peroxide antimalarial drug candidate

• Designed to provide a single-dose oral cure in humans.

• After success in Phase I trials, undergoing Phase IIa trials in malaria patients.

• A fast-acting against all asexual erythrocytic P.falciparum stages comparable to semisynthetic artemisinin derivatives.

• Good efficacy and prolonged blood concentrations.

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4.Drugs reversing Chloroquine Resistance >> > Experimental. Ca-Channel Blockers: Verapamil Phenothiazines : Desipramine Antihistaminic : Chlorpheniramine Vitamin E : Deficiency may afford protecton Erythocyte specific Ab encapsulated in

liposomes: to circumvent Chloroquine-resistance.

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The rigid tricyclic aromatic acridone core :The side-chain attachment at the central nitrogen atom provides a hydrogen bond acceptor needed for the chemosensitization function, and, together with the side chain at position 6, facilitates accumulation in the digestive vacuole (DV) via acid trapping

5.New chemosensitizing agents

New chemosensitizing agents Tricyclic acridone molecules with a short alkyl

amine chain attached to the central nitrogen atom could make chloroquine-resistant parasites susceptible to the drug again. (Chemo sensitizing action)

This action is attributed to blocking the PfCRT pump protein, meaning that the chloroquine can reach its target.•

This new class of antimalarial drug have dual role it can reverse the malaria parasites resistance to existing drugs and also have antimalarial action.

These are in early Preclinical phase of development.

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1) Glycolysis is another cytosolic pathway of interest Parasites depend on this - energy production

Plasmodial lactate dehydrogenase2) Malaria parasites cannot synthesize purines, rely on

salvage of host purines for nucleic acid synthesis viz Hypoxanthine

Hypoxanthine–guanine phosphoribosyltransferase

3) Proteases of Hb hydrolysis in food vacuole viz 1) Aspartic proteases - Plasmepsins Cysteine proteases - Falcipains Serine proteases

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7.Antimalarial Vaccine

Altruistic vaccine: it is a transmission blocking vaccine.

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Circumsporozoite protein The circumsporozoite (CS) protein is the pre-

erythrocytic antigen against which immune responses are most clearly linked to

Protection. Antibodies are primarily directed against the central

conserved repeat region. Most promising CSP candidates include

immunodominant B cell epitopes present in the central repeat (NANP) region and T cell epitopes from the C terminal portion of the molecule.

Numerous vaccine constructs have been developed that are directed against the CS protein.

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RTS,S/AS02 Vaccine Hybrid construct of the hepatitis B surface antigen

fused with a recombinant antigen derived from part of circum sporozoite protein ––CSP repeat region (R)

T-cell epitopes (T) fused to the hepatitis B surface antigen (S)

Co-expressed with unfused S antigen AS-02:Innovative adjuvant systems that was

critical to the success of this vaccine. Primarily for use in infants and young children in

sub saharan Africa

New Malarial Vaccines Status

Parasite stage

Vaccine Stage of Development

PreErythrocytic Stage

CSP C-ter peptide + Montanide ISA 720 Phase Ib

ICC-1132: Hybrid CSP multiepitope-HBc VLPs

Phase II

RTS,S: Hybrid P. falciparum CSP -HBsAg particles + AS02 adjuvant

APPROVED

DNA vaccines (including MuStDO-5:CSP/LSA-1/ LSA-3/EXP1/TRAP)

Phase I

Live recombinant FPV- or MVA-CSP+ LSA-1 epitope

Phase Ib

Live recombinant MVA-multiepitopestring + TRAP

Phase Ib

The PATH Malaria Vaccine Initiative (MVI) : a global program of the international nonprofit organization PATH. MVI was established in 1999 through a grant from the Bill & Melinda Gates Foundation.

GOAL: To develop an 80% efficacious malaria vaccine by 2025 that would provide protection for at least four years

RESULT Mosquirix :

First FDA Approved vaccine (July 2015). RTS,S type Pre-erythrocytic vaccine. Basically designed for children of Sub Sahara African

Countries. Dose: Three intramuscular injections of 10 μg, 25μg and 50

μg doses of RTS,S/AS02 delivered as fractional (0.1 ml, 0.25 ml) or standard (0.5 ml) volumes of the adjuvanted vaccine on a 0-1- and 3month schedule.

Safety: The most frequently general solicited symptoms related to vaccination were myalgia and fatigue and headache.

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8.ROLE OF GENOME SEQUENCING

Pattern for Spread of resistance is same globally. Max 4-8 point mutation is seen in within 200 KB of

chromosome 7.Method: Identify the infected individual Blood collection by Medical person Identification of altered gene Multiplication into complete genome

Development of mapping sequence of resistance for that region.

Used in African countries.In India ASSAM is first state to have genomic

database.76

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Acacia farnesiana

Carica papaya leaf extract

Cinnamonium bejolghota

Croton tiglium

Conclusion The emergence and spread of drug resistant malaria

represents a considerable challenge to controlling malaria.

WHO advocates Artemisinin combination therapy for uncomplicated falciparum malaria. Very few new drugs are in pipeline as compared to

existing targets. In such scenario Genetic maping and vaccines may play a

pivotal role in future. It is essential to ensure rational deployment of the few

remaining effective drugs, to maximize their useful therapeutic life.

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GOODMAN & GILLMAN’S The pharmacological basis of therapeutics. section VII ModulationChemotherapy of Micribial Diseases; 12th edition. vSan Diego, December 1, 2010.P.1383-18.

Biamonte M a, Wanner J, Le Roch KG. Recent advances in malaria drug discovery. Bioorg Med Chem Lett. Elsevier Ltd; 2013 May 15;23(10):2829–43. El Ahmadieh TY, Aoun SG, Daou MR, El Tecle NE, Rahme RJ, Graham RB, et al. New-generation oral anticoagulants for the prevention of stroke: Implications for neurosurgery. J Clin Neurosci. Elsevier Ltd; 2013 Oct;20(10):1350–6.

Beteck RM, Smit FJ, Haynes RK, N’Da DD. Recent progress in the development of anti-malarial drugs. Malar J. 2014 Jan;13(1):339.

Patil C, Katare S, Baig M, Doifode S. Fixed dose combination of arterolane and piperaquine: A newer prospect in antimalarial therapy. Ann Med Heal.2015;4(4):466–71.

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REFERENCES:

Naidoo I, Roper C. Mapping “partially resistant”, “fully resistant”, and “super resistant” malaria. Trends Parasitol. Elsevier Ltd; 2013 Oct;29(10):505–15.

Dunyo S, Sirugo G, Sesay S, Bisseye C, Njie F, Adiamoh M, et al. Randomized trial of safety and effectiveness of chlorproguanil-dapsone and lumefantrine-artemether for uncomplicated malaria in children in the Gambia. PLoS One. 2011 Jan;6(6):e17371.

Hobbs C, Duffy P. Drugs for malaria: something old, something new, something borrowed. F1000 Biol Rep. 2011:November24.(1):65–107.

Hoffman SL, Vekemans J, Richie TL, Duffy PE. The march toward malaria vaccines. Vaccine. Elsevier Ltd; 2015.

Guidelines for Diagnosis and Treatment of Malaria in India. 2014 www.nvbdcp.org.  

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Thank You