malaria recent advance-converted

Recent Advancement In
Pharmacotherapy Of Malaria
Dr. Javed Akhtar
Junior Resident
Dept. of Pharmacology & Therapeutics
KGMU, Lucknow

• Malaria is one of the major public health problems of the our
country
• As per world malaria report 2016, India contribute for 89% of
total incidence in south east Asia
• Majority of cases from north eastern state, hilly and tribal area
• Vector-borne disease
• Caused by protozoal parasite, genus Plasmodium
• Transmitted from person to person, by the bite of infected
female Anopheles mosquito

Properties P. Vivax P. Falciparum P. Malariae P. Ovale
Incubation
Period (Days)
Erythrocytic
Cycle (Hours)
14 12 28 17
48 36-48 72 48
Relapse Seen Not Seen Not Seen Seen
Recrudescence Not Seen Seen Seen Not Seen

• In india most case due to P. Falciparum(>50%) and P. Vivax
• Worldwide P. Vivax is most common
5th species, p. Knowlesi, is primarily a pathogen of monkeys but can
affect humans
• Reported in some asia part but not reported in india
• Cause acute illness, including severe disease
• Heavy parasitaemia
• Paroxysms of fever daily

Life cycle
• Definite host: Female Anopheles
• Intermediate host: Man
• Infective form to man: Sporozoites
• Infective form to mosquito: Gametocytes
• Infective form to man when transmitted by blood
tranfusion(rare): Merozoites

image source: google images

Stage
Responsible for
Clinical Use
Pre-Erythrocytic Cause of malaria Causal prophylaxis
Erythrocytic Symptoms Clinical cure
Suppressive prophylaxis
Exo-Erythrocytic Relapse of malaria Radical cure
Gametocytic Transmission of malaria Prevention of
transmission

Symptoms
First symptoms are nonspecific like headache, fatigue, muscle and joint
aches
• Cold Stage :chilly sensation followed by rigor, temperature rises
rapidly to 39-41°C, stage lasts for 15 miutes to 1 hour
• Hot Stage : feels burning hot, skin is hot and dry to touch, stage lasts
for 2 to 6 hours
• Sweating Stage : fever comes down with profuse sweating,
temperature drops rapidly to normal and skin is cool and moist, stage
lasts for 2 to 4 hours

Severe Malaria
According to WHO manifestation of one or more of the following:
• Coma (cerebral malaria)
• Metabolic acidosis
• Severe anaemia
• Hypoglycaemia
• Acute renal failure
• Acute pulmonary oedema
• If left untreated, severe malaria is fatal in the majority of cases

Diagnosis
MICROSCOPY : sensitivity is high
• Thick film – more reliable in searching for parasite
• Thin film – identifying the species of the parasite
SEROLOGICAL TEST : Malarial fluorescent antibody test usually
becomes positives two weeks or more after primary infection
RAPID DIAGNOSTIC TEST (RDT): Detection of circulating parasite
antigen with a simple dipstick format
pLDH and aldolase: all plasmodium species
HRP-2 Ag: for P.Falciparum

Classification of antimalarial drugs
1. Therapeutic classification
2. Chemical classification

image source: google images

Therapeutic classification
1. Prophylactic
Causal prophylaxis: (Primary tissue schizonticides)
– Destroy parasite in liver cells and prevent invasion of
erythrocytes
– Primaquine, proguanil
Supressives Prophylaxis:
– Supress the erythrocytic phase and thus attack of malarial fever
– Chloroquine, proguanil, mefloquine, doxycycline

2. Clinical cure: erythrocytic schizonticides
– used to terminate an episode of malarial fever
Fast acting high efficacy
– Chloroquine, quinine, mefloquine, atovaquone, artemisinin,
lumefantrine
Slow acting low efficacy drugs
– Proguanil, pyrimethamine, sulfonamides, tetracyclines

3. Radical cure: Eradicate all forms of P.vivax & P.ovale from the
body
– Supressive drugs + hypnozoitocidal drugs
– Primaquine 15 mg daily for 14 days
4. Gametocidal: Destroy gametocytes and prevent transmission
– Primaquine, artemisinin – against all plasmodia
– Chloroquine, quinine – P. Vivax
– Proguanil ,pyrimethamine – prevent development of sporozoites

Chemical Classification

DRUG CLASS
4-aminoquinolines
Quinoline-methanol
Cinchona Alkaloid
Biguanide
Diamonipyrimidine
8-aminoquinolines
Sulfonamide & Sulfone
Tetracyclines
Sesquiterpine Lactones
Aminoalcohols
Napthoquinone
EXAMPLES
Chloroquine (CQ), Amodiaquine (AQ), Piperaquine
Mefloquine
Quinine(q) , Quinidine
Proguanil (Chloroguanide)
Pyrimethamine
Primaquine
Sulfadoxine, Sulfamethopyrazine, Dapsone
Tetracycline ,Doxycycline, Clindamycin
Artesunate , Artemether ,Atreether
Halofantrine ,Lumefantrine
Atovaquone

Treatment of Malaria

Uncomplicated Malaria
P. Vivax and ovale
Chloroquine 600 mg (10mg/kg)
300 mg (5 mg/kg) after 8 hours
300 mg (5 mg/kg) after 24 hours
300 mg (5 mg/kg) after 24 hours
+
Primaquine 15 mg (0.25 mg/kg) daily x 14 days

If chloroquine resistance
Quinine 600 mg (10 mg/kg) 8 hourly x 7 days
+
Doxycycline 100 mg daily x 7 days or Clindamycin 600 mg 12 hourly x 7
days
+
Primaquine 15 mg (0.25 mg/kg) daily x 14 days
Alternately Artemisinin-based combination therapy + Primaquine

Chloroquine-sensitive P. falciparum malaria
Chloroquine 600 mg (10mg/kg)
300 mg (5 mg/kg) after 8 hours
300 mg (5 mg/kg) after 24 hours
300 mg (5 mg/kg) after 24 hours
+
Primaquine 45 mg (0.75 mg/kg) single dose (as gametocidal) on day 2

Artemisinin-based Combination Therapy (ACT)
• Due to emergence of CQ-resistant and multidrug-resistant P
falciparum
• As per WHO all cases of acute uncomplicated falciparum
malaria should be treated only by combining one of the
artemisinin compounds with another effective erythrocytic
schizontocide

• For companion: consider is its t 1⁄2 so that effective conc.
must be maintained for at least 3-4 asexual cycles of the
parasite, i.e. 6- 8 days
• Short t 1⁄2 drugs have to be given for 7 days
• Longer acting drugs can be given for 1-3 days
• Artemisinin rapidly kill > 95% plasmodia
• Leave only a small biomass of the parasites to be eliminated
by the long t 1⁄2 drug
• Reducing the chances of selecting resistant mutants

Advantages of ACT over other antimalarials are:
• Rapid clinical and parasitological cure
• High cure rates (>95%) and low recrudescence rate
• Absence of parasite resistance (the components prevent
development of resistance to each other)
• Good tolerability profile

The Who Recommended ACTS Include
Artesunate+ Sulfadoxine+
Pyrimethamine
Use
1st line drug for uncomplicated
falciparum Malaria
Artesunate+ Mefloquine
Artemether+ Lumefantrine
Uncomplicated falciparum malaria
MDR-falciparum malaria including MQresistance
Recrudescence prevented
Dihydroartemisinin+piperaquine
Artesunate+ Amodiaquine
CQ-resistant falciparum strains
1 st line for uncomplicated falciparum
malaria(Africa)

ACT regimens for uncomplicated falciparum malaria
Artemether (80 mg BD) + Lumefantrine (480 mg BD) x 3 days
Artesunate 100 mg BD (4 mg/kg/day) x 3 days+ Mefloquine 750 mg (15 mg/kg) on 2nd
day and 500 mg (10 mg/kg) on 3rd day (total 25 mg/kg)
Artesunate 200 mg (4 mg/kg)+ Amodiaquine 600 mg (10 mg/kg) per day x 3 days
Artesunate 100 mg BD (4 mg/kg/day) x 3 days + Sulfadoxine 1500 mg (25 mg/kg) and
Pyrimethamine 75 mg (1.25 mg/kg) single dose
Dihydroartemisinin-piperaquine
DHA 120 mg (2 mg/kg) + Piperaquine 960 mg (16 mg/kg) daily x 3 days
Children < 25 kg body weight: DHA not less than 2.5 mg/kg+ Piperaquine 20 mg/kg
daily x 3 days.

Treatment in pregnancy
P.vivax
P.falciparum/mixed
Chloroquine
1 st
trimester
2 nd and 3 rd
trimester
No primaquine
until delivery
Quinine 600mg
TDS with
clindamycin
20mg/kg
TDS/QID
7 days
Artesunate
+sulfadoxine
+pyrimethamine
× 3 days

Treatment of severe and complicated falciparum malaria
Artesunate:
2.4 mg/kg i.v. or i.m (t=0)
2.4 mg/kg after 12 hours
2.4 mg/kg after 24 hours
once daily for 7 days
Switch over to 3 day oral ACT

Artemether
3.2mg/kg i.m.on the 1 st day
1.6mg/kg daily for 7 days.
Switch over to 3 day oral ACT
α−β Arteether:
150 mg daily i.m. for 3 days in adults only
(5 days as per WHO)

Quinine diHCL
20mg/kg (loading dose) diluted in 10 ml/kg 5% dextrose or dextrose-saline in 4
hours
10 mg/kg (maintenance dose) i.v. infusion over 4 hours (in adults) every 8 hours
2 hours (in children) every 8 hours
Switch over to oral quinine 10mg/kg 8 hourly to complete the 7 day course
Dose should be reduced to 7 mg/kg 8 hourly, if to be continued beyond 48 hours

Chemoprophylaxis
Short-term chemoprophylaxis (less than 6 weeks)
• Doxycycline: 100 mg daily in adults and 1.5 mg/kg body weight for
children more than 8 years old
• 2 days before travel and continued for 4 weeks after leaving the
malarious area
Long-term chemoprophylaxis (more than 6 weeks)
• Mefloquine: 5 mg/kg body weight (up to 250 mg) weekly
• 2 weeks before and continue 4 weeks after leaving

Malaria vaccine

RTS,S
• Marketed as “Mosquirix”
• Recombinant vaccine
• consists of circumsporozoite protein (CSP) from the preerythrocitic
stage of P. falciparum parasites
• The antibodies produced following the administration of CSP
antigen, will prevent the invasion of the hepatocytes by the
parasites
• Thus the parasites (P. falciparum) are blocked from infecting
the liver

• Vaccine against P. falciparum and not against P. vivax malaria
• European Medicines Agency (EMA) approved the RTS,S
vaccine in July 2015
• Administered at 6 th , 10 th and 14 th week of infancy and a
booster dose at 18- 20 th month
• Vaccine offers 27% protection among infants between 6- 12
weeks and 36% efficacy among infants of 5-17 months

Summary
• As per world malaria report 2016, india contribute for 89% of total
incidence in south east asia
• Malaria is Vector-borne disease, Caused by protozoal parasite, genus
Plasmodium
• Transmitted from person to person, by the bite of infected female
Anopheles mosquito
• In india P. Falciparum(>50%) and P. Vivax
• Symptom: a cyclical occurrence of sudden coldness followed by
shivering and then fever and sweating
• Diagnosed by microscopy, Serological test, RDT kit

Treatment of uncomplicated malaria
Parasite
Males and Non-pregnant
Females
P. vivax Chloroquine (3 days)
+Primaquine (14 days)
Pregnancy 1st trimester
Chloroquine (3 days)
P. falciparum ACT Quinine ACT
Mixed ACT + Primaquine (14 days Quinine ACT
Pregnancy 2nd and 3rd
trimeste
Chloroquine (3 days)
Treatment of complicated/severe malaria
Parasite
Males and Non-pregnant
Females
P. falciparum Parenteral artemisinin followed
by Oral ACT
Pregnancy 1st trimester
Parenteral artemisinin
followed by Oral ACT
Pregnancy 2nd and 3rd
trimeste
Parenteral artemisinin
followed by Oral ACT

THANK YOU

Recent Advancement In Malaria

Tafenoquine
• Brand name – Krintafel
• Class – 8-aminoquinoline antimalarial drug
• Approved in – July 2018
• Manufactured by – GlaxoSmithKline
• Therapeutic areas – Malaria
• Specific treatment – Prevention of relapse of Plasmodium vivax
malaria

• The need for 14 daily doses of primaquine for effective relapse
prevention is the biggest hurdle in implementing antirelapse therapy
• Tafenoquine has a long plasma t 1⁄2 of 14-19 days (t 1⁄2 of primaquine is
6-8 hours)
• Continues to act for weeks after a single dose
• Tablets: 150 mg
• The recommended dose is a single dose of 300 mg administered as
two 150-mg tablets taken together KRINTAFEL in patients aged 16
years and older

Mechanism of action
• The molecular target of tafenoquine is not known
• Tafenoquine, an 8-aminoquinoline antimalarial
• Active against the liver stages including the hypnozoite (dormant
stage) of P. Vivax
• Causes red blood cell shrinkage in vitro
• Active against pre-erythrocytic (liver) and erythrocytic (asexual)
forms as well as gametocytes of p. Vivax

• Common adverse reactions (≥5%) were dizziness, nausea, vomiting,
headache, and decreased hemoglobin
CONTRAINDICATIONS
• G6PD deficiency or unknown G6PD status.
• Breastfeeding by a lactating woman when the infant is found to be
G6PD deficient or if G6PD status is unknown.
• Known hypersensitivity reactions to tafenoquine or other 8-
aminoquinolines

Bulaquine
• Brand Name: Aablaquin
• Manufactured by – Nicholas Piramal India Ltd
• Congener of primaquine developed in india
• Comparable antirelapse activity when used for 5 days
• Better tolerated in G6PD deficiency
• The recommended dose is 25mg once daily for 5 days
• Contraindicated in patients with rheumatoid arthritis, systemic lupus
erythematosus and co-administration of drugs known to cause
haemolysis

New agents in clinical development
Name : Artefenomel (+ ferroquine)
• Type/target: synthetic endoperoxide
• Activity spectrum: blood schizonticide for falciparum and
vivax
• Vision for development: single dose combination treatment
• Combine with ferroquine (FQ), a 4-aminoquinoline
• An advantage is neither of the constituent drugs has been
deployed as monotherapy previously
• Currently in phase 2b

Name: KAF156 (+ lumefantrine )
• Type/target: imidazolopiperazine; unknown mechanism of
action
• Activity spectrum: multi-stage (liver, blood and transmissionblocking)
• Vision for development: single dose multi-stage treatment
(with lumefantrine)
• Elimination half-life of 48.7 ± 7.9 h
• Single daily doses given
• Currently in a phase 2b

Name: Fosmidomycin (+piperaquine)
• Type/target: Inhibitor of 1-deoxy- D-xylulose 5-phosphate
reductoisomerase in isoprenoid biosynthesis pathway
• Activity spectrum: Uncomplicated PF blood schizonticide
• Vision for development: Combination therapy in areas with
no piperaquine resistance
• A Phase 2b trial in Ghanaian patients of all ages showed high
efficacy of fosmidomycin–piperaquine

Name: Cipargamin
• Type/target: Spiroindolone, pfATP4 inhibitor
• Activity spectrum: blood schizonticides for falciparum and
vivax
• Vision for development: To combine with longer-acting
partner drug not prone to PfATP4 mutation

Name: DSM265
• Type/target: Dihydroorotate dehydrogenase inhibitor
• Activity spectrum: Uncomplicated PF schizonticide, liver
stage activity
• Vision for development: Prevention (traveller’s market) and
partner drug in combination therapy
• In phase 2 development for treatment and prevention

Name: Sevuparin
• Type/target: Anti-adhesive polysaccharide derived from
heparin without antithrombin property
• Activity spectrum: Blocks merozoite invasion and
sequestration
• Vision for development: Adjunctive treatment for severe
malaria

Name: Methylene Blue
• Type/target: Phenothiazine derivative
Prevents haem polymerisation by inhibiting P. falciparum
glutathione reductase
• Activity spectrum: PF schizonticide and potent
gametocytocidal agent
• Vision for development: Part of combination with ACTs +
transmission blocking

Schematic
representation of
intra-erythrocytic
trophozoite showing
sites of action of
newer antimalarial
agents

PfSPZ vaccine
• Developed by Sanaria
• PfSPZ is the acronym of words: plasmodium falciparum (pf)
and sporozoites (SPZ)
• Clinical trials have been promising, with trials taking place in africa,
europe, and the US protecting over 80% of volunteers
• The PfSPZ vaccine candidate has granted fast track designation by the
uUS. Food and drug administration

Recent adavnces
• Tafenoquine, Bulaquine
• Drugs in clinical trail: Artefenomel (+ ferroquine), Cipargamin,
KAF156 (+ lumefantrine ), Fosmidomycin (+piperaquine),Sevuparin,
Methylene Blue
• Vaccine: RTS,S(appoved in some country )
• PfSPZ vaccine(in clinical trail phase 2)