antimalarial drug combination therapy by WHO

1. Artemisinin-based combination
therapy
Dihydroartemisinin & Piperaquine Phosphate

2. Malaria has killed millions & many more
have suffered from it….
Alexander the Great
(Died of malaria in 323 BC)
George Washington (1st US President,1789-1797)
(Periodic attacks of malaria)

3. One of oldest diseases known to mankind…
Still Continues To Strike Hard….

4. • A disease caused by plasmodium species of parasite
• Carried from person to person
• Transmitted by bite of infected female Anopheles mosquito
Malaria
Species of Plasmodium that infect humans are:
Plasmodium falciparum
Plasmodium vivax
Plasmodium ovale
Plasmodium malariae
P. falciparum infection is deadliest
Lancet.2014Feb22;383(9918):723-35.

5.  According to WHO estimates, released in December 2016:
 212 million cases of malaria in 2015.
 4,29, 000 deaths due to malaria in 2015; most of them children in
Africa.
 Between 2010 & 2015, Globally:
 Malaria incidence among populations at risk fell by 21%.
 Malaria mortality rates among populations at risk decreased by
29%.
 Malaria remains a major killer of children under five years old, taking
life of a child every two minutes.
http://www.who.int/mediacentre/factsheets/fs094/en/
DISEASE BURDEN

6. It’s especially hard on kids
75% of deaths are among African children
WHO | Fact Sheet: World Malaria Report 2016
CDC report 2016

7. Carrier (vector): Mosquitoes & humans
Lifecycle: 3 stages
1. Exo-erythrocytic stage: In human liver
2. Erythrocytic stage: In human red blood cells (RBCs)
3. Gametocytic (Sporogenic) stage: In gut of mosquito
FEBS J. 2007 Sep;274(18):4670-9.
LIFE CYCLE OF PLASMODIUM

8. Malarial Life cycle cont….
Mosquito bites, infects
human
Sporozoites enter
blood stream
Reach Liver & multiply
into Merozoites
Back to BloodstreamRupture RBC & produce
more Merozoites
Gametocytes produced
in Blood
Transmission to
Mosquito
FEBS J. 2007 Sep;274(18):4670-9.

9. 1. Infected RBCs stick together & block blood flow in various vital organs
resulting in organ damage.
Blocked
Capillary
Why falciparum causes complications?
2. RBCs stuck to capillary wall escape destruction in spleen.
This may lead to recrudescence i.e. reoccurrence of falciparum malaria
Sequestered
RBC
Parasitol Today. 1990 Aug;6(8):247-54.

10. CNS Cerebral malaria (coma, convulsion)
Renal Haemoglobinuria (Black water fever,
Oliguria, uremia)
Blood Severe anemia (Haemolysis and
dyserthropoisis)
Respiratory Acute Respiratory distress syndrome
Metabolic Hypoglycemia
Gastrointestinal Diarrhea, Jaundice, Splenic rupture
Malarial Complications

11. Cardinal symptoms:
• Fever with chills & shivering.
• Intermittent with/without periodicity.
• Fever often accompanied by:
– Headache
– Myalgia
– Arthralgia
– Anorexia
– Nausea & vomiting
At times, symptoms of malaria can be non-specific & mimic other
diseases like viral infections, enteric fever etc
Signs & Symptoms
Lancet.2014Feb22;383(9918):723-35.

12.  Two kinds of malaria: P. vivax & P. ovale can
occur again (relapsing malaria).
 Some parasites can remain dormant in liver
for several months up to about 4 years
after a person is bitten by an infected
mosquito.
 When these parasites come out of
hibernation & begin invading red blood
cells ("relapse"), person will become sick.
https://www.cdc.gov/malaria
MALARIA RELAPSE

13. • Person residing in malaria prone zones/ slums/ unhygienic
environment
• Small children
• Pregnant woman
• Non immune person/immunocompromised persons (HIV)
• Travelers from non-malaria endemic regions
Who is at highest risk?
Fact Sheet: World Malaria Report 2015

14. There are two directions falciparum malaria can take …
• Uncomplicated: represents common symptoms,
discussed earlier….
• Complicated: If not diagnosed or treated on time it
may progress to COMPLICATIONS/SEVERE MALARIA
which can be fatal e.g.
– Cerebral malaria
– Acute Respiratory Distress Syndrome (ARDS)
– Acute renal failure
– Sepsis (secondary infections)
FEBS J. 2007 Sep;274(18):4670-9.

15. Very important to diagnose & treat uncomplicated
malaria on time
Uncomplicated Complicated- - - - - -
Falciparum Malaria
FEBS J. 2007 Sep;274(18):4670-9.

16. Diagnostic methods that investigate & confirm malaria
Microscopic examination of
blood smear
Rapid diagnostic tests (e.g.:
PfHRP2 dipstick test,
Plasmodium LDH dipstick test)
Polymerase chain reaction
(PCR) analysis
2 or 3 blood smears tested every 8 to 12 hrs to confirm
diagnosis
-ve blood smear does not exclude malaria & +ve blood smear
does necessarily confirm a diagnosis of malaria
Malaria should be suspected by medical personnel in
anyone with fever who has recently seen in a malaria endemic
area.
Along with parasite detection test other test
recommended are CBC (WBC & platelet count ),
haemoglobin
Diagnosis
ArchPatholLabMed.2013Jun;137(6):805-11

17. Treatment approaches

18. Malaria Management: Aim
• Complete cure
• Prevention of progression of uncomplicated malaria to severe
disease
• Prevention of deaths
• Interruption of transmission
• Minimizing spread of drug resistant parasites.
Management of Malaria
Future Microbiol. 2011 Dec;6(12):1485-500.

19. Treatment: Expectations
Future Microbiol. 2011 Dec;6(12):1485-500.

20. Goals Causation
To alleviate symptoms
ERYTHROCYTIC STAGE
Symptoms are caused by
blood forms of the
parasite
To prevent relapses
EXO-ERYTHROCYTIC
(LIVER STAGE)
Relapses are due to
hypnozoites of P. vivax/
P. ovale
To prevent spread/
transmission
GAMETOCYTIC STAGE
Spread is through the
gametocytes
Classification
Blood schizonticidal
drugs
(chloroquine, quinine,
mefloquine & artesunate)
Tissue schizonticide
(primaquine)
Gametocytocidal drugs
(artesunate & primaquine)
Antimalarials: Classification
J Infect. 2016 Jun;72(6):635-49

21. • Chloroquine
• Quinine
• Mefloquine
• Sulfadoxine pyrimethamine
• Amodiaquine
• Lumefantrine
• Artemisinins (Artesunate, Artemether, Arteether)
• Primaquine
• Piperaquine
• Artemisinins (Artesunate, Artemether, Arteether)
Blood
schizonticidal
drugs
Tissue
schizonticidal,
gametocidal
drugs
Commonly used Antimalarial drugs
JInfect.2016Jun;72(6):635-49

22. Mosquito Human
Tissue
schizont-
icide
Blood
schizonticide
Gametocyto-
cidal

23. Treatment of uncomplicated
Plasmodium falciparum malaria
WHOGuidelinesforthetreatmentofmalaria.Thirdedition.2015

24. Treatment of uncomplicated Plasmodium
falciparum malaria in special risk group
WHOGuidelinesforthetreatmentofmalaria.Thirdedition.2015

25. Artemisinin derivatives are only class of anti-malarial
agents to which resistance outside Thai-Cambodia border
region has not been reported in vivo.
MalariaJournal2009,8(Suppl1):S5
WHO guidelines specifically recommend use of artemisinin-based
combination therapy (ACT) for treatment of Uncomplicated P
falciparum malaria.

26. Dihydroartemisinin (also known as dihydroqinghaosu, artenimol or DHA):
 Active metabolite of all artemisinin compounds
(artemisinin, artesunate, artemether, etc.)
 Also available as a drug in itself.
 It is a semi-synthetic derivative of artemisinin.
 Widely used as an intermediate preparation of other artemisinin-
derived antimalarial drugs.
 It is sold commercially in combination with piperaquine.
Artemisinin Derivatives

27. Piperaquine:
 A bisquinoline first synthesised in the 1960s.
 Used extensively in China & Indochina as prophylaxis & treatment
 Characterized by slow absorption & a long biological half-life, making it a
good partner drug with artemisinin derivatives which are fast acting but have
a short biological half-life.
 The fixed-dose combination dihydroartemisinin-piperaquine (Eurartesim) was
submitted for approval to the European Medicines Agency in 2009.

28. • Dihydroartemisinin main active metabolite of artemisinin
derivatives
• Achieves high Concentrations in red blood cells infected with P.
Falciparum
• Endoperoxide bridge of dihydroartemisinin appears essential to its
antimalarial activity, resulting in free radical damage to parasite
membrane systems
Dihydroartemisinin: Mechanism of action
Drugs 2012; 72 (7): 937-961

29. • Precise mechanism of action is unknown.
• It act similar to that of chloroquine, a close structural
analogue of piperaquine.
• Binds to toxic haeme within P. Falciparum & prevents it
detoxification
Piperaquine: Mechanism of action
Drugs 2012; 72 (7): 937-961

30. Rationale for Dihydroartemisinin/Piperaquine
Combination
 Resistance of P. falciparum to traditional antimalarial drugs is a growing
problem:
• Chloroquine , Sulfadoxine-pyrimethamine, Amodiaquine & Mefloquine
To combat spread of resistance:
• Short-acting but highly potent artemisinin derivative delivers a rapid reduction in
parasite biomass.
• Remaining parasites being removed by intrinsically less active but more slowly
eliminated partner drug i.e piperaquine.
• Endorsed by WHO , artemisinin-based combination therapies are now being
used in >50 countries where malaria is endemic.
Clin Infect Dis (2009) 49 (11): 1638-1640

31. Dihydroartemisinin-piperaquine is:
• Safe & highly effective treatment for uncomplicated falciparum or vivax
malaria.
• Efficacy assessed over 28—63 days has consistently exceeded 95% in
treatment of multidrug resistant falciparum malaria.
• More than 2600 patients have been treated with this combination in
prospective studies, mainly in Southeast Asia.
• Tolerability was uniformly good, & no serious adverse effects have been
identified.
• Dosing regimen has been simplified from four doses to once daily over 3
days.
Trans R Soc Trop Med Hyg (2007) 101 (9): 858-866.

32. Pharmacokinetics:
• Piperaquine, has a half-life of ~5 weeks, longest of all ACTS.
• DP could be the ACT with greatest post treatment prophylactic efficacy
due to longer half-life & sustained plasma levels of Piperaquine
compared to other ACTs such as AL.
MalariaResearchandTreatmentVolume2014(2014),ArticleID263674,20pages

33. Summary :
 Fixed-dose formulation with a convenient administration regimen (one
daily dose for 3 days, administered without food)
 Non inferior to artesunate plus mefloquine for uncomplicated
Plasmodium falciparum malaria in children & adults in Asia.
 No inferior to artemether/lumefantrine for uncomplicated P. falciparum
malaria in children in Africa.
 Generally well tolerated.
 Potential for QTc interval prolongation, but no evidence of clinically
significant arrhythmias to date.