Artemisinine compounds in malaria

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Artemisinine compounds in malaria

• Dr Rajesh Kumar
• MD (PGI), DM (Neonatology) PGI, Chandigarh, India
• Rani Children Hospital, Ranchi

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Importance of malaria in under 5
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Treatment objectives in malaria

• Uncomplicated malaria
• Cure the infection (28 days cure, both clinical
  and paracitological))
• To reduce transmission of infection
• To prevent emergence and spread of resistance
• Severe Malaria
• To prevent death
• To prevent neurological disability in cerebral
  malaria

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Definitions

• Severe Malaria
• Cerebral Malaria
• FM with coma (GCM lt11)
• Malaria with coma persisting gt30 min after
  seizure
• Hyperparacytemia

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Why Artemisinin

• Short half-life hence good for combination
• Rapid substantial reduction of the parasite
  biomass
• Rapid resolution of clinical symptoms
• Effective action against multi-drug resistant P.
  falciparum
• Reduction of gametocyte carriage
• No documented parasite resistance yet
• Few reported adverse effects.

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Severe malaria meta-analysis2653 patients in
16 trialsOlliaro P, Cochrane review 2002

• Quinine IV/IM
• Constant rate infusion / painful IM injection
• Narrow therapeutic range
• Hypoglycaemia, CVS, CNS toxicity

• Artemether IM
• PCT more rapid, but clinically equivalent.
• Coma recovery time and neurological sequelae
  similar
• Better survival than quinine (mortality odds
  ratio 0.61 0.46 0.82)

But IV / IM artesunte is likely to be
significantly better than IM artemether.
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MALARIA

• Malaria remains the worlds most devastating
  human parasitic infection, afflicting more than
  500 million people and causing from 1.7 million
  to 2.5 million deaths each year.
• (World Health Organisation, 1997)
• According to National Health Policy, 2002, the
  malaria cases in India in 2000 was 2.2 million.
• (Agarwal S. P. et al., The National Medical
  Journal of India, 2002)
• NMEP Report (1997) - Incidence of
• P. vivax - 60 to 70
• P. falciparum - 30 to 45

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DRUG RESISTANT MALARIA

• Malaria caused by Plasmodium resistant to usual
  antimalarials
• Incidence more common with P. falciparum
• May occur due to improper treatment and
  inadequate dosage of antimalarials
• Chloroquine resistant P. falciparum Common in
  India

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FALCIPARUM MALARIA

• More number of RBCs affected
• Cause serious complications like jaundice, renal
  failure, cerebral malaria
• Prognosis (outcome of disease) - usually grave.
• High incidences of P. falciparum - UP, Bihar,
  Jharkhand, Orissa, Karnataka, Rajasthan, Madhya
  Pradesh and Pondicherry

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ARTEMISININ DRUGS

• Artemisinin and its derivatives are renowned for
  their
• potent antimalarial activity.
• Immediate onset and rapid reduction of
  parasitaemia
• with complete clearance in most cases within 48
  hours
• Clinical recovery of the patient, e.g.
  defervescence is
• faster than with other antimalarials
• Efficacy is high even in areas with multidrug
  resistant strains.
  
• (Vries et al, Drugs, 1996)

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HISTORY

• Artemisinin is the extraction product from the
  herb Artemisia annua L.
• Was used in traditional Chinese Medicine for the
  treatment of febrile diseases.
• Artemisinin was isolated and its structure
  resolved by Chinese researchers in the early
  1970s
• (Klayman D. L. et al., Science, 1985)
• In 1979, the Chinese reported that artemisinin
  drugs are rapidly acting, effective and safe for
  the treatment of patients with P. vivax or P.
  falciparum infection
• (Tracy J. W. et al., Goodman Gilmans The
  Pharmacological Basis of Therapeutics, 10th Ed.,
  2001)

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CHEMISTRY

• Artemisinin is a so-called sesquiterpene with a
  
• molecular weight of 282
• (Webster H. K. et al., Trans R Soc Trop Med Hyg,
  1994)
• It is a tetracyclic structure with a trioxane
  ring and a
• lactone ring.
• The trioxane ring contains a peroxide bridge,
  the
• active moiety of the molecule.

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CHEMICAL STRUCTURE
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CHEMICAL STRUCTURE
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ARTEMISININ

• Artemisinin is not very soluble either in water
  or oil.
• This and its short elimination half life led to
  the search for the derivatives that had improved
  pharmacological properties as well as better
  antimalarial activity
• Converted to dihydroartemisinin, which is a
  potent antimalarial compound
• Available for oral and rectal use in several
  countries in Asia, especially in Vietnam
• (Sy N. D. et al, Am J Trop Med Hyg 1993)

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ARTEMISININ

• In Vietnam, available as suppository 100mg,
  200mg, 300mg, 400mg and 500mg suppository
• Oral formulation - 250mg capsule
• Dosage
• Adults and children 25mg/Kg on the first day
  followed by 12.5mg/Kg on the second and third day
  in combination with mefloquine (15mg/Kg) in a
  single dose on the second day. In some areas, a
  higher dose (25mg/Kg) of mefloquine may be
  required for a cure to be obtained.

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DERIVATIVES OF ARTEMISININ USED IN TREATMENT OF
MALARIA

• Artemether
• Arteether
• Artesunate

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ARTEMETHER

• Methyl ether of dihydroartemisinin
• Superior to intravenous quinine with respect to
• survival and parasite clearance
• Available as tablets, capsules and as IM
  injectable form
• In India, available as 40mg capsules and 80mg/ml
  ampoule

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ARTEMETHER CAPSULES - MONOTHERAPY
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ARTEMETHER CAPSULES MEFLOQUINE TABLETS
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(No Transcript)
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ARTEETHER

• Ethyl ether of dihydroartemisinin
• Therapeutically equivalent to quinine in
  cerebral malaria
• Available as ? arteether and ?/? arteether
• ? arteether developed by WHO and The Special
  
• Programme for Research and Training in Tropical
  Diseases (TDR)
• ?/? arteether developed by CDRI

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ARTEETHER

• A longer t1/2 beta and more lipophilic
  properties than artemether favouring accumulation
  in brain tissue and thus the treatment of
  cerebral malaria were regarded as advantages over
  the other compounds.
• Available as 150mg per 2ml ampoule

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RAPITHER - AB INJECTION (IM Only)
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ARTESUNATE

• Water soluble hemisuccinate derivative
• Used for oral, rectal, intravenous and
  intramuscular
• administration.
• Available as tablets and as powder with
  separate vial
• containing 5 sodium bicarbonate
• In India, available as 50mg tablets and 60mg/ml
  injection
• In China also available as 100mg suppository
  and in
• Switzerland available as 200mg rectocap

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ARTESUNATE TABLETS - MONOTHERAPY
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ARTESUNATE TABS MEFLOQUINE TABS
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ARTESUNATE INJECTION
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MECHANISM OF ACTION

• Exerts antimalarial activity by iron-mediated
  cleavage
• of the peroxide bridge and generation of an
  organic free
• radical.
• The interaction of artemisinin with haem in the
  parasite
• may turn out to be essential.
• Haem bound iron (but also free iron) may serve
  as a
• catalyst.
• The artemisinin radical binds subsequently to
• membrane proteins, and alkylation reactions
  eventually
• cause destruction of the parasite.
• (Vries et al, Drugs, 1996)

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ANTIMALARIAL EFFICACY

• Rapidly acting blood schizontocidal
  antimalarials
• against chloroquine sensitive and chloroquine
  resistant
• falciparum as well as vivax malaria
• They quickly arrest the ring or the trophozoite
  
• development and also prevent pathological
  sequelae
• Fever subsides and parasites are cleared rapidly
• Defervescence occurs within 2-3 days after drug
• administration
• Ninety percent clearance of asexual erythrocytic
  
• parasitaemia is usually observed within 4 hours
  
• (Valecha N. et al., Indian Journal of
  Pharmacology, 1997)

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ARTEMISININ DERIVATIVES EFFECTS ON ROSETTING
AND CYTOADHERANCE

• The process whereby erythrocytes containing
  mature forms of P. falciparum ahdere to
  microvascular endothelium is called
  cytoadherance. It thus disappears from
  circulation, known as sequestration.
• Erythrocytes containing mature parasites also
  adhere to uninfected erythrocytes, leading to the
  formation of rosettes.
• Cytoadherance and rosetting lead to
  microcirculatory obstruction in falciparum
  malaria, the consequence of which are reduced
  oxygen and substrate supply, anaerobic glycolysis
  and lactic acidosis, finally leading to
  complications of malaria. (Manson, 1997)
• All artemisinin drugs prevent the development of
  ring stage parasites to the more mature
  pathogenic stages that rosette and cytoadhere to
  capillaries (The use of artemisinin and its
  derivatives as antimalarial drugs - Report of a
  Joint CTD/DMP/TDR- WHO, 1998)

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EFFICACY OVER OTHER ANTIMALARIALS

• - Artesunate and artemether have been shown to
  clear parasitaemias more effectively than
  chloroquine and sulfadoxine/pyrimethamine
• - Meta analysis of mortality in trials indicated
  that a patient treated with artemether had at
  least an equal chance of survival as a patient
  treated with quinine
• - Artemisinin drugs cleared parasites faster than
  quinine in patients with severe malaria but fever
  clearance was similar
• - Parenteral artemether and artesunate are easier
  to use than quinine and do not induce
  hypoglycaemia
• (The use of artemisinin and its derivatives as
  antimalarial drugs - Report of a Joint
  CTD/DMP/TDR- WHO, 1998)

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• Mortality decreases by 40
• Hypoglycemia 25-30 with quinine and 10 with
  Artemisinin

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PHARMACOKINETICS

• Absorption of orally administered artemisinin or
  its
• derivatives seems to be rapid but incomplete
• Substantial hydrolysis of artesunate (probable
• complete) and artemether into
  dihydroartemisinin
• probably occurs even before absorption
• Elimination is mainly by hepatic metabolism
• (Leskovac V. et al., Comp Biochem Physiol, 1991)
• Arteether has much slower elimination
• Artesunate, artemether, arteether and probably
  also
• artemisinin itself are transformed into
  dihydro-
• artemisinin, which is subsequently converted
  into
• inactive metabolites

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COMBINATION THERAPY

• Chloroquine and pyrimethamine may antagonise the
  
• activity of artemisinin whereas mefloquine,
  quinine,
• primaquine and tetracycline potentiate
  artemisinin.
• (Chawira A. N. et al., Trans R Soc Trop Med Hyg
  1986 80 p. 334-5)
• The combination of artemisinin derivatives and
  mefloquine improves parasite clearance compared
  with either drug alone
• The above combination slows down the development
  of resistance to mefloquine, since the residuum
  of parasites remaining after the action of
  artesunate is exposed to more slowly eliminated
  mefloquine.
• There is little published data on combination
  therapy with drugs other than mefloquine.

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Artemisinin-based combination therapy in
uncomplicated malaria
Improve clinical cure rates Delay emergence of
resistance Reduce transmission
Widespread use of 1st line Rx with Artemisinin-ba
sed Combination Therapy
Cost effective
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ACT

• Antimalarial combination therapy (CT) is the
  simultaneous use of two or more blood
  schizonticidal drugs with different biochemical
  targets in the parasites and independent modes of
  action
• Fixed-combinations medicinal products
• Free-combinations (co-administered in separate
  tablets or capsules)
• Artemisinin-based combination therapy (ACT) is
  antimalarial combination therapy with an
  artemisinin derivative as one component of the
  combination

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• Widely established resistance to chloroquine and
  sulfadoxine-pyrimethamine
• Theoretical basis of CT are
• - protect individual drug against occurrence
  of resistance
• - to decrease rate of decline in efficacy
• - interrupt spread of resistant strains
• - decrease transmission in a region
• The degree of protection will depend on the
  frequency of genes resistant to the drugs in the
  combination already present in the parasite
  population and number of mutations to confer
  resistance.

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Combinations Recommended

• Artemether-Lumefantrine (Coartem)
• Artesunate (3 days) Amodiaquine
• Artesunate (3 days) SP
• 4. Artesunate (3 days) Mefloquine
• 5. Amodiaquine SP

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ACT (Artemether 20 mg Lumefantrine 120 mg
tablets)
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Dose of ACT

• The dose is Artemether 1.5 mg/kg and lumefantrine
  9 mg /kg at 0, 8, 24, 36, 48 and 60 hours.
• Lumefantrine absorption is enhanced by
  co-administration with fat.
• Low blood levels, with resultant treatment
  failure, could potentially result from inadequate
  fat intake,
• It is essential that patients or carers are
  informed of the need to take this ACT with milk
  or fat-containing food particularly on the
  second and third days of treatment.

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RESISTANCE TO ARTEMISININ DERIVATIVES

• There has been no reports of clinical resistance
  to the artemisinin drugs so far, although
  artemisinin- resistant strains of P. falciparum
  and P. yoelli have been developed in the
  laboratory.
• Clinical isolates and laboratory strains have
  been shown to vary in their sensitivities to
  these drugs but there is no evidence that this is
  related to clinical failure.
• (Wongsrichanalai et al. 1997)
• Clinical experience is that retreatment of
  recrudescence with the same artemisinin compounds
  is equally as effective as the initial
  treatment.

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ARTEMISININ AS ANTIGAMETOCYTE DRUG

• Artemisinin and its derivatives has a significant
  effect on gametocytogenesis, thus reducing
  transmission and consequently the spread of
  resistant strains
• They prevent gametocyte development by their
  action on the ring stages and on the early (stage
  I-III) gametocytes
• (Mehra and Bhasin, 1993)
• In studies including over 5000 patients in
  Thailand, it was shown that gametocyte carriage
  was significantly less frequent after treatment
  with artemisinin derivatives than after treatment
  with mefloquine.
• (Price R. N. et al., Lancet, 1996)
• The fast parasite killing is probably an
  important factor for reduction of gametocyte
  development.

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Effect of antimalarials on the infectivity of P f
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SAFETY OF ARTEMISININ DERIVATIVES

• The artemisinins are extremely well tolerated
  and virtually without adverse effects
• Toxicological studies in animals have shown that
  the toxicity of artemisinin, artemether and
  artesunate is much less than that of chloroquine.
  
• Significant adverse effects or signs of toxicity
  of the artemisinins have not been reported in
  human patients treated with therapeutic dosages

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SAFETY OF ARTEMISININ DERIVATIVES

• Common adverse effects - Headache, nausea,
  abdominal pain, vomiting, occasional diarrhoea,
  symptoms that are associated with with malaria
  and which resolve with appropriate treatment.
  Animal studies have demonstrated limited
  symptomatic and pathological evidence of
  neurotoxicity following the parenteral
  administration of high doses of either artemether
  or arteether
• There is no clinical evidence of serious
  neurotoxicity from the use of any artemisinin
  drug in man in prospective studies of over 10000
  patients.
• (The use of artemisinin and its derivatives as
  antimalarial drugs Report of a Joint
  CTD/DMP/TDR- WHO, 1998)

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ARTEMISININ AND PROPHYLAXIS

• Prophylaxis of malaria are not considered to be
  
• indications for the artemisinin group of drugs.

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ARTEMISININ IN CHILDREN

• Malaria kills more than 1 million children a year
  in the developing world, accounting for about
  half of all malaria deaths globally, most of them
  in Africa.
• In malaria endemic areas - Children under age of
  5 years - greater risk of dying
• Artemisinin drugs are well tolerated in children
• As per WHO recommendations, artemisinin
  derivatives are indicated in children over 6
  months of age

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STATUS OF ARTEMISININ DERIVATIVES

• World Health Organisation Recommends
  uncomplicated malaria treatment with ACT
• In Complicated malaria (in low transmission area)
• Artesunate IV or IM is the drug of choice
• In Complicated malaria (in high transmission
  area)
• Artesunate
• Artemether
• Quinine

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CONCLUSIONS

• Artemisinin derivatives are major advance in the
  treatment of malaria
• Only reliable treatment for highly drug resistant
  malaria
• More rapid clinical and parasitological response
• Combination therapy with mefloquine to reduce
  resistance
• No significant toxicity reported
• Well tolerated and efficacious in adults and
  children
• No convincing evidence of resistance
• Not to be used for prophylaxis

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IV artesunate in severe malaria

• For 10 kg child
• Dissolve in 6 ml and give 2.4 ml at admission,
  at 12 hours, at 24 hours ( use fresh vial every
  time)
• Once daily for 6 more days
• Mefloquine ½ tablet daily for 2 days on 2nd and
  3rd day