CHEMOTHERAPY AND NATIONAL DRUG POLICY IN MALARIA

CHEMOTHERAPY AND NATIONAL DRUG POLICY IN
MALARIA.

DR .G . C. SAHU
ROH&FW; GoI;
GoI;
AHMEDABAD

Dr.G.C Sahu/ROHFW/GoI/A'Bad 1

Infective vector mosq.bite Sporozoite inoculation
Liver cycle

Vec.mosq.picks up Gametocytes
Mosquito cycle
Repeatative RBC cycle

…. IN THE
…. IN THE
SEQUENCE
SEQUENCE LIFE CYCLE
LIFE CYCLE
OF
OF OF MALARIA
OF MALARIA
EVENTS…
EVENTS… PARASITE
PARASITE


4

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An effective treatment policy should aim to:

Reduce morbidity

Prevent the progression of uncomplicated disease
into severe and potentially fatal disease and thereby
reduce malaria mortality

Reduce the impact of placental malaria infection
and maternal malaria-associated anaemia through
malaria-associated
chemoprophylaxis or preventive intermittent therapy.

Prevent or delay the development of antimalarial
drug resistance by correct diagnosis and rational
treatment of all malaria positive cases.


Treatment of Malaria --- Aims Of Treatment

Aims Causation Therapy Drugs
Chloroquine,
Symptoms are
Blood quinine,
To alleviate caused by blood
schizonticidal pyrimethamine/s
symptoms forms of the
drugs ulphadoxine,
parasite
artemisinin
Relapses are due Tissue
To prevent
to hypnozoites of schizonticidal Primaquine
relapses
P. vivax/ P. ovale drugs
Primaquine for P.
Spread is through Gametocytocidal falciparum,
To prevent spread
the gametocytes drugs Chloroquine for
all other

Thus, in effect, a blood schizonticidal drug and primaquine should be
Thus, in effect, a blood schizonticidal drug and primaquine should be
administered to ALL types of malaria.
administered to ALL types of malaria.

Principles Of Treatment

Treatment of malaria depends on the following factors:

Type of infection.
Severity of infection.
Status of the host.
Associated conditions/ diseases.

Associated conditions/ diseases:
Treatment of malaria may have to be modified due to certain associated conditions/ diseases.
Treatment of malaria may have to be modified due to certain associated conditions/ diseases.
Therefore, all such should be carefully assessed before starting the patient on anti malarial
Therefore, all such should be carefully assessed before starting the patient on anti malarial
treatment.
treatment.
Pregnancy: Treatment of malaria in pregnancy may prove to be difficult due to contra indication for use of certain
Pregnancy: Treatment of malaria in pregnancy may prove to be difficult due to contra indication for use of certain
antimalarials. Chloroquine can be used safely in all trimesters of pregnancy. Artemisinin is not shown to have any
antimalarials. Chloroquine can be used safely in all trimesters of pregnancy. Artemisinin is not shown to have any
antimalarials.
deleterious effects on the fetus in animal studies and therefore can be considered if the situation demands. Quinine
deleterious effects on the fetus in animal studies and therefore can be considered if the situation demands. Quinine
can be used in pregnancy, but one should be watchful about hypoglycemia.
can be used in pregnancy, but one should be watchful about hypoglycemia.
hypoglycemia.

Epilepsy: Malaria as well as anti malarials can trigger convulsions. Mefloquine is better avoided in these patients.
Epilepsy: Malaria as well as anti malarials can trigger convulsions. Mefloquine is better avoided in these patients.
Cardiac disease: High-grade fever of malaria can exacerbate left ventricular failure and therefore, in all such
Cardiac disease: High- High-grade fever of malaria can exacerbate left ventricular failure and therefore, in all such
and
patients energetic management of malaria is called for. Fever should be controlled with anti-pyretics and tepid
patients energetic management of malaria is called for. Fever should be controlled with anti-
should anti-pyretics and tepid
sponging. Chloroquine, artemisinin, pyrimethamine/ sulphadoxine, tetracyclines and primaquine can be safely used in
sponging. Chloroquine, artemisinin, pyrimethamine/ sulphadoxine, tetracyclines and primaquine can be safely used in
Chloroquine, artemisinin, pyrimethamine/ sulphadoxine,
these patients. Quinine can also be used carefully. Mefloquine and halofantrine are better avoided in patients with
these patients. Quinine can also be used carefully. Mefloquine and halofantrine are better avoided in patients with
known cardiac illness.
known cardiac illness.

Hepatic insufficiency: None of the antimalarial drugs have any direct hepatotoxic effect. However,
Hepatic insufficiency: None of the antimalarial drugs have any direct hepatotoxic effect. However,
chloroquine is not advisable in patients with severe hepatic insufficiency.
chloroquine is not advisable in patients with severe hepatic insufficiency.

Renal failure: The initial dose of antimalarial drugs need not be reduced in patients with renal failure. However, if
Renal failure: The initial dose of antimalarial drugs need not be reduced in patients with renal failure. However, if
However,
the patient requires parenteral antimalarials even after three days and continues to be sick, then the dose can be
can be
the patient requires parenteral antimalarials even after three days and continues to be sick, then the dose can
reduced by one third to half of usual dose.
reduced by one third to half of usual dose.

Dermatitis: Concomitant use of chloroquine with gold salts and phenyl butazone should be avoided because all
Dermatitis: Concomitant use of chloroquine with gold salts and phenyl butazone should be avoided because all
the three can cause dermatitis.
the three can cause dermatitis.
Anti-malarials contra-indicated in pregnancy.
Anti-
Anti-malarials contra-
contra-indicated in pregnancy.

× Mefloquine::- 11 trimester
Mefloquine
Mefloquine:-
st
st
trimester

× SS-P combination:-- 11 and last trimester
-P combination:
combination:-
st
st
and last trimester

× Halo,Tetra,Doxy::- All trimester
Halo,Tetra,Doxy All trimester
Halo,Tetra,Doxy:-

× Primaquine::- All trimester.
Primaquine All trimester.
Primaquine:-

In an endemic area, malaria often presents with atypical manifestations

Atypical features are more common in the following situations:
Falciparum malaria
Falciparum malaria

Early infection
Early infection

Patients at extremes of age
Patients at extremes of age

Patients who are immune-compromised (extremes of age, malnourished, AIDS,
Patients who are immune-compromised (extremes of age, malnourished, AIDS,
tuberculosis, cancers, on immunosuppressive therapy etc.)
tuberculosis, cancers, on immunosuppressive therapy etc.)

Patients on chemoprophylaxis for malaria
Patients on chemoprophylaxis for malaria

Patients who have had recurrent attacks of malaria
Patients who have had recurrent attacks of malaria

Patients with end stage organ failure
Patients with end stage organ failure

Last but not the least, pregnancy.
Last but not the least, pregnancy.

INFORMATIONS ONE MUST HAVE BEFORE TREATING A
INFORMATIONS ONE MUST HAVE BEFORE TREATING A
CASE OF MALARIA.
CASE OF MALARIA.

THE TYPE OF SPECIES YOU ARE TREATING i e
P. VIVAX OR P. FALCIPARUM

THE STAGE OF PARASITES YOU ARE TREATING i.e
ASEXUAL STAGE(RING) OR SEXUAL STAGE(GAMETO)

THE TYPE OF TREATEMENT YOU ARE GIVING i.e
{PRESUMPTIVE TREATMENT OR RADICAL TREATMENT}
Type of severity of infection i.e complicated or non complicated.

THE TYPE OF AREA IN WHICH THE TREATMENT IS
GIVEN i.e. LOW-RISK AREA OR HIGH RISK AREA.

RESPONSE OF THE PARASITE TO THE DRUG GIVEN
i.e. SENSITIVE OR RESISTANT.


SCHIZONTICIDAL DRUGS:
CHLOROQUINE, AMODIAQUINE, QUININE,
QUINIDINE,PYREMETHAMINE, TRIMETHOPRIM,
PROGUANIL, SULFONAMIDES IN COMBN.
WITHPYREMETHAMINE, MEFLOQUINE, HALOFANTRINE,
ARTEMESININE.


GAMETOCIDAL AND ANTI-
RELAPSE DRUG(S) :

PRIMAQUINE

What would be the optimal anti-
malaria compound?(1)
The optimal anti-malaria compound must
have such six advantages therapeutically
as follows:
• High efficacy The 28-day cure rate should
be over 95% in multi-drugs resistant
falciparum malaria endemic areas
• Quick acting The development of
parasites should be stopped after the
initial dose, which is the key point to
reduce the incidence of cerebral malaria ,
thereby, reduced the mortality of malaria
Dr.G.C Sahu/ROHFW/GoI/A'Bad

What would be the optimal
anti-malaria compound?(2)
• Short treatment course The optimal
treatment course with better patients'
compliance would be once daily for
just two days.
• Low toxicity The incidence of side
effects should be less than 5%.

What would be the optimal
anti-malaria compound?(3)
• Preventing transmission It will be
advantages to control the prevalence of
malaria and very important for preventing
from the disease to neutralize and kill
quickly the gametocytes of falciparum
malaria
• Low cost It should be affordable for most
of the patients in malaria endemic areas of
the developing countries, so that those
patients could take the drug to cure
malaria.

Anti Malarial Drugs: Chloroquine

Mechanism of action:

The mechanism of action of chloroquine is unclear. Being
alkaline, the drug reaches high concentration within the food
vacuoles of the parasite and raises its pH. It is found to
induce rapid clumping of the pigment. Chloroquine inhibits
the parasitic enzyme heme polymerase that converts the
toxic heme into non-toxic hemazoin, thereby resulting in the
accumulation of toxic heme within the parasite. It may also
interfere with the biosynthesis of nucleic acids. Other
mechanisms suggested include formation of drug-heme
complex, intercalation of the drug with the parasitic DNA etc.


Anti Malarial Drugs: Quinine
Food Heme
Vacuo polyme
le rase
Non Toxic
Hemo Toxic Hemazoin
globin Heme (Malarial
Pigment)

Degradat ? Inhibited
ion by Quinine

Mechanism of action:

Quinine acts as a blood schizonticide although it also has gametocytocidal
activity against P. vivax and P. malariae. Because it is a weak base, it is
concentrated in the food vacuoles of P. falciparum. It is said to act by inhibiting
heme polymerase, thereby allowing accumulation of its cytotoxic substrate,
heme. As a schizonticidal drug, it is less effective and more toxic than
chloroquine. However, it has a special place in the management of severe
falciparum malaria in areas with known resistance to chloroquine.


Anti Malarial Drugs: Pyrimethamine/ Sulphadoxine

Pyrimethamine and sulphadoxine are very useful adjuncts in the treatment
Pyrimethamine and sulphadoxine are very useful adjuncts in the
of uncomplicated, chloroquine resistant, P. falciparum malaria.
resistant,

Anti malarial activity:

Pyrimethamine inhibits the dihydrofolate reductase of plasmodia and
Pyrimethamine inhibits the dihydrofolate reductase
thereby blocks the biosynthesis of purines and pyrimidines, which are so
the biosynthesis of purines and pyrimidines, which are
essential for DNA synthesis and cell multiplication. This leads to failure of
nuclear division at the time of schizont formation in erythrocytes and liver.
Availability: Pyrimethamine and sulphadoxine combined tablets are
Availability: Pyrimethamine and sulphadoxine
available, containing 25 mg of pyrimethamine and 500 mg of sulphadoxine
containing 25 mg of pyrimethamine and 500
in each tablet.

Dose of Pyrimethamine/sulfadoxine:
Pyrimethamine/sulfadoxine:
3 tablets as per the WHO recommendations


Anti Malarial Drugs:Mefloquine
Mefloquine was born during the Vietnam war, as a result of research into
Mefloquine was born war,
newer anti malarials, to protect the American soldiers from the multi drug
malarials, protect the American soldiers
resistant falciparum malaria. Nothing much has happened after that and
resistant falciparum malaria. Nothing
hence this 'new' drug should be restricted for use against multi drug
resistant falciparum only.
resistant falciparum only.

Anti malarial activity:

Mefloquine has been found to produce swelling of the P. falciparum food
Mefloquine has been found to produce swelling of the P. falciparum
vacuoles. It may act by forming toxic complexes with free heme that damage
heme that
membranes and interact with other plasmodial components. It is effective
against the blood forms of falciparum malaria, including the chloroquine
the
resistant types.

Availability: It is available as 250 mg tablets.
Dose: 15 mg/kg in a single dose. If the dose exceeds 1000 mg, the second dose
exceeds 1000 mg, the second dose
can be given after 4-8 hours to minimise gastric irritation. Total dose should
4-8 minimise
Dr.G.C exceed 1500 mg.
not Sahu/ROHFW/GoI/A'Bad 19

Artemesia annua
Sweet Annie
Sweet wormwood
Annual wormwood
Qinghao


Anti Malarial Drugs:
Anti Malarial Drugs: The Artemisinin Derivatives

It is the fastest acting anti malarial available.. It inhibits the development of the
It is the fastest acting anti malarial available It inhibits the development of the
trophozoites and thus prevents progression of the disease. It starts acting within
trophozoites and thus prevents progression of the disease. It starts acting within
12 hours.. It is also effective against the chloroquine resistant strains of P. falciparum.
12 hours It is also effective against the chloroquine resistant strains of P. falciparum.
These properties of the drug are very useful in managing complicated P. falciparum
These properties of the drug are very useful in managing complicated P. falciparum
malaria.
malaria.

Dose:
Artemether: 3.2 mg/kg intra muscularly as a loading dose, followed by 1.6 mg/kg
: 3.2 mg/kg intra muscularly as a loading dose, followed by 1.6 mg/kg
daily until oral therapy or a maximum of 7 days.
daily until oral therapy or a maximum of 7 days.
Arteether: 3 mg/kg once a day for 3 days, as deep intra muscular injection.
3 mg/kg once a day for 3 days, as deep intra muscular injection.
Artesunate: Oral- 5 mg/kg on the first day followed by 2.5 mg/kg on the second and
Oral- 5 mg/kg on the first day followed by 2.5 mg/kg on the second and
third days. Oral artesunate is not recommended in pregnancy.
third days. Oral artesunate is not recommended in pregnancy.
Parenteral- Loading dose of 2.4 mg/kg followed by 1mg/kg after 4 hours and 24 hours;
Parenteral- Loading dose of 2.4 mg/kg followed by 1mg/kg after 4 hours and 24 hours;
thereafter, 1.2 mg/kg daily for maximum of 7 days. For children, the recommended
thereafter, 1.2 mg/kg daily for maximum of 7 days. For children, the recommended
dose is 1.2 mg/kg/day for 5-7 days.
dose is 1.2 mg/kg/day for 5-7 days.


Site of Action

Artemisinin
Artemisinin

Conventional
Conventional
Treatment
Treatment

Dr.G.C Sahu/ROHFW/GoI/A'Bad Artemisinin
Artemisinin

Artemisinins


Anti Malaria Drugs: Primaquine

Primaquine is the essential co-drug with chloroquine in treating all
is the essential co-drug treating all
cases of malaria. It is highly effective against the gametocytes of all
effective against the gametocytes of all
plasmodia and thereby prevents spread of the disease to the mosquito
mosquito
from the patient. It is also effective against the dormant tissue forms of
patient. It is also effective tissue
P. vivax and P. ovale malaria, and thereby offers radical cure and
prevents relapses. It has insignificant activity against the asexual blood
the asexual blood
forms of the parasite and therefore it is always used in conjunction
therefore conjunction
with a blood schizonticide and never as a single agent.

Mechanism of action is not well understood. It may be acting by
generating reactive oxygen species or by interfering with the
electron transport in the parasite.

Availability: Primaquine is available as tablets containing 2.5, 7.5 and
Primaquine is available
15 mg of the salt.


Drug Drugs
Class
Blood Chloroquine, Quinine, Quinidine, Mefloquine,
Schizonto Halofantrine, Sulfonamides, Tetracyclines,
cidal Atovaquone, Artemisinin compounds
Tissue Primaquine, Proguanil, Pyrimethamine,
Schizonto
cidal

Gametocidal Primaquine

Hypnozoit Primaquine
ocidal


What is presumptive treatment? **
Presumption - In an area with high transmission of malaria, it should
be presumed that ALL cases of fever are due to malaria.
Treatment - First loading dose of chloroquine should be administered
immediately after collecting the blood specimen, even without waiting for
after collecting the blood specimen, waiting for
its report.

If the fever is indeed malaria, this treatment alleviates symptoms early,
alleviates symptoms early,
may be well before the test result is available.

If it is malaria, chloroquine also prevents the spread of malaria by
is malaria,
destroying the gametocytes of P. vivax (the more common malaria).

If it is not malaria, nothing is lost, for chloroquine at this dose is safe
this dose is safe
and has no adverse effects.

It cures early and more important, it prevents spread of P. vivax
It cures early and more important, it prevents spread of P. vivax
malaria.
malaria.
** Till recently , it was recommended treatment under the National
** Till recently , it was recommended treatment under the National
Malaria Eradication Programme(now NVBDCP) in India.
Malaria Eradication Programme(now NVBDCP) in India.

1 0
‐ 20
CY
LI OR
PO E F
R UG AF
D D S
IA AN
AR Y
AL DA ”
I  M   TO OW
A NT OR RR
L   E  F MO
ON A I AT T O
A TI PR
N PRO
E P
T H “A

THE  NATIONAL  ANTI  MALARIA DRUG POLICY‐2010
THE  NATIONAL  ANTI  MALARIA DRUG POLICY‐2010
“APPROPRIATE  FOR  TODAY  AND SAFE FOR TOMORROW”
“APPROPRIATE  FOR  TODAY  AND SAFE FOR TOMORROW”

Effective treatment of malaria under the National Drug Policy aims at:
treatment of malaria under the aims

Providing complete cure (clinical and parasitological) of
malaria cases
Prevention of progression of uncomplicated malaria into
severe malaria and thereby reduce malaria mortality
Prevention of relapses by administration of radical
treatment
Interruption of transmission of malaria by use of
gametocytocidal drugs
Preventing development of drug resistance by rational
treatment of malaria cases.

Treatment of uncomplicated malaria
All fever cases suspected to be malaria should be investigated by microscopy or
All fever cases suspected to be malaria should be investigated by microscopy or
RDT.
RDT.
1. P.vivax cases should be treated with chloroquine for three days and Primaquine
1. P.vivax cases should be treated with chloroquine for three days and Primaquine
for 14 days. Primaquine is used to prevent relapse but is contraindicated in
for 14 days. Primaquine is used to prevent relapse but is contraindicated in
pregnant women, infants and individuals with G6PD deficiency.
pregnant women, infants and individuals with G6PD deficiency.
Note: Patients should be instructed to report back in case of haematuria or high
Note: Patients should be instructed to report back in case of haematuria or high
colored urine /cyanosis or blue coloration of lips and Primaquine should be
colored urine /cyanosis or blue coloration of lips and Primaquine should be
stopped in such cases. Care should be taken in patients with anaemia.
stopped in such cases. Care should be taken in patients with anaemia.

2. P. falciparum cases should be treated with ACT (Artesunate 3 days +
2. falciparum cases should be treated with ACT (Artesunate 3 days +
Sulphadoxine-Pyrimethamine 1 day). This is to be accompanied by single dose
Sulphadoxine-Pyrimethamine 1 day). This is to be accompanied by single dose
primaquine preferably on day 2.
primaquine preferably on day 2.

3. Pregnant women with uncomplicated P. falciparum should be treated as
3. with uncomplicated P. falciparum should be treated as
follows:
follows:
1st Trimester: Quinine
1st Trimester: Quinine
2nd & 3rd Trimester: ACT
2nd & 3rd Trimester: ACT
Note: Primaquine is contra indicated in pregnant woman
Note: Primaquine is contra indicated in pregnant woman

5. In cases where parasitological diagnosis is not possible due to non-availability of
5. In cases where parasitological diagnosis is not possible due to non-availability of
either timely microscopy or RDT, suspected malaria cases will be treated with full
either timely microscopy or RDT, suspected malaria cases will be treated with full
course of chloroquine, till the results of microscopy are received. Once the
course of chloroquine, till the results of microscopy are received. Once the
parasitological diagnosis is available, appropriate treatment as per the species, is
parasitological diagnosis is available, appropriate treatment as per the species, is
to be administered.
to be administered.

6. Presumptive treatment with chloroquine is no more recommended.
6. Presumptive treatment with chloroquine is no more recommended.

7. Resistance should be suspected if in spite of full treatment with no history of
7. Resistance should be suspected if in spite of full treatment with no history of
vomiting, diarrhoea, patient does not respond within 72 hours, clinically and
vomiting, diarrhoea, patient does not respond within 72 hours, clinically and
parasitologically. Such cases not responding to ACT, should be treated with oral
parasitologically. Such cases not responding to ACT, should be treated with oral
quinine with Tetracycline // Doxycycline. These instances should be reported to
quinine with Tetracycline Doxycycline. These instances should be reported to
concerned District Malaria /State Malaria Officer/ROHFW for initiation of
concerned District Malaria /State Malaria Officer/ROHFW for initiation of
therapeutic efficacy studies.
therapeutic efficacy studies.


DRUG SCHEDULE FOR TREATMENT OF MALARIA
UNDER NVBDCP

1. Chloroquine: 25 mg/kg body weight divided over
Chloroquine:
three days i.e. 10mg/kg on day 1, 10mg/kg on day 2
and 5mg/kg on day 3.

2. Primaquine: 0.25 mg/kg body weight daily for 14
Primaquine:
days.

* Primaquine is contraindicated in infants, pregnant women and individuals with G6PD deficiency.
with
14 day regimen of Primaquine should be given under supervision.


Treatment of uncomplicated P.falciparum cases

Artemisinin based Combination Therapy (ACT)*
Artesunate 4 mg/kg body weight daily for 3 days
Plus
Sulfadoxine (25 mg/kg body weight) . Pyrimethamine
(1.25 mg/kg body weight) on first day.

* ACT is not to be given in 1st trimester of pregnancy.


Treatment of uncomplicated P.falciparum cases in
pregnancy

1st Trimester : Quinine salt 10mg/kg 3 times daily for 7 days.
Note: Quinine may induce hypoglycemia; pregnant women
should not start taking quinine on an empty stomach and
should eat regularly, while on quinine treatment.

2nd and 3rd trimester: ACT as per dosage given above.


Treatment of mixed infections (P.vivax + P.falciparum)
(P.vivax P.falciparum)
cases

All mixed infections should be treated
with full course of ACT and
Primaquine 0.25 mg per kg body weight
daily for 14 days.


Treatment of severe malaria cases:
Treatment of severe malaria cases: Severe malaria is an emergency
is an emergency
and treatment should be given as per severity and associated complications which can
and treatment should be given as per severity and associated complications which can
best be decided by the treating physician.. The guidelines for specific antimalarial
best be decided by the treating physician The guidelines for specific antimalarial
therapy is as follows:
therapy is as follows:

Artesunate: 2.4 mg/kg body weight IV or IM given on admission (time = 0
: 2.4 mg/kg body weight IV or IM given on admission (time = 0
h); then at 12 h and 24 h and then once a day.
h); then at 12 h and 24 h and then once a day.
(or)
(or)
Artemether: 3.2 mg/kg body weight IM given on admission and then 1.6
: 3.2 mg/kg body weight IM given on admission and then 1.6
mg/kg body weight per day.
mg/kg body weight per day.
(or)
(or)
Arteether: 150 mg IM daily for 3 days in adults only (not recommended for
Arteether: 150 mg IM daily for 3 days in adults only (not recommended for
children).
children).
(or)
(or)
Quinine: 20 mg/kg* body weight on admission (IV infusion or divided IM
: 20 mg/kg* body weight on admission (IV infusion or divided IM
injection) followed by maintenance dose of 10 mg/kg body weight 8 hourly.
injection) followed by maintenance dose of 10 mg/kg body weight 8 hourly.
The infusion rate should not exceed 5 mg salt/kg body weight per hour.
The infusion rate should not exceed 5 mg salt/kg body weight per hour.
(*loading dose of Quinine i.e. 20mg /kg body weight on admission may not be given if the patient has
(*loading dose of Quinine i.e. 20mg /kg body weight on admission may not be given if the patient has
already received quinine or if the clinician feels inappropriate).
already received quinine or if the clinician feels inappropriate).

Note:The parenteral treatment in severe malaria cases should be
given for minimum of 24 hours once started (irrespective of the
patient.s ability to tolerate oral medication earlier than 24 hours). 35

1.. After parenteral artemisinin therapy, patients will
receive a full course of oral ACT for 3 days.

2.. Those patients who received parenteral Quinine
therapy should receive:
receive:
Oral Quinine 10 mg/kg body weight three times a
day for 7 days (including the days when parenteral
Quinine was administered) plus Doxycycline 3
mg/kg body weight once a day or Clindamycin 10
mg/kg body weight 12-hourly for 7 days
12-hourly
(Doxycycline is contraindicated in pregnant women and children under 8 years of age).
(Doxycycline is contraindicated in pregnant women and children under 8 years of age).


Why injectable Arteether Over injectable Artesunate & injectable Artemether
in the National Drug Policy ???

Inj.ARTEETHER:

1. Immediate onset and rapid reduction of parasitaemia with
complete clearance in most cases within 48 hours
2. Clinical recovery of the patient, e.g. defervescence is faster
than with other antimalarials.
3. Therapeutically equivalent to quinine in cerebral malaria
4. 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.
5. Arteether has much slower elimination.[elimination half
6. life:Arteether-20 hrs;Artemether-6hrs;Artesunate-1hr]

Comparative Efficacy :
In Cerebral Malaria
Parameter Arteether Quinine

Coma recovery time 24.33 38.87
(hrs.)

6.67 27.27
Mortality (%)

Important for Rx
Most blood schizonticidal drugs prevent the development of the
Most blood schizonticidal drugs prevent the development of the
forthcoming erythrocytic cycle of parasitic development and hence
forthcoming erythrocytic cycle of parasitic development and hence
have no or little effect on the ongoing cycle that is already causing
have no or little effect on the ongoing cycle that is already causing
fever. Therefore, it would take at least 48 hours for the treatment to
fever. Therefore, it would take at least 48 hours for the treatment to
be effective.
be effective.

In severe P. falciparum malaria, oral antimalarials should not be
In severe P. falciparum malaria, oral antimalarials should not be
used. Vomiting, poor general health, poor compliance, erratic G.I.
used. Vomiting, poor general health, poor compliance, erratic G.I.
absorption due to splanchnic vasculopathy etc. make oral therapy
absorption due to splanchnic vasculopathy etc. make oral therapy
less reliable. Therefore, use only parenteral antimalarials. This also
less reliable. Therefore, use only parenteral antimalarials. This also
means that oral only antimalarials like Mefloquine and Halofantrine
means that oral only antimalarials like Mefloquine and Halofantrine
have no place in treating severe falciparum malaria.
have no place in treating severe falciparum malaria.

In all cases of P. falciparum malaria, the antimalarial drugs should
In all cases of P. falciparum malaria, the antimalarial drugs should
be chosen depending on the severity of the illness and the
be chosen depending on the severity of the illness and the
sensitivity pattern in the locality. Changing the drugs or adding the
sensitivity pattern in the locality. Changing the drugs or adding the
drugs in between is not advisable.
drugs in between is not advisable.


Chloroquine + Quinine
Chloroquine + Quinine
…..Important for Rx
…..Important Chloroquine + Mefloquine
Chloroquine + Mefloquine

Most antimalarial drugs have a long
Most antimalarial drugs have a long Quinine + Mefloquine
Quinine + Mefloquine
plasma half-life. Therefore, adding
plasma half-life. Therefore, adding
similar drugs half way through the
similar drugs half way through the Quinine + Primaquine
Quinine + Primaquine
treatment will only add to the
treatment will only add to the
adverse effects and not to the
adverse effects and not to the Quinine + Halofantrine
Quinine + Halofantrine
therapeutic benefit. The following
therapeutic benefit. The following
combinations should therefore be
combinations should therefore be Mefloquine + Primaquine
Mefloquine + Primaquine
avoided, concurrently or within a short
avoided, concurrently or within a short
interval:
interval: Administration of Primaquine and
Administration of Primaquine and
Pyrimethamine/sulphadoxine on the
Pyrimethamine/sulphadoxine on the
Do not exceed the maximum
Do not exceed the maximum
recommended dose of antimalarial same day is also not advisable. Both
same day is also not advisable. Both
recommended dose of antimalarial
drugs. All antimalarial drugs have a
drugs. All antimalarial drugs have a
sulpha and primaquine can
sulpha and primaquine can
narrow safety range and excess
narrow safety range and excess precipitate hemolytic crisis in
precipitate hemolytic crisis in
dose may lead to adverse effects..
dose may lead to adverse effects patients with Glucose 6-phosphate
patients with Glucose 6-phosphate
Moreover, larger dose does not offer
Moreover, larger dose does not offer
dehydrogenase deficiency.
dehydrogenase deficiency.
any superior antimalarial effect.
any superior antimalarial effect.

Pregnancy and lactation
Pregnancy and lactation

Infants below one year of age. In these two
Infants below one year of age. In these two
……..Important for Rx
……..Important categories, chloroquine should be given every week
categories, chloroquine should be given every week
as a suppressive chemoprophylaxis to prevent
as a suppressive chemoprophylaxis to prevent
relapse of vivax malaria. When these patients are fit
relapse of vivax malaria. When these patients are fit
for administration of primaquine, they should be
for administration of primaquine, they should be
primaquine,
given full therapeutic dose of chloroquine as well as
given full therapeutic dose of chloroquine as well as
Primaquine should primaquine.
primaquine.
primaquine.

be administered to ALL
administered to ALL Patients with known Glucose 6-phosphate
Patients with known Glucose 6-
6-phosphate
dehydrogenase deficiency
dehydrogenase deficiency
cases of malaria as
Concurrently with quinine, mefloquine and
Concurrently with quinine, mefloquine and
radical treatment except halofantrine into newer antimalarial drugs is scanty
halofantrine into newer antimalarial drugs is scanty
Research
Research
in the following and the parasite is fast developing resistance even
and the parasite is fast developing resistance even
for newer drugs. be usedwe deplete the newer drugs
for It should not Thus if we deplete the newer drugs
newer drugs. be used on the same day with
It should not Thus if on the same day with
situations where it is sulphadoxine. In such may not can be given the next
sulphadoxine. In such cases it havebe given the next
by misusing them, we may not can anything left for
sulphadoxine.
by misusing them, we cases it have anything left for
day.
day.
treating ALL DRUG RESISTANT malaria in the not-
treating ALL DRUG RESISTANT malaria in the not-
contraindicated: too-far-future.
too- far-
too-far-future.
not-

Therefore, newer anti malarial drugs should be
Therefore, newer anti malarial drugs should be
used only when definitely indicated and not
used only when definitely indicated and not
indiscriminately.
Do not misuse the indiscriminately.

These drugs should be used ONLY when
newer antimalarial These drugs should be used ONLY when
parasite index or other methods PROVE drug
parasite index or other methods PROVE drug
resistant malaria.
drugs. We need to resistant malaria.

In addition, artemisinin derivatives can be used
preserve them for future. In addition, artemisinin derivatives can be used
in cases of hyperparasitemia or life-threatening
in cases of hyperparasitemia or life-
life-threatening
complications on account of their ability to clear the
complications on account of their ability to clear the
parasitemia earlier compared to other anti malarial
parasitemia earlier compared to other anti malarial
Dr.G.C Sahu/ROHFW/GoI/A'Bad drugs.
drugs.

While most of the the clinical manifestations
of malaria are caused by the malarial
are caused by the malarial
infection per se………………
infection per se………………

• High grade fever as well as the side effects
of anti malarial therapy can also contribute
to the clinical manifestations.

• All these may act in unison, further
confusing the picture.

• In some cases, secondary infections like
pneumonia or urinary tract infection can add
to the woes.

All the above facts should
always be kept in mind.

Artemisinin based combinations- 1
combinations-
Artemisinin based combinations are known to improve cure rates, reduce the
Artemisinin based combinations are known to improve cure rates, reduce the
development of resistance and they might decrease transmission of drug-resistant
development of resistance and they might decrease transmission of drug-resistant
parasites. The total effect of artemisinin combinations (which can be simultaneous or
parasites. The total effect of artemisinin combinations (which can be simultaneous or
sequential) is to reduce the chance of parasite recrudescence, reduce the within-
sequential) is to reduce the chance of parasite recrudescence, reduce the within-
patient selection pressure, and prevent transmission..
patient selection pressure, and prevent transmission

Artesunate + Chloroquine
Very high chloroquine failure
rates (>60%) and sub-optimal
Efficacy efficacy of the combination
(<85% cure rate)

Not approved; Not a viable
option in areas with pre-
Status existing moderate to high
levels of P. falciparum
resistance to Chloroquine


Artemisinin based combinations - 2

Artesunate + Sulfadoxine/Pyrimethamine (SP)

Efficacy and advantages Well tolerated; Efficacy
dependent on the level of pre-
existing resistance to SP
Disadvantages Pharmacokinetic mismatch;
adverse effects to SP
Dose Artesunate 4mg/kg once daily
for 3 days and SP single dose
of 25mg/kg and 1.25mg/kg
respectively
Status Approved (in areas where SP
efficacy is high); Resistance to
SP limits the use


Artemisinin based combinations - 3

Artemether + Lumefantrine (Coartem,TM RiametTM)
(Coartem,TM RiametTM)

Efficacy and advantages As effective, and better
tolerated, as artesunate plus
mefloquine; No serious
adverse reactions documented
Disadvantages ?Irreversible hearing
impairment
Dose Artemether 1.5mg/kg and
Lumifantrine 9mg/kg at 0, 8, 24,
36, 48 and 60 hours
Status Approved; Not recommended
for use in pregnancy and
lactating women

Combination therapies recommended by
WHO

FDC
• Artemether/Lumefantrine

• Artesunate + amodiaquine
ACTs
• Artesunate + SP

• Artesunate + mefloquine


How and when can Artemisinin drugs
be affordable for most malaria patients
in the world?

Using compounds to replace the single-
ingredient drugs should be recommended.

Artemisinin drugs Alone：
• High consuming of Artemisinin
• High cost
• Long treatment course
Artemisinin compounds(ACT)：
• Low consuming of artemisinin
• Lower cost
• Short treatment course
• Low recrudescence, easy to finish the complete
treatment course.

Parasitological rationale for
combination treatment

• If for example 1 of 106 parasites is
resistant to treatment A and 1 of 106
parasites is resistant to treatment B, then
1 of 1012 will be resistant to both.
• A typical malaria patient would have 1010
parasites

Practical rationale for
combination therapy
• Most of the artemisinin drug combination
regimens last 3 days and are well tolerated
• Hence high compliance
• High compliance + high efficacy = high
effectiveness
• High effectiveness means long durability
• Long durability means rarer policy changes
with their inevitable costs and woes

Quick comparison between blood schizonticidal drugs
schizonticidal drugs
Chloroquine Sulpha/Pyri Quinine Mefloquine Quinghasu

Efficacy ++++ ++ +++ +++ +++++
+++++

Onset of action Rapid Slow Rapid Rapid Fastest
Fastest

Prototype drug, Only for Only for resistant Only for Reserved for drug
resistant
first choice for all uncomplicated, P. falciparum uncomplicated, multi
P. falciparum. However, it
falciparum.
cases resistant drug resistant may be considered in life
P. falciparum P. falciparum threatening complications
Use of P. falciparum due to its
rapid action

Parenteral Not useful in acute Drug of choice for Not to be used in Useful in severe
Use in severe preparation can be illness; can be co-
co- severe malaria; it was acute illness; can be malaria; may be
used in areas with prescribed with the only parenteral co-prescribed with
co- more effective and
P. falciparum sensitive strains other parenteral drug available for a artemisinin after better tolerated than
malaria antimalarials long time until
acute phase is over. quinine.
parenteral chloroquine
and artemisinin
arrived

Toxicity ++ +++ +++ +++ +

Almost none, only Allergy to sulpha Prior hypersensitive Epilepsy, psychosis, None
Contra indications advanced liver reactions heart block, ß blocker
disease use

Use in pregnancy Yes Only in 2nd trimester Only if warranted, Not in first trimester Yes, if the situation
Yes, if the situation
if warranted watch for demands
demands
hypoglycemia

Cost Cheapest Cheap Moderate Expensive Expensive
51

Malaria Parasite Resistance
• Mechanism of resistance is due to genetic
mutations in malaria parasite

Resistance
Resistance

More Drug Used Delayed Response

Increased Clinical Cases Recurrence of Infection

Increase Transmission Increased Gametocyte

The Acts of Commissions And Omissions IN MALARIA.
The Acts of Commissions And Omissions IN MALARIA.

Mis-diagnosis
Mis-diagnosis
In an endemic area, there may be a tendency to diagnose all cases of
In an endemic area, there may be a tendency to diagnose all cases of
fever as malaria, forgetting to even consider other causes. Whereas
fever as malaria, forgetting to even consider other causes. Whereas
Over-diagnosis
Over-diagnosis presumptive treatment with chloroquine in cases of fever is well
presumptive treatment with chloroquine in cases of fever is well
Obsession with malaria
Obsession with malaria accepted, sometimes, doctors may go beyond that and indulge in
accepted, sometimes, doctors may go beyond that and indulge in
and forgetting the OTHER presumptive treatment with newer drugs, (reserved for multi drug
and forgetting the OTHER presumptive treatment with newer drugs, (reserved for multi drug
causes of fever
causes of fever resistance falciparum malaria), even if the MP test is repeatedly
resistance falciparum malaria), even if the MP test is repeatedly
negative. Most often such cases turn out to be non-malarial fevers.
negative. Most often such cases turn out to be non-malarial fevers.
Therefore consider other causes of fever.
Therefore consider other causes of fever.

1. Malaria may not be considered as a possibility in places where iit is
1. Malaria may not be considered as a possibility in places where t is
not common-history of travel to malarious area should be elicited.
not common-history of travel to malarious area should be elicited.

2. It may not be considered in patients on chemoprophylaxis for
2. It may not be considered in patients on chemoprophylaxis for
Under-diagnosis
Under-diagnosis malaria. Chemoprophylaxis does not offer 100% protection and malaria
malaria. Chemoprophylaxis does not offer 100% protection and malaria
Forgetting malaria
Forgetting malaria should be therefore looked for in these patients.
should be therefore looked for in these patients.

3. Malaria can always co-exist with other infections in an endemic area.
3. Malaria can always co-exist with other infections in an endemic area.
Therefore, it should be considered even in patients with other obvious
Therefore, it should be considered even in patients with other obvious
infections causing fever.
infections causing fever.

Mis-report
Mis-report
Artifacts may be read as malarial parasites on
peripheral smear as well as QBC test. Dirty
False positive slides, contaminated stains, inexperienced
microscopist, recycled QBC tubes may be the
microscopist,
causes.

Malarial parasites may be missed and the test
reported as negative. Inadequate smear, dirty
stains, contaminated/deteriorated stains,
wrong buffer pH, inexperienced technician,
False negative incomplete examination of the slide, storage of
blood in anticoagulant before preparing the
smear etc. may contribute to this problem.


Mis-judgement of severity
Mis-judgement
Panic reaction to P. falciparum malaria is common among
Panic reaction to P. falciparum malaria is common among
patients and not uncommon among doctors, resulting in
patients and not uncommon among doctors, resulting in
over-reaction to the situation and over-treatment. Mild
over-reaction to the situation and over-treatment. Mild
anemia, mild icterus, headache etc. are common in
anemia, mild icterus, headache etc. are common in
falciparum malaria and need not necessarily imply severe
falciparum malaria and need not necessarily imply severe
Over-estimation
Over-estimation malaria. Such patients need not be treated with parenteral or
malaria. Such patients need not be treated with parenteral or
second line antimalarial drugs. Also it should not be
second line antimalarial drugs. Also it should not be
forgotten that some of the manifestations could be due to
forgotten that some of the manifestations could be due to
fever, drugs etc., and not necessarily due to severe malaria.
fever, drugs etc., and not necessarily due to severe malaria.

P. falciparum malaria can cause dramatic complications and
P. falciparum malaria can cause dramatic complications and
therefore one should be always looking for them. Patients
therefore one should be always looking for them. Patients
who are at for development of complications should be
who are at for development of complications should be
Under-estimation
Under-estimation ideally admitted for observation. Any indication of
ideally admitted for observation. Any indication of
complication should be properly managed. Neglecting the
complication should be properly managed. Neglecting the
signs like high fever, prostration, significant pallor and
signs like high fever, prostration, significant pallor and
jaundice, dehydration etc. may prove costly. Hypoglycemia
jaundice, dehydration etc. may prove costly. Hypoglycemia
may be easily missed.
may be easily missed.

IT MUST ALWAYS BE REMEMBERED THAT MALARIA IS A
LOCAL PHENOMENA AND ITS FOCAL NATURE IS DETERMINED BY
ITS FOCAL
THE FLIGHT RANGE OF THE LOCAL VECTOR(S)POPULATION .

AS LONG AS MALARIA PARASITES REMAIN IN THE HUMAN
BODY, IT IS MORE OR LESS PROTECTED FROM THE ENVIRONMENT
AND ITS DEVELOPMENT CONTINUES UNABATED EXCEPT FOR THE
INFLUENCE OF THE IMMUNITY OR ADMINISTRATION OF
APPRPRIATE ANTI-MALARIA DRUGS ..
ANTI-MALARIA


…..And


Level of parasitemia and clinical correlates

Parasitemia Parasites ccm/ l
ccm/ Remarks

0.0001-0.0004%
0.0001- 5-20 Sensitivity of thick blood film

0.002% 100 Patients may have symptoms below this level, where malaria is seasonal
seasonal

0.2% 10,000 Level above which immunes show symptoms

2% 100,000 Maximum parasitemia of P.vivax. and P.ovale

2-5% 100,000-250,000
100,000- Hyperparasitemia/severe malaria*, increased mortality
Hyperparasitemia/severe

10% 500,000 Exchange transfusion may be considered/high mortality

* WHO criteria for severe malaria are parasitemia > 10,000 / l and severe anemia (Hb < 5 g/l). Prognosis
(Hb g/l).
is poor if > 20% parasites are pigment containing trophozoites and schizonts and/or if > 5% of
neutrophils contain visible pigment.


Examination of blood smear

Demonstration of the parasite in a smear of the blood definitely establishes
Demonstration of the parasite in a smear of the blood definitely establishes
the presence of malaria.
the presence of malaria.

A negative finding on examination does not rule out malaria.. Only 50%
A negative finding on examination does not rule out malaria Only 50%
of children with malaria are smear positive, even on repeated examination.
of children with malaria are smear positive, even on repeated examination.

A positive finding on examination does not confirm clinical malaria,
A positive finding on examination does not confirm clinical malaria,
especially in patients from an endemic area, in whom a symptomatic parasitemia
especially in patients from an endemic area, in whom a symptomatic parasitemia
often exists.
often exists.

Both thick and thin films are essential.. If the parasitemia is light, a thin film
Both thick and thin films are essential If the parasitemia is light, a thin film
examination may miss the diagnosis. Thick films save time in diagnosis of scanty
examination may miss the diagnosis. Thick films save time in diagnosis of scanty
infections but make species identification of the parasite difficult.
infections but make species identification of the parasite difficult.

At least 100-200 fields of a thick film should be scrutinized before a
At least 100-200 fields of a thick film should be scrutinized before a
slide is reported as negative for malaria. In doubtful cases, the examination
slide is reported as negative for malaria. In doubtful cases, the examination
can be repeated after 4 hours.
can be repeated after 4 hours.

Various techniques to enhance the diagnostic utility of the peripheral blood smear
Various techniques to enhance the diagnostic utility of the peripheral blood smear
examination are in use. Fluorescent staining and microscopy, centrifugation,
examination are in use. Fluorescent staining and microscopy, centrifugation,
selective magnetic separation techniques, and other techniques have been used but
selective magnetic separation techniques, and other techniques have been used but
have only a moderate effect. Dr.G.C Sahu/ROHFW/GoI/A'Bad
have only a moderate effect.
60

Treatment of P. vivax malaria: A flow chart
Chloroquine + Primaquine
After 48 hours

Clinical Recovery Status quo / worse
Continue the treatment Suspect P. falciparum, repeat M.P. test at 48
Repeat the M.P. test on hrs.
(A thin smear examination is better for species
the 6th day identification and for assessing parasite count)

NEGATIVE
POSITIVE POSITIVE NEGATIVE
Cured
Consider
other causes
P. Falciparum P. Vivax of fever, may
Treat as possibly If the patient has be in
typical malarial association
chloroquine resistant
complications, treat as with malaria
P. falciparum;
otherwise, wait.

Treatment of P. falciparum malaria -A flow chart
-A
Complicated and
Uncomplicated and chloroquine
chloroquine sensitive
sensitive
Tab. Chloroquine + Primaquine Inj. Chloroquine +
Inj.
single dose Primaquine single dose

Status quo/ worse;
Better; parasite count reduced by
parasite count reduced
> 75%
by < 75%

Continue Consider resistance


Drugs for chloroquine resistant Pf malaria

Complicated
and
Uncomplicated and
Chloroquine
Chloroquine resistant
resistant

1. Inj.Quinine +
1. Inj.Quinine +
Pyrimethamine/Sulphadoxine
Pyrimethamine/Sulphadoxine
Use any one of the following combinations:
Use any one of the following combinations: 2. Inj. Quinine + Tetracycline /
2. Inj. Quinine + Tetracycline /
1. Tab.Quinine + Tab. Pyrimethamine/ Sulfa.
1. Tab.Quinine + Tab. Pyrimethamine/ Sulfa. Doxycycline
Doxycycline
2. Tab. Quinine + Tetracycline /doxycycline
2. Tab. Quinine + Tetracycline /doxycycline 3. Inj. Artemether / Arteether /
3. Inj. Artemether / Arteether /
3. Tab. Artesunate + Tab. Mefloquine
3. Tab. Artesunate + Tab. Mefloquine Artesunate + Mefloquine.
Artesunate + Mefloquine.
4.Tab.Mefloquine + Pyrimethamine/Sulpha.
4.Tab.Mefloquine + Pyrimethamine/Sulpha.

63

Clinical approach to cases of recurrent malaria

Recurrence Within 8-10 After 2 After 2
days weeks months

1st ?P. falciparum ?Re-infection ?Re-infection
possibility

2nd ?Compliance ?P. falciparum ?Relapse
possibility

Established antimalarial drugs
Drug Role Best features(s)
Best features(s) Limitation
Chloroquine TX of and CP against non-Pf
TX of and CP against non-Pf Very safe; low cost;
Very safe; low cost; Widespread R
Widespread R
and sensitive Pf parasites
and sensitive Pf parasites long half-life
long half-life

Quinine/quinidine
Quinine/quinidine Best TX for Pf malaria; low
Best TX for Pf malaria; low Limited R; rapidly
Limited R; rapidly Fairly toxic ((cinchonism,
Fairly toxic cinchonism,
cost
cost acting
acting cardiac)
cardiac)

Amodiaquine TX of R Pf malaria
TX of R Pf malaria Low cost
Low cost Toxicity (bone marrow,
Toxicity (bone marrow,
liver); R Common
liver); R Common

Mefloquine CP against R malaria; not
CP against R malaria; not Relatively little R,
Relatively little R, Moderately toxic (mostly
Moderately toxic (mostly
approved for TX in United
approved for TX in United though increasing;
though increasing; CNS); high cost; R in SE
CNS); high cost; R in SE
State
State long half-life
long half-life Asia
Asia
Fansidar TX of Pf malaria; no longer
TX of Pf malaria; no longer Relatively low cost;
Relatively low cost; Skin toxicity (can be fatal);
Skin toxicity (can be fatal);
recommended for CP
recommended for CP long half-life
long half-life increasing R
increasing R

Primaquine Eradication of chronic liver
Eradication of chronic liver Only drug for this
Only drug for this Hemolysis with G6Pd
Hemolysis with G6Pd
stage Pv,Po malaria
stage Pv,Po malaria indication
indication deficiency; increasing R
deficiency; increasing R

Progunil CP only (often with
CP only (often with Low cost; nontoxic
Low cost; nontoxic R common
R common
Chloroquine)
Chloroquine)
S-P Combinations
S-P Combinations CP only (often with
CP only (often with Low cost
Low cost R Common; skin rashes
R Common; skin rashes
Chloroquine)
Chloroquine)

Tetracycline Cp; TX of Pf malaria in
Cp; TX of Pf malaria in Low cost
Low cost Skin and gastrointestinal
Skin and gastrointestinal
Combination with quinine
Combination with quinine

New antimalarial drugs
Drug Role Best Feature(s)
Feature(s) Limitations
Halofantriine TX of Pf malaria; not
TX of Pf malaria; not Usually effective against R
Usually effective against R Variable bioavailability,
Variable bioavailability,
approved for CP
approved for CP Pf malaria
Pf malaria cardiac toxicity
cardiac toxicity

Artemisinin and
Artemisinin and TX of Pf malaria
TX of Pf malaria Rapidly acting; effective
Rapidly acting; effective Recurrence after TX fairly
Recurrence after TX fairly
related compounds
related compounds against multidrug-R
against multidrug-R common
common

Atovaquone ? TX of Pf malaria?
? TX of Pf malaria? Limited toxicity
Limited toxicity Limited studies so far
Limited studies so far
CP (Probably in
CP (Probably in show frequent recurrence
show frequent recurrence
combination with
combination with after TX
after TX
proguanil
proguanil

Pyronaridine ? TX of malaria
? TX of malaria Effective against R strains
Effective against R strains Studies limited to date
Studies limited to date

Desferrioxamine ? TX of severe Pf
? TX of severe Pf Well tolerated when used
Well tolerated when used Studies limited to date
malaria
malaria for iron overload
for iron overload

Azithromycin ? CP
? CP Limited toxicity
Limited toxicity Studies limited to date


Other Drugs for Chemotherapy of Malaria
Many drugs have been tested for
Many drugs have been tested for
Clindamycin: It acts
Clindamycin: It acts
their potential anti malarial effects.
their potential anti malarial effects.
Fluoroquinolones:
Fluoroquinolones:
Fluoroquinolones: by inhibiting the protein
by inhibiting the protein
Research into newer anti malarials
Research into newer anti malarials Both
Both synthesis by binding to
synthesis by binding to
being scanty, such attempts might
being scanty, such attempts might
throw up one or two candidates for
throw up one or two candidates for
ciprofloxacin
ciprofloxacin the 50s subunit of
the 50s subunit of
use in malaria, however, these
use in malaria, however, these and norfloxacin
and norfloxacin ribosomes. It can be
ribosomes. It can be
ribosomes.
drugs are yet to find a place in
drugs are yet to find a place in have been found to
have been found to used for drug resistant
used for drug resistant
standard anti malarial regimen.
standard anti malarial regimen.
Clindamycin, fluoroquinolones
Clindamycin, fluoroquinolones have anti malarial
have anti malarial malaria along with
malaria along with
Clindamycin,
like ciprofloxacin and
like ciprofloxacin and activity both in
activity both in quinine at a dose of 10
quinine at a dose of 10
Norfloxacin, azithromycin etc.
Norfloxacin, azithromycin etc.
Norfloxacin, vitro and in vivo.
vitro and in vivo. mg/kg 8 hourly for 5
mg/kg 8 hourly for 5
have been found to be effective
have been found to be effective However, results
However, results days. Adverse effects
days. Adverse effects
against malarial parasites.
against malarial parasites. include
are not consistent.
are not consistent. include
Atovaquone;
Atovaquone;
Atovaquone; pseudomembrane colitis
pseudomembrane colitis
Desferrioxamine;
Desferrioxamine;
Desferrioxamine; and skin rashes. In one
and skin rashes. In one
Pyronaridine; Piperaquine;
Pyronaridine; Piperaquine;
Pyronaridine; Piperaquine; study, a cure rate of only
study, a cure rate of only
WR-288, 605; and 566C80
WR-
WR-288, 605; and 566C80 50% was observed. (Hall
Atovaquone plus Proguanil:
Atovaquone plus Proguanil:
Proguanil: 50% was observed. (Hall
are drugs undergoing
are drugs undergoing A fixed dose combination of
A fixed dose combination of et al)
et al)
trials.
trials. atovaquone and proguanil
atovaquone and proguanil
hydrochloride (Malarone™) is now
Malarone™
hydrochloride (Malarone™) is now
approved for both treatment and
approved for both treatment and Pyronaridine: Structurally, it
Pyronaridine: Structurally, it
Pyronaridine:
prophylaxis of malaria. It is available
prophylaxis of malaria. It is available
malaria. resembles amodiaquine and has been
resembles amodiaquine and has been
as 250 mg atovaquone + 100 mg found to be highly effective against
found to be highly effective against
Azithromycin: Azithromycin
Azithromycin: Azithromycin as 250 mg atovaquone + 100 mg
chloroquine resistant strains in China.
chloroquine resistant strains in China.
proguanil per tablet for adults and
proguanil per tablet for adults and
is found to have anti malarial
is found to have anti malarial 62.5 mg atovaquone + 25 mg Piperaquine: Its activity is similar to
Piperaquine: Its activity is similar to
Piperaquine:
62.5 mg atovaquone + 25 mg that of chloroquine. A combination
activity and has been found to
activity and has been found to proguanil per tablet for children.. It that of chloroquine. A combination
chloroquine.
proguanil per tablet for children It with artimisinin is undergoing studies.
with artimisinin is undergoing studies.
be useful as a causal
be useful as a causal has been shown to be highly
has been shown to be highly WR-288, 605: It is 7.4 times more
WR-
efficacious in the treatment of WR-288, 605: It is 7.4 times more
prophylactic agent. It was
prophylactic agent. It was efficacious in the treatment of
uncomplicated malaria caused by active than primaquine as a tissue
active than primaquine as a tissue
uncomplicated malaria caused by
found to be effective at the
found to be effective at the Plasmodium falciparum, including
Plasmodium falciparum, including
falciparum,
schizonticidal drug. It has lesser
schizonticidal drug. It has lesser
dose of 300 mg stat, followed malaria that has been acquired in toxicity, good oral bio-availability
toxicity, good oral bio-
bio-availability
dose of 300 mg stat, followed malaria that has been acquired in
areas with chloroquine-resistant or
areas with chloroquine-
chloroquine-resistant or and longer half-life.
and longer half-
half-life.
by 250 mg daily for 7 days as
by 250 mg daily for 7 days as multidrug-resistant strains. The daily
multidrug-
multidrug-resistant strains. The daily
strains. Lumefantrine is an aryl alcohol
Lumefantrine is an aryl alcohol
a prophylactic agent against
a prophylactic agent against dose should be taken at the same
dose should be taken at the same related to quinine, mefloquine and
related to quinine, mefloquine and
chloroquine resistant P.
chloroquine resistant P. time each day with food or milk.
time each day with food or milk. halofantrine that is devoid of cardiac
halofantrine that is devoid of cardiac
falciparum infection. toxicity of halofantrine. It is being
toxicity of halofantrine. It is being
falciparum infection.
infection. halofantrine.
tried in combination with artemether.
tried in combination with artemether.
artemether.

The Primaquine Questions - Confusions in Primaquine Use In
Malaria
Often primaquine is not prescribed for falciparum malaria because it is not needed for attaining a cure of the infection. But it is
required to prevent the spread of falciparum infection because unlike in case of vivax malaria, Chloroquine does not sterilize the
To use or gametocytes of falciparum species. Therefore, if primaquine is not used in falciparum malaria, there will be a selective spread of P.
falciparum malaria, which may be even resistant to drugs. Therefore, do not forget to use primaquine in P. falciparum malaria-
not? prevent the spread of P. falciparum, prevent the spread of drug resistant strains! Primaquine is hence a must for both P.vivax and
P.falciparum infections.

What is the
0.25mg/kg/day (once a day) for 5 days in P. vivax; 0.75 mg/kg as single dose in P.
dose? falciparum.
In cases of P. vivax malaria, the National Malaria Eradication Programme (N.M.E.P.) in India recommends
*5 days or 14 Primaquine therapy for 5 days, whereas the standard literature recommends for 14 days. 5 days therapy is adequate in
most cases. In cases of relapse, a 14-day treatment is advisable.
days?
What is the At present, Primaquine is the only drug available for tissue schizonticidal activity in P. vivax
malaria and gametocytocidal activity in P. falciparum infection. Therefore, it must be used in both
alternative to these infections. Therefore, at present there are no alternatives to primaquine. Newer anti
primaquine? malarials like mefloquine or artemisinin derivatives are NOT substitutes for primaquine!

Is there
primaquine
Although resistance to primaquine has been reported from S. E. Asia and Africa, it is rare. Such
resistance? cases are managed with a higher dose of primaquine.

Primaquine or
‘parda’? In some hospitals, patients with malaria are made to lie inside mosquito nets, with the idea of
preventing the spread of the infection to the 'hospital mosquitoes' and hence to other patients.
(Mosquito Often these patients are not administered primaquine. Remember, mosquito nets may not prevent
nets) the spread of falciparum malaria, but Primaquine WILL.

G-6 P D Deficiency-Four most common variants out of 300+ known

All World
GdB Normal Activity Populations

Normal Activity; Acetic acid substituted for asparagine at Africa (most
GdA
position 126, Guanine for adenine at DNA position376 common variant)

8 - 20% Normal Activity; Methionine for Valine at position 67
and Aspartic Acid for Asparagine at position 126, Adenine for
GdA-
Guanine at position 202 and Guanine for Adenine at position
Africa
376

Iran, Iraq, India,
< 5% Normal Activity; Phenylalanine for Serine at
GdMed Pakistan, Greece,
position 188; Thiamine for Cytosine at position 563
Sardinia

Primaquine Treatment Regimens
1 tablet* per day x 14 days
G-6-PD NORMAL * The Indian programme
recommends 5 days RT regime to
all P.vivax cases.

3 tablets per week
G-6-PD deficiency
(Mild African form) for 8 weeks

G-6-PD deficiency 2 tablets per week for
(More severe 30 weeks
Mediterranean variety)-
Indian strain
•1 tablet consists of 26.3 mg pimaquine phosphate, 15 mg
primaquine base.
•…..So there is no absolute contraindication ! !

Potential Vaccines in Malaria.
Target Protection
Sporozoite anti-infection

Merozoite anti-parasite

Infected RBC anti-parasite

Exo-antigens anti-disease

Sexual stages anti-transmission

Malaria is a preventable infection that can be fatal if left untreated.
Currently, you cannot be vaccinated against malaria, but you can protect yourself
71

Characteristics of thick and thin blood smears

Thick Smear Thin Smear
Lysed RBCs Fixed RBCs

Many layers Single layer

Large volume Smaller volume

Good screening test Good species differentiation

Low density infection can be Low density infection can be
detected missed
Difficult to diagnose species Requires more time to read but
good for species diagnosis.


MALARIA--- THINK BEYOND CLINICAL CURE
SOME POINTS TO PONDER FOR PHYSICIANS
Ø CLINICAL CURE WITH APPROPRIATE BLOOD SCHIZONTICIDALS

Ø GAMETOCYTES,WHEN LATER SUCKED BY THE VECTOR
MOSQUITOS,DEVELOP IN THEIR BODY INTO DISEASE CAUSING
SPOROZOITES WHICH ARE TRANSMITTED AGAIN TO THE NEXT HEALTHY
PERSON BY THE MOSQUITO BITE –THUS ANOTHER HUMAN BEING FALLS
VICTIM TO THE DEADLY MALARIA .

Ø THIS TRANSMISSION OF MALARIA CAN BE PREVENTED BY
ADMINISTERING GAMETOCYTOIDAL DRUGS LIKE PRIMAQUINE AFTER
CONTROLLING THE ACUTE STAGES OF THE DISEASE .

Ø THE PRACTICE OF USING GAMETOCYTOCIDAL DRUGS SHOULD BE
CONSIDERED AS IMPORTANT AND SHOULD BECOME A PART OF
STANDARD TREATEMENT STRATEGY WHENEVER A CASE OF
P.FALCIPARUM IS ENCOUNTERED. ……contd

CHEMOTHERAPY AND NATIONAL DRUG POLICY IN MALARIA

CHEMOTHERAPY AND NATIONAL DRUG POLICY IN MALARIA

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