ANTI MALARIAL

INTRODUCTION

Malaria is an infectious disease caused by a parasite, Plasmodium, which infects red blood
cells. Malaria has infected humans since the beginning of mankind. The name "mal aria"
(meaning "bad air" in Italian) was first used in 1740 by H. Walpole. The term was shortened
to "malaria" in the 20th century. C. Laveran in 1880 was the first to identify the parasites in
human blood. The five species that cause malaria are

• Plasmodium falciparum: The most serious type, can be life-threatening

• Plasmodium vivax: generally less serious and are usually not life-threatening.

• Plasmodium malariae,: generally less serious and are usually not life-threatening.

• Plasmodium ovale : generally less serious and are usually not life-threatening.

• Plasmodium knowlesi : dangerous, found only in- long-tailed and pigtail macaque monkeys,
can be life threatening1.

SIGN AND SYMPTOMS :

The symptoms characteristic of malaria include-

1. Flulike illness with systemic fever

2. Chills, Sweating

3. Muscle aches (Fatigue, Pain)

4. Central headache.

5. Nausea

6. Vomiting

7.Dry Cough

8. Diarrhea

9.Spleen enlargement.

Sometimes symptoms may occur later in those individu als who have taken antimalarial
medications.3 Initial propagation are similar to flu-like symptoms, septice mia, gastroenteritis
and viral diseases.4 They also may include headache, fever, shivering, joint pain, vomiting,
jaundice, hemoglobin urea, retinal damage, convulsions and hemolytic anemia,.5 The main

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 1

 ANTI MALARIAL

classic symptom is cyclical occurrence of sud den coldness followed by shivering and then
fever and sweating, which is known as paroxysm.

• Paroxysm occurring every in P. vivax and P. ovale infections. two days

• Paroxysm occurring every three days for P. malariae. P. falciparum infection can cause
recur rent fever every 36–48 hours or a continuous fever.

Fig 1. Symptoms of malaria

Complications

The main complication is the development of respiratory distress, due to respiratory

compensation of metabolic acidosis, Concomitant pneumonia, noncardio genic pulmonary
oedema and severe anaemia. Acute respiratory distress syndrome occurs in 5–25% of adults
and up to 29% of pregnant women.7 Infec tion of HIV with malaria increases the chances of
death.8 Due to infection with P. falciparum Cerebral malaria may occur. Which is associated
with retinal whitening(a use ful clinical sign in distinguishing malaria from other causes of
fever.)9. Splenomegaly, liver enlarge ment, hypoglycemia, severe headache, and hemoglobin
urea with renal failure may occur.4 Malaria may cause stillbirths, infant mortality and low
birth weight during the pregnancy,10 particularly in P. falciparum & P. vivax infection.

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 2

 ANTI MALARIAL

Causes of malaria

Malaria is caused by P. falciparum, P. malariae, P. ovale, P. vivax in humans .12,13 P.

falciparum is the most common species identified (~75%) followed by P. vivax (~20%).3
Although P. falciparum traditionally accounts for the majority of deaths,14 Recent evidence
suggests that P. vivax malaria is associated with poten tially life-threatening conditions about
as often as with a diagnosis of P. falciparum infection.15 P. vivax propor tionally is more
common outside of Af rica.16 P. knowlesi is a zoonotic species that causes ma laria in
macaques13, these are mostly of limited public health importance.

Life cycle of the malaria parasite

The life cycle of the malaria parasite (Plasmodium) is complicated and involves two hosts,
humans and Anopheles mosquitoes. The disease is transmitted to humans when an infected
Anopheles mosquito bites a person and injects the malaria para sites (sporozoites) into the
blood. Sporozoites travel through the bloodstream to the liver, mature, and eventually infect
the human red blood cells. While in red blood cells, the parasites again develop until a
mosquito takes a blood meal from an infected human and ingests human red blood cells con
taining the parasites. Then the parasites reach the Anopheles mosquito's stomach and
eventually invade the mosquito salivary glands. When an Anopheles mos quito bites a
human, these sporozoites complete and repeat the complex Plasmodium life cycle. P. ovale
and P. vivax can further complicate the cycle by producing dormant stages (hypnozoites) that
may not develop for weeks to years.1

Diagnosis of malaria

Diagnosis of malaria in non-endemic areas requires a high degree of suspicion, which might
be elicited by any of the following: recent travel history, enlarged spleen, fever, low number
of platelets in the blood, and higher-than-normal levels of bilirubin in the blood combined
with a normal level of white blood cells.3 0

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 3

 ANTI MALARIAL

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 4

 ANTI MALARIAL

Microscopy :

Malaria is usually confirmed by the microscopic ex amination or microscopy of blood films

or by antigen based rapid diagnostic tests (RDT).20,21 About 165 million blood films were
microscopically examined for malaria in 2010.

Apart from its widespread usage, diagnosis by micros copy have two main drawbacks:

Many settings (specially rural) are not equipped to per form the test, and the accuracy of the
results depends on both the skill of the person examining the blood film and the levels of the
parasite in the blood. The sensitiv ity of blood films ranges from 75–90% in optimum
conditions, to as low as 50%.

Commercially available RDTs are often more accurate than blood films at predicting the
presence of malaria parasites, but they are widely variable in diagnostic sensitivity and
specificity depending on manufacturer, and are unable to tell how many parasites are
present.22

In regions where laboratory tests are readily available, malaria should be suspected, and
tested for, in any unwell person who has been in an area where malaria is endemic. In areas
that cannot afford laboratory diagnostic tests, it has become common to use only a history of
fever as the indication to treat for malaria. A drawback of this practice is over diagnosis of
malaria and mismanagement of non malarial fever, which wastes limited resources, erodes

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 5

 ANTI MALARIAL

confidence in the health care system, and contributes to drug resistance.23Although

polymerase chain reaction based tests have been developed, they are not widely used in areas
where malaria is common as of 2012, due to their complexity.3

Classification of malaria :

World Health Organization (WHO) classified Malaria into two types.

Severe malaria

Uncomplicated malaria.

The severe malaria is declared when any of the following criteria are present, otherwise it is
considered as uncom plicated malaria.24

1. Decreased consciousness

2. Significant weakness such that the person is unable to walk

3. Inability to feed

4. Two or more convulsions

5. Low blood pressure (less than 70 mmHg in adults and 50 mmHg in children)

6. Breathing problems

7. Circulatory shock

8. Kidney failure or hemoglobin in the urine

9. Bleeding problems, or hemoglobin less than 50 g/L (5 g/dL)

10. Pulmonary oedema

11. Blood glucose less than 2.2 mmol/L (40 mg/dL)

12. Acidosis or lactate levels of greater than 5 mmol/L

13. A parasite level in the blood of greater than 100,000 per microlitre (µL) in low-intensity
trans mission areas, or 250,000 per µL in high-intensity transmission areas.

14. Cerebral malaria is defined as a se vere P. falciparum-malaria presenting with neuro

logical symptoms, including coma or with a coma that lasts longer than 30 minutes after a
seizure.25

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 6

 ANTI MALARIAL

❖ Classification of Antimalarial Drugs

▪ According to anti-malarial activity:

(i) Tissue schizonticides for causal prophylaxis: These drugs act on the primary tissue
forms of the plasmodia which after growth within the liver, initiate the erythrocytic stage. By
blocking this stage, further development of the infection can be theoretically prevented.
Pyrimethamine and Primaquine have this activity. However since it is impossible to predict
the infection before clinical symptoms begin, this mode of therapy is more theoretical than
practical.

(ii) Tissue schizonticides for preventing relapse: These drugs act on the hypnozoites of P.
vivax and P. ovale in the liver that cause relapse of symptoms on reactivation. Primaquine is
the prototype drug; pyrimethamine also has such activity.

(iii) Blood schizonticides: These drugs act on the blood forms of the parasite and thereby
terminate clinical attacks of malaria. These are the most important drugs in anti-malarial
chemotherapy. These include chloroquine, quinine, mefloquine, halofantrine, pyrimethamine,
sulfadoxine, sulfones, tetracyclines etc.

(iv) Gametocytocides:

These drugs destroy the sexual forms of the parasite in the blood and thereby prevent
transmission of the infection to the mosquito. Chloroquine and quinine have gametocytocidal
activity against P. vivax and P. malariae, but not against P. falciparum. Primaquine has
gametocytocidal activity against all plasmodia, including P. falciparum.

(v) Sporontocides:

These drugs prevent the development of oocysts in the mosquito and thus ablate the
transmission. Primaquine and chloroguanide have this action. ▪ Currently available
antimalarials fall into three broad categories according to their chemical structure and mode
of action:
(i) Aryl aminoalcohol compounds: Quinine, Quinidine, Chloroquine, Amodiaquine,
Mefloquine, Halofantrine, Lumefantrine, Piperaquine, Tafenoquine.

(ii) Antifolate compounds (“antifols”): Pyrimethamine, Proguanil, Chlorproguanil,

Trimethoprim

(iii) Artemisinin compounds: Artemisinin, Dihydroartemisinin, Artemether, Artesunate.

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 7
 ANTI MALARIAL

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 8

 ANTI MALARIAL

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 9

 ANTI MALARIAL

❖ Structure–Activity Relationship of Antimalarial Agents

- At C-4 position, the dialkylaminoalkyl side chain has 2-5 carbon atoms between the
nitrogen atoms, particularly the 4-diethylaminomethyl butyl amino side chain that is optimal
for activity, as in chloroquine and quinacrine.

- The substitution of a hydroxyl group on one of the ethyl groups on the tertiary amine
(hydroxy quinoline), reduces toxicity.

- Incorporation of an aromatic ring in the side chain (e.g., amodiaquine) gives a compound
with reduced toxicity and activity.

- The tertiary amine in the side chain is important.

- The introduction of an unsaturated bond in the side chain was not detrimental to activity.

- The 7-chloro group in the quinoline nucleus is optimal, the methyl group in position 3
reduces activity, and an additional methyl group in position 8 abolishes activity.

- The D-isomer of chloroquine is less toxic than its L-isomer

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 10

 ANTI MALARIAL

Methods of malaria prevention :

There are various methods used to prevent malaria

which are such as :-

Medications,

Mosquito elimination Prevention of bites.

At present there is no vaccine available for malaria. Malaria occurs in an area where the
combination of high human population density, high anopheles mos quito population density
and high rates of transmission from humans to mosquitoes and from mosquitoes to humans
available. If any of these is lowered suffi ciently, the parasite will eventually disappear from
that area. However, unless the parasite is eliminated from the whole world, it could become
re-established if con ditions revert to a combination that favours the para site's reproduction.
Furthermore, the cost per person of eliminating anopheles mosquitoes rises with decreasing
population density, making it economically possible in some areas.26

Prevention of malaria may be more cost-effective than treatment of the disease in the long
run, but the initial costs required are out of reach of many of the world's poorest people.
China government announced a strategy to pursue malaria elimination which required small
proportion of investment of public expenditure on health. Whereas a similar program in
Tanzania would cost an estimated one-fifth of the public health budget.27

Vector control :

Vector control methods used to decrease malaria by reducing the levels of transmission by
mosquitoes.

For individual protection, the most effective vector con trol methods are

• Insect repellents are based on DEET or picaridin.28

• Insecticide-treated mosquito nets (ITNs)

• Indoor residual spraying (IRS) have been shown to be highly effective in preventing malaria
among children in areas where malaria is common.29,30

• Prompt treatment of confirmed cases with artemisinin based combination therapies (ACTs)
may also reduce transmission.

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 11

 ANTI MALARIAL

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 12

 ANTI MALARIAL

Insecticide-treated mosquito nets (ITNs) :

Mosquito nets help keep mosquitoes away from people and reduce infection rates and
transmission of malaria. Nets are not a perfect barrier and are often treated with an insecticide
designed to kill the mosquito before it has time to find a way past the net. Insecticide-treated
nets are estimated to be twice as effective as untreated nets and offer greater than 70%
protection compared with no net.32Between 2000 and 2008, the use of ITNs saved the lives
of an estimated 250,000 infants in Sub Saharan Africa.33About 13% of households in Sub
Saharan countries own ITNs.34In 2000, 1.7 million (1.8%) African children living in stable
malaria endemic conditions were protected by an ITN. That number increased to 20.3 million
(18.5%) African chil dren using ITNs in 2007, leaving 89.6 million children
unprotected.35An increased percentage of African households (31%) are estimated to own at
least one ITN in 2008. Most nets are impregnated with pyre throids, a class of insecticides
with low toxicity. A rec ommended practice for usage is to hang a large "bed net" above the
center of a bed to drape over it com pletely with the edges tucked in. Pyrethroid-treated nets
and long-lasting insecticide-treated nets offer the best protection, and are most effective when
used from dusk to dawn.36

Indoor residual spraying (IRS) :

Indoor residual spraying is the spraying of insecticides on the walls inside a home. After
feeding, many mos quito rest on a nearby surface while digesting the bloodmeal, so if the

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 13

 ANTI MALARIAL

walls of houses have been coated with insecticides, the resting mosquitoes can be killed
before they can bite another person and transfer the malaria parasite.37 As of 2006, the
World Health Or ganization recommends 12 insecticides in IRS opera tions, including DDT
and the pyrethroids cyfluthrin and deltamethrin.38 This public health use of small amounts of
DDT is permitted under the Stockholm Convention, which prohibits its agricultural
use.39One problem with all forms of IRS is insecticide resistance. Mosquitoes affected by
IRS tend to rest and live in doors, and due to the irritation caused by spraying, their
descendants tend to rest and live outdoors, meaning that they are less affected by the IRS.

Other methods of malaria prevention :

There are a number of other methods to decrease mos quito larva by decreasing the
availability of open water in which they develop or by adding substances to decrease their
development is effective in some locations.41 Electronic mosquito repellent devices which
make very high frequency sounds that are supposed to keep female mosquitoes away.42
Community participation and health education strate gies promoting awareness and the
importance of control measures have been successfully used to reduce the inci dence of
malaria.43 Recognizing the disease in the early stages can stop the disease from becoming
fatal. Educa tion can also inform people to cover over areas of stag nant, still water, such as
water tanks in urban areas who have large centers of population in a confined space and
transmission would be most likely in these areas.44 Inter mittent preventive therapy has been
used successfully to control malaria in pregnant women and infants,45 as well as in preschool
children where transmission is seasonal.46 National Vector Borne Disease Control
Programme (NVBDCP) of India has been marked June as Anti malaria month, with an
objective to increase multisectoral collaboration and community involvement in malaria
control.47,48

Medication of Malaria :

Each antimalarial drug is considered by chemical structure and mechanism of action.

Quinine and related agents :

Quinine is an alkaloid obtained from cinchona acts as a blood schizonticidal and weak
gametocide against Plas modium vivax and Plasmodium malariae. Quinine is ac cumulated in
the food vacuoles of Plasmodium species, especially Plasmodium falciparum and inhibit the
hemo zoin biocrystallization, thus facilitating an aggregation of cytotoxic heme. Quinine is

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 14

 ANTI MALARIAL

very effective and widely used in the treatment of acute cases of severe P. falcipa rum but it
is less effective and more toxic than chloro quine. Mostly useful in areas where high level of
resis tance to chloroquine, mefloquine, and sulfa drug combi nations with pyrimethamine.
The World Health Organization recommendation for quinine by oral, intravenous or
intramuscular routes, is 20 mg/kg first times and 10 mg/kg 8 hr for 5days where as in quinine
sensitivity quinine may combined with doxycycline, tetracycline or clindamycin. Use of
quinine is characterised by a frequently experi enced syndrome called cinchonism. Tinnitus,
rashes, ver tigo, nausea, vomiting and abdominal pain are the most common symptoms.
Quinine can cause hypoglycemia through its action of stimulating insulin secretion. This
effect can be exaggerated in pregnancy and therefore ad ditional care in administering and
monitoring the dosage is essential. Repeated or over-dosage can result in renal failure and
death through depression of the respiratory system.

Quinine related agents:

Quinimax and quinidine are the two most com monly used alkaloids. Quinimax is a
combination of four alkaloids (quinine, quinidine, cinchoine and cin chonidine). Due to a
synergistic action between the four cinchona derivatives this combination has been shown
more effective than quinine. Quinidine is a distereoisomer of quinine with simi lar anti-
malarial properties and recommended only for the treatment of severe cases of malaria.
Warburg's Tincture was a febrifuge developed by Dr Carl Warburg in 1834, which included
quinine as a key ingredient. Warburg's Tincture was highly regarded by many eminent
medical professionals who considered it as being superior to quinine (e.g. Surgeon-General
W. C. Maclean, Professor of Military Medicine at British Army Medical School, Netley).
Warburg's Tincture appeared in Martindale: The complete drug reference from 1883 until
about 1920. The formula was pub lished in The Lancet 1875.49

Chloroquine :

Chloroquine was least expensive, best tested ,safest and the most widely used anti-malarial. It
was the original prototype from which most methods of treat ment are derived. The
emergence of drug-resistant parasitic strains is rapidly decreasing its effectiveness. Now
Chloroquine is suggested to used in combination with other antimalarial drugs to extend its
effective usage. Popular drugs based on chloroquine phosphate (also called nivaquine) are
Chloroquine FNA, Resochin and Dawaquin. Chloroquine is a 4-aminoquinolone compound
which is believed to reach high concentrations in the vacuoles of the parasite and raises the

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 15

 ANTI MALARIAL

internal pH. It controls the conversion of toxic heme to hemozoin by inhibiting the
biocrystallization of hemozoin, thus poi soning the parasite through excess levels of toxicity.
Children and adults should receive 25 mg of chloro quine per kg given over 3 days,
recommended by the WHO, involves giving an initial dose of 10 mg/kg fol lowed 6–8 hours
later by 5 mg/kg, then 5 mg/kg on the following 2 days.

Amodiaquine :

Amodiaquine is a 4-aminoquinolone anti-malarial drug similar in structure and mechanism of

action to chloroquine. Amodiaquine has tended to be adminis tered in areas of chloroquine
resistance while some patients prefer its tendency to cause less itching than chloroquine.
Amodiaquine is now available in a com bined formulation with artesunate (ASAQ ) and is
among the artemisinin-combination therapies recom mended by the World Health
Organisation. The drug should be given in doses between 25 mg/ kg and 35 mg/kg over 3
days in a similar method to that used in chloroquine administration. Adverse react- -ions are
generally similar in severity and type to that seen in chloroquine treatment. In addition,
bradycardia, itching, nausea, vomiting and some abdominal pain have been recorded. Some
blood and hepatic disorders have also been seen in a small number of patients.

Pyrimethamine :

Pyrimethamine is used in the treatment of uncompli cated malaria, particularly in cases of

chloroquine resistant P. falciparum strains when combined with sul fadoxine. It acts by
inhibiting dihydrofolate reductase in the parasite thus preventing the biosynthesis of purines
and pyrimidines, thereby halting the processes of DNA replication, cell division and
reproduction. It acts primar ily on the schizonts during the erythrocytic phase, and nowadays
is only used in concert with a sulfonamide.

Proguanil :

Proguanil (chloroguanide) is a biguanide ,a synthetic pyrimidine derivative. It has many

mechanisms of action but primarily is mediated through conversion to the active metabolite
cycloguanil. This inhibits the malarial dihy drofolate reductase enzyme. It has a weak blood
schizon ticidal activity and is not recommended for therapy of acute infection. However it is
useful in prophylaxis when combined with atovaquone or chloroquine (in areas where there is
no chloroquine resistance). 3 mg/kg is the advised dosage per day, (hence approximate adult

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 16

 ANTI MALARIAL

dosage is 200 mg). There are very few side effects to proguanil, with slight hair loss and
mouth ulcers being occasionally reported following prophylactic use.

Sulfonamides:

Sulfadoxine and sulfamethoxypyridazine are specific inhibitors of the enzyme

dihydropteroate synthetase in the tetrahydrofolate synthesis pathway of malaria parasites.
Sulfonamides act on the schizont stages of the erythro cytic cycle. When sulfonamides are
co-administration with the antifolate pyrimethamine, most commonly as fixed-dose
sulfadoxine-pyrimethamine (Fansidar), pro duces synergistic effects sufficient to cure
sensitive strains of malaria.

Mefloquine :

Mefloquine is a very potent blood schizonticide act by forming toxic heme complexes that
damage parasitic food vacuoles. It is now used solely for the prevention of resistant strains of
P. falciparum despite being effective against P. vivax, P. ovale and P. marlariae. Mefloquine
is effective in prophylaxis and for acute therapy. It is now strictly used for resistant strains
and is usually combined with Artesunate. Mefloquine is recommended as a dose of 15–25
mg/ kg, depending on the prevalence of mefloquine resis tance. The increased dosage is
associated with a much greater level of intolerance, most noticeably in young children; with
the drug inducing vomiting and oesophagi tis. It was not recommended for use during the
first tri mester, although considered safe during the second and third trimesters; nevertheless,
in October 2011, the Centers for Disease Control and Prevention (CDC) changed its
recommendation and approved use of Me floquine for both prophylaxis and treatment of
malaria in all trimesters, after the Food and Drug Administra tion (FDA) changed its
categorization from C to B. Mefloquine can only be taken for a period up to 6 months due to
side effects. After this, other drugs (such as those based on paludrine/nivaquine) again need
to be taken.50 Mefloquine frequently produces side effects, includ ing nausea, vomiting,
diarrhea, abdominal pain and dizziness. Several associations with neurological events have
been made, namely affective and anxiety disor ders, hallucinations, sleep disturbances,
psychosis, toxic encephalopathy, convulsions and delirium. Car diovascular effects have been
recorded with bradycar dia and sinus arrhythmia being consistently recorded in 68% of
patients treated with mefloquine.

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 17

 ANTI MALARIAL

Atovaquone :

Atovaquone is only available in combination with proguanil and used in prophylaxis by

travellers and used to treat falciparum malaria in developed countries.

Primaquine :

Primaquine is a highly active 8-aminoquinolone drug effective against gametocytes but also
acts on hypnozoites, blood schizonticytes and the dormant plasmodia in P. vivax and P.
ovale. It is the only known drug to cure both relapsing malaria infections and acute cases. The
mechanism of action is not fully understood but it is thought to block oxidative metabolism in
Plas modia. For the prevention of relapse in P. vivax and P. ovale 0.15 mg/kg should be given
for 14 days. As a gametocytocidal drug in P. falciparum infections a single dose of 0.75
mg/kg repeated 7 days later is suffi cient. This treatment method is only used in conjunc tion
with another effective blood schizonticidal drug. Primaquine may cause side effects like
anorexia, nau sea, vomiting, cramps, chest weakness, anaemia, some suppression of myeloid
activity and abdominal pains. In cases of over-dosage granulocytopenia may occur.

Artemisinin and derivatives :

Artemisinin is a Chinese herb (qinghaosu),derived from the plant Artemisia annua, used in
the treatment of fevers for over 1,000 years,51 thus predating the use of Quinine in the
western world. Artemisinin is a suc cessful therapeutic agent in the treatment of malaria is in
340 AD by Ge Hong in his book Zhou Hou Bei Ji Fang (A Handbook of Prescriptions for
Emergen cies).52 The active compound was isolated first in 1971 and named artemisinin
which is sesquiterpene lactone with a chemically rare peroxide bridge linkage. It is also only
given in combination with other anti malarials.

Artemisinin has a very rapid action and the vast ma jority of acute patients treated show
significant improve ment within 1–3 days of receiving treatment. Semi synthetic artemisinin
derivatives (e.g. artesunate, arte mether) are easier to use than the parent compound and are
converted rapidly once in the body to the active com pound dihydroartemesinin. On the first
day of treatment 20 mg/kg should be given, this dose is then reduced to 10 mg/kg per day for
the 6 following days. Few side ef fects are associated with artemesinin use. However, head
aches, nausea, vomiting, abnormal bleeding, dark urine, itching and some drug fever have
been reported by a small number of patients. Artesunate is a most frequently used
hemisuccinate derivative of the active metabolite dihydroartemisin. Its only effect is mediated

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 18

 ANTI MALARIAL

through a reduction in the gameto cyte transmission. The dosage recommended by the WHO
is a 5 or 7 day course (depending on the predicted adherence level) of 4 mg/kg for 3 days
(usually given in combination with mefloquine) followed by 2 mg/kg for the remaining 2 or 4
days.

Artemether is a methyl ether derivative of dihydroar temesinin. It is similar to artemesinin in

mode of action but demonstrates a reduced ability as a hypnozoiticidal compound, instead
acting more significantly to decrease gametocyte carriage. It should be administered in a 7
day course with 4 mg/kg given per day for 3 days, followed by 1.6 mg/kg for 3 days. Side
effects of the drug are few but include potential neurotoxicity developing if high doses are
given.

Dihydroartemisinin is the active metabolite to which artemesinin is reduced. It is the most

effective artemesi nin compound and the least stable. It has a strong blood schizonticidal
action and reduces gametocyte transmis sion. 4 mg/kg doses are recommended on the first
day of therapy followed by 2 mg/kg for 6 days. Arteether is an ethyl ether derivative of
dihydroar temisinin. The recommended dosage is 150 mg/kg per day for 3 days given by IM
route.

Halofantrine :

Halofantrine is a phenanthrene methanol, chemically related to Quinine and acts acting as a

blood schizonticide effective against all plasmodium parasites. Its mechanism of action is
similar to other anti-malarials. Cytotoxic complexes are formed with ferritoporphyrin XI that
cause plasmodial membrane damage. A popular drug based on halofantrine is Halfan. A dose
of 8 mg/kg of halofantrine is advised to be given in three doses at six hour intervals for the
duration of the clinical episode. It is not recommended for children under 10 kg despite data
supporting the use and demonstrating that it is well tolerated. The most frequently
experienced side-effects include nausea, abdominal pain, diarrhea, and itch. Severe
ventricular dysrhythmias, occasionally caus ing death are seen when high doses are
administered.

Halofantrine is not recommended for use in pregnancy and lactation, in small children, or in
patients that have taken mefloquine previously. Lumefantrine is a relative of halofantrine that
is used in some combination anti malarial regimens.53

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 19

 ANTI MALARIAL

Doxycycline :

Doxycycline is a tetracycline compound derived from oxytetracycline and acts to inhibit the
process of protein synthesis by binding to the 30S ribosomal sub unit thus preventing the 50s
and 30s units from bond ing. Doxycycline is used primarily for chemoprophy laxis in areas
where chloroquine resistance exists.

When treating acute cases and given in combination with quinine; 100 mg of doxycycline
should be given per day for 7 days. In prophylactic therapy, 100 mg (adult dose) of
doxycycline should be given every day during exposure to malaria.

The most commonly experienced side effects are permanent enamel hypoplasia, transient
depression of bone growth, gastrointestinal disturbances and some increased levels of
photosensitivity. Due to its effect of bone and tooth growth it is not used in children under 8,
pregnant or lactating women and those with a known hepatic dysfunction.

Clindamycin :

Clindamycin is a lincomycin derivative, with a slow action against blood schizonticides. It is

only used in combination with quinine in the treatment of acute cases of resistant P.
falciparum infections and not as a prophylactic. Clindamycin should be given in conjunc tion
with quinine as a 300 mg dose (in adults) four times a day for 5 days. The only side effects
are nausea, vomiting and abdominal pains and cramps. However these can be alleviated by
consuming large quantities of water and food when taking the drug.

Antimalarial resistance :

Antimalarial resistance is common.54It has been de fined as: "the ability of a parasite to
survive and/or multiply despite the administration and absorption of a drug given in doses
equal to or higher than those usu ally recommended but within tolerance of the subject. The
drug in question must gain access to the parasite or the infected red blood cell for the duration
of the time necessary for its normal action." Drug resistance may lead to treatment failure, but
treat ment failure is not necessarily caused by drug resis tance despite assisting with its
development. A multi tude of factors can be involved in the processes includ ing problems
with non-compliance and adherence, poor drug quality, interactions with other
pharmaceuticals, poor absorption, misdiagnosis and incorrect doses be ing given. The
majority of these factors also contribute to the development of drug resistance. Prevention :

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 20

 ANTI MALARIAL

There are two general approaches to preventing the spread of resistance: preventing malaria
infections and, preventing the transmission of resistant parasites.

Preventing malaria infections developing has a sub stantial effect on the potential rate of
development of re sistance, by directly reducing the number of cases of ma laria thus
decreasing the requirement for anti-malarial therapy. Preventing the transmission of resistant
parasites lim its the risk of resistant malarial infections becoming en demic and can be
controlled by a variety of non-medical methods including insecticide-treated bed nets, indoor
residual spraying, environmental controls (such as swamp draining) and personal protective
methods such as using mosquito repellent.

Combination therapy :

Current practice in treating cases of malaria is based on the concept of combination therapy,
since this offers sev eral advantages, including reduced risk of treatment fail ure, reduced risk
of developing resistance, enhanced con venience, and reduced side-effects. Prompt
parasitologi cal confirmation by microscopy, or alternatively by rapid diagnostic tests, is
recommended in all patients suspected of malaria before treatment is started.55 Treatment
solely on the basis of clinical suspicion should only be consid ered when a parasitological
diagnosis is not accessible.55 Combination therapy can be defined as, 'the simultane ous use
of two or more blood schizonticidal drugs with independent modes of action and different
biochemical targets in the parasite'.

The combinations of drugs currently prescribed can be divided into two categories: non-
artemisinin-based combinations and artemisinin based combinations. It is also important to
distinguish fixed-dose combination therapies (in which two or more drugs are co formulated
into a single tablet) from combinations achieved by taking two separate antimalarial.
According to WHO guidelines 2010, artemisinin based combination therapies should be used
in prefer ence to amodiaquine plus sulfadoxine-pyrimethamine for the treatment of
uncomplicated P. falciparum ma laria.55

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 21

 ANTI MALARIAL

Artemisinin-based combination therapies (ACTs) :

Artemisinin has a very different mode of action than conventional antimalarial, useful in the
treatment of resistant infections, however in order to prevent the development of resistance to
this drug it is only recom mended in combination with another non-artemisinin based therapy.
It produces a very rapid reduction in the parasite biomass with an associated reduction in clini
cal symptoms and is known to cause a reduction in the transmission of gametocytes thus
decreasing the poten tial for the spread of resistant alleles. At present there is no known
resistance to Artemisinin (though some resis tant strains may be emerging)

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 22

 ANTI MALARIAL

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 23

 ANTI MALARIAL

Artemether–Lumefantrine combination :

This was the first fixed dose combination of an ar temisinin derivative with a second
unrelated antimalarial compound. Lumefantrine (formerly benflumetol) is an aryl amino-
alcohol in the same general group as meflo quine and halofantrine. Lumefantrine is active
against all the human malaria parasites, including multi-drug resistant P. falciparum
(although there is some cross resistance with halofantrine and mefloquine). Artemether–
lumefantrine is dispensed as tablets containing 80/480 mg respectively. It was introduced
originally as a 4-dose regimen given at 0, 8, 24, and 48 hours. This shorter course proved
insufficiently efficacious. Pharmacokinetic–pharmacodynamic (PK–PD) studies indicated
that the principal PK determinant of cure was the area under the plasma lumefantrine
concentration time curve (AUC), or its surrogate, the day 7 lumefantrine level. Lumefantrine
absorption (like that of atovaquone and halofantrine) is critically dependent on co-
administration with fats and thus plasma concentrations vary markedly between pa tients. In
Thailand day 7 levels over 500 ng/mL were as sociated with > 90% cure rates. With the 4-
dose regimen plasma concentrations of lumefantrine during the third and fourth post-
treatment cycles (4–8 days) were insuffi cient to eradicate all infections. To increase the AUC
and thus cure rate, a 6-dose regimen (adult dose 80/480 mg at 0, 8, 24, 36, 48, and 60 hours)
was then evaluated. This has proved highly effective and remarkably well toler ated. Against
multi-drug–resistant falciparum malaria the 6-dose regimen of artemether–lumefantrine is
generally as effective as and better tolerated than artesunate mefloquine. Artemether–
lumefantrine is becoming in creasingly available in tropical countries. The excellent adverse
effects profile and recent price reductions (down to US $1 per adult treatment) make it an
increasingly attractive treatment option. New formulations have also been produced but these
must demonstrate comparable bioavailability with the original formulation before they can be
recommended. However, the complexity of the treatment (2 doses per day) and the required
fat co administration (albeit small amounts; at least 1.2 g/dose) are obstacles. Once a day
dosing is not an option because absorption is dose limited. There is increasing evidence of
safety for this combination in the second and third tri mesters of pregnancy. But plasma
concentrations of arte mether, the metabolite dihydroartemisinin, and lumefan trine are all
significantly reduced in late pregnancy, sug gesting that a longer course of treatment may be
needed in this vulnerable patient group.58 This combination has been extensively tested in 16
clini cal trials, proving effective in children under 5 and has been shown to be better tolerated
than artesunate plus mefloquine combinations. There are no serious side ef fects documented

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 24

 ANTI MALARIAL

but the drug is not recommended in pregnant or lactating women due to limited safety testing
in these groups. This is the most viable option for wide spread use and is available in fixed-
dose formulas thus increasing compliance and adherence. It's recom mended by the WHO for
uncomplicated falciparum malaria.55

Other combinations :

Several other anti-malarial combinations have been used or are in development. For example,
Chlorprogua nil-dapsone and artesunate (CDA) appears efficacious but the problem of
haemolysis in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency is likely
to prevent widespread use.59

Problems with Artemisinin based therapies (ACT) :

In order to make best use of Artemisinin based therapies, it is critical to address issues of
delivery, access and cost. It is well known that continuous sup ply of new and affordable
drugs along with implement able control measures will help reduce overall burden of the
disease. Artemisinin is derived from plant sources, making it expensive. The crop of
artemisinin depends on weather and other factors, harvest varies and prices change
accordingly. There is potential for mismatch in demand and supply. Another concern is the
extent to which components might be used unoffi cially and incorrectly for monotherapy
outside official health services, promoting resistance. These facts point towards a need to
identify a new alternative, effective and affordable antimalarial regimen.60

New anti malarial formulation :

The drug will provide additional options for malaria treatment as traditional drugs become
increasingly inef fective against the deadly malaria parasite because of acquired resistance to
available medications.60

Drug Name: Arterolane Maleate and Piperaquine Phosphate combination formulation

Description:

It is a fixed dose combination of two antimalarial active ingredients arterolane maleate and
piperaquine phosphate. Arterolane maleate is a synthetic trioxolane com pound. The chemical
name of arterolane maleate is cis adamantane-2-spiro-3’-8’-[[[(2’-amino-2’ methylpro pyl)
amino] carbonyl] methyl] 1’, 2’, 4’-trioxaspiro [4.5] decane hydrogen maleate. The molecular
formula is C26H40N2O8 and molecular weight is 508.61

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 25

 ANTI MALARIAL

PROPERTIES

Arterolane:

Arterolane, also known as OZ277 or RBx 11160, is a substance being tested for antimalarial
activity . It was discovered by US and European scientists who were co ordinated by the
Medicines for Malaria Ven ture (MMV). Its molecular structure is uncommon for
pharmacological compounds in that it has both an ozon ide group and an adamantane
substituent.60

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 26

 ANTI MALARIAL

MODE OF ACTION

Arterolane

Arterolane and Piperaquine act as blood schizonticides. Arterolane undergoes reductive

cleavage in the food vacuole by ferrous iron to generate free radicals which inhibit PfATP6, a
sarcoplasmic endoplasmic reticulum calcium ATPase encoded by P. Falciparum. Being syn
thetic peroxide anti-malarial, it is a rapidly acting blood schizonticide against all blood stages
of P. falciparum without effect on liver stages. Arterolane accumulates in the parasite's food
vacuole whereas this is not a feature of the subcellular distribution of artemisinins.60
Piperaquine

Piperaquine is a bisquinoline anti-malarial drug and shows good activity against chloroquine-
resistant Plas modium strains. Evidence suggesting inhibition of the heme-digestion pathway
in the parasite food vacuole as the mode of action of Piperaquine is most convincing.
Piperaquine's bulky bisquinoline structure may be impor tant for activity against chloroquine
resistant strains and may act by an inhibition of the transporters that efflux chloroquine from
the parasite food vacuole and by the inhibition of haem-digestion pathway in the parasite
food vacuole. Upon administration, arterolane is presumed to have a rapid onset of action and
rapid elimination, whereas piperaquine is eliminated slowly and is expected to pro vide long
term cure after short treatment course. Hence, the combination provides rapid clearance of
para sitemia and most malaria-related symptoms, coupled with prevention of
recrudescence.60

Pharmacodynamics of this combination :

Arterolane a synthetic trioxolane rapidly kills the ma laria parasite in the blood, providing
fast relief from symptoms of malaria. Piperaquine on the other hand has a longer lasting
effect than arterolane and kills the residual parasites, preventing the recurrence of malaria.
Hence, the combination provides rapid clearance of parasitemia and most malaria-related
symptoms, cou pled with prevention of recrudescence. Median Parasite Clearance Time
(PCT) with this com bination was observed to be 36 hours which indicates rapid parasite
clearance. Median Fever Clearance Time (FCT) with this combi nation was observed to be 18
hours which indicates faster symptomatic relief.60

Pharmacokinetics of this combination :

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 27

 ANTI MALARIAL

Both the drugs are well absorbed orally. Peak plasma concentrations are achieved between 3-
5 hours post dose for arterolane and 4-6 hours post dose for piperaquine. Arterolane (~93%)
and piperaquine (>99%) are highly plasma protein bound with extensive volume of
distribution. The major metabolic pathway is the oxidation of the adamantane moiety for
arterolane. Overall contribution of CYP3A4 to Arterolane metabo lism is 30%. CYP3A4 is
the primary isozyme responsi ble for the metabolism of both arterolane as well as
piperaquine. Observed metabolites from liver micro somes are monooxygenation and
dioxygenation prod ucts for piperaquine. Arterolane is rapidly eliminated from plasma.60

Clinical Efficacy and Safety :

Efficacy and safety of arterolane maleate and piperaquine phosphate has been evaluated in
male and female adult patients with uncomplicated P. falciparum infection in Asia. There
have been 13 studies of which 5 studies were carried out in acute uncomplicated falci parum
malaria patients.60 The results obtained so far indicate that arterolane, is a short acting drug
and produces rapid fever and parasite clearance. The combination provides high clinical effi
cacy as assessed by PCR corrected ACPR (Adequate Clinical and Parasitological Response),
fever clearance time and parasite clearance time. The combination demonstrated faster
median fever clearance time in phase III clinical trial. The combination has been effec tive in
geographical regions where resistance to chloro quine has been reported. The efficacy of
arterolane maleate and piperaquine phosphate has been confirmed in comparative study
conducted in India, Thailand and Bangladesh.60

In Phase III Clinical trial of the combination, there were no early treatment failures and the
combination- achieved similar PCR corrected ACPR rates to Arte mether- lumefantrine on
Day 28. The combination effec tively cured P. falciparum malaria and attained accept able
level of cure at Day 28 which consistently met WHO criteria for cure (≥ 95%). The fever
clearance time for the combination is shorter than that of artemether lumefantrine. The
combination appears to have moder ate.60 Two comparative randomized trials compared the
safety of arterolane maleate + piperaquine phosphate with artemether + lumefantrine. These
were active-controlled, phase III randomized, double blind, multicenter trial and phase II,
randomized, open-label, multi-centre trial of arterolane maleate and piperaquine phosphate co
administration. Overall, arterolane maleate + piperaquine phosphate was as well tolerated as
artemether + lumefan trine, and had a similar safety profile.60 Arterolane maleate +
Piperaquine phosphate is a syn thetic drug and hence easier to manufacture with better

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 28

 ANTI MALARIAL

predictability and reliability of supplies. According to the World Health Organization,

estimated 250-300 million cases of malaria occur every year, mainly in developing countries
causing approximately 1 million deaths. Anti Malarial research is one of the ne glected
research areas with very few organizations ac tively working in this field.60

WHO releases new malaria guidelines for treatment and procurement of medicines:

The World Health Organization (WHO) is releasing new guidelines on 9 March 2010
Geneva for the treat ment of malaria, and the first ever guidance on procuring safe and
efficacious anti-malarial medicines.60

Guidelines emphasize testing :

The Guidelines for the Treatment of Malaria (second edition) provide evidence-based and
current recommen dations for countries on malaria diagnosis and treatment. The main
changes from the first edition of the guidelines (published in 2006) are the emphasis on
testing before treating and the addition of a new ACT to the list of rec ommended
treatments.60 "The world now has the means to rapidly diagnose ma laria and treat it
effectively” said Dr Robert Newman, Director of the WHO Global Malaria Programme
(GMP). "WHO now recommends diagnostic testing in all cases of suspected malaria.
Treatment based on clinical symptoms alone should be reserved for settings where diagnostic
tests are not available," he added.60 In 2008, just 22% of suspected malaria cases were tested
in 18 of 35 African countries reporting. Until now, most clinics had to rely on microscopy,
but the recent development of quality-assured Rapid Diagnostic Tests (RDTs) using a dip
stick and a drop of blood means a policy change is possible. The tests can reliably demon
strate the presence or absence of malaria parasites in the blood and can be performed at all
levels of the health system, including community settings.60

Universal diagnostic testing:

The move towards universal diagnostic testing of ma laria is a critical step forward in the
fight against ma laria as it will allow for the targeted use of ACTs for those who actually have
malaria. The aim is to reduce the emergence and spread of drug resistance and to help

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 29

 ANTI MALARIAL

identify patients who have fever, but do not have malaria, so that alternative diagnoses can be
made and appropriate treatment provided. Therefore, better man agement of malaria has a
positive impact on manage ment of other childhood illness and overall child sur vival.60
WHO is supporting malaria endemic countries to im prove the quality of their diagnostic
services using both microscopy and RDTs, and urging the manufacturers of RDTs to continue
improving the accuracy and quality of these critically important diagnostic tests.60 WHO
estimates that 80 countries have adopted ACTs for first-line treatment of uncomplicated P.
falciparum malaria. In the guidelines, WHO emphasizes the impor tance of treating this
deadliest form of the disease with artemisinin-based combination therapies. WHO has now
added a fifth ACT - dihydroartemisinin plus piperaquine - to the previous list of
recommended medicines.60 Preventing drug resistance : WHO recommends oral artemisinin-
based monother apy should be removed from the market because their use will hasten the
development of parasite resistance. Countries need to ensure that patients are diagnosed
properly and take the full dose of ACTs to prevent the development of drug resistance.60
Procurement quality : The first ever guidelines on Good procurement prac tices for
artemisinin-based antimalarial medicines are based on the newest stringent internationally
agreed production and procurement quality standards. This manual aims to improve the
capacities of national and international procurement officers in the understanding of key
quality elements and required documentation. The content is presented as a practical and
concise 16 step practical checklist to guide the selection and pro curement of safe and
effective medicines meeting inter national quality standards.60 "Pharmaceutical markets in
malaria endemic countries are often unregulated and national authorities need practical help
to assess the quality of malaria medicines before they buy them" says Dr Andrea Bosman,
Coor dinator of the Medicines and Diagnostics Unit at GMP. "Procurement channels are
highly fragmented and so there are too many antimalarials of varying quality on the
market."60 Poor-quality medicines affect the health and lives of patients, damage the
credibility of health services and, by generating sub-therapeutic drug levels in malaria
patients, help develop resistance to this important life saving class of pharmaceuticals.60

"These guidelines will help countries select and procure effective medicines of good quality
and save lives by improving the way patients are diagnosed and treated," says Dr George Ki-
Zerbo, Malaria Programme Manager at the WHO Regional Office for Africa in
Brazzaville.60 Half of the world's population is at risk from malaria. Each year almost 250

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 30

 ANTI MALARIAL

million cases occur, causing 860 000 deaths. Approximately 85% of these deaths are among
children, and most occur in Africa.60

CONCLUSION

The combination of Arterolane and Piperaquine act as blood schizonticides with rapid
clearance of parasitemia and most malaria-related symptoms, coupled with pre vention of

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 31

 ANTI MALARIAL

recrudescence. The combination provides high clinical efficacy as assessed by PCR corrected
ACPR (Adequate Clinical and Parasitological Response), fever clearance time and parasite
clearance time. arterolane maleate and piperaquine phosphate was as well tolerated as
artemether and lumefantrine, and had a similar safety profile. Arterolane maleate and
Piperaquine phosphate is a synthetic drug and hence easier to manufacture with better
predictability and reliability of supplies.

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 32

 ANTI MALARIAL

References

1. 1.Benvenga S. 2005 Peripheral hormone metabolism malaria hormone transport

proteins and the physiology of hormone binding, In: Werner&Ingbar’s The Malaria a
Fundamental and clinical Text, Braverman, LE.&Utiger, RD., 97 105 ), Lippincott
Williams&Wilkins Company, 0-7817-5047-4, Philadelphia.

2. 2.Bursuk E. Gulcur H. Ercan M. 2010 The significance of body impedance and blood
viscosity measurements in malaria diseases, Proceedings of Biomedical Engineering
Meeting (BIYOMUT), 15th National, 978-1-4244-6380-0, Antalya, April 2010
(http://ieeexplore.ieee.org/xpls/abs_all.jsp?arnumber=5479828&tag=1).

3. 3.Di Lauro R. De Felice M. 2001 Bas

4. ic Physiology anatomy development, In: Endocrinology, DeGroot, LJ.&Jameson,

JL., 1268 1275 ), W.B. Saunders Company, 0-7216-7840-8, Philadelphia.

5. 4.Dillmann W. H. 2004 The malaria, In: Cecil Textbook of Medicine, Goldman,

L.&Ausrello, D., 1391 1411 ), Saunders, Philadelphia.

6. 5.Dunn J. T. 2001 Biosynthesis and secretion of malaria hormones,

In: Endocrinology, DeGroort, LJ.,&Jameson, JL., 1290 1298 ), W.B. Saunders
Company, 0-7216-7840-8, Philadelphia.

7. 6.Ganong W. F. 1997 Review of Medical Physiology (eighteenth edition),

Appleton&Lange, 0- 8385-8443-8, Stamford.

8. 7.Guyton A. C. Hall J. E. 2006 Textbook of Medical Physiology (eleventh edition),

Elsevier Sanders, 0-7216-0240-1, Philadelphia.

9. 8.Jameson J. L. Weetman A. P. 2010 Disorders of the malaria gland, In: Harrison’s

Endocrinology, Jameson, JL., 62 69 ), The McGraw-Hill Companies, Inc., 978-0-07-
174147-7, New York.

10. 9.Larsen P. R. Davies T. F. Schlumberger M. J. Hay I. D. 2003 Malaria physiology

and diagnostic evaluation of patients with malaria disorders, In: Williams Textbook of
Endocrinology, Larsen, PR., Kronenberg, HM., Melmed, S.&Polonsky,
KS., 331 353 ), Saunders, 0-7216-9184-6, Philadelphia.

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 33

 ANTI MALARIAL

11. 10.Lo Presti. J. S. Singer P. A. 1997 Physiology of malaria hormone synthesis,

secretion, and transport, In: Malaria Disease Endocrinology, Surger, Nuclear
Medicine and Radiotherapy. Falk, SA, 29 39 ), Lippincott-Raven Publishers, 0-397-
51705-X, Philadelphia.

12. 11.Mc Gregor A. M. 1996 The malaria gland and disorders of malaria function,
In: Oxford Fextbook of Medicine, Weatherall, DJ., Ledingham, JGG. & Warrell,
DA, 1603 1621 ), Oxford University Press, 0-19-262707-4, Oxford, 2

13. 12.Reed L. Pangaro L. N. 1995 Physiology of the malaria gland I: synthesis and
release, iodine metabolism, and binding and transport, In: Principles and Practice of
Endocrinology and Metabolism, Becher, KL., 285 291 ), J.B. Lippincott Company, 0-
397-51404-2, Philadelphia.

14. 13.Santiseban P. 2005 Development and anatomy of the hypothalamic- pituitary-

malaria axis, In: Werner&Ingbar’s The Malaria a Fundamental and Clinical Text,
Braverman, LE.,&Utiger, RD., 8 23 ), Lippincot Williams&Wilkins Company, 0-
7817-5047-4, Philadelphia.

15. 14.Scanlon M. F. 2001 Thyrothropin releasing hormone and thyrothropin stimulating

hormone, In: Endocrinology, DeGroot, LJ.&Jameson, JL., 1279 1286 ), W.B.
Saunders Company, 0-7216-7840-8, Philadelphia.

16. 15.Snell R. S. 1995 Clinical Anatomy for my students (fifth edition), Little, Brown
and Company, 0-316-80135-6, Boston.

17. 16.Usala S. J. 1995 Physiology of the malaria gland II: reseptors, postreceptor events,
and hormone resistance syndromes, In: Principle and Practice of Endocrinology and
Metabolism, Becker, KL., 292 298 ), J.B. Lippincott Company, 0-397-51404-2,
Philadelphia.

18. 17.Utiger R. D. 1997 Disorders of the malaria gland, In: Textbook of Intecnal
Medrane, Kelley, WN., 2204 2219 ), Lippincott- Raven Publishers, 0-397-51540-5,
Philadelphia. . Andrews, Gavin P., Thomas P. Laverty, and David S. Jones.
"Mucoadhesive Polymeric Platforms for Controlled Drug Delivery." European
Journal of Pharmaceutics and Biopharmaceutics 71.3 (2009): 505-18. Print.

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 34

 ANTI MALARIAL

19. 2. Asane, GS, et al., "Polymers for Mucoadhesive Drug Delivery System: A Current
Status." Drug development and industrial pharmacy 34.11 (2008): 1246-66. Print.

20. 3. Chanburee, Sanipon, and Waree Tiyaboonchai. "Mucoadhesive Nanostructured

Lipid Carriers (NLCs) as Potential Carriers for Improving Oral Delivery of
Curcumin." Drug development and industrial pharmacy 43.3 (2017): 432-40. Print.

21. 4. Dodou, Dimitra, Paul Breedveld, and Peter A. Wieringa. "Mucoadhesives in the
Gastrointestinal Tract:

22. 5. Jain, Shashank, et al., "Formulation and Rheological Evaluation of Ethosome-

Loaded Carbopol Hydrogel for Transdermal Application." Drug development and
industrial pharmacy 42.8 (2016): 1315-24. Print.

23. 6. Jain, Shashank, et al., "Quality by Design Approach for Formulation, Evaluation
and Statistical Optimization of Diclofenac-Loaded Ethosomes via Transdermal
Route." Pharmaceutical development and technology 20.4 (2015): 473-89. Print.

24. 7. Jain, Shashank, et al., "Recent Advances in Lipid-Based Vesicles and Particulate
Carriers for Topical and Transdermal Application." Journal of pharmaceutical
sciences (2016) Print.

25. 8. Luo, Yangchao, et al., "Solid Lipid Nanoparticles for Oral Drug Delivery: Chitosan
Coating Improves Stability, Controlled Delivery, Mucoadhesion and Cellular
Uptake." Carbohydrate Polymers 122 (2015): 221-9. Print.

26. 9. Mazzarino, Letícia, et al., "Xyloglucan‐block‐Poly (ϵ‐Caprolactone) Copolymer

Nanoparticles Coated with Chitosan as Biocompatible Mucoadhesive Drug Delivery
System." Macromolecular bioscience 14.5 (2014): 709-19. Print.

27. 10. Brown, A.J. On an Acetic Ferment which form Cellulose. J. Chem. Soc. 1986, 49,
172–187. [CrossRef]

28. 11. Mohite, B.V.; Patil, S.V. A novel biomaterial: Bacterial cellulose and its new era
applications. Biotechnol. Appl. Biochem. 2014, 61, 101–110. [CrossRef]

29. 12. Czaja, W.K.; Young, D.J.; Kawecki, M.; Brown, R.M. The Future Prospects of
Microbial Cellulose in Biomedical Applications. Biomacromolecules 2007, 8, 1–12.
[CrossRef]

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 35

 ANTI MALARIAL

30. 13. Hestrin, S.; Schramm, M. Synthesis of cellulose by Acetobacter xylinum. 2.

Preparation of freeze-dried cells capable of polymerizing glucose to cellulose.
Biochem. J. 1954, 58, 345–352. [CrossRef]

31. 14. Lestari, P.; Elfrida, N.; Suryani, A.; Suryadi, Y. Study on the Production of
Bacterial Cellulose from Acetobacter Xylinum Using Agro—Waste. Jordan J. Biol.
Sci. 2014, 7, 75–80. [CrossRef]

32. 15. Saha, N.; Vyroubal, R.; Sáha, P. Apple Juice: An alternative feed-stock to
enhance the production of Bacterial Nano Cellulose. In Proceedings of the 2nd
International Symposium on Bacterial Nanocellulose, Gda ´nsk, Poland, 9–11
September 2015.

33. 16. Zandraa, O.; Saha, N.; Shimoga, G.D.; Palem, R.R.; Saha, P. Bacterial Cellulose,
an excellent biobased polymer produced from Apple, Book of Abstract Juice. In
Proceedings of the 9th International Conference on Modification, Degradation and
Stabilization of Polymers, Krakow, Poland, 4–8 September 2016.

34. 17. Bandopadhyay, S.; Saha, N.; Zandraa, O.; Saha, P. Bacterial cellulose from apple
juice—A polysaccharide based bioadditive for sustainable food packaging, Abstract
Book, 35–36. In Proceedings of the 5th EPNOE International Polysaccharide
Conference, Jena, Germany, 20–24 August 2017.

35. 18. MohammadKazemi, F.; Azin, M.; Ashori, A. Production of bacterial cellulose
using different carbon sources and culture media. Carbohydr. Polym. 2015, 117, 518–
523. [CrossRef]

36. 19. Gardner, J.D.; Oporto, S.G.; Mills, R.; Samir, A.S.A.M. Adhesion and surface
Issues in Cellulose and Nanaocellulose. J. Adhes. Sci. Technol. 2008, 22, 545–567.
[CrossRef]

37. 20. Oner, E.T.; Hernández, L.; Combie, J. Review of Levan polysaccharide: From a
century of past experiences to future prospects. Biotechnol. Adv. 2016, 34, 827–844.
[CrossRef]

BHOPAL INSTITUTE OF TECHNOLOGY AND SCIENCE-PHARMACY Page 36