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Page
1

ANTIMALARIAL THERAPY

Presented By:


Payal

Mondal


Priyadarshini
. K.


Prachi

Gaikwad


Pratik

Gada


Parvez

Shaifi


CRANFIELD BATCH No.8

Page
2

CONTENTS


INTRODUCTION


VECTORS


LIFECYCLE OF PLASMODIUM


SIGNS AND SYMPTOMS


DIAGNOSIS


ANTIMALARIAL THERAPY


RECENT ADVANCES


CASE STUDY


CLINICAL TRIAL OF ANTI
MALARIAL DRUG

Page
3





Malaria has been known since time
immemorial, but previously it was
thought that "miasma" (bad air or gas
from swamps
-

"mal air
ia
") caused the
disease.



Systematic control of malaria started after
the discovery malaria parasite by
Laveran in 1889 (for which he received
the Nobel Prize for medicine in 1907)



The demonstration by Ross in 1897 that
the mosquito was the vector of malaria.



INTRODUCTION


Page
4

MALARIA



One of the most important infectious
diseases in world.


Caused by a parasite protozoan
called
Plasmodium
.



Four types:
-


Plasmodium
vivax



Plasmodium
ovale


Plasmodium
malariae


Plasmodium
falciparum


Plasmodium
knowlesi

is now
established as the fifth Plasmodium
species to cause malaria in humans

(seen in Thailand and Sweden)




electron micrograph
of

Plasmodium
falciparum

Page
5

Page
6

VECTORS





The parasite's primary (definitive)
hosts and transmission vectors are
female mosquitoes of the
Anopheles

genus, while humans and other
vertebrates are secondary hosts.



Plasmodium

falciparum
, a species
most likely to be transmitted by the
mosquito
Anopheles

gambiae
.



A.
gambiae

complex is the chief
vector in Africa and
A.
freeborni

in N.
America.


Page
7

LIFECYCLE OF
PLASMODIUM

Page
8


Page
9

SIGNS AND SYMPTOMS




Depends on :


the
parasitemia
,


the presence of the organism in different
organs



the parasite burden


incubation period varies generally
between 10
-
30 days


headache, vague pains in the bones and
joints, chilly sensations and fever.


chill and fever follow a cyclic pattern
(paroxysm)


paroxysm is due to the rupture of
infected erythrocytes and release of
parasites.




patient experiences
euphoria, and
profuse perspiration
and the temperature
begins to drop.

Fever is associated
with severe
headache, nausea
(vomiting) and
convulsions

the body
temperature begins
to climb and reaches
103
-
106 degrees F
(39
-

41degrees C)..

chilly sensation that
progresses to teeth
chattering, overtly
shaking chill and
peripheral
vasoconstriction
resulting in cyanotic
lips and nails

cold stage

for about an hour

PAROXYSM

Page
11


CLASSIFICATION

OF MALARIA

According to severity of illness, malaria can be broadly classified into two types
-


Uncomplicated (Benign)

and

Complicated (Malignant
).

UNCOMPLICATED MALARIA


R敬慴楶敬y mil摥r 摩獥s獥


G敮敲慬ly 捡c獥s 批 P. viv慸


S敬摯m f慴慬


T桥 捨c湣n 潦 i湶潬v敭敮e 潦 潴桥o 潲o慮猠(捯浰ci捡瑩c湳⤠i猠m畣u l敳献


Al獯⁲敦敲e敤 t漠慳aU湣nm灬i捡瑥搠M慬慲楡.

COMPLICATED MALARIA


S敶敲e


R慰i搠摯w湨ill 捯cr獥


C慵獥s m慩湬y 批 P. f慬捩灡r畭u慮搠r慲敬y 批 P. viv慸.


P潯r 灲潧湯獩猠(潵t捯浥c


N潷慤慹猠"獥s敲攠m慬慲楡" 潲o"捯浰ci捡瑥搠m慬慲楡" 慲攠畳u搠m潲攠fr敱略湴ly t漠摥獣si扥 t桩猠ty灥 潦 m慬慲楡

Page
12

DIAGNOSIS


Diagnosis is based on
symptoms and detection of
parasite in
Giemsa

stained
blood smears


CBC


Electrolytes



"Think Mosquito bite"

DIAGNOSIS


Plasmodium
falciparum

ring
trophs

in a single
red blood cell from a human blood smear.

Note the size of the infected cell RBC
compared with the uninfected RBC.

Page
14

NEWER DIAGNOSTIC
TECHNIQUES

Page
15

Objectives & Use of
Antimalarials


To prevent and treat clinical attack of malaria.


To completely eradicate the parasite from the patients
body.


To reduce the human reservoir of infection
-

cut down
transmission to mosquito.


ANTIMALARIAL THERAPY:



Causal prophylaxis (
Pre
-
erythrocytic

stage in liver
)


Suppressive prophylaxis(
Erythrocytic

phase
)


Clinical cure (
Erythrocytic

schizontocides

)


Radical Cure.(
Hypnozoites

+
Erythrocytic





schizonts
)


Suppressive Cure


Gametocidal
.

Page
16

Classification of
Antimalarial

drugs

1.
4
-
Aminoquinolines


Chloroquine

,
Amodiaquine
.

2.
Quinoline

methanol

Mefloquine
.

3.
Acridine


Mepacrine
.
(
Atarbrine,Quinacrine
)

4.
Cinchona alkaloid

Quinine.



5.
Biguanides


Proguanil
.


(
chloroguanide
)

6.
Diaminopyrimidines

Pyrimethamine
.

Page
17

7.
8
-
Aminoquinolines

Primaquine,


Bulaquine
.

8.
Sulfonamides &
sulfones

Sulfadoxine
,
Sulfamethopyrazine
,
Dapsone
.


9.
Tetracyclines


Tetracycline,
Doxycycline
.


10.
Sesquiterpine

lactones

Artesunate
,
Artemether

,
Arteether
.


11.
Phenanthrene

methanol

Halofantrine
.


12.
Naphthoquinone


Atovaquone
.

Page
18

Chloroquine


Rapidly acting
erythrocytic

schizonticide


Acts on all species of Plasmodium

MOA:


Actively concentrated by sensitive
intraerythrocytic

plasmodia: higher
concentration in infected RBC


increase vesicular pH


摥杲慤慴楯渠潦
Hb

by parasitic
lysosomes



䥮桩扩瑩潮o
潦⁣潮癥牳楯渠潦
桥he


桥h潺潩n

批b
景牭慴楯渠潦
䍨汯牯r畩n

桥he

捯c灬數e


damage of
plasmodial

membrane.



Quinine,
mefloquine
,
mepacrine

acts in
an same manner.

Page
19

Aritimisinin

derivatives


Active principle of plant
Artemisia
annua
.


Used in
chinese

traditional medicines.


Active against
P.
falciparum
.


Rapidly acting blood
schizontocide


MOA:


Endoperoxide

bridge in molecule
interacts with
heme

in parasite




捬c慶慧攠牥汥慳攠桩杨汹 晲敥f牡摩r慬a
獰散楥i


扩湤猠瑯t浥浢牡湥⁰牯瑥楮n
捡畳敳 汩灩搠
灥牯硩摡瑩潮
Ⱐ摡浡来g
endoplasmic reticulum, inhibit protein
synthesis and causes
lysis

of the
parasite.


Page
20

Adverse effects:


nausea, vomiting, itching,
abdominal pain, and drug
fever.


Abnormal bleeding, first
degree AV block, transient
reticulopenia

and leucopenia.


Drug interactions.

Uses:


Chloroquine

resistant malaria


Severe and complicated
malaria

Page
21

ARTIMISININ COMBINATION
THERAPY ( ACT)


Artesunate
-
mefloquine


Artesunate

-
sulfadoxine
-
pyrimethamine


Artesunate

-
amodiaquine


Artesunate

-
chloroquine


Artemether
-
lumefantrine


Dihydroartemisinin
-
piperaquine


Page
22

THE MAIN CAUSE OF THE
RESURGENCE IS DRUG RESISTANCE
.



Rising
resistance to
antimalarial

drugs



Universal
Chloroquine

resistance to
Plasmodium
falciparum



Development of resistance not only
compromises the efficacy of existing
antimalarial

drugs but also threatens to pre
-
maturely terminate the useful therapeutic life
of new
antimalarial

drugs



Lack of effective, affordable and appropriate
treatment options


Page
23

CHALLENGES IN DEVELOPMENT OF
NEW TREATMENT FOR MALARIA




Between
1975 and 1999, only four of the
almost 1,400 new drugs developed
worldwide were
antimalarial
, and all were
at least in part the products of publicly
funded
research




Significant R & D
effort
and funding
required to develop new
treatments




Distribution of the treatment is difficult
due to the remoteness of the areas in
which the disease is most prevalent and
poor health systems in malaria endemic
countries


Page
24

RECENT ADVANCES

Malaria Drug Through Genetic
Engineering



Artemisinin

is the most effective treatment
for malaria and the best drug for treating
resistant forms




Artemisinin

is made from the sweet
wormwood plant found in China and
Vietnam.


But supplies of the plant are
limited. And it takes a lot of plant material to
get enough of the drug to treat one patient



Placed genes from the wormwood plant into
a yeast organism and got it to produce large
amounts of
artemisinic

acid.


This acid can
be made into the drug
artemisinin

in just a
few chemical steps.

Page
25

GENETICALLY MODIFIED
MOSQUITO


Mosquitoes genetically
engineered for malaria
resistance can outcompete
their wild counterparts



By producing a peptide called
SM1 that blocks
Plasmodium

from invading the mosquito's
gut, thus interrupting the
parasite's development. Since
it is not a naturally occurring
peptide, SM1 doesn't activate
the mosquito's immune system

Page
26

REVERSING ANTIMALARIAL
RESISTANCE


A malaria parasite gene called

pfcrt
”,
already confirmed as the culprit behind
resistance to the drug
chloroquine

in the
malaria species Plasmodium
falciparum
,
may be responsible for resistance to
several other
antimalarial

drugs



In
chloroquine
-
resistant malaria,
mutations in

pfcrt


may encourage
chloroquine

to "leak" out of the vacuole
before it has a chance to stop the
heme

detoxification process



By
modifyng

this gene resistance to
chloroquine

can be reversed

Page
27

VACCINES FOR MALARIA


Immunization with irradiated
sporozoite

will confer
protection against infection



Antigens can be used for
immunization in order to
create antibody against the
sporozoite
.

Page
28

Page
29

CASE STUDY


One Traveler's Ordeal with Severe Malaria


Mr.
Ver

Wys

suffered from malaria at Haiti


Neglected Anti malarial


Illness in Lake Charles


Diagnosis


Treatment



Malaria Visits a Child in Africa


Ramadhani

Shida

Mashaka
*

was only 8
months old when he got seriously ill


Home treatment


Seeking treatment outside the home


A happy ending

Page
30

CLINICAL TRIAL OF ANTI
MALARIAL DRUG

1.
Phase 1 Studies of AQ
-
13, a
Candidate
Aminoquinoline

Antimalarial
, in Comparison
With
Chloroquine
.

2.
Efficacy, Safety and
Pharmacokinetic of
Artequin

TM
P.
Falciparum

Malaria.

3.
Effectiveness of
Artemisinin

Combination Regimens in
Falciparum

Malaria (ACT).

Page
31

Phase 1 Studies of AQ
-
13, a Candidate
Aminoquinoline

Antimalarial
, in Comparison With
Chloroquine
.


Sponsor: Tulane University Health
Sciences Center.


Collaborator: National Institutes of Health
(NIH).


Phase 1.


Study Type: Interventional.


Ages Eligible for Study.


Genders Eligible for Study.


Inclusion Criteria: Healthy adult
volunteers.


Exclusion Criteria: Chronic medications
with the exception of oral
contraceptives,


Pregnancy,


Breast
-
feeding.

Page
32

Efficacy, Safety and Pharmacokinetic of
Artequin

TM P.
Falciparum

Malaria.


Sponsor: Albert Schweitzer
Hospital.


Collaborator:
Mepha

Ltd.


Phase II.


Study Type: Interventional.


Genders Eligible for Study.


Accepts Healthy Volunteers.


Inclusion Criteria.


Exclusion Criteria.

Page
33

Effectiveness of
Artemisinin

Combination
Regimens in
Falciparum

Malaria (ACT).


Sponsor:
Medecins

Sans
Frontieres
.


Collaborators:
Mahidol

University

University of Oxford Disease Control,
Department of Health, Myanmar.


Phase IV.


Study Type: Interventional.


Ages Eligible for Study:


Genders Eligible for Study:


Inclusion criteria.


Exclusion criteria.

Page
34

Key Figures

WHAT HAS TO BE DONE:



More than

700 million insecticide
-
treated
bednets



half of those in Africa



More than

200 million of doses of
effective treatment



Indoor spraying for around

200 million
homes

annually



Approximately

1.5 billion diagnostic
tests

annually


Page
35

WHAT IT WILL COST



In 2010,

$6.2 billion

will be needed



From 2011 to 2020, roughly

$5
billion

per year will be need to sustain
the gains of control measures



In addition, about

$1 billion

per year
will be needed for

research and
development

of new prevention and
treatment tools


Page
36

REFRENCES




www.malaria.org



World Health Organization


Article


http://www.who.int/en/



"Engineering a
mevalonate

pathway in
Escherichia coli for production of
terpenoids
," by
Vincent J. J. Martin, Douglas J.
Pitera
,
Sydnor

T.
Withers, Jack D. Newman, and Jay D.
Keasling
,
appeared in Nature Biotechnology, 1 July 2003.


ANTIIMALARIALS By
-

K D
Tripathi
, Essentials
of medical pharmacology, 5
th

edition
Jaypee

publications.


www.anopheles.com

Page
37

THANK YOU

Page
38

TIME HAS COME TO COUNT MALARIA
OUT

World Malaria day
(
25 April)
-

A Day to Act



Blue Ribbon Campaign


Launched by Malaria


Foundation International

Page
39

Back up slides


Page
40





Do NOT be fooled into thinking white
blood cells are
Plasmodium
parasites!
White blood cells are larger in size than
the red blood cells, and have a large,
darkly staining, bi
-
lobed nucleus.

Page
41

A mature
Plasmodium
falciparum

gametocyte.

Page
42



According to severity of illness, malaria can be broadly classified into two types
-


Uncomplicated (Benign)

and

Complicated (Malignant
).

UNCOMPLICATED MALARIA


Relatively milder disease


G敮敲慬ly 捡c獥s 批 P. viv慸


S敬摯m f慴慬


T桥 捨c湣n 潦 i湶潬v敭敮e 潦 潴桥o 潲o慮猠(捯浰ci捡瑩c湳⤠i猠m畣u l敳献


Al獯⁲敦敲e敤 t漠慳aU湣nm灬i捡瑥搠M慬慲楡.

COMPLICATED MALARIA


S敶敲e


R慰i搠摯w湨ill 捯cr獥


C慵獥s m慩湬y 批 P.
f慬捩灡r畭

慮搠r慲敬y 批 P.
viv慸
.


P潯r 灲潧湯獩猠(潵t捯浥c


N潷慤慹猠"獥s敲攠m慬慲楡" 潲o"捯浰ci捡瑥搠m慬慲楡" 慲攠畳u搠m潲攠fr敱略湴ly t漠
摥獣si扥 t桩猠ty灥 潦 m慬慲楡