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
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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
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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.
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14
NEWER DIAGNOSTIC
TECHNIQUES
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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
.
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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
.
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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
.
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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
瑯
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.
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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.
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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
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21
ARTIMISININ COMBINATION
THERAPY ( ACT)
•
Artesunate
-
mefloquine
•
Artesunate
-
sulfadoxine
-
pyrimethamine
•
Artesunate
-
amodiaquine
•
Artesunate
-
chloroquine
•
Artemether
-
lumefantrine
•
Dihydroartemisinin
-
piperaquine
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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
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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.
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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
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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
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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
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