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CURRICULUM VITAE

• Name :Muhamad Rusdi bin Ahmad Rusmili


• Citizenship : Malaysian
• Marital status: Single
• Affiliation : Department of Basic Medical Sciences, Kulliyyah of Pharmacy,
International Islamic University Malaysia
• Academic Position : Assistant Professor (DS 51)
• Appointment status: Full Time
• Phone : +6012 3165591
• Email : rusdirusmili@iium.edu.my
• Staff directory page : http://www.iium.edu.my/staff-details?id=5591
EDUCATION
• Bachelor in Pharmacy (Hons) (2007, International Islamic University Malaysia,
Malaysia)
• Doctor of Philosophy (Medicine) in Pharmacology (2015, Monash University,
Australia)
EMPLOYMENT
• Assistant Lecturer at International Islamic University Malaysia (2007-2015)
• Assistant Professor at International Islamic University Malaysia (2015- )
PROFESSIONAL MEMBERSHIPS AND CASUAL MEMBERSHIP
• International Society on Toxinology Member (2012- )
• Malaysian Society on Toxinology Member (2015- )
• Malaysian Nature Society (2015- )
Neurotoxicity in Snake Bite

By
Muhamad Rusdi Ahmad Rusmili B.Pharm (Hons), Ph.D
Department of Basic Medical Sciences
Kulliyyah of Pharmacy
International Islamic University Malaysia
Kuantan Campus, Pahang, Malaysia
Outcome of the presentation
• Explanation on snake bite and snake envenoming
• The medically important snake species with prominent neurotoxic
activity
• The common neurotoxic syndromes caused by snake envenoming
• Brief introduction on the types of neurotoxins
• Venom variation and its effects on the management of snake
envenoming
Snake bite Vs Snake Envenoming
• Snake bite ≠ Snake envenoming
• Non-venomous/mildly venomous snake can bite but
without significant effect
• Python bite can cause serious laceration but not
envenoming ( constrictors are known to hunt, kill and
eat human!!!! ) A man was eaten by a reticulated python in
• Not all snake bite is caused by venomous snake species Perak, Malaysia

• Even with confirmed venomous snake bite, there


is 1/3 chance that the venomous snake doesn’t
envenomed
• Snake envenoming is more serious than snake
bite
Laceration caused by reticulated python in
Malaysia

*Picture adapted from Dr. Khaldun’s Snakebite and Envenomation Management in Malaysia
Snake families and general venom effects
Venomous
Snake families

Elapidae Hydrophiidae Viperidae Colubridae

Myotoxic Cytotoxic Coagulopathic


Renal toxicity Myotoxic
Coagulopathic
Neurotoxic
+cytotoxic in cobra & king cobra
+ coagulopathy in Australasian elapids
Examples of venomous snake based on the
families

An elapid A viperid

A sea snakes A colubrid


Medically important snakes in Indonesia

Australasian snake
species

South East Asian


snake species

There are a lot more medically important species in Indonesia!!!


Medically important venomous species with
dominant neurotoxic activity in Indonesia
According to Guideline for the Management of snake-bite from WHO SEARO :
Medically important venomous species with
dominant neurotoxic activity in Indonesia
Before Wallace line:

Equatorial spitting cobra King Cobra


Naja sumatrana Ophiophagus hannah
Medically important venomous species with
dominant neurotoxic activity in Indonesia
Before Wallace line:

Banded krait Malayan krait


Bungarus fasciatus Bungarus candidus
Medically important venomous species with
dominant neurotoxic activity in Indonesia
Before Wallace line:

Red-headed krait Malayan blue coral snake


Bungarus flaviceps Calliophis bivirgata
Medically important venomous species with
dominant neurotoxic activity in Indonesia
• After Wallace line

Brown snake
Pseudonaja spp
Taipan
Oxyuranus spp
Medically important venomous species with
dominant neurotoxic activity in Indonesia
• After Wallace line

Ikaheka snake
Death adder
Micropechis ikaheka
Acanthophis spp
Available in Malaysia and
Unique to Indonesia Unique to Malaysia
Indonesia

Ophiophagus hannah Naja sputatrix


Naja sumatrana Pseudoechis spp
Bungarus candidus Pseudonaja textilis Naja kaouthia
Bungarus fasciatus Acanthophis spp
Bungarus flaviceps Micropechis ikaheka
Medically important venomous species with
dominant neurotoxic activity in Indonesia
• Throughout the ocean

Beaked sea snake Annulated sea snake


Hydrophis schistosa Hydrophis cynocinctus
Medically important venomous species with
dominant neurotoxic activity in Indonesia
• Throughout the ocean

Peron’s sea snake Spine-bellied sea snake


Acalyptophis peronii Hydrophis curtus
Medically important venomous species with
dominant neurotoxic activity in Indonesia
Medically important venomous species with
dominant neurotoxic activity in Indonesia

• Eastern Russell’s viper (Dabioa russelli siamensis @ Dabioa siamensis)


• The western Russell’s viper (Dabioa russelli russeli @ Dabioa russelli) is known for its
neurotoxicity effect
• There reports on the features of neurotoxicity in cases reported in Indonesia
• But the reports are quite old and no recent case reports available
Examples of neurotoxic features seen in
systemic Asian snake envenoming
External ophthalmalgia
Ptosis
Dysphagia
Dyspnea
Abdominal cramps
Peripheral paralysis
Respiratory paralysis
Sri Lankan krait bite
site.
Types of neurotoxin affecting neuromuscular
junction
• The neurotoxins can be divided into 2 major
types :

• Presynaptic neurotoxin Based on


binding sites
• Postsynaptic neurotoxin at the
neuromuscu
lar junction

Different species have different composition of


pre- and postsynaptic neurotoxins
The snake venom presynaptic neurotoxins

• Enzymatic phospholipase A2.


• May have multiple subunits.
• 2 different subunits in Beta-bungarotoxin
• Bind and disrupting the ACh release from
presynaptic terminal.
• Work in three phase.
• Initial binding inhibition
• Transient enhancement of Ach release
• Complete inhibition
• After binding and damage, it will require
sometime for the nerve to recover.
• Partially irreversible
The snake venom postsynaptic neurotoxins
• Three finger toxin family
• Multiple activities e.g cytotoxic, antiplatelet,
neurotoxic
• Can works by affecting aminergic and Ach
receptor
• Effect on the ACh receptor is more important !!
• Can be divided into 3 major classes based on
molecular features and affinity
• Short neurotoxin
• Long neurotoxin
• Non-conventional neurotoxin
• Kappa neurotoxin
• Reversible
Venom variation and its effects on • Venom from each species is unique.
the management of neurotoxic • Even from similar species but different
syndromes of snake envenoming locality can have different venom!!!
• There is a need to know the local species
or invasive species
• An antivenom designed for/with a
particular species may not useable to
treat envenoming by other species.
• Unless, it there is cross-neutralization.
• Need to know where to get the
antivenom!!
• Giving an antivenom that doesn’t
cover a particular species will only
exhausting your limited supply.
• And cost the patient more!!!
Methodology- Chick biventer
1. Easy
2. Robust
3. Cheap
4. Multi-purposes – neurotoxicity,
myotoxicity, antivenom studies,
agonist studies
5. Able to differentiate presynaptic
and postsynaptic blockade
Methodology- Chick biventer
Examples of chick biventer cervicis muscle traces for neurotoxin
Chick_100713

12:00:20.000 AM

Control/not neurotoxic
6
Channel 4 (g)

0.3ug/ml b-btx bf + 4bpb


2
ach

ach
cch

cch
-0 7
kcl

kcl
1

12:26:37.750 AM
10:00
2
20:00
3
30:00 40:00 50:00 1:00:00 1:10:00 1:20:00 1:30:00 1:40:00 1:50:00

Chick_BCPostRusdi_NawalScorpie041012(1)_myotox
2:00:00 2:10:00 2:20:00 2:30:00 2:40:00 2:50:00 3:00:00
11
3:10:00
12
3:20:00
13

T90 = Time required to reduce


6

Postsynaptic neurotoxin 90% of the original twitch


4

height response to electrical


Channel 2 (g)

2
1ug/ml alpha-bungarotoxin

0
stimulation
ach

ach
cch

cch
ckl

kcl
3 4 8 11 22 26 28
30:00 40:00 50:00 1:00:00 1:10:00 1:20:00 1:30:00 1:40:00 1:50:00 2:00:00 2:10:00 2:20:00 2:30:00 2:40:00 2:50:00 3:00:00

Chick_100713(2)

12:09:10.000 AM
6

4 Presynaptic neurotoxin
Channel 4 (g)

2
0.1ug/ml BF B-btx

0
cch
ach

ach

cch
3 11
kcl

kcl
20:00 40:00 1:00:00 1:20:00 1:40:00 2:00:00 2:20:00 2:40:00 3:00:00 3:20:00 3:40:00 4:00:00 4:20:00 4:40:00 5:00:00
2 4 5 14 15 16
Specific Objectives
• To re-examined the neurotoxicity of the venoms by
using chick biventer
• To test the efficacy of monovalent antivenoms and
Neuro Polyvalent antivenom
Specific Methodology

Add
Ach, CCh, KCl

Add
Antivenom

Add Add sample


Ach,CCh,KCl 1-3 H (venom/toxin)
Neurotoxicity of the venoms

% C h a n g e f r o m in it ia l t w it c h h e ig h t

% C h a n g e f r o m in it ia l t w it c h h e ig h t
120
250
100 V e h ic le c o n tr o l V e h ic le c o n tr o l

1  g /m l B C 200 1  g /m l B C
80 1 0 u  /m l B C
1 0  g /m l B C 150
60 T90 =13 min 100
40

20
T90 = 61 min 50

* * * *
* * 0
0

l
h

C
C

K
A

C
0 20 40 60 80 100
T im e ( m in )
% C h a n g e f r o m in it ia l t w it c h h e ig h t

% C h a n g e f r o m in it ia l t w it c h h e ig h t
120 250
V e h ic le c o n tr o l V e h ic le c o n tr o l

100 200 1  g /m l B F
1  g /m l B F
1 0  g /m l B F
80 1 0  g /m l B F 150

60 T90 =22 min 100

40 50

20
T90 = 62 min * * * *
0
* *

l
h

C
0

K
C

C
A
0 20 40 60
T im e ( m in )
80 100
There are nAChR receptors that are not
blocked
Neutralization by monovalent antivenoms
% C h a n g e fr o m in itia l tw itc h h e ig h t

100 Neurotoxicity by the


1 0  g /m l B C venoms was attenuated by
80 1 0  g /m l B C + 1 x B C A V
* prior tissue incubation with
1 0  g /m l B C + 3 x B C A V
60 recommended dose of
* 1 0  g /m l B C + 5 x B C A V
antivenoms (1x) and
40
prevented by incubation
20
with higher dose (3x) of
monovalent antivenom
0
0 20 40 60 80 100
T im e ( m in )
% C h a n g e fr o m in itia l tw itc h h e ig h t

100
*
80
* 1 0  g /m l B F
60 1 0  g /m l B F + 1 x B F A V
1 0  g /m l B F + 3 x B F A V
40
1 0  g /m l B F + 5 x B F A V

20 When given at higher concentration before


0
neurotoxicity starts, monovalents work at higher
0 20 40 60 80
concentration.
T im e ( m in )
Neutralization by Neuro polyvalent antivenom

% C h a n g e fr o m in itia l tw itc h h e ig h t
Neurotoxicity by the
100
* venoms was attenuated by
80 prior tissue incubation with
recommended dose of
60 1 0  g /m l B C
1 0  g /m l B C + 1 x N P V
antivenoms (1x) and
40
1 0  g /m l B C + 3 X N P V prevented by incubation
20
with higher dose (3x) of
polyvalent antivenom
0
0 20 40 60 80 100
T im e ( m in )
% C h a n g e fr o m in itia l tw itc h h e ig h t

100
1 0  g /m l B F
* 1 0 u g /m l B F + 1 x N P V

1 0 u g /m l B F + 3 X N P V
50

When given at higher concentration before


0
neurotoxicity starts, NPV works at higher
0 20 40 60 80 100 concentration
T im e ( m in )
Cross-neutralization by monovalents
Neurotoxicity by the
venoms was not
attenuated by prior
% C h a n g e fr o m in itia l tw itc h h e ig h t

100
1 0  g /m l B C tissue incubation with
1 0  g /m B F higher dose (3x) of
80
1 0  g /m l B C v s 3 x B F A V
different species
monovalent antivenom
60 1 0  g /m l B F v s 3 x B C A V

40

20

0
0 10 20 30
T im e ( m in )

There is no cross- neutralization effect!!!!!


Addition of antivenoms at t90

Addition of monovalent antivenoms at t90 for both venoms did not reverse
neurotoxicity. However, addition of polyvalent antivenom at t90 partially
reversed neurotoxicity caused by B.fasciatus but not B.candidus
Important messages from the presentation
• A snake bite is not necessarily a snake envenoming
• Neurotoxicity is one of the symptoms of snake envenoming
• Neurotoxicity can be caused by types of toxin
• Presynaptic
• Postsynaptic
• Know the local snake species
• Get your pharmacist to buy/stock the correct antivenom
• Use the correct antivenom
• Give antivenom as soon as possible
Acknowledgement

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