This seminar is my attempt to discuss screening of anti-emetic drugs using different animal models. The materials used in the presentation is derived from different standard textbooks, internet and journals. Please feel free to suggest ways to improve it.
2. INTRODUCTION
PATHOGENESIS OF VOMITING
CLASSIFICATION OF ANTI EMETIC
DRUGS
CHOICE OF ANIMALS AND EMETOGENS
PARAMETERS OBSERVED
INVIVO MODELS
INVITRO MODELS
HUMAN MODELS
Contents
3. INTRODUCTION
NAUSEA: Non observable subjective
feeling of having an urge to vomit.
EMESIS
ACUTE EMESIS (occurs within minutes and
resolves within 24 h)
DELAYED EMESIS (occurs after 2-3 days)
BREAKTHROUGH EMESIS (emesis occurring
after the prophylactic antiemetic treatment)
4. RETCHING: Attempt to vomit w/o
expulsion of vomitus.
EJECTION: Expulsion of vomitus
forcefully through mouth and nose.
12. PARAMETERS ASSESSED
Behavioral changes
Latency to first retching and vomiting
Number of vomiting episodes
Conditioned flavor avoidance (PICA) in
rats and mouse
13. DRUG INDUCED EMESIS
MODELS
1.
• Cisplatin- induced emesis model
2.
• Apomorphine- induced emesis model
3.
• CuSO4- induced emesis model
4.
• Methotrexate- induced emesis model
14. Cisplatin-induced emesis
model
Causes Both Acute And Delayed Emesis
Used as emetogen to evaluate acute emesis.
Solvent normal saline at 70oC followed by
slow cooling to 40oC
15. Described by Gylys et al.
Used to evaluate antiemetic properties of 5-HT3
receptor antagonists.
TEST GROUP:
Test drug is administered.
Ten mins later, cisplatin is
administered IV at a dose
of 3.2mg/kg/ml.
OBSERVATIONFOR
5HOURS
Dogs with no
obvious toxicity
are retested
after an interval
of 4 weeks.
CONTROL GROUP:
Vehicle is administered.
Ten mins later, cisplatin is
administered IV at a dose
of 3.2mg/kg/ml.
Cisplatin-induced dog model
16. Cisplatin-induced cat model
Described by John et al.
Cats of either sex, 2-6 kg.
TEST GROUP
Cisplatin is administered IV at
a dose of 3- 7.5 mg/kg/ml over
4 m.
Immediately after this, Test
drug is administered.
OBSERVATIONFOR
4HOURSFOREMETICEPISODES
Cisplatin is administered IV at
a dose of 3- 7.5 mg/kg/ml over
4 m.
Immediately after this, Vehicle
is administered.
17. Animals are subjected to overnight fasting.
Cisplatin-induced ferret model
TEST GROUP
Test drug and Cisplatin (IV at a
dose of 10 mg/kg/ml) are
administered.
If Test drug is given orally, give
cisplatin 30 mins later.
OBSERVATIONFOR
4HOURSFOREMETIC
EPISODES
CONTROL GROUP
Vehicle and Cisplatin (IV at a
dose of 10 mg/kg/ml) are
administered.
18. Pigeon model S. murinus
model
Rat model
4 mg/kg IV 20 mg/kg IP 3-10 mg/kg IP
Duration
between
administration of
drug/ vehicle
and cisplatin
depends upon
expected time of
drug action
Duration between
administration of
drug/ vehicle and
cisplatin is 30
mins.
Cisplatin is
administered 30
mins after rats
have been pre-
treated with
drug/ vehicle.
Observed for
emetic episodes
Observed for 2h
for behavioral
changes as well
as emetic
Observe for pica
(ingestion of
non-food
substances)
19. Apomorphine- induced
emesis model
Apomorphine is an opiate that acts as a
potent central dopamine agonist
directly at the area prostrema via
dopamine receptors.
As the vestibular pathways are also
involved in apomorphine-induced
emesis, the active animals develop
emesis readily than sedated and
immobile animals.
20. Dogs most sensitive followed by ferret.
Use of apomorphine in cats is
controversial as administration of
apomorphine can cause excitation in
cats.
Suncus murinus is unresponsive to
apomorphine.
21. Dog model Ferret model Rat model
0.3 mg/kg SC 0.25 mg/kg SC 10 mg/kg IP
Duration between
administration of
drug and
apomorphine
depends upon
expected time of
drug action
Duration between
administration of
drug and
apomorphine is
30 mins.
Apomorphine is
administered to
rats pre-treated
with drug/
vehicle.
Observed for
emetic episodes
Observed for 60
mins for
behavioral
changes as well
as emetic
Observe for pica
(ingestion of non-
food substances)
22. Copper sulfate-induced emesis
model
COPPER SULFATE (CuSO4)
Powerful oxidizing agent and an irritant to mucosa
membranes. If administered orally, it causes irritation
of gastric mucosa and leads to nausea and vomiting.
Solvent: Distilled water
23. Dog model Cat model
100 mg/kg via an
orogastric tube
40 mg/kg orally
Observed for 1 hour for
emetic episodes
Cats are administered test
drug/ vehicle followed by
oral administration of
threshold dose of CuSO4.
Dogs with no obvious
toxicity are retested after
an interval of 2 weeks.
Observed for emetic
episodes
24. Ferret model Sun murinus
model
Chick model
40 mg/kg orally 40 mg/kg
intragastric
50 mg/kg orally
Drug/ vehicle
pretreated ferrets
are administered
CuSO4.
Duration between
administration of
drug and CuSO4
is 30 mins.
Duration between
administration of
drug and CuSO4
is 10 mins.
Observed for
latency and
frequency of
emetic episodes
Observed for 60
mins for emetic
episodes
Observed for
latency and
frequency of
emetic episodes
25. MTX- induced Delayed emesis
model
Animals: Dogs, cats, ferrets & shrews.
MTX is prepared by dissolving in 5% Dextrose.
Test drug/vehicle is administered at 24, 36, 48
&60 h after MTX.
Observed under video camera for 72h.
Animals can be retested with MTX at least 6
weeks later
26. Motion-induced emesis model
o Dogs are probably as sensitive to motion-
induced emesis as man.
COMMONLY USED MODELS
o CAT MODEL
o SUNCUS MURINUS MODEL
o RAT MODEL
27. Cat model Suncus murinus
model
Rat model
Vertical
oscillations at 0.3
Hz through a
distance of 75 cm
Horizontal
oscillations of 4
cm at 1 Hz for 10
min
60 min double
rotations
Repetitive licking,
salivation often
dripping out of
mouth, or
vomiting
Emetic episodes
are noted during
motion as well as
after motion
cease
↑ kaolin intake
indicates motion
sickness
↑ latency/
↓frequency of
emesis in cats
pretreated with
drug indicates
* Animal can be
exposed only
twice in 1 week
d/t adaption to
motion stimuli
↓ kaolin intake in
rats pretreated
with drug
indicates
antiemetic action
28. Radiation- induced emesis
model
RADIATION INDUCED EMESIS
MODEL
oDOG MODEL
oFERRET MODEL
oRAT MODEL
Ferrets are most sensitive to
radiations followed by dogs. Cats are
resistant to radiations.
29. Dog model Ferret model Rat model
60Co; 8 Gy
administered to
total body
surface
60Co; 201 cGy 4Gy of total body
irradiation
(abdominal >
head irradiation)
One group gets
drug & other
group gets no
medications
Emesis incidence
of 100% is
reported at 201
cGy in ferret
Exposure to
radiation induces
pica in rats
↑ latency/
↓frequency of
emesis in cats
pretreated with
drug indicates
antiemetic action
↑ latency/
↓frequency of
emesis in cats
pretreated with
drug indicates
antiemetic action
↓ kaolin intake in
rats pretreated
with drug
indicates
antiemetic action
30. Model for anticipatory nausea &
vomiting
Anticipatory nausea and vomiting is
described as conditioned response to
cues present at the time of exposure to
toxins as a result of pairing.
Often ass. with cancer chemotherapy.
31. S. murinus
model
•Either sex, 20-50 g
•Weaned at 20 days
•Housed in transparent cages
•Obs. Chamber well illuminated
LiCl 100 mg/kg IPVehicle
Observed (45 min); 2nd /3rd conditioning trial after 72 h,
144h
Test group Control group
6 days later
LiCl 100 mg/kg IPVehicle
Test drug or vehicle is administered
Physiological saline is given
Observe for emetic episodes
32. Rat
model
4 conditioning trials (using LiCl) 72 hours apart
Drug/ vehicle is given to the rats
72 hours after 4th conditioning trial
0.1% saccharin sol. is delivered via surgically implanted
cannulae every 5 min for 1 min (6inj in 30m)
Rats are observed for gaping (equivalent to emesis)
GAPING
33. In vitro models
Used to demonstrate the
pharmacological activity of newer anti-
emetic agents.
5-HT3 # are the most potent of all anti-
emetics.
The experimental drugs can be
evaluated for 5-HT3 receptor
antagonist activity using in vitro
34. 5-HT3 Receptor antagonists
1. Distal colon (20mm) of
GP
2. Krebs-Henseleit solution
3. 2-methyl-5-HT (Agonist)
4. Tropisetron (Antagonist)
5. Temp: 37˚C
6. Vol. (Inner bath) 10 mL
7. pH: 7.3- 7.5
↑
TROPISETRON
↑ ↑
↑ conc./doses of 2-methyl-5-HT
No effect of 2-
methyl-5-HT
PictorialRepresentationOnly
35. Human Models
Apomorphine induced:
Apomorphine, 0.05 mg/kg, SC is an appropriate
challenge dose for testing compounds for
antiemetic activity in normal human
volunteers.
Ipecac induced
Healthy men are given single 5-minute
infusions of ondansetron 30 minutes before
oral administration of 30 ml syrup of
ipecacuanha. Emetic episodes and nausea
are assessed over an 8-hour period.
38. Drug name Class Indication Approval year
Granisetron 5-HT3 # CINV Aug 2016
Dronabinol oral
sol.
CB-1 #,
CB-2 #
CINV Jul 2016
Rolapitant NK-1# CINV Sep 2015
Netupitant +
Palonosetron
NK-1# +
5-HT3 #
CINV Oct 2014
Doxylamine
succinate +
Pyridoxine HCl
DR
H1# Nausea
and
vomiting of
pregnancy
Apr 2013
39. REFERENCES
Drug screening methods by SK Gupta
The Pharmacological Basis of Therapeutics
Goodman & Gilman- 12th edition.
Basic and clinical Pharmacology Betram G
Katzung- 12 th Edition
J Clin Pharmacol. 1978 Feb-Mar;18(2-3):95-9.An
apomorphine-induced vomiting model for
antiemetic studies in man Proctor JD, Chremos
AN, Evans EF, Wasserman AJ.
Clin Pharmacol Ther. 1993 Jul;54(1):53-
7.Ipecacuanha-induced emesis: a human model
for testing antiemetic drug activity.Minton N1,
Swift R, Lawlor C, Mant T, Henry J.