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Pharmacological evaluation of anti Pharmacological evaluation of anti emetic drugsemetic drugs

By

Sunpreet Kaur

M.PHARM ( Pharmacology)

Department of Pharmacology

I.S.F. College of Pharmacy, Moga-142001, I.S.F. College of Pharmacy, Moga-142001, Punjab (India)Punjab (India)

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Emesis

Emesis (vomitting) is defined as ejection or expulsion of gastric contents through mouth and is often a forceful event.

It generally viewed as protective reflexes that serve to rid the stomach and intestine from toxic substances and prevent their further ingestion.

This is accompanied by multiple autonomic phenomena including salivation, shivering and vasomotor changes.

During prolonged episodes of emesis, marked behavioral changes including lethargy, depression, and withdrawal may occur.

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Phases of emesis

Emesis (vomitting) is a complex process thatconsists of three phases:Pre-ejection phase gastric relaxation and

retroperistalsis.Retching rhythmic action of respiratory muscles

preceding vomiting and consisting of contraction of abdominal and intercostal muscles and diaphragm against a closed glottis

Ejection intense contraction of the abdominal muscles and relaxation of the upper esophageal sphincter.

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Process of emesis

Process of emesis can be mediated by:

Chemoreceptor trigger zone (CTZ)

Nucleus tractus solitarius (NTS)

Vestibular system

Vagus nerve

Physiology of emesis

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Emetic and anti-emetic activity

Assessment of emetic and anti-emetic activity in dogs .

Anti-emetic activity in ferrets.

Assessment of emetic and anti-emetic activity in pigeons

Activity against motion-induced emesis

Foot tapping in gerbils

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Assessment of emetic and anti-Assessment of emetic and anti-emetic activity in dogs emetic activity in dogs

Purpose:- Burkman described this model in dogs by use of apomorphine, it is used to evaluate anti emetic drugs as well as neuroleptic drugs.

PROCEDURE

Beagle dogs (weighing15 and 20 kg) are used.

Each dog is given 200 g food 30 min prior to an assay session.

The threshold emetic dose of APOMORPHINE HCl is administer by giving single doses at 5 day intervals in gradually increasing or decreasing manner.

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The starting dose is 22 mg/kg i.m and is subsequently increased (or decreased) as required.

After every third or fourth dose of the emetic, the animals receive an equivalent volume of vehicle under similar conditions in order to detect the presence of a conditioned emetic response.

The threshold dose is defined as the concentration provoking an emetic episode.

The threshold emetic dose is relatively stable for a given group of dogs over a period of 2 months.

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In the anti-emetic assay, dogs whose apomorphine threshold emetic dose has been determined receive various concentrations of the potential anti-emetic drug at a given time interval prior to apomorphine.

The dose initially selected for the anti-emetic is a fraction of the acute LD50 of this drug in mice.

A new threshold dose is estimated in the presence of the test anti-emetic and compared to the threshold dose in the presence of the reference standard chlorpromazine.

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EVALUATION

Using the threshold doses, the relative potency of an emetic compared to apomorphine, or the relative potency of an anti-emetic compared to chlorpromazine is calculated

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Anti-emetic activity in ferrets

PURPOSE AND RATIONALE

The ferret is a well established animal model of emesis which responds to cancer chemotherapeutic agents in a manner similar to that observed in man.

The animals react with vomiting and retching after challenge with central (loperamide and apomorphine), peripheral (CuSO4), or mixed central and peripheral (ipecacuanha, cisplatin) emetic stimuli.

The model has been used to test the anti-emetic properties of 5-HT3 receptor antagonists and tachykinin NK1 receptor antagonists.

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PROCEDURE

Adult male ferrets weighing 1 to 1.5 kg are randomly assigned to the different treatment groups.

Each animal is anesthetized by inhalation with methoxyflurane.

A jugular vein is cannulated and exteriorized from the outside of the neck.

Following recovery from the anesthesia, the animals are dosed with the test drug or the standard or the vehicle 30 min prior i.v. administration of 10 mg/kg cisplatin.

The numbers of retches and vomits occurring following the administration of the emetogen are recorded in each animal for 5 h.

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EVALUATION

Duration of action of the compounds is assessed by determining the period of time for which the inhibitory effects remain significantly different from vehicle controls.

Statistical analysis of the data is performed by a repeated measure analysis of variance (ANOVA).

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Assessment of emetic and anti-emetic activityin pigeons

PURPOSE AND RATIONALE

Emesis in pigeons can be induced by various agents.

This method used for standardisation of cardiac glycosides but now also for emesis evaluation.

More recently, dose response curves of emesis have been determined for various agents and anti-emetic effects were evaluated.

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Assessment of emetic and anti-emetic activityin pigeons

PROCEDURE:

Male White Carneaux pigeons are kept in individual stainless steel cages at constant temperature and humidity.

They are maintained at 90% of their free-feeding body weights by once-daily feeding of approximately 20 g Purina Pigeon Checkers.

All testing is conducted during the illuminates phase of the light-dark cycle.

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On test days, the birds are fed

5 min before the start of an emetic trial.

Animals are divided into 2 groups

Test Group

(Test drug is given)

Control Group

( Vehicle is given)

15 minute after administration of test drug, following drugs are used to induce vomiting like cisplatin (10mg/kg), emetin

(10-20 mg/kg)

The animals are observed for vomiting during 2h.

PROCEDURE:

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If vomiting occurs, the pigeons are given an additional 20 g of feed before being returned to their home cages at the conclusion of the observation period.

Individual subjects are allowed a recovery period of at least 3 days between each drug test.

EVALUATION

ED50 values for with 95% confidence limits are calculated for the activity of emetic substances, as well as for the inhibition of emesis by anti-emetic drugs after a high dose of the emetic compound.

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Activity against motion-induced emesis

Rationale:- The housemusk screw is an small insectivore that has been shown to exhibit emesis when exposed to linear horizontal motion.

PROCEDURE

Adult male (body weight range 55–90 g) and female (body weight range 35–50 g) are used.

The animals receive a dose of the test drug or vehicle in a volume of 4 ml/kg before 15 min of motion testing.

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The animals are placed in a Perspex chamber (11 cm wide × 22 cm long × 11 cm high) that is attached to the platform of a shaker set to execute a linear horizontal movement of 4 cm at a frequency of 1 Hz along the long axis of the chamber

The animals are allowed approximately 3 min to become adapted to the chamber before exposure to motion for a period of 5 min, during which the number and timing of emetic episodes are recorded.

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Animals are divided into 2 groups

Test Group Control Group

15 minute after administration of test drug and vehicle motion testing is done

Animals made gently placed on shaker

Then shaker is started for period of 5 minutes, during this time no. of vomitings are recorded

Control groups show higher no. of vomittings

PROCEDURE :

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EVALUATION

Group results are expressed as mean ±SEM.

And student’s t-test is used as a measure of significance.

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Foot tapping in gerbils

PURPOSE AND RATIONALE

Foot tapping in gerbils is a centrally mediated behavior that has been claimed to be highly predictive for NK1 antagonists to prevent cisplatin-induced retching in ferrets

A simple in vivo assay for CNS mediated emesis.

PROCEDURE

Mongolian gerbils of either sex weighing 35–70 g are selected

Gebrils are made anesthetized by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein through a skin incision in the neck, using blunt dissection to clear surrounding salivary gland and connective tissues.

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Test compounds or vehicle are administered using an injection volume of 5 ml/kg i.v.

The wound is closed and a second incision is made in the midline of the scalp to expose the skull.

The highly selective, peptidase-resistant NK1 receptor agonist GR73 632 is infused directly into the cerebral ventricles (3 pmol in 5 μl i.c.v.) by vertical insertion of a cuffed 27-gauge needle to a depth of 4.5 mm below bregma.

The scalp incision is closed and the animal allowed to recover from anesthesia in a clear Perspex observation box (25 × 20 × 20 cm).

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The duration of hind foot stepping is then recorded continuously for 5 min using a stopclock.

The time relapse from induction to recovery from anesthesia, with intervening i.v. and i.c.v. injections is about 3–4 min.

EVALUATION

Data are subjected to one-way analysis of variance (ANOVA), followed by Dunnett’s or Newman-Keuls multiple comparison t-tests.

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