Evaluation of drugs for vomiting
- Nausea and vomiting are amongst the most common and distressing symptoms observed in a variety of conditions such as pregnancy, peptic ulcer, gastrointestinal infections, and surgery and as adverse effect of treatment with a wide range of drugs especially the cancer-chemotherapeutic agents.
- Emesis= retching + vomit
- Acute emesis usually occurs within a few minutes to several hours of exposure to emetogen. It usually resolves within 24 h.
- Delayed emesis is observed more than 24 h after the institution of cancer chemotherapy. It usually peaks at 48-72 h and can continue for 6-7 days.
- Vomiting centers:
- Rat, mouse, rabbit, GP and hamster lack vomiting reflex as is seen in human.
- Vomiting reflex is present in other mammalian species such as dogs, monkey, cat, pigs, reptiles, fishes and amphibians & house musk shrew (Suncus murinus),
- Pica is analogus to vomiting in rodents
- Dogs, cats and monkeys cant be used for repetive testing as they have good learning experience.
- Ferret is widely accepted animal model as its emesis resembles closest to human
1. Drugs: cisplatin and methotrexate, apomorphine and copper sulfate.
In vitro model:
5HT3 antagonism of guinea pig colon of 20 cm after giving the agonist.
Antagonism DRC bioassay is performed.
- Selective 5-HT3 receptor antagonist competitively inhibits the contractile responses to 2-methyl-5-HT or it can enhance the inhibitory activity of another selective 5-HT3 antagonist like tropisetron
- 5-HT3 receptor antagonist will fail to affect the contractile response evoked by acetylcholine receptor agonist carbachol
The cancer chemotherapeutic drugs act by directly stimulating the enterochromafn cells in small intestinal mucosa to secrete serotonin. Serotonin is thought to stimulate vagal afferent fibers through 5-HT3 receptors located at the vagal afferent terminals. Sensory signals reach the area postrema to initiate nausea and emesis.
Apomorphine is a derivative of morphine and induces vomiting by stimulating central dopamine receptors.
Copper sulfate is an irritant to gastrointestinal mucosa and its oral administration initiates emesis by stimulating the vagal afferents.
Other drugs used as emetogens include cyclophosphamide, doxorubicin, morphine, nicotine, etc.
Other useful emetogens used in experimental studies include motion stimulus, which induces emesis through vestibular pathways and radiations acting through early peripheral and late central serotonergic pathways.
1. Latency to retching & vomiting
2. Number of vomit episodes.
3. Nausea is measured by increases in the incidence of swallowing, lip licking, backward walking, burrowing, curling up, rearing or decreases in locomotor activity.
4. Rats expressing pica behavior show increase in the wet weight of stomach, which can be measured at the end of the experiment.
5. Increased gastric emptying is indictive of anti-emesis.
- An interval of at least 1 min is needed to separate one emetic episode from the next.
- Episodes of retching and vomiting are considered separate when animal changes position in the observation cage or when the interval between the retches and/or vomiting is more than 5 seconds.
|Cisplatin induced emesis model: Used especially for early phase emesis.||Dog (most sensitive) Cat Ferret Pigeon Suncus marinus Rat||Dogs: Drug given iv à Observation for 5 hours for number of retching & vomit episodes Cats: slow ivà Delayed and early emesis monitored under video monitoring Ferret: Same Rat: Cisplatin à Feed kaolin (pica) à Measure kaolin intake, food intake and body weight.|
|MTX: Delayed emesis model||Dogs Cats Ferret Suncus marinus||MTX à Test drug administered 24,36,48,60 hours after MTX administration Animals are kept under observation soon after MTX administration till 72 h. It is preferable to use a video camera with automatic night photographic system so as to provide with a continuous record of animal behavior for 72 h post MTX treatment|
|Apomorphine||Dogs Ferret Suncus marinus Rat||Dog is given sc and everything is same Ferret is allowed to habituate in observational cage for 4-5 days before giving emetogenic drug so as to observe both emetic episodes and behavioural changes|
|Copper sulphate (irritant to mucous memb)||Dog Cats Ferret Suncus marinus 4 day old chicks||Oral à 1 hour à Emesis. Test drug are given before oral administration of copper sulphate.|
|Motion sickness induced models||Cats Suncus marinus Rats||Cats are placed in a Plexiglas chamber on a circular platform. Chambers are suspended front he ceiling by springs. A gentle push is applied to initiate and maintain the vertical oscillations. Motion sickness is characterized by Repetitive licking, salivation often dripping out of the mouth, or vomiting. Suncus marinus: Suncus murinus after receiving the test drug/vehicle are placed individually in transparent cages, which are then kept on a reciprocal shaker. Shaker is then started to give a horizontal oscillation Emetic episodes are noted during motion as well as after the motion ceases. Rats: 60 min double rotation can induce increased kaolin intake indicating motion-induced emesis.|
|Radiation induced||Ferret > Dogs. Cats resistant||60 cobalt is given to total body surface. Mid abdominal radiation is given usually. Ferret : bilateral 60-Co gamma radiation at 201 cGy. 100% emesis. Rat: Total body or abdominal radiation is given. 4gy.|
|Suncus marinus model for anticipatory nausea nd vomiting||Anticipatory nausea and vomiting, often associated with cancer chemotherapy, is described as the conditioned response to cues present at the time of exposure to toxins as a result of pairing. Weaned at 20 days à Housed in transparent cages with mirror to observe ventral surface. One group receives Lithium chloride and other saline. Episodes of retching and vomiting observed for 45 minutes. Same process repeated for 3 times in 6 days which leads to conditioning. Shrews of either sex weighing 20-50 g are used. All animals included in the study are weaned at the age of 20 days. They are individually housed and maintained under standard laboratory conditions. Animals are housed in transparent cages with a mirror fitted at the bottom so as to allow the observation of the ventral surface of the shrews. Observation chambers are kept in a well-illuminated room with a video camera fitted to record the activities of shrews. Animals are then divided into test and control groups. All animals now receive three conditioning trials 72 hrs apart. Within each group (study, control) half the animals receive of lithium chloride while the other half will receive the vehicle intraperitoneally just before they are put in the observation chambers. The episodes of vomiting and retching are observed over next 45 minutes. Lithium treated animals develop retching and vomiting during these conditioning trials. Six days after completing the three conditioning trials the animals receive two test trials 72 hours apart. On the day of trial the animals are frst injected with the test drug/vehicle and returned to their home cages. Thirty minutes later all animals are injected with 60 ml/kg of physiological saline just before putting them in observation chambers. The shrews are then observed and behavioris video recorded for next 45 minutes. Finally four groups of animals i.e. test drug-lithium conditioned, test drug-saline conditioned, vehicle-lithium conditioned and vehicle-saline conditioned are compared to evaluate efficacy of test drug. The shrews display conditioned retching upon exposure to a context associated with drug-induced vomiting in vehicle treated lithium conditioned group. The frequency of retching can be more than that during the last conditioning trial. Decreased frequency of retching episodes in drug treated lithium conditioned group indicates efficacy of drug against anticipatory vomiting. T The cannabinoids have been found to be effective against anticipatory nausea and vomiting however, 5-HT3antagonists are not as effective.|
Patients: Post-operative/ Post-ctx/ Pregnancy
1. % of complete response defined as no vomiting no retching no rescue therapy.