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Copper sulfate, given orally in an emetic dose, decreased the absorption of therapeutic doses of acetylsalicylic acid or lithium carbonate, more than was expected judging from the recovery of salicylic acid in the vomit. Ten volunteers participated.
The psychopharmacological properties of RU 24213 were compared to those of other dopaminergic agonists (apomorphine, dexamphetamine, bromocriptine and L-dopa) in various behavioural tests. In naive mice the drug reduced the locomotor hyperactivity in the primary exploratory phase and produced stimulation in the subsequent stabilized activity period. In rats it provoked dose-related stereotypies, specially gnawing and sniffing. It delayed the cataleptic state induced by prochlorperazine without affecting its intensity. In animals unilaterally lesioned with 6-OHDA in the nigro-striatal pathway, RU 24213 caused contralateral turning. It exhibited relatively weak emetic and anorexic effects in dogs. Core temperature recordings in rats revealed a biphasic hypo- and hyperthermic activity. In drug interaction studies it was obsers in rats with unilateral electrolytical striatal lesion. The results obtained suggest that RU 24213 stimulates dopamine receptors both directly and indirectly. In this respect it could be compared to bromocriptine but unlike this latter compound it has an immediate effect which is of shorter duration.
This review examines the various clinical options used to elicit gastric emptying, viz. drug-induced emesis, mechanical pharyngeal stimulation, gastric lavage, and catharsis. Apomorphine and syrup of ipecac are the 2 drugs most frequently used for induction of emesis. Both agents act centrally and, in addition, syrup of ipecac has a peripheral action. Toxins ingested or foods previously eaten may inhibit or enhance emetic action by interfering with mediating and conducting mechanisms. Studies indicate that both syrup of ipecac and apomorphine are similarly effective in inducing emesis; however, apomorphine has a shorter reaction time compared with syrup of ipecac. There are more risks involved with the use of apomorphine, since it causes central nervous system and respiratory depression. Syrup of ipecac has been shown to be relatively safe when used in its recommended dosage for emesis. However, several toxicities have been reported with the use of the fluid extract of ipecac. Emesis is contraindicated in patients who are obtunded or comatose, and in patients who have ingested stimulants, some hydrocarbons, or corrosives. Mechanical pharyngeal stimulation is a simple method of inducing emesis; however, it is often unsuccessful and rarely recovers a significant portion of the gastric contents. Gastric lavage is a procedure which has been relied upon for over a century. Its effectiveness is dependent on the nature, form, and dosage of the poison, latency between time of ingestion and lavage, and technique. In clinical experiments studying gastric lavage, it has been noted that the procedure is most beneficial 1 to 2 hours postingestion for the majority of poison ingestions. Lavage also provides an excellent route for activated charcoal and selected antidotes. Gastric lavage may pose several risks to the patient, including obstruction and contamination of the airways and oesophageal damage. Contraindications for gastric lavage are similar to those for emesis except that it may be safer to use in obtunded, comatose, or uncooperative patients. Cathartics used during initial poisoning therapy are usually the saline cathartics. They elicit an osmotic reaction in the small intestine which results in increased intraluminal fluid bulk, hyperperistalsis, and subsequent propulsion of contents. Cathartics have also been shown to stimulate the secretion of cholecystokinin, which is thought to have similar effects on the intestine. Cathartics have not been shown to significantly enhance drug elimination from the gastrointestinal tract.(ABSTRACT TRUNCATED AT 400 WORDS)
A comparison of the biological activity of isomers with varying alkyl substitutions on the heterocyclic nitrogen of benzhydro[f]quinoline derivatives was made. The secondary amines did not inhibit adrenergic transmission. The trans-isomer of the secondary amine was 0.5 as active as norepinephrine when evaluated for positive chronotropic action in anesthetized cats. The trans-isomers of the N-alkyl derivatives produce inhibition of responses produced by stimulation of cardioaccelerator nerves with doses of 1--5 mumol/kg. Likewise potent emetic activity (dog) and rotational behavior (rat) was observed with the N-alkyl derivatives when administered subcutaneously. The cis-isomers were much less active. The neuronal inhibitions in cats were antagonized by haloperidol 100 micrograms/kg, except the cis-isomer of the N-ethyl derivate which required phentolamine, 2 mg/kg. In general, the transisomers were more potent in contracting the isolated rabbit aorta. This response appeared to be mediated through an alpha-adrenergic mechanism since phentolamine blocked these responses. The trans-isomer TL-305 was effective in relaxing methacholine contracted guinea-pig trachea through a beta-adrenergic mechanism since propranolol blocked this response.
In order to investigate whether different receptor populations mediate emesis induced by intracerebroventricular (i.c.v.) and intravenous (i.v.) apomorphine, adult beagle dogs were tested with various doses of the drug with and without central and peripheral pretreatment with the dopamine antagonist sulpiride. The threshold dose of apomorphine to induce emesis by i.c.v. injections was 30-50 times lower than via the i.v. route, while the response latencies after i.c.v. administration were typically longer and the number of bouts of vomiting greater. I.v. pretreatment with sulpiride was more effective than i.c.v. pretreatment in blocking emesis induced by i.v. apomorphine, whereas both i.v. and i.c.v. sulpiride effectively blocked vomiting after i.c.v. apomorphine. Finally, in separate experiments, surgical interruption of blood flow in the region of the area postrema permanently abolished the emetic response to i.c.v. apomorphine, but only transiently disrupted emesis induced by i.v. apomorphine. These data suggest the possibility that i.v. and i.c.v. apomorphine-induced emesis may be mediated by separate dopamine receptors on the cerebrospinal fluid-side and blood-side of the area postrema.
RU 24969 was administered s.c. to cats and found to elicit emesis with a maximally effective dose of 1.0 mg/kg. 5-Methoxytryptamine was found to have lower efficacy and to produce a higher incidence of non-specific effects while trifluoromethylphenylpiperizine (TFMPP) was devoid of emetic effects. The emesis elicited by 1.0 mg/kg of RU 24969 was not altered by pretreatment with phentolamine, haloperidol, yohimbine or (-)-propranolol, indicating that catecholamines played no role in this response. The emesis was prevented by metergoline and methysergide but not by ketanserin, cyproheptadine, mesulergine, ICS 205,930, methiothepin, trimethobenzamide or BMY 7378. An indirect argument is presented that implicates a role for 5-HT1D sites. This conclusion must remain tentative until drugs selective for this site are synthesized and tested. The emesis was also prevented by 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT), confirming that this drug has a general antiemetic effect in cats.
The emetic profile of action of cisplatin 5 and 10 mg/kg i.p. was investigated in the ferret over a 72 and 24 hr period respectively. The 5-HT3 receptor antagonists ondansetron and alosetron markedly antagonized or abolished the emesis during the "acute phase" and, whilst antagonizing the emesis during the delayed phase, also revealed a 5-HT3 receptor antagonist resistant component. These cisplatin paradigms may provide models relevant to the study of acute and delayed emesis induced by cisplatin in man.
Glutamate may be a key transmitter in the emetic reflex arc. The present investigation focussed on the involvement of the NMDA subtype of glutamate receptors in cisplatin-induced emesis. Ferrets were injected with cisplatin (10 mg/kg i.v.) and either of the non-competitive NMDA receptor antagonists dextromethorphan or memantine, or the competitive receptor antagonist CGS 19755. In order to determine whether there is a synergism between NMDA blockers and 5-HT3 receptor antagonists, a submaximal dose of granisetron (0.05 mg/kg) was given alone or in combination with either dextromethorphan or memantine. The latency for the onset of emesis as well as the total number of vomits and retches over 3 hr were determined. In controls, the latency for emesis was 73 +/- 6 min and the total number of vomits and retches 143 +/- 17. The corresponding figures for animals treated with dextromethorphan, 10 and 20 mg/kg, were 89 +/- 19 min (p > 0.05) and 50 +/- 17 (p = 0.008), and 113 +/- 18 min (p > 0.05) and 22 +/- 9 (p = 0.004), respectively. At 10 mg/kg, dextromethorphan failed to enhance the antiemetic effect of granisetron which by itself provided 90% inhibition. While memantine (2.5 or 5.0 mg/kg) did not have an effect per se, it tended to reduce the antiemetic effect of granisetron. CGS 19755 (10 mg/kg) provided a partial protection against cisplatin-induced emesis (latency: 111 +/- 23, number of vomits and retches 30 +/- 11). None of the NMDA receptor antagonists was free of behavioural effects (e.g. some sedation) at antiemetic doses. It is concluded that NMDA receptor antagonists may afford protection against cisplatin-induced emesis but the specificity of this effect is uncertain since it may relate to general CNS depression.
In Amazonian Peru and Ecuador leaf decoctions of the rainforest holly Ilex guayusa with high caffeine concentrations are used as a morning stimulant. After daily ingestion, ritualistic vomiting by male Achuar Indians, better known as Jívaros, reduces excessive caffeine intake, so that blood levels of caffeine and biotransformed dimethylxanthines do not cause undesirable CNS and other effects. Emesis is learned and apparently not due to emetic compounds.
The anti-emetic potential of CP-122,721 ((+)-2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpi peridine), CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), CP-100,263 ((-)-(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine), RP 67580 ((3R, 7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] po-hydroisoindol-4-one), FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-in-dole-3-yl)carbonyl-L-propyl] -N-methyl-N-phenylmethyl-1-3-(2-naphthyl)-alaninamide) and GR 82334 ([D-Pro9[spiro-g-lactam]Leu10]-physalaemin-(1-11)) was investigated to inhibit nicotine (5 mg/kg, s.c.)-, copper sulphate pentahydrate (120 mg/kg, intragastric)- and motion (4 cm horizontal displacement at 1 Hz for 5 min)-induced emesis in Suncus murinus. A 30 min intraperitoneal pre-treatment with CP-122,721, CP-99,994, RP 67580 and FK 888 significantly (P < 0.05) antagonized nicotine-induced emesis with ID50 values of 2.1, 2.3, 13.5 and 19.2 mg/kg, respectively CP-100,263, the less active enantiomer of CP-99,994, was inactive at doses up to 10 mg/kg. Infusion of GR 82334, CP-122,721, CP-99,994 and FK 888 into the dorsal vagal complex of the hindbrain also antagonized nicotine-induced emesis yielding ID50 values of 1.1, 3.0, 3.3 and 58.0 microg/dorsal vagal complex, respectively RP 67580 and CP-100,263 were inactive. RP 67580 and FK 888 failed to antagonize copper sulphate-induced emesis but CP-122,721 and CP-99,994 were active yielding ID50 values of 2.2 and 3.0 mg/kg, i.p., respectively. CP-99,994 also completely prevented motion-induced emesis at 10 mg/kg, i.p. (P < 0.05) and RP 67580 produced a significant reduction of motion-induced emesis at 10 mg/kg, i.p. (P < 0.05). These studies provide evidence of a central site of action of tachykinin NK1 receptor antagonists to inhibit nicotine-induced emesis in S. murinus and confirm the broad profile of inhibitory action. The rank order of potency of the antagonists following the intra-dorsal vagal complex administration suggests that the S. murinus tachykinin NK1 receptor has a unique pharmacological profile.
Gastric decontamination remains an important element in the therapy of pediatric poisoning; however, several issues remain unresolved. Additional studies, particularly in the clinical setting, are necessary to establish optimal therapeutic recommendations. Based on the data presented in this review, the following general recommendations can be made for gastric decontamination in children: If it is necessary to remove an ingested toxin, ipecac syrup is the preferred method if contraindications to its use are not present. The dose should be 30 ml in children older than 1 year of age and 10 ml in children 6 to 12 months of age. Pending further studies, the use of emetics in children younger than 6 months of age cannot be generally recommended, particularly in the home setting. Gastric lavage should be considered to be of very limited use in pediatric patients. Lavage using small nasogastric tubes, except under special circumstances, is nonproductive and cannot be advocated. If it must be used, a large-bore orogastric hose should be used. Administration of activated charcoal prior to lavage should be considered. In situations in which prompt induction of emesis is not possible or contraindications to emesis exist, activated charcoal followed by, or mixed with, a cathartic (preferably sorbitol) should be used as an alternative to removal of gastric contents. Patients with significant symptoms from ingestion requiring hospitalization should receive repeat doses of charcoal and cathartic until symptoms resolve. Activated charcoal should be given in conjunction with other appropriate therapies. Although the data to substantiate this recommendation are limited, particularly in pediatric patients, it is a benign therapy that holds promise of increasing drug elimination.
Although the public debate about the legalization of marijuana has continued for as long as 25 years, few controlled studies have been conducted to assess its potential medical benefits. The present study examined the antiemetic effect of smoked marijuana cigarettes (8.4 and 16.9 mg Delta(9)-tetrahydrocannabinol [THC]) compared to a highly potent antiemetic drug, ondansetron (8 mg) in 13 healthy volunteers. Nausea and emesis were induced by syrup of ipecac. Marijuana significantly reduced ratings of "queasiness" and slightly reduced the incidence of vomiting compared to placebo. Ondansetron completely eliminated the emetic effects of ipecac. These findings support and extend previous results, indicating that smoked marijuana reduces feelings of nausea and also reduces emesis in this model. However, its effects are very modest relative to ondansetron, and the psychoactive effects of marijuana are likely to limit its clinical usefulness in the general population.
Various drugs are commonly used for the many gastrointestinal problems that are routinely seen in dogs and cats. Many of these drugs are briefly reviewed in this article. Anecdotal as well as documented findings are provided that will hopefully allow the clinician to use them wisely and effectively in the many clinical situations that arise daily. Emetics, although not used for gastrointestinal problems, are also reviewed because of their obvious connection with the gastrointestinal tract.
A novel series of 2,5-dihydropyrazolo[4,3-c]quinolin-3-ones has been prepared. These compounds showed good PDE 4 inhibitory activity and weak affinity for rolipram's binding site. They also exhibited a good anti-inflammatory profile without emetic side effects.
Monophenolic (2-(dipropylamino)indans and related compounds have been synthesized and tested for central dopamine-receptor stimulating activity, using biochemical and behavioral tests in rats and emesis tests in dogs. The active compounds possess similar relative potencies in eliciting the three different dopamine-receptor mediated effects measured. 4-Hydroxy-2-(dipropylamino)indan was the most potent of the new compounds. The corresponding 5-hydroxy analogue was less active. 4-Hydroxy-2-[(dipropylamino)methyl]indan is a new type of dopaminergic agent with a phenylpropylamine moiety in its framework instead of the phenylethylamine structure, common to most dopamine-receptor agonists. This compound was 10-20 times less active than apomorphine. 6,7,8,9-Tetrahydro-1-hydroxy-N,N-dipropyl-5H-6-benzocycloheptenylamine and 5-hydroxy-2-[(dipropylamino)methyl]tetralin were both inactive. Since the intramolecular distances between functional groups in the indans studied here are different from those in, for example, apomorphine, it is concluded that a certain variation of these distances can be accepted by the receptor. It could also be demonstrated that the position of the OH group on the aromatic ring is of importance for the activity and that emetic activity may be associated with dopaminergic agonists of the indan as well as of the tetralin type of structure.
The title compounds have been synthesized and evaluated for emetic effects in the dog, actions on the cardioaccelerator nerve in the cat, pecking in pigeons, and for behavioral effects following both peripheral and direct intracerebral injection into the nucleus accumbens and caudate-putamen of the rat. Generally, in the series studied, the N,N-diethyl and N,N-di-n-propyl congeners of dopamine displayed notably high degrees of activity. However, the test compounds exerted differing effects on peripheral and central dopamine receptors and in the area postrema. Differentiations of the activities of the different homologues within the brain were also shown.
Two series of N-substituted 2-aminoindan systems have been prepared: 4,5-dihydroxy-2-aminoindan (1) has a hydroxylation pattern analogous to the alpha conformer of dopamine, and 5,6-dihydroxy-2-aminoindan (2) has a hydroxylation pattern of the beta conformer of dopamine. All members of both series demonstrated only extremely weak binding to calf caudate homogenate. Certain N-alkylated 4,5-dihydroxyindans were violent emetics in the dog and were potent in blockade of the effect of stimulation of the cardioaccelerator nerve of the cat. In contrast, the 5,6-dihydroxy series displayed low or no activity/potency in these assays. Conformational analysis of the 2-aminoindan system is described and discussed.
Mice were subjected to a taste aversion conditioning procedure in which they drank water, familiar saccharin, or novel saccharin, followed by injection of either NaCl or the emetic agent LiCl. Immunohistochemistry was used to localize phosphorylated MAP kinase (ppERK) and phosphoCREB (pCREB) in the brain shortly after conditioning. An examination of insular cortex and amygdala revealed specific phosphorylation of MAP kinase by novel saccharin and LiCl, and CREB by LiCl. Pairing of novel saccharin with LiCl was the only stimulus sufficient to increase ppERK and pCREB immunoreactivity in the lateral amygdala, suggesting this as a site of CS-US convergence. ppERK immunoreactivity was localized to both nuclear and non-nuclear compartments, suggesting multiple functional roles of MAP kinase during learning.