Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction of S 21007 [5-(4-benzyl piperazin-1-yl)4H pyrrolo [1,2-a]thieno[3,2-e]pyrazine] with serotonin 5-HT3 receptors was investigated using biochemical, electrophysiological and functional assays. Binding studies using membranes from N1E-115 neuroblastoma cells showed that S 21007 is a selective high affinity (IC50 = 2.8 nM) 5-HT3 receptor ligand. As expected of an agonist, S 21007 stimulated the uptake of [14C]guanidinium (EC50 approximately 10 nM) in NG 108-15 cells exposed to substance P, and this effect could be prevented by the potent 5-HT3 receptor antagonist ondansetron. In addition, like 5-HT and other 5-HT3 receptor agonists (phenylbiguanide and 3-chloro-phenylbiguanide), S 21007 (EC50 = 27 microM) produced a rapid inward current in N1E-115 cells. The 5-HT3 receptor agonist action of S 21007 was also demonstrated in urethane-anaesthetized rats as this drug (120 micrograms/kg i.v.) triggered the Bezold-Jarisch reflex (rapid fall in heart rate), and this action could be prevented by pretreatment with the potent 5-HT3 receptor antagonist zacopride. Finally, in line with its 5-HT3 receptor agonist properties, S 21007 also triggered emesis in the ferret. Evidence for 5-HT3 receptor antagonist-like properties of S 21007 was also obtained in some of these experiments since previous exposure to this compound prevented both the 5-HT-induced current in N1E-115 cells and the Bezold-Jarisch reflex elicited by an i.v. bolus of 5-HT (30 micrograms/kg) in urethane-anaesthetized rats. These data suggest that S 21007 is a selective 5-HT3 receptor agonist which can exhibit antagonist-like properties either by triggering a long lasting receptor desensitization or by a partial agonist activity at 5-HT3 receptors in some tissues.
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PMID:Interaction of S 21007 with 5-HT3 receptors. In vitro and in vivo characterization. 898 86

The activity of a selective tachykinin NK1 receptor antagonist, PD 154075 ([(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3) Ph), was examined in radioligand binding studies, in a [Sar9,Met(O2)11]substance P-induced foot-tapping model in the gerbil, and in cisplatin-induced acute and delayed emesis in the ferret. In radioligand binding studies, PD 154075 showed nanomolar affinity for the human, guinea-pig, gerbil, dog and ferret NK1 receptors with an approximate 300 times lower affinity for the rodent NK1 receptor. Using NK2,NK3 receptors and a range of other receptor ligands, PD 154075 was shown to exhibit a high degree of selectivity and specificity for the human type NK1 receptor. Following subcutaneous administration PD 154075 dose dependently (1-100 mg/kg) antagonised the centrally mediated [Sar9,Met(O2)11] substance P-induced foot tapping in the gerbil with a minimum effective dose (MED) of 10 mg/kg. The ability of PD 154075 to readily penetrate into the brain following oral administration was confirmed by its extraction and high performance liquid chromatography assay from the rat brain. PD 154075 was shown to achieve a relatively fast and sustained brain concentration (brain/plasma ratios ranged from 0.27 to 0.41 during the time period of 0.25-12 h). Further pharmacokinetic studies revealed that the absolute oral bioavailability of PD 154075 in the rat was (mean +/- S.D.) 49 +/- 15%. PD 154075 (1-30 mg/kg, i.p.) dose dependently antagonised the acute vomiting and retching in the ferret measured for 4 h following administration of cisplatin (10 mg/kg, i.p.) with a MED of 3 mg/kg. The administration of a lower dose of cisplatin (5 mg/kg, i.p.) in the ferret induces both an acute (day 1) and delayed (days 2 and 3) phase of emesis. The i.p. administration of PD 154075, 10 mg/kg three times a day for 3 days, almost completely blocked both the acute and delayed emetic responses. In the same study, the 5-HT3 receptor antagonist ondansetron (1 mg/kg, i.p., t.i.d.) was also very effective against the acute emetic response observed during the first 4 h following cisplatin, but it was only weakly active against the delayed response. In conclusion, PD 154075 is a selective and specific high affinity NK1 receptor antagonist with good oral bioavailability which is effective against both acute and delayed emesis induced by cisplatin in the ferret.
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PMID:The tachykinin NK1 receptor antagonist PD 154075 blocks cisplatin-induced delayed emesis in the ferret. 906 90

1. The NK1 receptor antagonist CP-99994 has been shown to prevent vomiting elicited by both peripherally and centrally acting emetogens in ferrets and dogs. These results have now been extended to another stimulus, provocative motion, and another species, the cat. 2. CP-99994 displaced [3H]-substance P from cat cortex with IC50 of 0.52 +/- 0.08 nM. Following s.c. administration, peak plasma drug levels were achieved at 30 min. The plasma drug half life was 1.4 h. 3. Subcutaneous administration of CP-99994 inhibited motion-induced vomiting in the cat with an ED50 of 144 micrograms kg-1 but did not change the epiphenomena associated with provocative motion in the cat over the dose range of 30 to 300 micrograms kg-1. The antiemetic effect of CP-99994 can be attributed to antagonism of the NK1 receptor because its enantiomer, CP-100,263, which is 900 fold weaker as an NK1 antagonist, had no effects on any response to provocative motion. 4. The inhibitory effect of CP-99994 on motion-induced retching and vomiting is consistent with a central site of antiemetic action, potentially at the level of the motor nuclei responsible for these behaviours. 5. An investigation into whether the failure of CP-99994 to alter the epiphenomena will also predict a lack of anti-nausea effects in man will provide critical information on the neural organization of the emetic reflex.
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PMID:The effect of CP-99994 on the responses to provocative motion in the cat. 911 85

Chemotherapy-induced emesis has a major adverse impact on patients undergoing therapy for various malignancies, and this has led to considerable research in this field. Most investigative efforts have concentrated on the acute phase of emesis that occurs within the first 24 hours after chemotherapy, and significant strides forward have been made with this problem. Better control of acute emesis with newer agents such as the serotonin 5-HT3 receptor antagonists has focused increasing attention on a second phase of nausea and vomiting, known as delayed emesis, which occurs more than 24 hours after chemotherapy. This delayed phase is often not as well controlled with the antiemetics that have proven effective in acute emesis, and contributes to the distress associated with emetogenic chemotherapy. Most of the available data on delayed emesis are based on studies with cisplatin-based regimens, with much less understanding of delayed nausea and vomiting induced by non-cisplatin-based chemotherapy. Nevertheless, it is evident that the patterns of delayed emesis associated with cisplatin and non-cisplatin chemotherapy have distinct differences. The control of delayed emesis, especially following cisplatin, remains a therapeutic challenge. Contributing to the lack of progress has been the absence of an experimental model to help in elucidating the pathophysiology of delayed emesis and in the evaluation of new therapeutic approaches. The combination of metoclopramide and dexamethasone, although superior to placebo in randomised trials, provides only moderate control of delayed emesis following high-dose cisplatin. The 5-HT3 receptor antagonists that are effective in the prevention of acute emesis with cisplatin have failed to make a major impact on the delayed phase. When combined with dexamethasone, these agents provide no additional benefit to that achieved using dexamethasone alone or dexamethasone combined with metoclopramide. With non-cisplatin chemotherapy, corticosteroids and 5-HT3 receptor antagonists are the most useful agents. Efforts are ongoing to identify more effective treatments for delayed emesis. One novel approach involves the blockade of substance P binding to neurokinin-1 (NK1) receptors. This article reviews what is currently known about chemotherapy-induced delayed emesis, with a focus on treatment strategies.
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PMID:Drug treatment of chemotherapy-induced delayed emesis. 911 14

The ability of tachykinin NK1 receptor antagonists to inhibit GR73632 (D-Ala-[L-Pro9,Me-Leu8]substance P-(7-11))-induced foot tapping in gerbils was employed as an indirect measure of brain penetration and this was compared with their ability to prevent acute emesis induced by cisplatin in ferrets. (+)-GR203040 ((2S,3S and 2R,3R)-2-methoxy-5-tetrazol-1-yl-benzyl-(2-phenyl-piperidin- 3-yl)-amine), CP-99,994 ((2S,3S)-cis-3-(2-methoxybenzylamino)-2-phenyl piperidine) dihydrochloride), and L-742,694 (2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-3-(S)-phenyl-4-(5-(3-oxo-1,2, 4-triazolo)methylmorpholine) potently inhibited GR73632-induced foot tapping (ID50 < or = 0.85 mg/kg), and acute retching induced by cisplatin (ID50 < or = 0.18 mg/kg). RPR100893 ((3aS,4S,7aS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-[(S)-2-(2-m ethoxyphenyl)proprionyl] perhydroisoindol-4-ol) was not a potent antagonist of retching (ID50 4.1 mg/kg) or foot tapping (ID50 > 10 mg/kg). High doses (3-10 mg/kg) of CGP49823 ((2R,4S)-2-benzyl-1-(3,5-dimethylbenzoyl)-N-[(4-quinolinyl)methyl] -4-piperineamine) dihydrochloride), FK888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-indol-3-yl)carbonyl-L-propyl]-N-methy l-N-phenylmethyl-L-3-(2-naphthyl)-alaninamide), and LY303870 ((R)-1-[N-(2-methoxybenzyl)acetylamino]-3-(1H-indol-3-yl)-2-[N-(2-(4-(pi peridinyl)piperidin-1-yl)acetyl)amino]propane) were required to inhibit foot tapping; these agents were not anti-emetic in this dose range. SR140333 ((S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane; 3-10 mg/kg) failed to inhibit foot tapping or emesis. Affinities for the human and ferret tachykinin NK1 receptor were highly correlated (r = 0.93, P = 0.0008). Inhibition of foot tapping in gerbils, but not NK1 receptor binding affinity, predicted anti-emetic activity in ferrets (r = 0.75, P < 0.01). These findings confirm that the anti-emetic activity of tachykinin NK1 receptor antagonists is dependent on brain penetration.
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PMID:In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists. 919 73

1. The effect of the tachykinin neurokinin1 (NK1) receptor antagonist GR203040 on cyclophosphamide (CYP)-induced bladder damage was investigated in rats and ferrets. The 5-hydroxytryptamine3 receptor antagonists ondansetron and granisetron were similarly examined in ferrets. 2. In the rat, GR203040 (10 and 30 mg/kg i.p.) reduced the CYP-induced plasma protein extravasation in the bladder by 44% and 73%, respectively (P < 0.05 and 0.005; cf. CYP controls); in the ferret, a 57% reduction (P < 0.005) was observed after GR203040 (0.3 mg/kg SC). No decrease was observed in ferrets with either ondansetron or granisetron (1 mg/kg SC). 3. GR203040 attenuated the CYP-induced damage in the rat and ferret bladder, at the same dose in the ferret previously shown to inhibit CYP-induced emesis.
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PMID:The NK1 antagonist GR203040 inhibits cyclophosphamide-induced damage in the rat and ferret bladder. 925 7

The mammalian tachykinins (substance P, neurokinin A, and neurokinin B) are widely distributed throughout the central and peripheral nervous systems, where they act as neurotransmitters or neuromodulators. Historically, the tachykinins have been implicated in a wide variety of biological actions such as pain transmission, neurogenic inflammation, smooth muscle contraction, vasodilation, secretion, and activation of the immune system. Their effects are mediated via specific G-protein-coupled receptors (NK1, NK2, and NK3 receptors). The development of nonpeptide receptor antagonists revealed species differences in neurokinin-receptor pharmacology, and the recent cloning of human neurokinin receptors has led to development of compounds with optimized affinity for the human target receptor. The neurokinin-receptor antagonists have been used in preclinical experiments to confirm the physiological roles of the tachykinins. Importantly, it is now recognised that these agents can inhibit the actions of tachykinins released from peripheral nerves, and for the NK1-receptor antagonists (the most widely studied class of neurokinin-receptor antagonists) central sites of action have also been demonstrated. These studies support the development of neurokinin-receptor antagonists as potentially exploitable drug therapies in humans, particularly in the treatment of pain and emesis.
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PMID:Neurokinin-receptor antagonists: pharmacological tools and therapeutic drugs. 927 38

Systemic tachykinin NK1 receptor antagonists and resiniferatoxin are known to abolish vomiting mediated by vagal afferents. Emetic vagal afferents have been shown to make synaptic contact with neurons in the medial solitary nucleus. These results suggest that substance P participates in the synapse as a mediator. To examine this possibility, the effects of 4th-ventricular application of capsaicin (0.033-33 mM, 20-30 microl) and resiniferatoxin (1.6-160 microM, 20-30 microl) on the activity of neurons in the medial solitary nucleus and fictive retching induced by vagal stimulation were observed in paralyzed decerebrate dogs. Capsaicin (33 mM) and resiniferatoxin (160 microM) initially increased the neuronal firing and occasionally produced retching, then abolished both neuronal and retching responses. However, stimulation of the medial solitary nucleus continued to provoke retching. Field potential changes in the medial solitary nucleus evoked by pulse-train vagal stimulation decreased in amplitude, but did not disappear. Latencies of neuronal firing and evoked potentials were about 300 ms. These results suggest that emetic vagal afferents are capsaicin-sensitive C fibers which may have substance P as an excitatory transmitter or modulator.
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PMID:Capsaicin in the 4th ventricle abolishes retching and transmission of emetic vagal afferents to solitary nucleus neurons. 947 34

The tachykinin NK1 receptor antagonist, GR205171 ([2-methoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-(2S-phenyl -piperidin-3S-yl)-amine), is a potent inhibitor of emesis induced by a wide variety of emetogens. This is in contrast to 5-HT3 (5-hydroxytryptamine3) receptor antagonists, such as ondansetron, which have a more restricted antiemetic profile. The present study evaluated the efficacy of GR205171, in comparison with ondansetron to block the acquisition of a conditioned taste aversion induced by either apomorphine (0.25 mg kg(-1) s.c.) or by amphetamine (0.5 mg kg(-1) s.c.) in rats. Pretreatment with GR205171 (0.1-1.0 mg kg(-1) s.c.) and ondansetron (0.001-0.1 mg kg(-1) s.c.) produced a dose-dependent blockade of conditioned taste aversions evoked by apomorphine. In contrast, the acquisition of conditioned taste aversions induced by amphetamine was inhibited by GR205171 (0.3-0.5 mg kg(-1) s.c.), but only attenuated by ondansetron (0.001-0.1 mg kg(-1) s.c.). These results suggest that tachykinin NK1 receptor antagonists may have potential in the treatment of drug-induced conditioned aversive behaviour and nausea.
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PMID:GR205171 blocks apomorphine and amphetamine-induced conditioned taste aversions. 972 44

Tachykinin NK1 receptor antagonists injected into the medulla oblongata are known to abolish vomiting induced by vagal afferent stimulation. Emetic vagal afferents have been shown to synapse with neurons in the medial solitary nucleus (mNTS), which suggests that substance P is a transmitter in the synapse. To examine this possibility, the effects of GR205171, an NK1 receptor antagonist, on retching and mNTS neuronal responses to the stimulation of abdominal vagal afferents were investigated in decerebrate dogs. GR205171 (0.05-0.7 mg kg-1, i.v.) abolished retching induced by either vagal or mNTS stimulation within 5 min. Firing of mNTS neurons in response to pulse-train and sustained vagal stimulation did not change even after the abolition of retching. Similarly, GR205171 did not have any effects on mNTS evoked potentials induced by pulse-train vagal stimulation. In about 20% of mNTS neurons, the peak firing frequency was facilitated to about 150% with repetitive pulse-train vagal stimulation. This facilitation remained even after the abolition of retching. Administration of GR205171 (1 mg ml-1, 30 microliters) into the 4th ventricle abolished retching, with latencies in excess of 120 min These results suggest that substance P does not participate in synaptic transmission between emetic vagal afferents and mNTS neurons in dogs.
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PMID:The tachykinin NK1 receptor antagonist GR205171 prevents vagal stimulation-induced retching but not neuronal transmission from emetic vagal afferents to solitary nucleus neurons in dogs. 974 89


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