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 effects of the putative dopamine agonist, ciladopa hydrochloride (AY 27,110) a non-ergot compound, were investigated in animal models of dopaminergic activity to evaluate its possible role in the treatment of Parkinson's disease. Ciladopa induced stereotyped behavior in both rats and guinea pigs. Unlike apomorphine, however, ciladopa did not produce a maximum behavioral response, i.e. stereotyped gnawing. Pretreatment with haloperidol and sulpiride blocked the effects induced by ciladopa. Pretreatment with reserpine and alpha-methyl-p-tyrosine did not alter the behavioral effects of ciladopa. Ciladopa caused contralateral rotation in rats with unilateral lesions of the substantia nigra induced by 6-hydroxydopamine. Ciladopa induced vomiting in dogs. Small doses of ciladopa decreased locomotor activity in rats, an effect presumably mediated by presynaptic autoreceptors. The chronic injection of both subthreshold and suprathreshold doses of ciladopa failed to induce behavioral supersensitivity. Ciladopa binds to D-2 dopamine receptors in the mammalian caudate nucleus. These data indicate that ciladopa can cause stimulation of central dopaminergic receptors and that the drug is a partial dopamine agonist with direct-acting properties. Ciladopa differs from other available dopaminergic drugs and may possess therapeutic advantages for the treatment of Parkinson's disease.
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PMID:Evaluation of ciladopa hydrochloride as a potential anti-Parkinson drug. 377 30

The experiments concerned the pharmacology of the enantiomers of the phenethyl-analogue (3-phenethyl-PP) of the putative dopamine (DA) autoreceptor agonist 3-PPP. In contrast to the almost equipotency of 3-PPP enantiomers, the phenethyl enantiomers showed marked stereoselectivity. S(+)-3-Phenethyl-PP had 25 times higher affinity to D-2 DA receptors in vitro than the R(-)-enantiomer. In vivo a similar potency difference was seen for the inhibition of motility, induction of circling behaviour in 6-OHDA-lesioned rats and emetic effect in dogs. None of the enantiomers induced stereotypy and hypermotility in normal rats or in rats pretreated with reserpine and alpha-methyl-p-tyrosine. In test models for antidopaminergic activity only slight activity of either enantiomer was observed. The S(+)-enantiomer had no antagonistic effect against apomorphine- and amphetamine-induced stereotypies, no cataleptogenic activity and only partially antagonized amphetamine-induced hypermotility. Apomorphine-induced emesis was weakly antagonized. The results indicate a greater and higher selectivity of S(+)-3-phenethyl-PP for DA receptors mediating sedation compared with 3-PPP enantiomers which previously have been shown to exert significant effects on postsynaptic DA receptors. Thus S(+)-3-phenethyl-PP may be a more selective model compound for the differential study of effects elicited by stimulation of pre- and postsynaptic DA receptors.
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PMID:Effects of S (+)-3-phenethyl-PP, a putative dopamine autoreceptors agonist with greater autoreceptor selectivity than 3-PPP enantiomers. 614 47

Those structural features of enkephalins (ENK) responsible for in vitro organ bath and receptor binding activity have been investigated in detail in the conscious, chronically instrumented dog. Amide analogs of Leu5-ENK display reduced activity, which is restored by D-Ala2 substitutions. N-terminal L-Tyr is required for full opiate activity. Although proven delta-receptor agonists do appear generally more active, distinctions made in vitro between mu and delta binding are not apparent in the complex hemodynamic responses which occur in the intact unanesthetized dog. The amphibian skin peptide dermorphin, which contains D-Ala2, elevates heart rate, systemic arterial pressure, and induces vomiting with near maximal activity at a dose of 1.0 microgram/kg; this activity is inhibited by naloxone. This activity, coupled with dermorphin's apparent presence in mammalian tissue, suggests that it may represent another peptide factor in cardiovascular regulation. In the conscious dog, ENK elevate heart rate and systemic arterial pressure; this activity does not appear to be fully explained by in vitro receptor models.
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PMID:Enkephalin analogs and dermorphin in the conscious dog: structure-activity relationships. 716 98

The putative dopamine (DA) autoreceptor agonists, N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and 6, 7-dihydroxy-2-dimethylaminotetralin (TL-99) were compared with apomorphine in a series of tests indicative of DA receptor activation. All three agents displaced [3H] apomorphine and [3H] spiroperidol from DA recognition sites in rat brain and caused contralateral turning in the 6-hydroxydopamine lesioned rat. Apomorphine and TL-99 were generally more potent than 3-PPP. All three agents were also active at the DA autoreceptor that controls the synthesis of dopamine as indicated in vivo using the gamma-butyrolactone (GBL) procedure and in vitro using a synaptosomal preparation. In addition, all agents produced emesis in beagles. clear differences in the drugs' actions were observed in other test procedures. In the rat, apomorphine was the only compound which caused stereotypy or rotation following a reversible KCI-induced lesion of the striatum. Conversely, TL-99 and 3-PPP lacked activity in these procedures. Presumably, activity in these two tests indicates postsynaptic DA receptor activation. Each of the putative autoreceptor agonists produced a monotonic dose-related decrease in the mouse locomotor activity as opposed to the biphasic effect exerted by apomorphine. This action on the mouse locomotor activity, coupled with the results for the GBL test, provides an index of autoreceptor activation. In contrast to 3-PPP, both apomorphine and TL-99 increased locomotor activity in animals pretreated with reserpine and alpha-methyl-p-tyrosine and caused rotation in unilaterally caudectomized mice. In these test procedures thought to reflect activity at the postsynaptic DA receptor, TL-99 differed in its action from 3-PPP in a manner which suggests 3-PPP may be a more selective DA autoreceptor agonist.
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PMID:Pharmacological profiles of the putative dopamine autoreceptor agonists 3-PPP and TL-99. 731 20

Intracerebroventricular injection of dopamine (0.5-4.0 mg) produced dose-dependent and short-lasting emesis (1-8 min) in cats, which was abolished after ablation of the area postrema. Relatively selective alpha 2-adrenoceptor antagonists (yohimbine and idazoxan) and a mixed alpha 1- and alpha 2-adrenoceptor antagonist (tolazoline), but not a non-selective alpha 1-adrenoceptor antagonist (prazosin), injected intracerebroventricularly inhibited the emesis induced by intracerebroventricular dopamine. However, dopamine receptor antagonists (chlorpromazine, droperidol, spiperone, domperidone, triflupromazine, sulpiride and metoclopramide), an antimuscarinic drug (atropine), a ganglionic blocking agent (mecamylamine), an opioid receptor antagonist (naloxone) and a 5-HT receptor antagonist (methysergide), all injected intracerebroventricularly, had no significant effect on emesis evoked by intracerebroventricular dopamine. The emetic response to intracerebroventricular dopamine was attenuated in cats pretreated with intracerebroventricular reserpine, 6-hydroxydopamine, alpha-methyl-p-tyrosine and hemicholinium-3. It is postulated that dopamine-induced emesis is mediated through the release of noradrenaline acting at alpha 2-adrenoceptors and that it depends on the integrity of monoaminergic and possibly cholinergic structures within the area postrema. It appears, therefore, that the emetic effect of intracerebroventricular dopamine is mediated by adrenergic rather than dopaminergic mechanisms in the area postrema, at least in the cat.
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PMID:The role of alpha-adrenergic mechanisms within the area postrema in dopamine-induced emesis. 771 46

The emetic effect of clonidine injected into the cerebral ventricles through chronically implanted cannulae was investigated in unanaesthetized cats. Clonidine (0.1-300 micrograms) induced dose-dependent and shortlasting emesis. The emesis induced by the supramaximal dose of clonidine (100 micrograms) was not abolished after the ablation of area postrema. Both the alpha 2 adrenoceptor blocking agent idazoxan and the mixed alpha 1 and alpha 2 adrenoceptor antagonist phenoxybenzamine, injected intracerebroventricularly, attenuated or abolished the emesis induced by clonidine (100 micrograms). On the other hand, the alpha 2 adrenoceptor blocking agent yohimbine, the alpha 1 adrenoceptor blocking drug prazosin and the non-selective beta-adrenoceptor antagonist propranolol, injected into the cerebral ventricles, had no significant effect on clonidine-induced emesis. The antimuscarinic drug atropine injected into the cerebral ventricles prevented the clonidine-induced emesis in a dose-dependent manner. The dopamine antagonist chlorpromazine, the 5-hydroxytryptamine blocking agent methysergide and the histamine H1 and H2 receptor antagonists, antazoline and cimetidine, injected intracerebroventricularly reduced or abolished the emesis produced by clonidine. The ganglionic blocking substance mecamylamine and the opioid antagonist naloxone, all injected into the cerebral ventricles, had no significant effect on clonidine-induced emesis. In cats pretreated with the intracerebroventricular competitive inhibitor of the synthesis of catecholamines, alpha-methyl-p-tyrosine, as well as with the inhibitor of acetylcholine synthesis hemicholinium-3, the emesis caused by clonidine was depressed or abolished. The clonidine-induced emesis was also abolished when catecholamine stores were depleted by intracerebroventricular reserpine. However, the clonidine-induced emesis was not significantly changed when 5-hydroxylryptaminergic nerve terminals were damaged by 5,6-dihydroxytryptamine. It follows, therefore, that cholinergic and noradrenergic mechanisms are of basic importance for the emetic action of clonidine. With regard to receptors, the emesis induced by clonidine injected into the cerebral ventricles, is mediated at least in part through alpha-adrenoceptors, muscarinic cholinoceptors, 5-hydroxytryptamine receptors and H1 and H2 histamine receptors. These receptors appear to be located mostly presynaptically and they transmit emetic impulses to neurones integrating them into emesis. However, the direct effect of clonidine on postsynaptic receptors cannot be excluded, particularly when muscarinic and 5-hydroxytryptamine receptors are implicated. Taken together, these results point to the existence of a multitransmitter pathway/s outside the area postrema, subserving the central regulation of emesis.
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PMID:Clonidine-induced emesis: a multitransmitter pathway concept. 926 44

Tyrosinemia type l is an inherited metabolic disorder attributable to deficiency of fumarylacetoacetate hydrolase, a terminal enzyme in the degradation pathway of tyrosine. Affected individuals may present with any of a number of signs and symptoms, including failure to thrive, fever, vomiting, diarrhea, hepatomegaly, ascites, jaundice, renal Fanconi syndrome, or conditions such as rickets and hepatocellular carcinoma.1 If untreated, the patient may die of acute liver failure before the second year of life, or from chronic liver failure or hepatocellular carcinoma before the end of the second decade of life.2 Although overt liver failure with coagulopathy may be part of the presentation of tyrosinemia, a significant coagulopathy in the absence of overt signs of liver disease has not been emphasized as a clue to the diagnosis of this condition. We report two tyrosinemic infants who presented with severe coagulopathies and no other signs of liver failure to stress this diagnostic point.
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PMID:Tyrosinemia type 1 should be suspected in infants with severe coagulopathy even in the absence of other signs of liver failure. 1004 78

Hereditary tyrosinemia results from an inborn error in the final step of tyrosine metabolism. Neurological manifestations have been reported in nearly half of patients during illness to have characteristics of altered consciousness, weakness, anorexia, vomiting, and pain in the extremities and abdomen. His physical findings and laboratory results pointed out acute pancreatitis. There have been some reports of acute and chronic pancreatitis in patients with metabolic diseases; however, this is the first case with tyrosinemia type I who exhibited clinical and biochemical findings of acute pancreatitis during neurological crisis. The presented case suggests the possibility that the pancreas is affected in neurological crisis. The determination of amylase concentration both in serum and urine samples of further cases will clarity the association between pancreatitis and neurological crisis.
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PMID:Neurological crisis mimicking acute pancreatitis in tyrosinemia type I. 1077 Jan 19

Using the technique of site-directed mutagenesis, point mutants of human PDE4A have been developed in order to identify amino acids involved in inhibitor binding. Relevant amino acids were selected according to a peptidic binding site model for PDE4 inhibitors, which suggests interaction with two tryptophan residues, one histidine and one tyrosine residue, as well as one Zn(2+) ion. Mutations were directed at those tryptophan, histidine, and tyrosine residues, which are conserved among the PDE4 subtypes (PDE4A-D) and lie within the high-affinity 4-[3-(cyclopentoxyl)-4-methoxyphenyl]-2-pyrrolidone (rolipram) binding domain of human PDE4A (amino acids 276-681 according to the PDE4A sequence L20965). Truncations to this region do not alter enzyme activity or inhibitor sensitivity. The mutants were expressed in COS1 cells, and the recombinant cyclic nucleotide phosphodiesterase (PDE) forms have been characterized in terms of their catalytic activity and inhibitor sensitivities. Tyrosine residues 432 and 602, as well as histidine 588, were found to be involved in inhibitor binding, but no interaction was detected between tryptophan and PDE inhibitors tested. To test the possibility that other amino acids are of importance for hydrophobic interactions, selected phenylalanine residues were also mutated. We found phenylalanine 613 and 645 to influence inhibitor binding to PDE4. The significant differences in the inhibitor sensitivities of the mutants show that the various inhibitors have different enzyme binding sites. Based on the assumption that the known side effects of PDE4 inhibitors (like emesis and nausea) are caused directly by selective inhibition of different conformation states of PDE4, our results may be a hint to differ between PDE4 inhibitors, which have emetic side effects (like rolipram), and those that do not have side effects (like N-(3,5-dichlorpyrid-4-yl)-[1-(4-fluorbenzyl)-5-hydroxy-indol-3-yl]-glyoxylateamide [AWD12-281]) by the differences of their binding sites and in that context contribute to the development of novel drugs. Furthermore, the identification of amino acid interactions proposed by the peptidic binding site model, which was used for the mutant selection, verifies the PrGen modeling as a useful method for the prediction of inhibitor binding sites in cases where detailed knowledge of the protein structure is not available.
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PMID:Identification of inhibitor binding sites of the cAMP-specific phosphodiesterase 4. 1130 46

PTK787/ZK 222584 (PTK/ZK) is an oral potent and selective inhibitor of the vascular endothelial growth factor (VEGF)-mediated Flt-1 and KDR receptor tyrosine kinases. PTK/ZK has been shown to reduce growth and microvasculature in subcutaneously implanted human tumor xenografts in nude mice. A clinical difficulty in evaluating angiogenesis inhibitors has been the usefulness of conventional study endpoints. Therefore, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has been studied as a pharmacodynamic marker of efficacy of PTK/ZK. Phase I studies are under way evaluating the optimum dose and schedule of oral PTK/ZK administered continuously to patients with advanced cancers of types known to overexpress VEGF. To date, particularly in patients with liver metastases from colorectal cancer treated with PTK/ZK, DCE-MRI has been a useful predictor of the biological response of VEGF-receptor inhibition. Toxicities have been manageable and have included lightheadedness, ataxia, nausea, vomiting, and hypertension. Stabilization of disease for >/= 6 months has been seen in heavily pretreated patients receiving PTK/ZK at higher doses. Preliminary data suggest that PTK/ZK can be administered safely on a continuous daily dosing schedule, efficacy data look promising, and DCE-MRI correlates with biological response. DCE-MRI will be used to guide dose optimization of PTK/ZK and perhaps of other angiogenesis inhibitors in future studies.
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PMID:Vascular endothelial growth factor receptor tyrosine kinase inhibitors: PTK787/ZK 222584. 1280 93


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