Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027497 (nausea)
 23,468 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ten patients with severe dementia due to Alzheimer's disease (AD) or multi-infarct dementia (MID) or both, were treated with the precursor amino acids of the neurotransmitters serotonin and dopamine. The precursor amino acids (PAA) were given orally in a preparation that included tyrosine (4 gm daily) and 5-hydroxy-tryptophan (5-HTP) (800 mg daily), plus carbidopa (100 mg daily) as an aromatic amino-acid decarboxylase inhibitor. Diagnosis was established by an electroencephalogram, brain scan, computerized axial tomographic scan, and in one case by necropsy findings. Serial clinical evaluations and measurements of neuropsychologic function were performed. Levels of homovanillic acid (HVA) and 5-hydroxyindole-acetic acid (5-HIAA) were determined before and after administration of probenecid. Side effects of the PAA therapy were diarrhea, drowsiness, nausea, vomiting and agitation, all of which were controlled by reducing the dosage. One patient with MID and one with AD+MID showed clinical and psychologic improvement, but the others did not improve. Analysis of the cerebrospinal fluid for HVA and 5-HIAA before and after the probenecid test indicated some improvement in the metabolic turnover of these acid metabolites of serotonin and dopamine after administration of their precursor amino acids.
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PMID:Neurotransmitter precursor amino acids in the treatment of multi-infarct dementia and Alzheimer's disease. 30 Nov 48

The dorsal vagal complex of the medulla oblongata, comprising the nucleus tractus solitarii, the area postrema and the dorsal motor nucleus of the vagus nerve, is an important brainstem regulatory center for the autonomic nervous system. The major afferent input from abdominal and thoracic viscera to this region is via vagal sensory neurons which have their cell bodies in the nodose ganglion. Autoradiography has been used to study the effects of unilateral nodose ganglionectomy on receptor binding sites in this region of the brain for the neurotransmitters acetylcholine, norepinephrine, and opioids. Nodose ganglionectomy had no discernible effect on alpha 2 noradrenergic ([3H]p-aminoclonidine) or mu opioid [( 3H]Tyr-D-Ala-Gly-(NMePhe)-Gly-ol) binding sites. However, ganglionectomy did produce a 25% decrease in [3H]quinuclidinyl benzilate (muscarinic cholinergic) binding in the subnucleus gelatinosus of the solitary nucleus, and a marked decrease in [3H][D-Pen5]enkephalin (delta opioid) binding in the dorsomedial subnucleus of the nucleus tractus solitarii, ipsilateral to the lesion. These data suggest that muscarinic cholinergic and delta opioid receptors may be present on terminals of vagal afferent neurons that project to these specific brainstem regions. Since these vagal afferent neurons are known to arise, at least in part, from the gastrointestinal tract, it is possible that cholinergic and/or opioid receptors modulate specific autonomic functions associated with gastric sensory information such as satiety or nausea and emesis.
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PMID:Nodose ganglionectomy selectively reduces muscarinic cholinergic and delta opioid binding sites in the dorsal vagal complex of the cat. 255 41

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

Conditioned taste aversion (CTA) is a well established learning and memory paradigm in rats and mice that is considered to be a special form of classical conditioning. Rodents--as well as many other species including man--learn to associate a novel taste (CS) with nausea (US), and as a consequence avoid drinking fluid with this specific taste. In contrast to other types of classical conditioning, even CS-US intervals lasting several hours lead to an aversion to the gustatory CS. With increasing CS-US delay duration, however, the aversion against the CS gradually decreases. Mice differ from rats in their reaction to the CS as well as the US. They tolerate a much higher concentration of saccharin and they do not show any clear signs of nausea when injected with the US. Advantages of this task are its relative independence of motor behavior, well described pathways for the CS and partly the US, and the wealth of available anatomical and pharmacological data implying several brain structures (e.g. parabrachial nucleus, amygdala, insular cortex), neurotransmitters and their receptors (e.g. cholinergic system, NMDA-receptors), and cellular processes (e.g. expression of immediate early genes, Ras-MAP kinase signaling pathway, CREB phosphorilation, protein tyrosine phosphorilation, protein synthesis) in CTA. The CTA paradigm has also been successfully used to phenotype mouse mutants.
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PMID:Conditioned taste aversion as a learning and memory paradigm. 1168 12

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

On May 5, 2003, gefitinib (Iressa; ZD1839) 250-mg tablets (AstraZeneca Inc.) received accelerated approval by the United States Food and Drug Administration as monotherapy for patients with locally advanced or metastatic non-small cell lung cancer after failure of both platinum-based and docetaxel chemotherapies. Information provided in this summary includes chemistry manufacturing and controls, clinical pharmacology, and clinical trial efficacy and safety results. Gefitinib is an anilinoquinazoline compound with the chemical name 4-quinazolinamine,N-(3-chloro-4-flurophenyl)-7-methoxy-6-[3-(4-morpholinyl)propoxy]. It has the molecular formula C(22)H(24)ClFN(4)O(3). Gefitinib is often referred to as a "specific" or "selective" inhibitor of epidermal growth factor receptor. Studies demonstrate, however, that gefitinib inhibits the activity of other intracellular transmembrane tyrosine-specific protein kinases at concentrations similar to those at which it inhibits the epidermal growth factor signal. Maximum plasma concentrations resulting from clinically relevant doses are 0.5-1 microM or more, well within the IC(50) values of several tyrosine kinases. No clinical studies have been performed that demonstrate a correlation between epidermal growth factor receptor expression and response to gefitinib. Gefitinib is 60% available after oral administration and is widely distributed throughout the body. Gefitinib is extensively metabolized in the liver by cytochrome P450 3A4 enzyme. Over a 10-day period, approximately 86% of an orally administered radioactive dose is recovered in the feces, with <4% of the dose in the urine. After daily oral administration, steady-state plasma levels are reached in 10 days and are 2-fold higher than those achieved after single doses. Gefitinib effectiveness was demonstrated in a randomized, double-blind, Phase II, multicenter trial comparing two oral doses of gefitinib (250 versus 500 mg/day). A total of 216 patients were enrolled. The 142 patients who were refractory to or intolerant of a platinum and docetaxel comprised the evaluable population for the efficacy analysis. A partial tumor response occurred in 14% (9 of 66) of patients receiving 250 mg/day gefitinib and in 8% (6 of 76) of patients receiving 500 mg/day gefitinib. The overall objective response rate (RR) for both doses combined was 10.6% (15 of 142 patients; 95% confidence interval, 6.0-16.8%). Responses were more frequent in females and in nonsmokers. The median duration of response was 7.0 months (range, 4.6-18.6+ months). Other submitted data included the results of two large trials conducted in chemotherapy-naive, stage III and IV non-small cell lung cancer patients. Patients were randomized to receive gefitinib (250 or 500 mg daily) or placebo, in combination with either gemcitabine plus cisplatin (n = 1093) or carboplatin plus paclitaxel (n = 1037). Results from this study showed no benefit (RR, time to progression, or survival) from adding gefitinib to chemotherapy. Consequently, gefinitib is only recommended for use as monotherapy. Common adverse events associated with gefitinib treatment included diarrhea, rash, acne, dry skin, nausea, and vomiting. Interstitial lung disease has been observed in patients receiving gefitinib. Worldwide, the incidence of interstitial lung disease was about 1% (2% in the Japanese post-marketing experience and about 0.3% in a United States expanded access program). Approximately one-third of the cases have been fatal. Gefitinib was approved under accelerated approval regulations on the basis of a surrogate end point, RR. No controlled gefitinib trials, to date, demonstrate a clinical benefit, such as improvement in disease-related symptoms or increased survival. Accelerated approval regulations require the sponsor to conduct additional studies to verify that gefitinib therapy produces such benefit.
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PMID:United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets. 1497 17

There is no effective treatment for melanoma, a fatal skin cancer occurring with increasing frequency. Dietary tyrosine restriction lowers systemic tyrosine and suppresses the growth of melanoma in mice, but this is not tolerated by human resulting in nausea, vomiting, and weight loss. We report here the successful use of oral polymeric microcapsules containing tyrosinase to lower the systemic tyrosine level in the rats. We found that microencapsulated tyrosinase incubated with intestinal content of rats selectively lowered the tyrosine level. We then studied the daily oral administration of microencapsulated tyrosinase in rats of one dose a day, two doses a day, and three doses a day over a period of up to 22 days. With three doses a day, the tyrosine levels in the test group decreased to 68.8% of the control group by day 4 and then decreased to 52.6% after this and remained at this level throughout the 22 days test period. This is the level shown earlier by other workers using dietary restriction of tyrosine to result in suppression of growth of melanoma. However, unlike dietary tyrosine restriction, oral tyrosinase microcapsules did not result in adverse effects nor significant differences in growth (weight gain) when compared to the control group. This approach can also be used for the lowering of systemic tyrosine in hypertyrosinemia, an inborn error of metabolism.
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PMID:Effects of long-term oral administration of polymeric microcapsules containing tyrosinase on maintaining decreased systemic tyrosine levels in rats. 1499 21

Melanoma is now the fifth most common type of cancer in North America. At present, there is no optimal treatment for this cancer. However, the lowering of the tyrosine level can inhibit the growth of melanoma. Unfortunately, this diet restriction cannot be humanly tolerated and causes vomiting, nausea, and severe body weight loss. To prevent these problems, we are studying a new approach involving the preparation intermolecularly crosslinked hemoglobin and tyrosinase for intravenous injection. In this article we describe the method of preparation and the structural and functional properties of polyhemoglobin-tyrosinase. We evaluate the effects of varying glutaraldehyde ratio, crosslinking time, and enzyme concentration on the enzyme activity of polyhemoglobin-tyrosinase. We also optimize the molecular weight distribution of polyhemoglobin-tyrosinase. The stability of polyhemoglobin-tyrosinase at 37 degrees C is much more stable when compared to noncrosslinked tyrosinase solution. Animal studies show that a higher degree of polymerization correlates with a longer circulation time of polyhemoglobin-tyrosinase, and the optimal crosslinking time is 24 hours. One intravenous injection of polyhemoglobin-tyrosinase lowers the plasma tyrosine to about 10% of its original level within one hour.
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PMID:In vitro and in vivo enzyme studies of polyhemoglobin-tyrosinase. 1516 60

Melanoma is an increasingly common fatal skin cancer. Many groups are carrying out research on potential treatments for melanoma. One of these approaches has shown that lowering tyrosine can inhibit the growth of melanoma in cell cultures and of B16BL6 melanoma in mice. However, humans cannot tolerate tyrosine-restricted diets for lowering tyrosine because of nausea, vomiting and weight loss. We report here our preparation and characterization of a novel soluble polyhaemoglobin-tyrosinase complex. This preparation prevents native tyrosinase from having adverse effects and from rapid removal after injection. The preparation inhibited murine B16F10 melanoma cell growth in culture and delayed its growth in a mice model. Intravenous injection of the preparation lowers the systemic tyrosine level without causing adverse effects such as vomiting and weight loss in mice. It is therefore possible that this complex could be useful in the treatment of human melanoma.
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PMID:In vitro and in vivo effects of polyhaemoglobin-tyrosinase on murine B16F10 melanoma. 1517 88

Melanoma now represents the fifth most common cancer in North America and it has increased dramatically in the past decade. One of the approaches shows that lowering of tyrosine level can inhibit the growth of melanoma in cell culture and in mice bearing B16BL6 melanoma. However, human cannot tolerate the tyrosine restricted diets for lowering tyrosine due to nausea, vomiting, and severe body weight loss. We therefore prepare a novel soluble polyhemoglobin-tyrosinase complex. Our studies show that this preparation can lower systemic tyrosine level in normal animals. This preparation also prevents the native tyrosinase from having adverse effects and from rapid removal after injection. In cell culture study, we find that this preparation inhibits the growth of murine B16F10 melanoma culture. Furthermore, in animal studies we observe that daily intravenous injection of this polyhemoglobin-tyrosinase preparation significantly delays the growth of B16F10 melanoma in mice, without causing adverse effects or changes in the growth of the treated animals.
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PMID:Polyhemoglobin-tyrosinase, an oxygen carrier with murine B16F10 melanoma suppression properties: a preliminary report. 1527 34


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