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)

Propionyl-CoA carboxylase (PCC) catalyzes the biotin-dependent carboxylation of propionyl-CoA to d-methylmalonyl-CoA in the mitochondrial matrix. Human PCC is a dodecamer composed of pairs of nonidentical alpha and beta subunits encoded by PCCA and PCCB genes, respectively. Deficiency of PCC results in propionic acidemia (PA), a metabolic disorder characterized by severe metabolic ketoacidosis, vomiting, lethargy, and hypotonia. To date, almost 60 mutations have been reported in both genes. Exon 15 of the beta subunit is one of the two sites where a number of mutations have been identified in PA patients. In the primary betaPCC sequence, these mutations lead to three substitutions (R512C, L519P, and N536D), three truncations (R499X, R514X, and W531X), and one insertion (A51_R514insP). We expressed these mutant proteins in Escherichia coli in which the GroESL complex was overexpressed. The only mutation that does not impact the stability of mutant betaPCC in bacteria is W531X. The remaining mutations lead to either complete (L519P, N536D) or partial (R499X, R512C, A513_R514insP, and R514X) degradation of the mutant subunits. Size-exclusion chromatography revealed that R512C and W531X do not affect the assembly of alphaPCC and betaPCC to active oligomers. Specific activities for these mutant proteins, however, were only 3.9 and 10% of the wild type, respectively. Taken together, the carboxyl-terminal portion of 40 amino acid residues of the beta subunit affects the stability and the assembly of the alpha and beta subunits as well as the carboxylation of propionyl-CoA.
Mol Genet Metab 2000 Dec
PMID:Changes in the carboxyl terminus of the beta subunit of human propionyl-CoA carboxylase affect the oligomer assembly and catalysis: expression and characterization of seven patient-derived mutant forms of PCC in Escherichia coli. 1113 55

Recently, we reported structurally novel PDE4 inhibitors based on 1,4-benzodiazepine derivatives. The main interest in developing bezodiazepine-based PDE4 inhibitors is in their lack of adverse effects of emesis with respect to rolipram-like compounds. A large effort has thus been made toward the structural optimization of this series. In the absence of structural information on the inhibitor binding mode into the PDE4 active site, 2D-QSAR (H-QSAR) and two 3D-QSAR (CoMFA and CoMSIA) methods were applied to improve our understanding of the molecular mechanism controlling the PDE4 affinity of the benzodiazepine derivatives. As expected, the CoMSIA 3D contour maps have provided more information on the benzodiazepine interaction mode with the PDE4 active site whereas CoMFA has built the best tool for activity prediction. The 2D pharmacophoric model derived from CoMSIA fields is consistent with the crystal structure of the PDE4 active site reported recently. The combination of the 2D and 3D-QSAR models was used not only to predict new compounds from the structural optimization process, but also to screen a large library of bezodiazepine derivatives.
J Comput Aided Mol Des 2001 Sep
PMID:CoMFA and CoMSIA 3D-quantitative structure-activity relationship model on benzodiazepine derivatives, inhibitors of phosphodiesterase IV. 1177 90

In order to elucidate the precise mechanism of ipecac syrup (TJN-119) on the occurrence of vomiting, we examined the effects of ipecac syrup on the abdominal afferent nerve activity as well as on the 5-HT levels of the ileum and area postrema in ferrets. Oral administration of TJN-119 (0.5 mg/kg) produced a significant increase in afferent abdominal vagus nerve activity which lasted approximately 1 hour. The maximum response induced by TJN-119 was estimated to be 219 +/- 18% of the pre-injection level. Cephaeline or emetine, the main alkaloids of ipecac syrup, also demonstrated similar effects on afferent vagus nerve activity. TJN-119 increased the 5-HT content in the ileum but not in the area postrema. These observations illustrate possible mechanisms that may act at peripheral sites. It was recently reported that TJN-119 has a high affinity to 5-HT4 receptors (Hasegawa et al., unpublished data). These results suggest that 5-HT4 receptors may be involved in the emetic action of TJN-119.
Res Commun Mol Pathol Pharmacol 2000
PMID:Pharmacological aspects of ipecac syrup (TJN-119)-induced emesis in ferrets. 1191 11

In order to elucidate 5-HT release influenced by PGE2 in the background of the anticancer drug-induced emesis, the effect of nabumetone, a COX-2 inhibitor, on the release of 5-HT from the isolated rat ileum was investigated. PGE2 produced a concentration-dependent increase (10(-9) to 10 M) and decrease (10(-8) to 10(-6) M) in 5-HT release. Arachidonic acid also demonstrated a similar bell-shaped 5-HT release. The arachidonic acid-induced 5-HT release at 3 x 10(-6) M (313.04 +/- 25.90%) was significantly inhibited by the concomitant perfusion with BRL10720 (10(-6) M) (161.98 +/- 19.4%, p<0.01), an active metabolite of nabumetone, or indomethacin (3 x 10(-7) M)(190.01 +/- 16.19%, p<0.05). BRL10720 (10(-6) M)(428.57 +/- 51.72%, p<0.05) significantly inhibited the increase in 5-HT release induced by cisplatin (10(-6) M)(748.56 +/- 136.31%), suggesting that PGE2would be involved in cisplatin-induced 5-HT release. The increase in 5-HT release from the isolated ileum 72 hrs after cisplatin administration, in a delayed-emesis animal model, was significantly inhibited by the in vivo 3-day administration of nabumetone or BRL10720, but was not affected by the 3-day administration of dexamethasone. After 72 hours, however, the in vivo 3-days administration of nabumetone, BRL10720 or dexamethasone had no effect on the increase in ileal 5-HT levels induced by cisplatin. The use of COX-2 inhibitors to ameliorate delayed emesis induced by cisplatin-based anticancer chemotherapy has been proposed. On the other hand, there is a possibility that dexamethasone works through a mechanism other than 5-HT release in delayed emesis.
Res Commun Mol Pathol Pharmacol
PMID:The effects of nabumetone, a cyclooxygenase-2 inhibitor, on cisplatin-induced 5-hydroxytryptamine release from the isolated rat ileum. 1209 Mar 50

Malonyl-CoA decarboxylase (E.C.4.1.1.9) catalyzes the conversion of malonyl-CoA to acetyl-CoA. Although the metabolic role of this enzyme has not been fully defined, it has been reported that its deficiency is associated with mild mental retardation, seizures, hypotonia, cadiomyopathy, developmental delay, vomiting, hypoglycemia, metabolic acidosis, and malonic aciduria. Here, we isolated a cDNA clone for malonyl CoA decarboxylase from a rat brain cDNA library, expressed it in E. coli, and characterized its biochemical properties. The full-length cDNA contained a single open-reading frame that encoded 491 amino acid residues with a calculated molecular weight of 54, 762 Da. Its deduced amino acid sequence revealed a 65.6% identity to that from the goose uropigial gland. The sequence of the first 38 amino acids represents a putative mitochondrial targeting sequence, and the last 3 amino acid sequences (SKL) represent peroxisomal targeting ones. The expression of malonyl CoA decarboxylase was observed over a wide range of tissues as a single transcript of 2.0 kb in size. The recombinant protein that was expressed in E. coli was used to characterize the biochemical properties, which showed a typical Michaelis-Menten substrate saturation pattern. The Km and Vmax were calculated to be 68 microM and 42.6 micromol/min/mg, respectively.
J Biochem Mol Biol 2002 Mar 31
PMID:Rat malonyl-CoA decarboxylase; cloning, expression in E. coli and its biochemical characterization. 1229 32

Valproic acid is a widely used drug in the treatment of epilepsy and, compared to other anticonvulsant drugs, is considered safe. The most common side effects of valproic acid ingestion or therapy are transient nausea, vomiting, abdominal cramps, and diarrhea. Most of these complaints are mild. However, more serious adverse reactions can occur such as hepatotoxicity and pancreatitis. It has been proposed that, whenever possible, valproic acid not be used in the younger child, the child with a severe seizure disorder or other neurological disorders, mental retardation, developmental delay, organic brain disease, congenital abnormalities, or the child who is taking multiple anticonvulsant drugs, as these factors may increase the likelihood of hepatotoxicity and/or pancreatitis. In the present report, we describe a fatal case of acute hemorrhagic pancreatitis in a four and a half-year-old Hispanic female child who was receiving valproic acid in combination with another anticonvulsant drug for control of focal seizures. The patient also received the macrolide antibiotic azithromycin. For pediatricians and forensic pathologists valproic acid-induced pancreatitis can be a challenging diagnosis which must not be mistaken for abdominal trauma. We discuss the workup of the patient and differential diagnosis.
Pediatr Pathol Mol Med
PMID:Pathological case of the month: sudden death in a child as a result of pancreatitis during valproic acid therapy. 1239 3

As scintigraphy with [(111)In-DTPA(0)]octreotide has become a standard technique in analysing somatostatin receptor-receptor positive lesions such as neuroendocrine tumours, a logical next step is peptide receptor radionuclide therapy (PRRT). Initial studies on PRRT were performed with high doses of [(111)In-DTPA(0)]octreotide, and recently other radionuclides coupled to other somatostatin analogues have been used for this purpose. However, the dose delivered to the kidney is a major dose-limiting factor. Amino acid solutions have previously been used to reduce renal uptake of radioactivity, but these solutions have some disadvantages, i.e. their hyperosmolarity and their propensity to cause vomiting and metabolic changes. In this study we tested various amino acid solutions in patients receiving [(111)In-DTPA(0)]octreotide PRRT in order to assess their safety and their capacity to inhibit the renal uptake of radioactivity. Patients served as their own non-infused control. Renal radioactivity at 24 h following the injection of [(111)In-DTPA(0)]octreotide was inhibited by (1) a commercially available amino acid solution (AA) (21%+/-14%, P<0.02), (2) by 25 g (17%+/-9%, P<0.04), 50 g (15%+/-13%, P<0.04) or 75 g of lysine (44%+/-11%, P<0.001) and (3) by a combination of 25 g of lysine plus 25 g of arginine (LysArg) (33%+/-23%, P<0.01). Fluid infusion alone (500, 1,000 or 2,000 ml of saline/glucose) did not change renal uptake of radioactivity. In patients studied with 75 g of lysine (Lys75) and LysArg, serum potassium levels rose significantly. Maximal potassium levels were within the toxic range (6.3, 6.7 and 6.8 mmol/l) in three out of six patients infused with Lys75, whereas with LysArg the highest concentration measured was 6.0 mmol/l. Electrocardiographic analysis did not reveal significant changes in any of the patients. Vomiting occurred in 50% of patients infused with AA, but in only 6% of patients receiving no amino acid infusion (controls) and 9% of patients receiving LysArg. We conclude that co-infusion of Lys75 or LysArg results in a significant inhibition of renal radioactivity in PRRT, allowing higher treatment doses and thus resulting in higher tumour radiation doses. Because Lys75 produced serious hyperkalaemia, it is not suitable for clinical use. LysArg, however, is effective in offering renal protection in PRRT and is safe.
Eur J Nucl Med Mol Imaging 2003 Jan
PMID:Safe and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine. 1248 4

This study evaluates the immunological response following weekly 2h infusions of recombinant human N-acetylgalactosamine 4-sulfatase (rh4S) in Mucopolysaccharidosis VI (MPS VI) cats. The results of three trials (Trial "A": 9 month duration with onset at 3-5 months of age, n = 5; and Trials "B" and "C": 6 month duration starting at birth, n = 9) were compared. No detrimental effects were noted throughout Trials B and C. Temporary hypersensitivity reactions (e.g., vomiting, diarrhoea) occurred in four cats in Trial A and were alleviated by increasing the dose of antihistamine premedication and the duration of infusion. All cats in Trial A developed antibodies to rh4S (range of final titres: 1041-134,931). All cats treated from birth showed negligible titres (range: < 50-598). In vitro inhibition of rh4S activity (up to 47%) was demonstrated with plasma from four cats with elevated titres. Significant reduction of urinary glycosaminoglycan concentration in all cats indicated the ability of rh4S to metabolize stored substrates regardless of the presence of circulating antibodies. Similarly, lysosomal storage in reticuloendothelial cells and fibroblasts of kidney interstistium, dura and skin was reduced in all cats irrespective of their antibody titre although cats with elevated titre had less beneficial effect on cardiovascular tissues (aorta smooth muscle cells, heart valve fibroblasts). Overall improvement in the disease condition (at physical, neurological, and skeletal levels) was most pronounced for cats treated from birth compared with cats treated at a later age.
Mol Genet Metab 2003 Mar
PMID:Replacement therapy in Mucopolysaccharidosis type VI: advantages of early onset of therapy. 1264 61

Enterohemorrhagic Escherichia coli are harmful human pathogens capable of causing bloody diarrhea and vomiting. An important serotype commonly associated with human illness is the E. coli O157:H7 serotype. Unlike other real-time polymerase chain reaction (PCR) methods for identifying E. coli O157:H7, this study describes the development and optimization of a real-time PCR method targeting a conserved point mutation at +93 in the uidA (gusA) gene that is unique to O157:H7, distinguishing it from non-O157:H7 serotypes. A TET-labeled Minor Groove Binder (MGB) DNA probe was designed for use in a 5' nuclease PCR assay. Using a panel of two E. coli O157:H7 strains, three E. coli non-O157:H7 strains, and one non-E. coli species, the assay was optimized for the specific detection of the E. coli O157:H7 strains. Optimal conditions were identified at high anneal/extend temperatures, low magnesium concentrations, and low probe concentrations, resulting in correct identification of E. coli O157:H7 and non-O157:H7 strains. The improved specificity of MGB probes for single base pair mismatches such as the +93 uidA mutation provides a novel approach towards rapid identification of E. coli O157:H7.
Mol Cell Probes 2003 Dec
PMID:Optimization of a 3'-minor groove binder-DNA probe targeting the uidA gene for rapid identification of Escherichia coli O157:H7 using real-time PCR. 1460 77

We examined the effects of granisetron, a 5-HT3-receptor antagonist, on the release of serotonin (5-hydroxytryptamine, 5-HT) from the isolated ileum and on histopathological changes of the intestine in a delayed-emesis rat model. The rats were studied 72 hours after receiving an intraperitoneal (i.p.) dose of cisplatin (5 mg/kg). The 5-HT content in the isolated ileum 72 hours after administration was significantly higher in the cisplatin group (26.0 +/- 3.0 ng/mg protein, p < 0.001) than in the non-drug control group (9.6 +/- 0.6 ng/mg protein). The increase in 5-HT content in the cisplatin group was significantly inhibited in rats pretreated with granisetron (17.5 +/- 2.2 ng/mg protein, p < 0.05). The release of 5-HT from the isolated ileum was significantly greater in the cisplatin group (11,963.0 +/- 2,104.6 ng x hr/g tissue, p < 0.01) than in the non-drug control group (2,861.0 +/- 210.7 ng x hr/g tissue). The increased 5-HT release from the isolated ileum in the cisplatin group was significantly inhibited in rats pretreated with granisetron (3,359.8 +/- 494.3 ng x hr/g tissue, p < 0.01). Disarrangement of intestinal villi, luminal dilatation of crypts and decreased numbers of goblet cells were observed in the cisplatin group. The group pretreated with granisetron showed mild macroscopic and histopathological changes, but no significant weight loss. The histopathological changes of the intestinal mucosa were apparently associated with the release of 5-HT. Our results suggest that 5-HT release from the enterochromaffin cells, accompanied by histopathological changes of the intestinal mucosa, is involved in the onset of delayed emesis after administration of cisplatin. These findings suggest that treatment with granisetron before the administration of anticancer drugs may prevent delayed emesis and intestinal disturbances associated with anticancer drugs.
Res Commun Mol Pathol Pharmacol 2002
PMID:Effects of granisetron, a 5-HT3 receptor antagonist, on 5-hydroxytryptamine (5-HT) release from the isolated ileum in a delayed-emesis rat model. 1463 14


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