Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003123 (anorexia)
 13,794 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Congenital methylmalonic aciduria (MMA) is a metabolic disorder inherited by an autosomal recessive trait. The metabolic block is located in the catabolic pathway of propionyl-CoA to succinyl-CoA. Biochemically, four enzymatic defects have been recognized, i.e.: 1. Methylmalonyl-CoA racemase. 2. Methylmalonyl-CoA mutase apoenzyme. 3. Synthesis of desoxyadenosyl-cobalamine. 4. Disturbance at an earlier level of cobalamine metabolism which causes defective synthesis of both vitamin B12-coenzymes. These four enzymatic defects express themselves in three ways: non-vitamin B12-dependent MMA (defects 1 and 2); vitamin B12-dependent MMA (defect 3); MMA associated with homocystinuria (defect 4). The various forms of MMA cannot be distinguished clinically from one another. The disorder manifests itself during the first few days to weeks of life. Principal symptoms and signs are: anorexia, vomiting, muscular hypotonia and metabolic acidosis. The diagnosis is established by determination of methylmalonic acid in plasma, cerebrospinal fluid and urine, as well as by assay of enzyme activities in leukocytes, liver tissue or cultured fibroblasts (from biopsied skin). A prenatal diagnosis is feasible by the examination of cultured amnion cells, amniotic fluid and maternal urine. Therapy of non vitamin B12-dependent MMA calls for reduction of protein intake, particularly that of precursors of methylmalonic acid, such as methionine, threonine, isoleucine and valine. The treatment of vitamin B12-dependent forms is accomplished by i.m. injection of high doses of vitamin B12. No definite statement can be made as yet with regard to long-term prognosis and normalcy of mental development in treated children.
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PMID:[Methylmalonic aciduria. Classification, diagnosis and therapy (author's transl)]. 31 93

The nutritional effects of low-protein diets are difficult to assess in humans. Normal and uraemic growing rats were therefore fed: a moderately low-protein (12%) reference diet (diet R), two 5% casein diets, one supplemented with essential amino acids (AA) (diet A) and the other with their keto acids (diet K), and a 7% casein diet isonitrogenous with diet K (diet L). Appetite and growth of both uraemic and control rats were identical on diets R and A and were reduced on diets K and L. Stunting was prominent in rats fed diet L and more severe than in those on diet K. Diet K induced marked anorexia in controls. This effect was smaller in uraemic rats, which were all anorectic, regardless of the diet. Plasma essential AA were similar in rats on diets R and A but low in control rats fed diets L and K. In particular, diet K did not improve the branched-chain AA levels although it produced better growth than diet L. Plasma and muscle threonine were surprisingly elevated in rats on the semi-synthetic diets A and K, despite identical or lower consumptions. Regardless of the diet, uraemia resulted in unchanged or increased plasma essential AA, despite reduced appetite and stunting. Uraemia caused a marked rise in some non-essential AA. Muscle essential AA, except for threonine, were essentially unaltered and did not correlate with growth or uraemia.
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PMID:Growth, free plasma and muscle amino-acids in uraemic rats fed various low-protein diets. 186 87

Histidine (His) is elevated in plasma and brain during protein deficiency as well as in several pathological conditions, leading to the possibility of a direct effect on central nervous system (CNS) function. In this study, groups of weanling rats were fed diets containing graded levels of casein or a single indispensable amino acid (IAA: Leu, Val, Ile, Phe, Trp, Thr, Met or Lys) in order to produce nutritionally-deficient states. Body weight gains and food intakes were recorded daily for 2 wk. Whole brain and serum samples were obtained and analyzed for amino acid (AA) content. All weight gain and food intake responses could be predicted by the Saturation Kinetics Model. The only consistent pattern observed in AA profiles which could be correlated with food intake was an increase in brain His concentrations. Limiting dietary casein or IAA elevated brain His above controls 2.5- and 1.5-fold, respectively. Food intake was generally depressed by 50% at brain His concentrations above 105 nmol/g. Since His is the precursor of the depressant neurotransmitter histamine (HA), systemic increases may be significant in that HA could be a possible cause of the anorexia observed in protein and IAA deficiency.
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PMID:Brain histidine and food intake in rats fed diets deficient in single amino acids. 291 35

The effect of anterior cingulate cortex lesions on dietary intake and adaptation of disproportionate amounts of amino acids was examined. Rats with bilateral electrolytic lesions in the anterior cingulate cortex and sham-operated rats were fed, in turn, amino acid basal, imbalanced or devoid diets involving threonine and isoleucine as the growth limiting amino acids, and then a low protein (6% casein) followed by a high protein (75% casein) diet. Lesions of the anterior cingulate cortex did not prevent the initial depression in food intake of the amino acid imbalanced diets, but shortened the duration of anorexia associated with dietary amino acid imbalances. Cingulate lesions did not influence the food intake of rats fed amino acid devoid diets. When switched from a low protein to a high protein diet, animals bearing lesions and sham-operated controls reduced markedly their initial food intake and adapted to the high protein diet in similar manner. It was concluded that the initial food intake depression associated with a dietary amino acid imbalance is a direct response to postingestive cues which influence food intake. Moreover, that the difference in adaptive intakes of the cingulate cortex lesioned animals who ingested a diet of imbalanced amino acids or of high protein, indicates that separate mechanisms act to control food intake of animals fed diets containing imbalanced amino acid mixtures or diets with excessive amounts of protein.
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PMID:Cingulate lesions and behavioral adaptation to amino acid imbalanced diets. 640 12

To study the possible role of several amino acids on feeding in the anorexia of aging, we have measured plasma and cerebrospinal fluid (CSF) concentrations of 22 amino acids in 14 elderly persons with idiopathic anorexia and 10 healthy subjects with normal weight in a similar age range. Plasma and CSF amino acid concentrations and CSF homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels were all measured by HPLC methods. Elderly anorectic subjects had significantly lower levels of glutamic acid but increased concentrations of glutamine in both plasma and CSF compared to controls. Likewise, a significant increase of histidine, threonine, alanine, arginine, valine, methionine, isoleucine, leucine, phenylalanine, tryptophan, ornithine and lysine was found in CSF, but not in plasma, from patients with anorexia. Besides, the CSF histidine/LNAA (large neutral amino acids) and tryptophan/LNAA ratios were elevated in anorectic patients as compared with controls of similar age. In addition, we found higher CSF concentrations of HVA and 5-HIAA, as well as a positive correlation between CSF LNAA and either HVA (r = 0.74, p = 0.002) or 5-HIAA (r = 0.61, p = 0.020) concentrations in elderly anorectics. CSF tryptophan correlated positively with 5-HIAA levels (r = 0.59, p = 0.026) and CSF tyrosine with HVA levels (r = 0.77, p = 0.002). Our results suggest that changes in the CSF concentration of amino acids could contribute to an increased biogenic amine metabolism in the central nervous system of elderly anorectic subjects, possibly increasing the synaptic liberation of biogenic amines involved in the appetite regulation.
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PMID:Altered cerebrospinal fluid amino acid pattern in the anorexia of aging: relationship with biogenic amine metabolism. 769 27

The carboxyl-terminal tripeptide of alpha-MSH(1-13), Lys-Pro-Val, antagonizes anorexia induced by interleukin-1 beta (IL-1). The present studies were undertaken to determine if the Lys-Pro dipeptide portion of this tripeptide likewise antagonizes anorexia induced by ICV administration of 0.5 pmol IL-1 in rats previously deprived of food. This dose of Lys-Pro did significantly attenuate the IL-1-induced anorexia, but only for 1 h after infusion. Simultaneous administration of a larger dose (5.0 pmol) of Lys-Pro reversed the IL-1-induced anorexia during both the 0-1-h and 2-4-h periods. In addition, both 0.5 and 5.0 pmol of the D-substitute tripeptide, Lys-D-Pro-Thr (LDPT), similarly attenuated the IL-1-induced anorexia. The ICV administration of 5.0 pmol Lys-Pro also did not have any significant effects on food consumption. These results indicate that the dipeptide Lys-Pro may have a short-term antagonistic action against the anorexia induced by IL-1, and it is possible that this action may be partially mediated by the blockade of IL-1 on its own receptor.
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PMID:The dipeptide Lys-Pro attenuates interleukin-1 beta-induced anorexia. 838 84

In most animals, ingestion of a diet lacking an essential amino acid (EAA) gives rise to anorexia within a few hours. The first signal in this feeding response may be the fall in plasma levels of the limiting EAA. In the present study, we measured plasma amino acid levels and food intake after the first exposure to either a threonine-devoid (THR-DEV) or corrected (COR) diet in 16 rats bearing a chronic jugular catheter for blood sampling. Food intake was reduced 165 min (p<0.05) after presentation of the THR-DEV diet. Analysis of the feeding pattern showed that intake was reduced via a four-fold lengthening of the second inter-meal interval. Plasma threonine levels started to fall between 30 and 60 min after onset of the meal (p<0.05). These results, observed in the same rats, lend further support for an early modification of the plasma amino acid pattern in relation to the decrease in feeding of a diet that is EAA deficient.
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PMID:Rapid fall in plasma threonine followed by increased intermeal interval in response to first ingestion of a threonine-devoid diet in rats. 1062 26

Food intake decreases and a conditioned taste aversion is induced when rats are fed a diet that is devoid of an indispensable amino acid. The purpose of this study was to characterize the meal patterns associated with (1) the onset of anorexia after the initial recognition of a threonine deficiency and (2) after the development of the conditioned taste aversion to this deficient diet. When rats ate the threonine-devoid diet for the first time, meal patterns were characterized by an increase in intermeal interval (IMI) between 3 and 6 h after food presentation, which was followed by a decrease in meal size and ingestion rate, between 6 and 12 h. Meal patterns on days 2 and 10 were associated with expression of the taste aversion, characterized by meals of smaller size, longer duration and by a reduction in ingestion rate, without variations in either IMI or meal frequency. Meals of the threonine-deficient group were composed of more frequent bouts, smaller size and shorter duration, with large within-meal pauses, which accounted for the reduced ingestion rate. This study presents the first analysis in terms of feeding patterns and meal microstructure of a conditioned taste aversion induced by a food rather than a toxin.
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PMID:Feeding patterns and meal microstructure during development of a taste aversion to a threonine devoid diet. 1216 90

Sorafenib is an oral multikinase inhibitor that inhibits Raf serine/threonine kinases and receptor tyrosine kinases involved in tumor growth and angiogenesis. It has demonstrated preclinical and clinical activity in several tumor types. Sorafenib 400 mg twice daily (bid) has been approved in several countries worldwide for the treatment of renal cell carcinoma. This review summarizes key safety, pharmacokinetic, and efficacy data from four phase I, single-agent, dose-escalation studies with sorafenib in patients with advanced refractory solid tumors (n = 173). These trials followed different treatment regimens (7 days on/7 days off, n = 19; 21 days on/7 days off, n = 44; 28 days on/7 days off, n = 41; or continuous dosing, n = 69) to establish the optimum dosing schedule. Sorafenib was generally well tolerated; most adverse events were mild to moderate in severity up to the defined maximum-tolerated dose of 400 mg twice daily (bid). The most frequently reported drug-related adverse events at any grade included fatigue (40%), anorexia (35%), diarrhea (34%), rash/desquamation (27%), and hand-foot skin reaction (25%). Sorafenib demonstrated preliminary antitumor activity, particularly among patients with renal cell carcinoma or hepatocellular carcinoma: overall, two of 137 evaluable patients achieved partial responses and 38 (28%) had stable disease. Although there was high interpatient variability in plasma pharmacokinetics across these studies, this was not associated with an increased incidence or severity of toxicity. Preliminary studies suggest that phosphorylated extracellular signal-related kinase in tumor cells or peripheral blood lymphocytes may be a useful biomarker for measuring and, ultimately, predicting the effects of sorafenib. Based on these findings, continuous daily 400 mg bid sorafenib was chosen as the optimal regimen for phase II/III studies. Trials are ongoing in renal cell carcinoma, hepatocellular carcinoma, melanoma, and non-small cell lung cancer.
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PMID:Safety, pharmacokinetics, and preliminary antitumor activity of sorafenib: a review of four phase I trials in patients with advanced refractory solid tumors. 1747 Jun 85

It is known that plasma serine and threonine concentrations are elevated in rats chronically fed an essential amino acid deficient diet, but the underlying mechanisms including related gene expressions or serine and threonine concentrations in liver remained to be elucidated. We fed rats lysine or valine deficient diet for 4 weeks and examined the mRNA expressions of serine synthesising (3-phosphoglycerate dehydrogenase, PHGDH) and serine/threonine degrading enzymes (serine dehydratase, SDS) in the liver. Dietary deficiency induced marked elevation of hepatic serine and threonine levels associated with enhancement of PHGDH mRNA expression and repression of SDS mRNA expression. Increases in plasma serine and threonine levels due to essential amino acid deficiency in diet were caused by marked increases in hepatic serine and threonine levels. Proteolytic responses to the amino acid deficiency may be lessened by storing amino radicals as serine and inducing anorexia through elevation of threonine.
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PMID:Adaptational modification of serine and threonine metabolism in the liver to essential amino acid deficiency in rats. 1858 86


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