Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of ethylenediamine in different regions of the rat and guinea-pig small intestine were investigated pharmacologically using isolated gut-bath preparations. In the guinea-pig, ethylenediamine caused concentration-dependent neurally mediated contractions or biphasic responses (contraction followed by relaxation). The contractions could be prevented by muscarinic and GABAA receptor antagonists. Ethylenediamine-evoked relaxations and depression of electrically evoked cholinergic twitch responses were blocked by desensitization to baclofen. However, in the rat intestine, the primary response to applied ethylenediamine was a concentration-dependent, non-desensitizing relaxation, evidently due to a direct action of ethylenediamine on the muscularis since it was unaffected by tetrodotoxin or GABAergic blockade.
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PMID:Differences in the effects (in vitro) of ethylenediamine on the guinea-pig and rat intestine. 234 Aug 58

Recent studies have clarified the critical role that polyglutamylation plays in methotrexate (MTX) action. Polyglutamate derivatives of MTX bind to dihydrofolate reductase (DHFR) with affinities comparable to the monoglutamate, but their retention in cells results in a sustained block in tetrahydrofolate (FH4) synthesis. One important element in the selectivity of MTX action is the preferential buildup and retention of these polyglutamyl forms in susceptible tumor cells as compared to host cells of the bone marrow or gastrointestinal mucosa. This selectivity in the accumulation of MTX polyglutamyl forms has now been further shown to play an important role in the selectivity of leucovorin rescue and may provide a unique new approach to nucleoside protection as well. This paper reviews the current understanding of the biochemical basis for leucovorin rescue and its selectivity. Important elements in leucovorin rescue are reactivation of DHFR with depression of cellular dihydrofolate (FH2) and provision of folate substrate to circumvent the block in FH4 synthesis. Selectivity of leucovorin rescue may be attributed to direct inhibition by MTX polyglutamyl forms, as well as FH2 polyglutamates that accumulate in their presence, at the levels of thymidylate synthase and transformylation during purine nucleotide biosynthesis. The presence of cellular MTX polyglutamates impairs reactivation of endogenous DHFR activity by leucovorin metabolites, and the resultant maintenance of high cellular levels of cellular FH2 and the polyglutamyl derivations of MTX impair the utilization of added FH4 in susceptible tumor cells. This paper also develops the concept of "early" nucleoside protection in antifolate therapy. In this approach, nucleosides are administered simultaneously with a pulse of MTX to provide early host protection from the cytotoxic effects of modest doses of MTX. Cessation of protection occurs at a time when extracellular and intracellular monoglutamate has fallen to low levels, and the polyglutamyl forms of the drug are present in susceptible tumors but not in host tissues of the gut and bone marrow. Data are presented to demonstrate that increased doses of MTX can be administered in normal and tumor-bearing animal systems as well as in humans by this technique.
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PMID:Biochemical factors in the selectivity of leucovorin rescue: selective inhibition of leucovorin reactivation of dihydrofolate reductase and leucovorin utilization in purine and pyrimidine biosynthesis by methotrexate and dihydrofolate polyglutamates. 244 54

A 25-month-old boy ingested six sustained-release verapamil tablets, each containing 240 mg of drug. Charcoal and cathartic were given but were never passed per rectum. Third-degree heart block, hypotension, and hypocalcemia were only transiently responsive to calcium infusions, inotropic agents, and epicardial pacing. Cardiopulmonary arrest with electromechanical dissociation ensued. Standard cardiopulmonary bypass was used to allow sufficient time for liver detoxication. Serum levels of verapamil fell during the bypass procedure, and the patient's cardiac status improved. However, continued absorption of drug after bypass resulted in a level of 4 mg/L, unresponsive circulatory failure, and death. Early, aggressive gut decontamination and the potential value of cardiopulmonary bypass procedures in poisoning that lead to cardiac depression are emphasized.
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PMID:Extracorporeal bypass for the treatment of verapamil poisoning. 266 72

In model experiments with mongrel dogs, intestinal strangulation obstruction was induced by occluding the superior mesenteric veins, and a rise in the inorganic phosphate value of the blood was observed. The high inorganic phosphate values of the fluid exuding from the strangulated bowel suggest that intestinal factors associated with the strangulated bowel may be partly responsible for this elevated phosphatemia. However, hyperphosphatemia was also found in a model experiment in which the route through which the fluid was absorbed into the blood from the peritoneal cavity was interrupted by keeping the strangulated bowel in an intestinal bag. After this, in the model experiments in which a systemic blood pressure depression curve with a percentage reduction similar to that of the decreasing arterial blood pressure resulting from strangulation was produced (by exsanguination, and even by exsanguination with adequate perfusion of the gut), plasma inorganic phosphate values also increased. Therefore it is undeniable that systemic factors other than the above-mentioned local factors are related to the rise in plasma inorganic phosphate values in experimental strangulation obstruction. Because it is not possible to assert that phosphatemia is specific to intestinal strangulation, the importance of a rise in inorganic phosphate values in the early diagnosis of intestinal strangulation cannot be considered very great.
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PMID:The causes and value of hyperphosphatemia in experimental strangulation obstruction. 281 22

Serum calcitriol and the free calcitriol index together with factors considered to regulate calcitriol production were measured in eleven patients with moderate chronic renal failure (MCRF) and eleven age- and sex-matched normal subjects. Although the serum dialysable calcium levels were similar in the two groups, there was depression of calcitriol levels and an elevation of PTH and nephrogenous cyclic AMP (NcAMP) levels in the MCRF patients. Furthermore, plasma phosphate levels were higher and the renal phosphate threshold was depressed in this patient group. When all subjects were grouped together calcitriol was positively correlated with GFR. When calcitriol levels were factored for GFR, to permit an assessment of calcitriol production per unit functioning renal mass, there was no significant difference between normal and MCRF subjects. To determine whether reserve for calcitriol production existed, six of the MCRF patients and six of the age- and sex-matched normal subjects received a low calcium diet for one week supplemented by cellulose phosphate to bind calcium within the gut. In both groups there was a significant rise in calcitriol, although the absolute levels were much lower in the MCRF patients than the normal subjects. These results suggest that calcitriol deficiency is a major feature of MCRF despite marked hyperparathyroidism. The rise in calcitriol levels in MCRF suggests persistent reserve secretory capacity in this condition. Therefore, the low serum calcitriol concentration may be due not only to structural renal damage, but also to suppression of calcitriol formation perhaps due to altered renal phosphate handling.
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PMID:Calcitriol deficiency with retained synthetic reserve in chronic renal failure. 283 40

In a 6-week clinical trial 4 dose regimens of 3'-azido-3'-deoxythymidine (AZT), a thymidine analogue with potent anti-viral activity against HTLV-III in vitro, were examined in 19 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC). AZT was given intravenously for 2 weeks, then orally for 4 weeks at twice the intravenous dose. AZT was well absorbed from the gut and crossed the blood-brain barrier. Therapeutic levels were maintained with 5 mg given intravenously or 10 mg given orally every 4 h. Treatment was not limited by side-effects, the commonest of which were headaches and depression of white-cell counts. 15 of the 19 patients had increases in their numbers of circulating helper-inducer T lymphocytes (p less than 0.001) during therapy, 6 who were anergic at entry showed positive delayed type hypersensitivity skin test reactions during treatment, 2 had clearance of chronic fungal nailbed infections without specific anti-fungal therapy, 6 had other evidence of clinical improvement, and the group as a whole had a weight gain of 2.2 kg. Also, with the highest dose regimen cultures of peripheral blood mononuclear cells for HTLV III became negative.
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PMID:Administration of 3'-azido-3'-deoxythymidine, an inhibitor of HTLV-III/LAV replication, to patients with AIDS or AIDS-related complex. 286 2

In September 1984 some sheep in a flock of 250 suffered depression, anorexia, incoordination and difficulty in rising; 50 ewes and weaners died. Post mortem examination revealed petechial bleeding, massive acute liver necrosis and in some animals degeneration of the kidney tubules. The rumen and gut contained many larvae of the blue-black birch sawfly (Arge pullata). Laboratory and field observations indicated that these were the cause of the illness.
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PMID:Sawfly poisoning in sheep and goats. 289 Dec 13

The effect of intraperitoneal infection on small-bowel flora and on systemic immunity was studied in a rat model, with use of the delayed-type hypersensitivity (DTH) response to keyhole limpet hemocyanin (KLH) as a measure of global immunologic integrity. Twenty-four hours after the induction of peritonitis by cecal ligation and puncture, concentrations of Escherichia coli in the proximal gastrointestinal tract increased from fewer than 10(3) colony-forming units (CFU)/ml to more than 10(9) CFU/ml, and the DTH response decreased from 10.0 +/- 0.2 to 2.1 +/- 0.4 mm. To assess the contribution of this altered luminal flora to the observed suppression of DTH scores, cecal ligation without puncture was performed in a group of animals whose endogenous flora had been suppressed by administration of oral neomycin. Oral administration of live antibiotic-resistant E. coli to the study animals resulted in significant DTH depression compared with controls given saline solution (2.7 +/- 0.4 vs 4.4 +/- 0.4 mm, p less than 0.005), even though the gastrointestinal tract was anatomically intact. Similar depression was seen if the challenge was limited to the small bowel as a result of the prior performance of an ileostomy and occurred in the absence of significant systemic or portal levels of viable bacteria. The results suggest that gut endotoxin plays a role in the immunosuppression associated with peritonitis.
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PMID:Small-bowel bacterial overgrowth and systemic immunosuppression in experimental peritonitis. 304 43

The use of inhibitors of monoamine oxidase (MAO) in the treatment of some forms of depression has been marred by the occurrence of unpleasant or even fatal side effects. Of these the most serious has been the risk of sudden hypertensive crises following the ingestion of food or drink containing indirectly-acting sympathomimetic amines such as tyramine (cheese effect). This effect, due to long lasting or irreversible inhibition of MAO in the gut and vasomotor neurones is much less obvious with the new generation of reversible inhibitors. Acceptance into clinical practice of these agents will depend upon the provision of clear and unequivocal evidence that there is little or no risk of unexpected cheese effects. The use of in vitro methods has provided a most sensitive way of revealing and measuring any such propensity in these new agents including moclobemide, cimoxatone and toloxatone. Use of isolated smooth muscles, such as the vas deferens and anococcygeus muscles of the rat together with vascular smooth muscle, typified by the perfused mesenteric arterial bed may be used as reliable preliminaries to in vivo and human volunteer studies in an attempt to introduce into clinical medicine an antidepressant that acts through the inhibition of MAO but carries little or no risk of the cheese effect.
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PMID:Some in vitro effects of moclobemide and other MAO inhibitors on responses to sympathomimetic amines. 328 89

To examine the relation between ethanol-induced microvascular and absorptive changes, we have investigated the effect of 16,16-dimethyl prostaglandin E2 on the jejunal intraluminal plasma albumin loss (which was taken as a measure of microvascular changes) and the inhibition of water, sodium, and glucose transport caused by intraluminal ethanol. A group of 8 dogs received intravenously 16,16-dimethyl prostaglandin E2 at a dose of 0.1 microgram/kg as a bolus followed by 0.05 microgram/kg.hour for 2 h (prostaglandin-treated group). A second group of 8 dogs received no 16,16-dimethyl prostaglandin E2 (untreated group). In each dog of both groups, one jejunal segment was perfused with an ethanol-free solution (control segment) and an adjacent segment was perfused with the same solution containing 6% (wt/vol) ethanol (ethanol-perfused segment). The albumin loss (mg/g dry gut wt.90 min, mean +/- SE) by the control and the ethanol-perfused segments was 0.76 +/- 0.23 and 8.29 +/- 1.27, respectively, in the untreated group, and 0.66 +/- 0.23 and 4.81 +/- 0.67, respectively, in the prostaglandin-treated group. The ethanol-induced increase in albumin loss was significant in both groups, but was significantly lower (p less than 0.05) in the prostaglandin-treated group than in the untreated group. Intraluminal ethanol depressed net water, sodium, and glucose transport by 74%, 52%, and 22%, respectively, in the untreated group, and by 92%, 65%, and 38%, respectively, in the prostaglandin-treated group. The magnitude of this depression did not differ significantly between the two groups. As 16,16-dimethyl prostaglandin E2 attenuated the ethanol-induced plasma albumin loss, but not the inhibition of water, sodium, or glucose transport, we conclude that the microvascular and the absorptive changes produced by ethanol are not mediated by the same mechanism.
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PMID:16,16-Dimethyl prostaglandin E2 alleviates jejunal microvascular effects of ethanol but not the ethanol-induced inhibition of water, sodium, and glucose absorption. 333 41


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