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)

A new series of GABAB receptor antagonists, based on short-chain baclofen analogues has been investigated. In guinea-pig isolated ileal preparations, the GABAB receptor-mediated, baclofen-induced depression of cholinergic twitch responses was reversibly and competitively antagonised by the short-chain baclofen analogues 3-amino-3-(p-chlorophenyl)propionic acid (apparent pA2 = 3.5), 2-amino-2-(p-chlorophenyl)ethanephosphonic acid (apparent pA2 = 3.8), and 2-amino-2-(p-chlorophenyl)ethanesulphonic acid apparent pA2 = 4.0). The corresponding des-chloro analogues were all less active. These compounds represent another class of GABAB receptor antagonists which may cross the blood-brain barrier.
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PMID:Short-chain baclofen analogues are GABAB receptor antagonists in the guinea-pig isolated ileum. 166 17

1. The effects of metabotropic glutamate receptor agonists on excitatory synaptic transmission in the CA1 region of rat hippocampal slices (11-30 days) were studied using extracellular and whole-cell patch-clamp recording techniques. 2. Trans-1-amino-1,3-cyclopentanedicarboxylic acid (trans-ACPD; 25-100 microM) reversibly depressed excitatory postsynaptic currents (EPSCs) without affecting presynaptic fibre excitability or EPSC reversal potential. 3. Ibotenate (25 microM) or L-glutamate (250 microM), in the presence of the N-methyl-D-aspartate (NMDA) receptor antagonist, D-2-amino-5-phosphonovaleric acid (APV, 50-75 microM), depressed the EPSC amplitude while inducing no detectable inward current. L-2-Amino-4-phosphonobutyrate (L-AP4, 25-100 microM), the phosphonic derivative of glutamate, also depressed EPSC amplitude and caused no detectable inward current. 4. The NMDA receptor-mediated component of the EPSC recorded in the presence of the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 20-30 microM) was depressed by trans-ACPD, L-AP4, or quisqualate (1-2 microM). 5. The response to ionophoretic application of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) was unaffected by trans-ACPD or L-AP4 although the simultaneously recorded EPSC was strongly depressed. In addition, paired-pulse facilitation (50-75 ms interstimulus interval) was reversibly enhanced by trans-ACPD or L-AP4. These results indicate that the depression of synaptic transmission likely was mediated by a presynaptic 'autoreceptor'. 6. The effects of trans-ACPD or L-AP4 on synaptic transmission decreased significantly over ages 12-30 days and were minimal in adult (greater than 80 days) slices. 7. The depression of synaptic transmission caused by trans-ACPD or L-AP4 was not altered following the induction of long-term potentiation (LTP). 8. The results indicate that metabotropic glutamate receptor agonists suppress excitatory synaptic transmission in CA1 pyramidal cells by an action at a presynaptic site. This effect is developmentally regulated and is maximally expressed during the first postnatal month.
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PMID:Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus. 166 53

Long-term depression (LTD) in the intact cerebellum is a decrease in the efficacy of the parallel fiber-Purkinje neuron synapse induced by coactivation of climbing fiber and parallel fiber inputs. In cultured Purkinje neurons, a similar depression can be induced by iontophoretic glutamate pulses and Purkinje neuron depolarization. This form of LTD is expressed as a depression of alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA)-mediated current, and its induction is dependent on activation of metabotropic quisqualate receptors. The effect of inhibitors of protein kinase C (PKC) on LTD induction was studied. Inhibitors of PKC blocked LTD induction, while phorbol-12,13-diacetate (PDA), a PKC activator, mimicked LTD. These results suggest that PKC activation is necessary for the induction of cerebellar LTD.
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PMID:Participation of postsynaptic PKC in cerebellar long-term depression in culture. 172 Dec 43

A new non-N-methyl-D-aspartate (non-NMDA) glutamate receptor antagonist, GYKI 52466, was tested on L-glutamate (Glu)-, kainate (KAI)- and NMDA-induced responses in vivo, using both extracellular recording of antidromic field potentials and intracellular recording from rat abducens motoneurones. Intravenous (5-10 mg/kg) or iontophoretic applications of GYKI 52466 blocked the Glu-induced depression of antidromic field potentials only. Furthermore, intravenous application of ketamine blocked the NMDA-induced depression only. Iontophoretic application of GYKI 52466 reduced the Glu-induced neuronal depolarization but not those induced by NMDA and KAI. Our results show a selective blockade of Glu responses by GYKI 52466, probably by acting at the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subtype in rat abducens motoneurones.
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PMID:GYKI 52466 antagonizes glutamate responses but not NMDA and kainate responses in rat abducens motoneurones. 183 Mar 80

Nonsalicylate, nonsteroidal anti-inflammatory drugs (NSAIDs) can be divided into 4 chemical classes: acetic acids, fenamic acids, oxicams and propionic acids. Most NSAID overdoses result in a benign outcome. Of 50,614 exposures reported to poison centres in the United States in a 2-year period, 131 (0.26%) had a major outcome, with 10 deaths. Despite the generally mild effects reported in large patient series, isolated case reports have documented serious toxicity, such as seizures, hypotension, apnoea, coma and renal failure. The majority of these consequences occur after ingestion of substantial quantities by adults attempting suicide. Rarely, with ibuprofen and piroxicam, children who ingest small amounts in accidental exposure develop serious toxicity. Typical signs and symptoms of NSAID overdose include nausea, vomiting, headache, drowsiness, blurred vision and dizziness. Seizures are rarely documented across all NSAID classes, with the exception of mefenamic acid (where seizures occur in over one-third of cases), or following massive ingestion of other agents. Drugs in the propionic acid group have produced metabolic acidosis, respiratory depression and coma in severe cases. Ibuprofen is the agent with the most published data on overdose, probably because it is available without a prescription in many countries. Symptoms are unlikely after ingestion of 100 mg/kg or less, and are usually not life-threatening unless more than 400 mg/kg is ingested. There is some relationship between plasma concentrations and the potential for development of symptoms, but plasma concentrations have no impact on treatment decisions. Treatment of NSAID overdose is entirely supportive. Recent trends in emergency department procedures regarding gastric decontamination are evolving towards the recommended administration of activated charcoal without gastric emptying in patients presenting more than 1 hour after ingestion, although gastric lavage, followed by administration of activated charcoal, may be advisable in patients who present earlier. Home administration of syrup of ipecac is still recommended if treatment is given shortly after ingestion, with a few exceptions: for example, ipecac is contraindicated after ingestion of mefenamic acid or ibuprofen in amounts greater than 400 mg/kg. Urine alkalinisation and diuresis have been recommended to enhance the elimination of NSAIDs, based on a pKa in the range of 3 to 5. However, because the drugs are universally highly protein bound, with little unchanged renal excretion, this technique is not likely to be beneficial. Haemodialysis is also unlikely to enhance elimination, but may be required if oliguric renal failure develops. Multiple dose activated charcoal may be useful in enhancing elimination of NSAIDs with long half-lives, such as piroxicam and sulindac.
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PMID:Toxic effects of nonsteroidal anti-inflammatory drugs in overdose. An overview of recent evidence on clinical effects and dose-response relationships. 219 51

We present the case of a 17-year-old girl who ingested 24 to 36 g fenoprofen as a suicidal gesture. She presented with coma, hypotension, metabolic acidosis, and respiratory depression within four hours of ingestion. The most common adverse effects of the nonsteroidal anti-inflammatory drugs occur in both therapeutic and toxic doses and include gastrointestinal upset, blood dyscrasias, and analgesic nephropathy. The propionic acid derivatives of nonsteroidal anti-inflammatory drugs, including fenoprofen and ibuprofen, are rarely associated with severe toxic effects. This is the first report of pure fenoprofen overdose presenting as coma and metabolic acidosis.
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PMID:Nonsteroidal anti-inflammatory drugs and coma: a case report of fenoprofen overdose. 232 22

1. The present paper reports the effects of dietary modifications on the diurnal pattern of concentrations of certain metabolites and hormones in the peripheral blood of lactating dairy cows. The cows were given fixed rations of hay and high-cereal concentrates in the proportions of 30:70 or 10:90 (w/w). The concentrates were given in either two or six equal meals daily; the hay was given twice daily. 2. Previous reports of the same experiment had shown that milk-fat yield and concentration were reduced by increasing the proportion of concentrates in the diet and increased by more frequent feeding of the concentrates. These changes could be explained in part by changes in rumen volatile fatty acid (VFA) proportions and mean daily concentrations of VFA, particularly propionic acid, and insulin in the peripheral blood, but these factors failed to explain all the increase in milk-fat concentration caused by more frequent feeding. 3. Analysis of blood samples taken at hourly intervals for 24 h at two stages of lactation showed that, in the cows fed six times daily, the concentrations of metabolites and hormones remained relatively constant over the day. In the cows fed twice daily, the concentrations of VFA, 3-hydroxybutyric acid and insulin all increased after both meals whereas the concentrations of glucose and growth hormone tended to fall. The concentration of non-esterified fatty acids tended to increase overnight and fall rapidly after the morning feed. The concentrations of glucagon, thyroxine and prolactin showed no clear pattern in relation to meals. The postprandial responses of propionate, insulin and growth hormone were greater with the higher concentrate diet. 4. The maximum concentration and the diurnal range of concentrations were reduced by more frequent feeding of both diets in the case of propionic acid and of the higher concentrate diet in the case of insulin, but the effects on insulin concentrations of more frequent feeding of the lower concentrate diet were smaller and not significant. The maximum concentration and the diurnal range of concentrations of growth hormone were unaffected by meal frequency. 5. It is concluded that the severity of milk-fat depression in cows fed twice daily is increased by the rapid rise in propionic acid concentration in the peripheral blood after a meal, which in turn increases insulin secretion and may be accompanied by a suppression of growth hormone release. This causes lipogenesis to be diverted towards adipose tissue at the expense of the mammary gland.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Feeding frequency for lactating cows: diurnal patterns of hormones and metabolites in peripheral blood in relation to milk-fat concentration. 305 1

1. The present paper reports the effects on rumen fermentation and plasma metabolites and hormones of giving fixed rations of hay and high-cereal concentrates at different meal frequencies to lactating cows. In Expt 1 the total ration was given in two and twenty-four meals daily and in Expts 2-4 the concentrates were given in two and five or six meals and the hay in two meals daily. The diets contained 600-920 g concentrates/kg. 2. In Expt 1, minimum rumen pH was higher but mean pH was lower when cows were given their ration in twenty-four meals/d rather than two meals/d. 3. In all the experiments, the effects of increased meal frequency on the molar proportions of rumen volatile fatty acids (VFA) were small and not significant, although there was a general tendency for the proportion of acetic acid to increase and that of propionic acid to fall. Increasing the proportion of concentrates in the diet reduced the proportion of acetic acid and increased the proportions of propionic and n-valeric acids. 4. In Expt 3, more frequent feeding was found to reduce the concentration of non-esterified fatty acids in the blood, but changes in other metabolites were small and not significant. Increasing the proportion of concentrates in the diet reduced the concentrations of acetic acid and 3-hydroxybutyric acid and increased the concentrations of propionic acid and glucose. 5. The mean daily concentration of insulin in the blood was reduced by more frequent feeding of the higher-concentrate diet but not of the lower-concentrate diet. The concentration of glucagon also tended to fall with more frequent feeding. Increasing the proportion of concentrates in the diet increased the concentration of insulin. 6. More frequent feeding reduced the depression in milk-fat concentration caused by feeding the low-roughage diets. About three-quarters of the variation in milk-fat concentration could be related to changes in rumen VFA proportions, but the relations for the two meal frequencies had different intercepts although similar curves. The results suggest that milk-fat depression on low-roughage diets with twice-daily feeding was due to a change in rumen VFA proportions accompanied by elevated plasma insulin concentrations. The improvement in milk-fat concentration due to more frequent feeding could be explained partly by the small change in rumen VFA proportions and partly by a reduction in mean plasma insulin concentrations, but these mechanisms did not fully account for the milk-fat responses observed.
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PMID:Feeding frequency for lactating cows: effects on rumen fermentation and blood metabolites and hormones. 331 80

For most grain, except corn and sorghum, 90% or more of starch is normally fermented in the rumen. With corn, up to 30% or more could escape ruminal fermentation; most of the starch escaping fermentation would be digested in the small intestine or fermented in the large intestine. The capacity for digestion of raw starch in the small intestine is limited to 100 to 200 g/d in sheep. Gelled starch could be digested in quantities up to 200 to 300 g/d. The capacity would ultimately be limited by lack of enzymes involved in hydrolysis of short chain di- and oligosaccharides and also by capacity for absorption of glucose. Starch fermented in the cecum leads to an increase of N loss in the feces. In some instances, the high propionic acid proportion arising from fermentation of starch exceeds the capacity of the liver for metabolism. In growing lambs and goats, this creates problems of synthesis of branched-chain fatty acids in adipose tissue and, in dairy cows, problems of low milk yield and milk fat production. The low ruminal pH that often occurs when starchy grain is included in diets for ruminants can cause depression in fiber digestion. Some of these problems can be overcome by reducing extent of cereal processing and other methods that prevent low ruminal pH. It is concluded that due to limited capacity for starch digestion postruminally and high animal variability, deliberate attempts to increase postruminal digestion of starch are unlikely to be beneficial and are likely to create potential digestive problems.
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PMID:Starch digestion and utilization in ruminants. 379 53

Sixteen sheep, each fitted with cannulas in the rumen and proximal duodenum, were given four diets in the chopped or ground and pelleted form, at fixed intakes at intervals of 2 h. The sheep were closely shorn and exposed to temperatures of 22-25 degrees or 1-4 degrees for four periods of 45 d. Flow of duodenal digesta by reference to the markers CoEDTA and 103Ru-phenanthroline, chewing behaviour and particle size of rumen and duodenal digesta were measured. Apparent digestibility of organic matter (OM) in the gastrointestinal tract was depressed (P less than 0.05) by grinding and pelleting the diet, and by exposure of sheep to cold ambient temperatures. This was attributable to depression (P less than 0.01) by 0.1 of OM digestion in the reticulo-rumen. No effects on intestinal digestion of OM were observed. Cold ambient temperatures did not affect the content, but increased the rate of digestion for pelleted diets but not for chopped diets, of potentially-degradable cell-wall constituents of ground dietary material incubated in nylon-bags in the rumen. Retention times of markers of the particulate and liquid phases of rumen digesta were not significantly (P less than 0.05) affected by ambient temperature, despite significant (P less than 0.001) increases in the rate of contraction of the reticulum. Retention time of 103Ru-phenanthroline in the intestines was not affected by cold exposure. Cold exposure was associated with depression (P less than 0.05) of volatile fatty acids concentration in the rumen and elevated (P less than 0.05)pH. Molar proportions of acetic and isovaleric acid were reduced (P less than 0.01), accompanied by increased (P less than 0.001) proportions of propionic acid during cold exposure. Cold exposure and pelleting of the diets were both associated with reduction in digesta particle size in the rumen. Duodenal particle size was not affected by cold exposure. Pelleting of the diet markedly reduced (P less than 0.001) duration of chewing and number of chews/d during eating and rumination. Cold exposure of sheep resulted in a faster (P less than 0.01) rate of eating of the diets. When allowed to express their voluntary feed consumption during a 10 d period, intakes of chopped diets were increased by 0.13 (P less than 0.01) by cold exposure, in contrast to lack of significant change in sheep given pellets.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Influences of cold exposure on digestion of organic matter, rates of passage of digesta in the gastrointestinal tract, and feeding and rumination behaviour in sheep given four forage diets in the chopped, or ground and pelleted form. 406 59


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