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)

3,7-Dimethyl-1-propargylxanthine (DMPX), a caffeine analog that exhibits in vitro selectivity for A2-adenosine receptors, compared to A1-adenosine receptors, has now been investigated with respect to in vivo potency and selectivity. DMPX potently and selectively blocked the actions of the potent A2 adenosine agonist, 5'-N-ethylcarboxamidoadenosine (NECA), in DBA/2 mice, compared to blockade of the same responses elicited by the selective A1-adenosine agonist, N6-cyclohexyladenosine (CHA). DMPX was 57-fold more potent versus NECA-induced hypothermia than versus CHA-induced hypothermia and 11-fold more potent versus NECA-induced behavioral depression than versus CHA-induced behavioral depression. The hypothermia is mediated by peripheral receptors, based on blockade by 8-(p-sulfophenyl)theophylline (PSPT), while the behavioral depression is centrally mediated, based on lack of blockade by PSPT. DMPX was 28- and 15-fold more potent than caffeine in blocking peripheral and central NECA-responses, respectively. DMPX was equipotent with caffeine versus CHA-induced hypothermia and 2.5-fold more potent than caffeine versus CHA-induced behavioral depression. The motor stimulating potency of DMPX (ED50 10 mumol/kg) was slightly greater than caffeine.
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PMID:3,7-Dimethyl-1-propargylxanthine: a potent and selective in vivo antagonist of adenosine analogs. 319 54

Theophylline, a methylated xanthine closely resembling caffeine and theobromine, is a widely used pharmaceutical agent for the treatment of respiratory disorders and certain acute cardiovascular conditions. The National Toxicology Program has conducted 13-week subchronic toxicity studies in F344 rats and B6C3F1 mice (10 animals/group) following administration of theophylline via the diet or by gavage. Administration of theophylline in the feed (0, 1000, 2000, and 4000 ppm) resulted in no mortality or body weight effects in F344 rats, but did induce periarteritis of the arteries adjacent to mesenteric lymph nodes and the pancreas, particularly arterioles in the latter. Also observed in rats dosed with theophylline via the diet was an increased severity of chronic nephropathy in males, especially at the high dose. Administration of theophylline at the same concentrations in the feed to B6C3F1 mice resulted in no mortality, but terminal body weights were significantly decreased in all dosed groups. An increased incidence of hepatocellular glycogen depletion was observed in male and female mice, and this change is believed to represent a physiological alteration exacerbated by the administration of theophylline. Administration of theophylline by gavage to F344 rats (0, 37.5, 75, and 150 mg/kg) resulted in the early death of one high-dose male and female and significantly decreased or increased terminal body weights of high-dose males and females, respectively. Similar to the results of the dosed-feed study, male and female rats receiving theophylline by gavage demonstrated a dose-related increase in the incidence and severity of perivascular inflammation of mesenteric arteries. Gavage administration of theophylline to B6C3F1 mice (0, 75, 150, and 300 mg/kg) resulted in the early death of all high-dose females and 3/10 high-dose males and significant depression of terminal body weights in high- and mid-dose males and low-dose females. As in the dosed-feed study, the primary histopathologic change in the mouse subchronic gavage study was hepatocellular glycogen depletion, although in this case it was seen only in females. In summary, the major target organs for orally administered theophylline in 13-week subchronic toxicity studies appear to be the mesenteric arteries in F344 rats and the liver in B6C3F1 mice. On the basis of organ weight changes and/or minor histopathologic effects, many other tissues were also affected, particularly the kidneys in dosed-feed male rats and the uterus in gavage-dosed female rats.
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PMID:Subchronic toxicity of orally administered (gavage and dosed-feed) theophylline in Fischer 344 rats and B6C3F1 mice. 322 Feb 18

The effect of the chaotropic cation guanidinium on tension generation was investigated in voltage-clamped intact and mechanically skinned muscle fibres of the frog. When sodium was replaced by guanidinium in the solution a 20-mV shift of the sigmoidal activation curve towards less negative potentials was recorded. A similar shift in the voltage dependence of mechanical inactivation did not occur. The plateau phase of contractures activated by long-lasting depolarizations was significantly shortened in the presence of 77.5 mM guanidinium. In a second set of experiments, charge displacement currents were measured using the cut fibre preparation. Apparently, guanidinium had no effect on the voltage dependence of intramembrane charge movement. On the other hand, this cation caused a distinct increase in the amount of charge necessary to reach the contraction threshold at rheobase voltage from 12.4nC microF-1 to 23.4nC microF-1. Experiments on skinned fibres containing an operating sarcoplasmic reticulum demonstrated that 5 mM guanidinium diminished caffeine-induced tension development and substantially delayed the onset of the contractile response. However, guanidinium did not impair calcium-induced tension development of the contractile apparatus. These results suggest that the inhibitory action of guanidinium on excitation-contraction coupling is due to a depression of calcium release from the sarcoplasmic reticulum.
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PMID:Effects of guanidinium on EC coupling and tension generation in frog skeletal muscle. 326 38

Chronic, heavy caffeine ingestion may cause or exacerbate anxiety and may be associated with depression and increased use of antianxiety drugs. Caffeine may cause anxiety and panic in panic disorder patients and may aggravate the symptoms of premenstrual syndrome. Chronic users who are caffeine-sensitive may have symptoms of caffeinism at relatively low doses. Individuals who regularly consume moderate to heavy amounts of caffeine may develop caffeinism, or they may show signs of caffeine withdrawal syndrome after abstaining from the drug.
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PMID:Psychotropic effects of caffeine. 328 1

Skinned fiber bundles from papillary muscle of rabbits were used to study the effects of ryanodine (1) on direct Ca2+ activation of the contractile proteins, and (2) on direct Ca2+ uptake and release from the sarcoplasmic reticulum (SR). Caffeine (25 mM) was used to release Ca2+ from the SR and to generate a tension transient. Each tension transient occurred after sequential immersion of the fiber bundles into five solutions: loading (uptake phase, [U]) and releasing (release phase, [R]). The height of free Ca2+-activated tension development of the contractile proteins, and the area of the tension transient generated by caffeine were assessed. (1) The direct free Ca2+-activated tension development of the contractile proteins was not significantly affected by ryanodine up to 0.1 mM, either at the submaximal or maximal free Ca2+ concentrations. (2) Ryanodine (1 nM-1 microM), in U, R, or in U and R, did not significantly change the immediate caffeine-induced tension transients. In the same preparation after ryanodine treatments, the second control caffeine-induced tension transients (C2, no ryanodine) were decreased in a dose-dependent manner (IC50 = 50 nM, 10 nM, 10 nM for R, U, and U and R, respectively). The depression caused by ryanodine on the SR was "activity"-dependent and not readily reversible. Total calcium content in the SR of C2 was not significantly changed by small quantities of ryanodine (less than 0.1 microM) and was decreased with greater amounts of ryanodine (greater than or equal to 0.1 microM). Thus, at low concentrations of ryanodine, the negative inotropic action is due to decrease Ca2+ release from the SR; at high concentration of ryanodine, it is due to decrease in calcium accumulation in the SR.
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PMID:Effects of ryanodine on skinned myocardial fibers of the rabbit. 335 52

Caffeine increases anxiety in people with anxiety disorders. To determine whether caffeine exerts a similar effect in depression, the authors compared retrospective reports of caffeine intake and symptoms produced by caffeine ingestion in patients with panic disorder, patients with major depression, and control subjects. Panic patients consumed less caffeine and reported more symptoms than depressed or control subjects. Although depressed patients did not differ from control subjects in caffeine intake or most symptoms, more depressed patients reported that caffeine induced anxiety. These data support prior reports that panic patients have increased sensitivity to caffeine; some depressed patients may also have increased sensitivity.
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PMID:Anxiogenic effects of caffeine on panic and depressed patients. 335 68

The triazolobenzodiazepine triazolam, applied iontophoretically onto rat cerebral cortical neurons, potentiated the magnitude and duration of adenosine-elicited depressions of spontaneous activity. Triazolam did not enhance the depressions evoked by adenosine 5'-N-ethylcarboxamide, an uptake resistant analog of adenosine, suggesting that potentiation of adenosine resulted from an inhibition of adenosine uptake. With larger application currents, triazolam depressed the firing of cortical neurons. This action was blocked by the adenosine antagonist caffeine (20 mg/kg, i.v.) implying that the depression resulted from an accumulation of endogenously released adenosine.
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PMID:Potentiation of adenosine-evoked depression of rat cerebral cortical neurons by triazolam. 337 Apr 71

Rats treated chronically with caffeine become tolerant to caffeine-induced stimulation of locomotor activity and cross-tolerant to theophylline. This study was performed to determine if the cross-tolerance between these two methylxanthine drugs is symmetrical. Symmetrical cross-tolerance produced by two different drugs implies a common underlying mechanism of action. Separate groups of rats were given scheduled access to drinking bottles containing either drug-free tap water or 1.0 mg/ml theophylline solution. Daily theophylline intake averaged 59 mg/kg. Dose-effect curves were determined in both control and theophylline-treated groups for 5 drugs: the methylxanthines theophylline and caffeine, a nonxanthine psychomotor stimulant, d-amphetamine, and the adenosine analogs R(-)-N6-2-(phenylisopropyl)adenosine and 5'-(N-ethyl)carboxamidoadenosine. All drugs were injected i.p. and locomotor activity was measured for 30 min beginning 35 min later. Rats that were maintained chronically on theophylline were completely tolerant to the locomotor activity stimulant effects of acutely administered theophylline and cross-tolerant to caffeine-induced stimulation of locomotor activity. In contrast, both control and treated groups were fully responsive to the stimulant effects of d-amphetamine. Low doses of the adenosine analogs produced stimulation of locomotor activity in both groups of rats. Higher doses produced a dose-dependent depression of locomotor activity in control rats; curves for the theophylline-treated rats were shifted to the right of the control curves. Thus, adenosine antagonist activity of theophylline remained evident at a time of complete tolerance to the stimulant effect of the drug on locomotor activity.
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PMID:Tolerance and cross-tolerance to theophylline-induced stimulation of locomotor activity in rats. 337 67

Pharmacokinetics of antipyrine, hexenal, phenylbutasone and caffeine was studied in experiments on splenectomized male rats. It was found that the half-life of all the drugs increased and plasma clearance decreased. Total protein binding assessed by using congo red decreased to a certain degree after splenectomy. The main factor modifying pharmacokinetics of drugs following splenectomy is believed to be depression of biotransformation processes in the liver.
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PMID:[Pharmacokinetic characteristics of drugs in experimental splenectomy]. 337 18

Acute caffeine administration increases cortisol and converts the dexamethasone suppression test (DST) to nonsuppression in normal humans; data concerning chronic administration as well as effects in depressed patients are minimal. To determine whether caffeine intake influenced DST results in depression, we retrospectively studied the relationship between regular daily caffeine consumption and pretreatment DST status in major depressives. Daily intake was not correlated with either post-DST cortisol levels or symptom ratings. These data suggest that chronic caffeine use is unlikely to be a major factor in dysregulation of the hypothalamic-pituitary-adrenal axis in depression, perhaps because of the development of tolerance.
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PMID:Chronic caffeine consumption and the dexamethasone suppression test in depression. 339 18


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