[Toxicity of coffee and caffeine].
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Animals↗
Biomedical subjects
O Strubelt
Publications and source records attributed to O Strubelt.
Enhancement by glutathione depletion of ethanol-induced acute hepatotoxicity in vitro and in vivo.
Ethanol at initial concentrations between 0.75 and 6 g/l produced a dose-dependent release of the enzymes glutamic-pyruvic-transaminase and sorbitol dehydrogenase (GPT, SDH) from the isolated perfused rat liver. At the concentration of 6 g/l, it also decreased the oxygen consumption and elevated the calcium content of the isolated livers. These toxic effects of ethanol were significantly enhanced in livers, the glutathione content of which had been depleted by pretreatment with phorone. Ethanol-induced toxicity in glutathione-depleted isolated livers could be prevented both by inhibition of alcohol dehydrogenase with 4-methylpyrazole and of xanthine oxidase with allopurinol. In rats, in vivo, 1.6 g/kg ethanol injected intravenously produced a small increase in serum GPT and SDH concentrations 4 h after its administration. This increase in enzyme activities was several-fold higher and longer lasting in rats pretreated with phorone. Glutathione depletion per se did not induce hepatotoxicity in vitro or in vivo. Since glutathione is involved in several lines of defense against oxidative damage, our results of an enhanced susceptibility of glutathione-depleted livers to ethanol toxicity favour the hypothesis that ethanol exerts its hepatotoxic action via an activation of molecular oxygen.
Alanine Transaminase↗
Hepatotoxicity of acetaldehyde in rats.
The ability of acetaldehyde to initiate hepatotoxicity as evidenced by enzyme leakage, hepatic fat accumulation and histological alterations was studied in rats. Neither oral nor intraperitoneal treatment with acetaldehyde had any hepatotoxic effect, even following aldehyde dehydrogenase inhibition by disulfiram. This is probably due to the inability of exogenously added acetaldehyde to penetrate liver cell membranes. In contrast, acetaldehyde derived metabolically from ethanol was capable of inducing moderate hepatotoxicity when it accumulated upon pretreatment with disulfiram. Acetaldehyde may thus be partly responsible for alcohol-induced liver damage.
Acetaldehyde↗
Alcohol-induced hepatotoxicity: a role for oxygen free radicals.
Perfusion of isolated rat livers with ethanol at a concentration of 2 g/l (%o) resulted in a release of glutamate-pyruvate-transaminase (GPT) and sorbitol dehydrogenase (SDH) into the perfusate as markers of toxicity. Inhibition of alcohol dehydrogenase by 4-methylpyrazole or of aldehyde dehydrogenase by cyanamide totally abolished ethanol hepatotoxicity despite of a severalfold increase in acetaldehyde concentration in the perfusate. Addition of superoxide dismutase or catalase clearly suppressed the ethanol-induced release of GPT and SDH, suggesting that .O2- and H2O2 are involved in this process. Also, chelation of iron ions by means of desferrioxamine displayed a clear inhibitory action, suggesting the involvement of an iron-catalyzed Haber-Weiss-reaction leading to the formation of .OH radicals in the hepatotoxic response to ethanol. Our data suggest that during the metabolism of acetaldehyde primary reactive oxygen species (.O2-, H2O2) are produced which may interact to yield hydroxyl or .OH-like radicals, which possibly represent the hepatotoxic principle of ethanol.
Alanine Transaminase↗
Failure of coffee to inhibit the pharmacodynamic activity of morphine in vivo.
High doses of caffeine-containing as well as decaffeinated instant coffee neither inhibited morphine-induced analgesia in mice nor the morphine-induced fall of blood pressure, heart rate and respiratory rate in rats. On the contrary, caffeine-containing coffee even enhanced the analgesic effects of morphine in mice. Coffee thus does not exhibit opiate-antagonizing activity in the whole organism in vivo. The very weak morphine-antagonistic efficacy of coffee powder in the myenteric plexus-longitudinal muscle preparation from the guinea pig ileum is of no practical importance.
Analgesia↗
Influence of extracellular calcium on allyl alcohol-induced hepatotoxicity.
The role of calcium in allyl alcohol-induced hepatotoxicity was investigated in the isolated haemoglobin-free perfused rat liver. At a Ca++ concentration of 2.5 mmol/l in the perfusate, allyl alcohol (initial concentration 1.17 mmol/l) produced an enhanced release of GPT and SDH from the liver, an increase in the lactate/pyruvate ratio of the perfusate, a decrease in hepatic oxygen consumption and an increase of both hepatic calcium and malondialdehyde content. In the absence of Ca++ in the perfusate, no hepatic calcium accumulation occurred with allyl alcohol, but all other signs of hepatic damage were as severe as with 2.5 mmol/l Ca++. On the other hand, high extracellular Ca++ (5 mmol/l) alone led to a threefold increase of liver calcium but produced only marginal hepatotoxicity and only slightly enhanced the hepatotoxic effects of allyl alcohol. The concentrations of allyl alcohol in the perfusate were not altered at different Ca++ concentrations. In conclusion, the primary allyl alcohol-induced hepatotoxic injury does not appear to depend upon an influx of extracellular calcium.
1-Propanol↗
Experimental investigations on the antidotal treatment of nifedipine overdosage.
Rats anesthetized with pentobarbital and ventilated artificially were infused with 0.5 mg/kg X min nifedipine. They exhibited a sharp decline of blood pressure, heart rate, cardiac output and peripheral resistance and died after 62.3 +/- 5.3 min of infusion. In the ECG, sinus bradycardia followed by AV-dissociation and an escape rhythm originating from the AV-node or the bundle of His occurred. The survival time of nifedipine-infused rats increased by 100% and more upon additional infusion with calcium chloride, calcium gluconate, isoproterenol or dopamine and by 50% after prenalterol. Epinephrine, norepinephrine, angiotensin amide and the plasma expander polygeline were ineffective in this respect. All drugs prolonging the survival time elevated the cardiac output. Ca++ and dopamine also increased the blood pressure whereas isoproterenol accelerated the escape rhythm. Similar cardiovascular changes as in rats occurred in rabbits infused with 0.2 mg/kg X min nifedipine, the survival time without antidotal treatment amounting to 46.3 +/- 7.9 min. Calcium chloride more than doubled the survival time in rabbits, too, but isoproterenol and dopamine proved to be ineffective. Excess calcium did not overcome the inhibitory effects of nifedipine on pacemaker activity, atrioventricular conduction and peripheral resistance. The antidotal efficacy of calcium appears to be attributable to a reversal of the negative inotropic activity of nifedipine. In conclusion, Ca++ seems to be the drug of choice for the antidotal treatment of nifedipine intoxication.
Animals↗
[Antidote therapy in poisonings by calcium antagonists].
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Antidotes↗
Inhibition of the carrageenan-induced rat paw edema by glutathione-depleting agents.
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Animals↗
Alcohol potentiation of liver injury.
Alcohol enhances the activity of many but not of all hepatotoxic agents. Not only high toxic doses but also amounts commonly consumed today by many people are active in this respect. An induction of the hepatic microsomal drug-metabolizing system leading to an increased metabolism of the hepatotoxic agents to toxic radicals is the best established cause for ethanol-induced potentiation of liver injury. In the case of CCl4, hepatic hypoxia resulting from an ethanol-induced hypermetabolism may participate in the enhanced hepatotoxic response. Changes in the overall pharmacokinetics of the hepatotoxins, depletion of hepatic glutathione, and an increase of lipid peroxidation seem not to be implicated in potentiation of liver injury by ethanol. People regularly consuming alcohol may run a higher risk of being injured by hepatotoxic agents than abstainers. Thus, interactions between ethanol and other hepatotoxic agents should be envisaged as a possible additional factor in ethanol-induced human liver damage explaining, at least partially, the great variation in the sensitivity of man to the hepatotoxic effects of alcohol.
Animals↗
Evaluation of antidotes against the acute cardiovascular toxicity of propranolol.
Rats anesthetized with pentobarbital and ventilated artificially were intoxicated with 1 mg/kg X min propranolol i.v. After 30 min heart rate, mean arterial blood pressure and peripheral resistance had dropped by about 50% and cardiac output by about 25% and were stable for up to 120 min. Isoprenaline proved to be the best antidote for the treatment of propranolol intoxication antagonizing the bradycardia by 76% and the hypotension completely. The antagonistic activities of orciprenaline and prenalterol were lower than those of isoprenaline. Dopamine, adrenaline and noradrenaline antagonized propranolol-induced hypotension but did not considerably influence the bradycardia whereas dobutamine was nearly ineffective in both respects. Glucagon and aminophylline displayed some chronotropic activity without influencing propranolol-induced hypotension. Calcium chloride, on the other hand, produced a moderate elevation of blood pressure but only a small chronotropic activity, and atropine was inactive in both respects. Isoprenaline also restored the cardiac function of propranolol-poisoned rats if administered by infusion and, furthermore, increased the lethal dose of propranolol from 77 to 165 mg/kg. The strong antagonistic activity of isoprenaline against propranolol-induced cardiovascular depression was also confirmed by experiments in pigs. In conclusion, isoprenaline is the most active antidote for the treatment of propranolol intoxication in the rat though the administration of massive doses are required. The vasodilatory effect of isoprenaline can be overcome by the additional administration of a vasoconstricting agent like dopamine.
Animals↗
Antidotal treatment of the acute cardiovascular toxicity of verapamil.
Rats anaesthetized with pentobarbital and ventilated artificially were infused with 0.15 mg/kg/min. verapamil; without antidotal treatment, they died after 51.1+/-7.1 min. The survival time more than trebled upon an additional infusion with calcium chloride, epinephrine, isoprenaline, orciprenaline or prenalterol and nearly doubled upon administration of a plasma expander. It was not increased, however, by treatment with angiotensin or atropine. The infusion of verapamil declined the arterial blood pressure by 75%, and heart rate, cardiac output and peripheral resistance by about 50%; in the ECG, sinus bradycardia followed by AV-dissociation with nodal rhythm occurred. All antidotes that raised the lethal dose of verapamil increased the cardiac output. Calcium and the sympathomimetics with alpha-adrenergic activity also counteracted the verapamil-induced hypotension. Calcium did not influence the ECG alterations produced by verapamil, while the sympathomimetics restored the sinus rhythm or accelerated the nodal pacemaker. Calcium, epinephrine and isoprenaline also antagonized the strong decrease of left-ventricular dp/dt max. induced by verapamil. In conclusion, calcium as well as sympathomimetic amines are potent antidotes against the cardiovascular toxicity of verapamil, the latter being superior to calcium in their ability to improve pacemaker activity and AV-conduction.
Animals↗
[Antidotal treatment of acebutolol poisoning].
In rats, the intravenous infusion with acebutolol lead to a dose dependent decrease of arterial blood pressure, heart rate, cardiac output and total peripheral resistance, to sinus bradycardia, widening of the QRS complex, 1st and 2nd degree AV-block and intraventricular conductance disturbances. Nine possible antidotes were administered i.v. to rats which had been infused with 2 mg/kg X min acebutolol for 60 min. Isoprenaline proved the best antidote against acebutolol antagonizing the bradycardia by 88% and the hypotension completely. The activities of orciprenaline and prenalterol were lower than those of isoprenaline. Dopamine, epinephrine and norepinephrine antagonized acebutolol-induced hypotension, but did not influence considerably the bradycardia. Glucagon, on the other hand, antagonized the acebutolol-induced bradycardia by 47% but exerted only a small activity on the hypotension. Aminophyllin and calcium were nearly ineffective as antidotes against acebutolol. Isoprenaline and dopamine infused simultaneously restored heart rate, arterial blood pressure and cardiac output of acebutol-poisoned rats. The survival time of rats infused with 4 mg/kg X min acebutolol was doubled by the additional infusion of 0.2 mg/kg X min isoprenaline. The antagonistic activity of a treatment with isoprenaline and dopamine against the cardiovascular toxicity of acebutolol was confirmed in rabbits.
Acebutolol↗
Fasting increases the concentrations of carbon tetrachloride and of its metabolite chloroform in the liver of mice.
Fasting mice for 24 h strongly enhanced hepatic triglyceride concentrations as well as the hepatic levels of carbon tetrachloride (CCl4) and chloroform (CHCl3) after i.p. injection of 0.1 ml/kg CCl4. The ratio CHCl3:CCl4 was lower in the livers of the fasted than in those of the fed mice. Fasting-induced steatosis leading to an increased affinity of the liver to a lipophilic compound like CCl4 is considered to be the cause for the increase in CCl4 hepatotoxicity induced by fasting in mice.
Animals↗
Relations between gastric glutathione and the ulcerogenic action of non-steroidal anti-inflammatory drugs.
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Animals↗
The pathophysiological profile of the acute cardiovascular toxicity of sodium fluoride.
The intravenous infusion of sodium fluoride (2 mg/kg X min) into anesthetized rats caused a progressive fall in arterial blood pressure, cardiac output, heart rate and peripheral resistance. Respiratory rate increased during the first 20 min of infusion resulting in increased oxygen and decreased carbon dioxide blood concentrations. Total body oxygen consumption decreased after 30 min of NaF infusion by 29%, whereas the respiratory quotient (RQ) increased from 0.8 to 1.06. Death occurred after a mean dose of 79.6 +/- 4.6 mg/kg NaF. The terminal cardiac event before death was atrioventricular block followed immediately by asystole. Artificial ventilation did not influence the cardiovascular and the lethal effects of fluoride infusion. The plasma concentrations of total and ionized calcium decreased upon NaF infusion. The infusion of extra calcium did not prevent NaF-induced cardiovascular failure but decreased plasma fluoride levels and increased the lethal dose of NaF by 17% (not significant). In isolated atria and perfused hearts in vitro, NaF decreased the force of contraction in a dose-dependent manner. In conclusion, cardiovascular failure resulting from the direct cardiodepressive and vasodilatating effects of fluoride (and not from respiratory depression or hypocalcemia) accounts for the lethal outcome of fluoride intoxication.
Animals↗
Fasting accelerates the in vivo metabolism of carbon tetrachloride in rats.
Exposure of fed and fasted rats to CC1(4) vapor (114 ppm) for 6 h in a closed system increased serum enzyme activities (GOT, GPT, SDH) only in fasted animals. The in vivo metabolism of CC1(4), studied in the same system, was accelerated by fasting; the half-life of the elimination phase being reduced by approx. 33%. The enhanced susceptibility to CC1(4) induced by fasting seemed to be due to the accelerated bioactivation of CC1(4) to the toxic trichloromethyl free radical.
Alanine Transaminase↗