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M Younes

Publications and source records attributed to M Younes.

At least 235 records · Page 13Linked to original sources

[Effect of (+)-catechin on the pharmacokinetics of carbamazepine in rabbits].

The influence of (+)-catechin ((+)-cyanidanol-3, Catergen) on the absorption, distribution and elimination of the anti-convulsant drug carbamazepine was studied in rabbits. At a dose of 200 mg/kg p.o. (+)-catechin caused a delayed absorption of carbamazepine (40 mg/kg p.o.), as evidenced by a shift of tmax from 2 h in controls to 6 h in (+)-catechin-treated animals. The maximum concentrations as well as the elimination half-lives for carbamazepine were not different in both groups. After reducing the dose both for (+)-catechin (50 mg/kg p.o.) and carbamazepine (10 mg/kg p.o.) the observed effect on the absorption no longer occurred. Repeated oral administration of carbamazepine (10 mg/kg p.o.) for 5 days showed no differences in the maximum concentrations at the expected tmax (2 h) for controls and (+)-catechin-treated animals.

Animals↗

Glutathione-S-transferase and GSH-peroxidase activities during the state of GSH-depletion leading to lipid peroxidation in rat liver.

Depletion of hepatic glutathione (GSH) in phenobarbital-induced rats by phorone (diisopropylidene acetone; 0.25 g/kg i.p.) or vinylidene chloride (VDC; 0.5 g/kg i.p.) led to an enhanced lipid peroxidation in vitro as evidenced by the measurements of malondialdehyde and conjugated dienes. During this state of GSH-depletion inducing lipid peroxidation no significant alterations in the activity of hepatic GSH-peroxidase were observed whereas the GSH-S-transferase activities towards an aryl substrate (CDNB) and an epoxide substrate (1,2-epoxy(p-nitrophenoxy)propane) significantly decreased under the treatments with VDC. The GSH-reductase activity was significantly reduced after treatment with either agent. These results clearly indicate 1st, that GSH-S-transferases are involved in the conjugation of GSH to VDC, 2nd, that GSH peroxidase remains unaffected during lipid peroxidation induced by GSH-depletion as a consequence of treatment with phorone or VDC, and 3rd, that the availability of reduced GSH may be decreased further under these conditions due to the lower content of glutathione reductase.

Animals↗

Mechanistic aspects of enhanced lipid peroxidation following glutathione depletion in vivo.

Several agents known to conjugate with glutathione (GSH) were administered to phenobarbital-induced rats resulting in a more or less pronounced depletion of hepatic GSH. In vitro incubations showed that a large enhancement of spontaneous lipid peroxidation was observed when the GSH content was below 1 mumol/g liver. This effect was inhibited by addition of exogenous GSH in a concentration-dependent manner, the GSH-concentration yielding 50% inhibition (I50) being 1 microM. Using phorone (diisopropylidene acetone), which proved to be the most potent GSH-depletor, the time- and dose-dependence of the GSH-depletion and the consequent lipid peroxidation was studied. Again it was assured that the GSH concentration must reach a critical value of about 20% of the initial hepatic GSH content, before an enhanced lipid peroxidation is seen. Employing scavengers of excited oxygen species no evidence was found for the involvement of free oxygen radicals. Hepatoprotective agents and inhibitors of mixed-function oxidases exerted a more or less pronounced inhibitory action. Our findings are further support of our previous postulate that GSH depletion per se might lead to an increased lipid peroxidation, possibly due to its lack as a part of the cellular defence system against endogenous toxic intermediates.

Animals↗

Enhancement of benzo(a)pyrene-induced sister chromatid exchanges as a consequence of glutathione depletion in vivo.

Pretreatment of Chinese hamsters with phorone (diisopropylidene acetone) decreased hepatic glutathione (GSH) content to about 20% of the control level after 2 hours. The GSH S-transferase activities were not affected. As a consequence of reduced detoxication by GSH the potency of 3,4-benzo(a)pyrene to induce sister chromatid exchanges in vivo in bone marrow cells was significantly enhanced. Chemically induced distinct alterations in metabolism of mutagens/carcinogens are proposed as experimental models for pharmacogenetic and toxigenetic studies.

Animals↗

Temporal changes in effectiveness of a constant inspiratory-terminating vagal stimulus.

When an electrical stimulus is applied to the cervical vagus during inspiration it results in earlier termination of that phase. We investigated the temporal behavior of the effect of such a stimulus in the interval between its application and inspiratory termination to gain insight into the central processing of these signals. In pentobarbital-anesthetized cats we determined the threshold for inspiratory termination by delivering stimulus trains of constant duration to one vagus nerve at different times after inspiratory onset. The threshold frequency was obtained when the other nerve was unstimulated and when it was stimulated using trains of constant frequency (conditioning stimulus) beginning soon after inspiratory onset. The difference in threshold between the two test indicated the effectiveness of the conditioning stimulus in reducing threshold for inspiratory termination. The effectiveness of the conditioning stimulus increased progressively, reached a peak value at approximately 0.8 s, and progressively declined thereafter. This behavior indicates substantial integrative and accommodative processing of inspiratory terminating vagal inputs.

Afferent Pathways↗

A model for the relation between respiratory neural and mechanical outputs. I. Theory.

A model for the conversion of respiratory neural output to mechanical output, and vice versa, is described. Neural output was expressed in terms of isometric pressure generated at passive functional residual capacity. The mechanical response time constant of respiratory muscle was assumed to be 0.06 s. The effect of volume and configuration on pressure output was modeled after the data of Grassino et al. (J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 44: 829-839, 1978). Equations were developed to examine the effect of different configurational pathways during inspiration. We utilized Hill's hyperbolic force-velocity relation to model the effect of flow on pressure output. The pressure asymptote of the hyperbola was considered to be similar to that in other skeletal muscles (0.25 isometric pressure). The flow asymptote was derived from data obtained during maximal voluntary inspiration. A major feature of the model is the dependence of volume, configuration, and flow-related pressure losses on level of inspiratory activity. The practical effect of potential errors and the overall accuracy of the model are presented in the two succeeding communications.

Animals↗

A model for the relation between respiratory neural and mechanical outputs. II. Methods.

In the preceding communication we developed a model for the conversion of neural output to mechanical output. We were left with two qualitative uncertainties, namely, the relation between neural output and isometric pressure, and the behavior of inspiratory muscles during expiratory flow; and two quantitative uncertainties concerning the effect of configurational pathway on pressure output, and the slope of the pressure-flow relation. For each of the above uncertainties we made certain assumptions based on indirect evidence but defined reasonable error limits. In the present communication we describe the method of implementing the model and evaluate the significance, in terms of spirometric output, of possible errors in the assumptions. Volume and flow profiles were generated from different neural output profiles. Analysis was repeated when the different assumptions were systematically altered within the limits set by the previous theoretical analysis. We conclude that the pattern of inspiratory muscle activation during spontaneous breathing and the existence of several mechanical interactions within the respiratory system combine to render spirometric output fairly insensitive to most potential errors in our assumptions.

Biomechanical Phenomena↗

A model for the relation between respiratory neural and mechanical outputs. III. Validation.

In the preceding two communications we described a model for the relation between respiratory neural and mechanical outputs. In the present report we test the accuracy of the model in predicting volume and flow from occlusion pressure wave forms, and vice versa. We performed single-breath airway occlusions in 21 unconscious subjects and determined the time course of occlusion pressure. We also measured the passive properties of the respiratory system. The time course of volume and flow was predicted from the occlusion pressure wave forms, and the results were compared with the spontaneous breaths immediately preceding occlusion. Inspiratory duration, shape and amplitude of occlusion-pressure wave forms, and the passive properties of the respiratory system varied widely among subjects. There was good agreement between predicted and observed values in all cases. Except for some prolongation of inspiration (Hering-Breuer reflex), diaphragmatic activity did not change during occlusion. Since occlusion pressure is proportional to inspiratory activity, we conclude that the model described provides a good approximation of the relation between inspiratory activity and spirometric output.

Adolescent↗

Effects of thyroid dysfunction on the metabolism of halothane, enflurane and methoxyflurane in rats.

The effect of thyroid dysfunction on the metabolism of halothane (100 ppm), enflurane (100 ppm) and methoxyflurane (300 ppm) was investigated during application by inhalation. In male rats the elimination half-lives from the atmosphere of the exposure system amounted to 0.76h for halothane, 6.84h for enflurane and 0.64h for methoxyflurane. Hyperthyroidism due to three daily injections of 0.1 mg/kg triiodothyronine i.p. significantly shortened the half-lives of all three inhalation anesthetics. Hypothyroidism due to operative removal of the thyroid gland affected the metabolism of halothane only as evidenced by a prolongation of the elimination half-life while enflurane and methoxyflurane half-lives remained unchanged. The observed differences in metabolic rates are explained by different metabolic pathways of the three compounds. They may be important for the manifestation of toxic effects.

Animals↗

Effects of liver injury and cholestasis on microsomal enzyme activities and metabolism of halothane, enflurane and methoxyflurane in vivo in rats.

1. Cholestasis (bile-duct ligation 24 h before) had no effect on rat liver microsomal protein content, cytochrome P-450 or cytochrome c reductase activity, but depressed aniline hydroxylase activity and aminopyrine demethylase less so. Pretreatment with CCl4 (24 h before) decreased rat liver cytochrome P-450, aniline hydroxylase and aminopyrine demethylase. 2. Halothane, enflurane and methoxyflurane are metabolized via different pathways, resulting in different metabolic elimination rates in our exposure system (methoxyflurane greater than halothane greater than enflurane). Elimination half-lives of the three compounds from the atmosphere of the exposure system were three times longer in CCl4-injured rats; cholestasis had a weaker effect (30-50% increase). 3. Dehalogenation of enflurane, which is the preferred pathway, is affected to the same extent as the cytochrome P-450-dependent hydroxylation of halothane and the O-dealkylation of methoxyflurane.

Anesthetics↗

[Inhibition and acceleration of the metabolism of enflurane and methoxyflurane in rats (author's transl)].

Rats exposed to enflurane (100 ppm) or methoxyflurane (300 ppm) in a closed all glass-system eliminated these anesthetics from the atmosphere of the system with a half-life of 6.84 h for enflurane and 0.64 h for methoxyflurane. 24 h-fasting had no influence on these elimination half-lives. An oral load of ethanol (4.8 g/kg p.o.) only prolonged the half-life for methoxyflurane. Pretreatment with diethyl maleate (1 ml/kg i.p.), dimethylsulfoxide (DMSO, 1 g/kg i.p.) or dithiocarb (100 mg/kg i.p.) prolonged the elimination half-life of both enflurane and methoxyflurane. An accelerated metabolic elimination was only observed in DDT-pretreated rats exposed to enflurane; other inducers of the microsomal mixed-function oxidase system like phenobarbital or rifampicine had no significant influence on the in vivo metabolism of both enflurane or methoxyflurane.

Animals↗

Inhibition of the hepatotoxicity of paracetamol and its irreversible binding to rat liver microsomal protein.

Dithiocarb and (+)-cyanidanol-3-prevented paracetamol-induced liver injury in rats in vivo. Both, as well as two other antihepatotoxic agents, deanol and DMSO, inhibited covalent binding of [3H]-paracetamol to rat liver microsomal proteins in vitro. Dithiocarb and (+)-cyanidanol-3 were the most effective inhibitors. The concentrations of the antidotes yielding 50% inhibition (I50) valued 1 . 8 x 10(-5) M for dithiocarb and 2 . 1 x 10(-5) M for (+)-cyanidanol-3.

Acetaminophen↗

Relation between respiratory valve dead space and tidal volume.

We measured the "effective" dead space of five commonly used respiratory valves: Hans Rudolph valve, two-way J valve, triple-J valve, and modified Otis-McKerrow valves without and with vane. The dead space was measured using a technique that mimicked the operation of valves during ordinary laboratory procedures. The valves were ventilated with tidal volumes ranging from 0.35-3.00 liters and at different frequencies. With all valves, there was a marked tendency for "effective" dead space to be tidal volume dependent. The measured dead space approached the water-displacement volume of the common chamber of the valve only at tidal volumes in excess of 2.0 liters. The relation between valve dead space and tidal volume was independent of frequency.

Mathematics↗