Limits of the MEGX test in the selection of liver grafts for transplantation.
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Adenosine↗
Biomedical subjects
A Lemoine
Publications and source records attributed to A Lemoine.
Prophylactic OKT3: practical considerations for the prevention of first-dose reactions.
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Azathioprine↗
Major pathway of imipramine metabolism is catalyzed by cytochromes P-450 1A2 and P-450 3A4 in human liver.
The metabolism of imipramine by human liver microsomes was examined using a combination of five strategies. Human hepatic microsomes produced N-desmethylimipramine (84%), 2-hydroxyimipramine (10%), and 10-hydroxyimipramine (6%). Preincubation of human hepatocytes in culture with beta-naphthoflavone and macrolides exclusively induced the formation of desmethylimpramine (552%, p < 0.05, and 234%, p < 0.003, respectively). Correlations were obtained between rates of imipramine demethylation and cytochrome P-450 (P-450) 1A2 (r = 0.88, p < 0.001) and P-450 3A (r = 0.80, p < 0.02) concentrations in human liver microsomal preparations from 13 different subjects. Anti-P-450 1A2 and anti-P-450 3A antibodies selectively inhibited N-demethylation (80% and 60%, respectively). N-Demethylation was completely inhibited when anti-1A2 and anti-3A were added simultaneously. Kinetic studies with human microsomes confirm the contribution of two different enzymes in the N-demethylation. The Km of 1A2 was similar to the high affinity Km in human liver microsomes, whereas the Km of 3A was similar to the low affinity Km in human liver microsomes. P-450 1A2 was apparently more efficient than 3A4 (lower Km and higher Vmax) but was expressed in much lower concentration. Human P-450s 1A2 and 3A4 expressed in yeast efficiently produced desmethylimipramine. These results suggest that P-450 1A2 and P-450 3A4 are the major enzymes involved in imipramine N-demethylation in human hepatic microsomes. Similar experiments were conducted using P-450 2D6, and they confirmed that P-450 2D6 catalyzes imipramine 2-hydroxylation. Interindividual variations in 3A4 hepatic content may explain the large variations in imipramine blood levels observed after uniform dosages and thus may explain the variations in clinical efficacy. Caution might be advised in the clinical use of tricyclic antidepressants when drugs are also administered that induce or inhibit P-450s 3A4 and 1A2.
Adult↗
Incidence of adverse reactions to cyclosporine after liver transplantation is predicted by the first blood level.
Despite the availability of whole-blood cyclosporine assays, the different responses of individual patients to its administration after transplantation continue to pose clinical problems, particularly with respect to toxicity. Fifty-seven recipients of first orthotopic liver transplants were studied between January 1992 and July 1992. Initial immunosuppression was carried out with azathioprine, methylprednisolone and cyclosporine, at a dose of 1 mg/kg/day adjusted to achieve blood levels between 400 and 600 ng/ml. Cyclosporine levels were measured 12 hr after the start of intravenous administration and correlated with the occurrence of toxic complications. Twelve patients experienced toxic complications in the first 7 days after orthotopic liver transplantation. These were neurological in six patients (of whom four also had kidney failure) and renal complications in the other six patients. All complications were reversed by reducing or stopping administration of cyclosporine. We noted excellent correlation between the occurrence of complications and cyclosporine whole-blood levels (p < 0.0001) despite the fact that levels did not exceed the therapeutic range. However, no correlation was observed between toxicity and cumulative dosage. In this study we were able to demonstrate that a standardized dose of cyclosporine does not prevent the occurrence of toxic side effects even when cyclosporine whole-blood levels are subsequently maintained in the therapeutic range. This highlights the importance of the first dose of cyclosporine and consequent early postoperative blood levels and indicates that these problems are unlikely to be overcome until a method of predicting individual requirements can be established in clinical practice.
Adolescent↗
Lidocaine metabolite formation in the liver donor as a predictive test for the safe and efficient introduction of cyclosporine in the recipient.
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Adolescent↗
Characterization of mitochondrial imidazoline-guanidinium receptive sites (IGRS) in liver.
Some imidazoline and guanidinium antihypertensive drugs display high affinity for a nonadrenergic membrane protein, the imidazoline-guanidinium receptive site (IGRS), which is insensitive to catecholamine and physically distinct from alpha 2-adrenoceptor. In the present report, we characterized IGRS in human and rabbit liver using [3H]idazoxan as radioligand. By performing subcellular fractionation, we showed a significant increase in [3H]idazoxan binding sites on membrane fractions enriched in cytochrome oxidase activity, a mitochondrial marker. A further enrichment in [3H]idazoxan binding (53-fold with respect to the homogenate) was found in a purified preparation of mitochondrial outer membranes. This localization of IGRS will facilitate the characterization of its functional activity in liver.
Animals↗
Subcellular distribution of imidazoline-guanidinium-receptive sites in human and rabbit liver. Major localization to the mitochondrial outer membrane.
Imidazoline-guanidinium-receptive site (IGRS) is a membrane protein that, even if recognized by a series of imidazoline and guanidinium alpha 2-adrenergic compounds, is insensitive to catecholamine and physically distinct from alpha 2 receptors (Parini, A., Coupry, I., Graham, R. M., Uzielli, I., Atlas, D., and Lanier, S. M. (1989) J. Biol. Chem. 264, 11874-11878). In the present report, we defined the subcellular localization of IGRS by performing binding studies with the imidazoline radioligand [3H]idazoxan. Binding studies on subcellular fractions of homogenates from human and rabbit liver showed a significant increase in [3H]idazoxan binding in a membrane fraction enriched in cytochrome oxidase activity, a specific marker for mitochondria. The enrichment in [3H]idazoxan binding sites correlates closely with cytochrome oxidase activity in the nuclear, mitochondrial, plasma membrane, microsomal, and soluble fractions (r = 0.966, p less than 0.002) but not with the specific markers for other cell compartments, suggesting a major localization of IGRS in mitochondria. Separation of inner and outer mitochondrial membranes by digitonin treatment showed that [3H]idazoxan binding correlates positively with monoamine oxidase (r = 0.960) and negatively with cytochrome oxidase (r = -0.950) activities. In addition, in highly purified preparations of outer mitochondrial membranes obtained by hypotonic shock, [3H]idazoxan binding activity was 12.5-fold enriched with respect to intact mitochondria. Taken together, these data show, for the first time, that IGRS in human and rabbit liver are mainly associated with the outer mitochondrial membranes. This demonstration of the major mitochondrial localization of IGRS will facilitate the characterization of its functional activity in liver.
Animals↗
Pharmacokinetics of fotemustine and BCNU in plasma, liver and tumor tissue of rats bearing two lines of Walker 256 carcinoma.
The plasma and tissue pharmacokinetics of fotemustine (diethyl-1-[3-(2-chlorethyl)-3-nitrosoureido]-ethylphosphonate+ ++) and BCNU (1,3-bis-[2-chlorethyl]-1-nitrosourea) were investigated in healthy control rats and in animals bearing either the nitrosourea-sensitive line A (W256/A) or the nitrosourea-resistant line B (W256/B) of Walker 256 carcinoma. The antitumor activities of these nitrosoureas were similar following i.v. doses ranging from 10 to 40 mg/kg. For both drugs, the survival of tumor-bearing rats was lower in the W256/B than in the sensitive W256/A line. Some sex differences were observed, female rats being more responsive than males to both drugs. Nitrosourea concentrations were assayed in plasma and tissues by differential pulse polarography so as to assess whether the pharmacokinetics could explain the differences in antitumor activity. The antineoplastic effects of fotemustine seemed to be influenced by its pharmacokinetics. The plasma AUC of the intact nitrosourea was higher in females than in males. Fotemustine was cleared 2-5 times more slowly than BCNU from tumor tissue, and its clearance was higher in W256/B- than in W256/A-bearing rats. This suggests that the antitumor activity in the responsive line might partly be due to longer exposure of the growing tumor to the drug. The distribution volume of both nitrosoureas in plasma was higher in tumor-bearing animals than in healthy controls, indicating that the tumor tissue probably constitutes an additional distribution space.
Animals↗
Metabolism of the chloroethylnitrosoureas.
1. The chemical degradation and metabolism of the 2-chloroethylnitrosoureas (CENUSs) have been critically reviewed with the objective of gaining a better understanding of factors that could aid in the design of new, more effective, anticancer drugs. 2. The CENUs are chemically unstable under normal physiological conditions and can rapidly degrade to give a variety of reactive intermediates capable of carbamoylating proteins and/or alkylating both proteins and DNA. 3. Carbamoylation is thought to make a minimal contribution to the cytotoxic effect of the CENUs, although it may be involved in some of the unwanted side-effects. It would seem desirable, therefore, to design new CENUs with low carbamoylating activity. 4. The main action of the CENUs is by alkylation of DNA via a chloroethyldiazo-hydroxide intermediate. Chloroethylation is important, as opposed to hydroxyethylation, since the former leads to inter-strand DNA cross-linking via an intramolecular rearrangement with the removal of chloride. It is this inter-strand cross-linking which prevents subsequent DNA repair and loss of cytotoxicity. 5. Metabolism usually, although not exclusively, leads to deactivation of the CENUs either by dechlorination or denitrosation of the molecule, generally with the former being the dominant route. These reactions occur very rapidly, and before chemical degradation can take place, and can be an important determinant in the final cytotoxicity. Moreover, both these pathways involve the cytochrome P-450 system and can be induced with phenobarbital.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Conflict between psoas and total hip prosthesis].
This conflict leads to a chronic irritation of the psoas by the antero-medial part of the cup, but it has been poorly described in the past. A study of six patients suffering from this trauma, and who were re-operated revealed that the muscle was worn thin in front of the prominent cup. In the case of 4 of the 6 patients pain had started to occur shortly after total hip replacement. The following symptoms were noted among all 6 patients: pain was suffered during flexion--extension movements--walking up stairs--arising from a chair. Pressure on the medial part of the groin was painful, especially during active elevation of the lower limb. Passive mobility was normal and painless. Psoas bursitis was observed in three cases. The main cause of this conflict is the protrusion of the cup beyond the antero-medial edge of the acetabulum; this protrusion may be either due to a bone graft or a bit of cement, but most often an acetabular insufficiency (congenital dysplasia) favors the formation of this anterior overhang. The spiral cup screwed into the bone can be especially aggressive when it protrudes. Treatment includes the resection of the overhang, but post-operative results will be uncertain unless the resection is really complete. In the case of 4 patients the results of such an intervention were only mild to poor. This problem can be avoided by proper care and preventive measures in the original replacement avoiding all projections beyond the anterior edge of the acetabulum--cup, bone graft, cement, especially if dysplasic.(ABSTRACT TRUNCATED AT 250 WORDS)
Aged↗
Hormonal regulation of microsomal flavin-containing monooxygenase: tissue-dependent expression and substrate specificity.
The substrate- and tissue-dependent hormonal regulation of flavin-containing monooxygenase (EC 1.14.13.8) was studied in male and female rats. Hypophysectomy of males reduced liver microsomal N,N-dimethylaniline N-oxidation, thiobenzamide S-oxidation, and imipramine N-oxidation, although the reduction was not as marked with the latter substrate. Castration also reduced flavin-containing monooxygenase-dependent activities, but not to the same extent as hypophysectomy. Administration of growth hormone or testosterone to hypophysectomized males only partially restored basal activities. In female rats, hypophysectomy had no effect on N,N-dimethylaniline N-oxidation or thiobenzamide S-oxidation and actually stimulated imipramine N-oxidation (98%). These effects were demonstrated to be tissue- and sex-dependent. For example, hypophysectomy markedly (300%) enhanced imipramine N-oxidation in male kidney and significantly decreased the same activity in male and female lung. Correlations between levels of the enzyme determined by immunoquantitation (with antibody to the rat liver enzyme) and activities toward these three substrates, in male and female liver, lung, and kidney, also provide evidence for the existence of multiple forms of flavin-containing monooxygenase, which appear to be under different hormonal regulation.
Animals↗
Evidence for the presence of distinct flavin-containing monooxygenases in human tissues.
Catalytic activities and substrate specificity of flavin-containing monooxygenase were examined in human tissues. During incubation with imipramine, human hepatic microsomes efficiently carried out cytochrome P450-dependent reactions but not the formation of N-oxide, while in kidney imipramine N-oxide was the only metabolite formed during in vitro incubation. The production of imipramine N-oxide was essentially due to flavin-containing monooxygenase as shown by thermal inactivation. In contrast, thiobenzamide and dimethylaniline were actively transformed by both human liver and kidney flavin-containing monooxygenase. Neither the modification of pH nor the solubilization of microsomal membranes increased imipramine N-oxidation in human liver. Kinetic analysis indicated a poor affinity (about 7 mM) of human liver microsomes for imipramine versus 0.3 mM in kidney. Immunological studies were undertaken to support enzymatic data. Antibodies raised against rat liver flavin-monooxygenase reacted strongly with human kidney microsomes but extremely weakly with liver microsomes. The relative amount of immunochemically determined protein correlated well with imipramine N-oxidation activity. A dose-dependent inhibition of imipramine N-oxidation by anti-flavin-monooxygenase antibodies was observed in human kidney, as well as in rat kidney and liver. Taken together, the results can be interpreted by the possible existence in human tissues of distinct flavin-containing monooxygenases exhibiting a partial overlapping substrate specificity. The protein involved in imipramine N-oxidation is missing from human liver but actively carries out the reaction in kidney, while another protein catalyzes the oxidation of thiobenzamide and dimethylaniline in both tissues.
Animals↗
A monoclonal antibody against an adult-specific cuticular protein of Tenebrio molitor (Insecta, Coleoptera).
To study the sequential expression of the epidermal program in the mealworm Tenebrio molitor, monoclonal antibodies were prepared against the water-soluble proteins from preecdysial adult cuticle. Among the 16 clones obtained, one of them (named K2F6) recognized a 20-kDa antigen, found only in adult extracts but not in the larval or pupal ones, as revealed by immunoblot analysis. Our results strongly suggest an epidermal origin for this protein. The monoclonal antibody K2F6 fails to react with water-soluble proteins from fat body and hemolymph taken during the deposition of the 20-kDa antigen. Electron microscopic immunogold localization of this antigen showed that it is secreted, just after epicuticle deposition, in the 30 first-deposited preecdysial lamellae of sternal and elytral cuticles only. The sclerotizing process, which modifies the physicochemical properties of these cuticles, does not prevent the immunoreaction. When the expression of the adult program was inhibited by application of a juvenile hormone analog (ZR 515), the water-soluble proteins from different pupal-adult intermediates were never recognized by the monoclonal antibody K2F6 using immunoblot analysis. These results support the conclusion that this 20-kDa antigen is a protein specific for the sclerotized cuticle of the adult stage.
Animals↗
Clinical conditions requiring elevated dosages of vitamins.
With a normal and varied food intake, the vitamin supply is often sufficient to avoid vitamin deficiency. Since synthetic vitamins have become available, it has become possible to take with one dose the amount of vitamins normally taken up from food in one year. In these pharmacological doses vitamins must therefore be considered as drugs. And in pharmacological doses, their actions are often different and not directly linked to their physiological activity. Two types of pathologic state are unquestionably the concern of vitaminotherapy: More or less specific and intense vitamin deficiencies: Rickets, scurvy, beri beri, pellagra, vitamin deficiency related to alcohol consumption, polyneuritis, encephalopathy, malabsorption, mucoviscidosis, etc. Genetic defects of vitamin metabolism: Prescriptions for these cases represent only a tiny part of the vitamin pharmaceutic market. The prescription of vitamins as adjuvants in other pathologic states without vitamin deficiency, such as neurological pains, psychosis, prevention of common cold, alopecia, anemia, asthenia, carpal tunnel defect, etc., is frequent. The results may be good; however, in some cases, the efficacy is due to chance or placebo effect, and there is no scientific or experimental evidence of beneficial activity. At the moment, the pharmacological vitamin research is very active. New products with vitamin-like structures are being synthesized for specialized therapeutic applications. They will in the near future probably replace elevated and mega-doses for clinical prescription, except, of course, for the treatment of vitamin deficiency. On the other hand, the use of multivitamin preparations in nutritional dosage will greatly increase.
Drug Prescriptions↗
Expression of cytochrome P-450 isozymes in the liver of hypophysectomized rats. Evidence for different regulation mechanisms concerning P450IIB and P450IIIA subfamilies.
1. Monooxygenase activities have been examined in rat liver to determine the effects of castration and hypophysectomy on cytochrome P-450 species. In adult males, hypophysectomy caused a decrease of total P-450 concentration, aniline hydroxylase, benzopyrene hydroxylase, benzphetamine demethylase, testosterone hydroxylase and imipramine hydroxylase and demethylase activities. The treatment of hypophysectomized animals with human growth hormone or testosterone did not restore the full activity. 2. When probed with antibodies, microsomes from hypophysectomized males and females exhibited an intense reaction with a polyclonal anti-(phenobarbital-induced P-450) which was not observed with a monoclonal antibody of anti-(phenobarbital-induced P-450). 3. These microsomal preparations also reacted with an antibody raised against a developmentally regulated P-450. No sex difference could be detected with this antibody. Furthermore, administration of human growth hormone to hypophysectomized males prevented this immunoreaction. 4. Total RNA has been prepared from the same liver; when probed with cDNAs, no changes occurred in the content in P-450 b/e, PB 24 (a constitutive member of the phenobarbital subfamily) and phenobarbital-inducible mRNA for UDP-glucuronosyltransferase. 5. In contrast, P-450 mRNA induced by pregnenolone 16 alpha-carbonitrile was modulated by hormonal manipulations: lower in females and castrated males than in intact males, increased in both sexes after hypophysectomy. Treatment of hypophysectomized males with human growth hormone abolished this rise in pregnenolone-16 alpha-carbonitrile-induced P-450 mRNA accumulation. Data collected in this study support the assumption that hypophysectomy acts differently on the regulation of various P-450 isozymes and that this regulation clearly does not involve the phenobarbital subfamily of P-450s.
Aniline Hydroxylase↗
Plasma fat-soluble vitamins and alcohol consumption.
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Adult↗
[Plasma retinol, carotenoids and tocopherols: biological variations between 18 and 45 years of age].
Variation factors of plasma retinol, carotenoids and vitamin E, and particularly sex and alcohol consumption, were studied on a sample of 271 males and females aged between 18 and 45 years. For analysis needs two subsamples were constituted: I (males and females with alcohol consumption less than or equal to 43 g/day) and II (males only). Sex and level of alcohol intake were two independent variation factors of plasma retinol and carotenoids. Associated with triglyceride and cholesterol for I and with triglyceride and ponderal index for II, they explained 40% of the total variance of plasma retinol. For carotenoids, the other associated independent variables were cholesterol, vitamin A and energy intake (r2 = 23% of explained variance). And for plasma vitamin E, neither sex nor alcohol consumption was a significant predictor of the model, the only variation factors being plasma lipids and age for I (r2 = 37%) and the same parameters associated with ponderal index for II (r2 = 55%).
Adult↗
Dietary behavior of French men according to alcohol drinking pattern.
Relationships of alcohol consumption with diet were studied in 216 French men aged 18-44. The sample was divided on the basis of alcohol intake in the preceding 7 days: controls (less than or equal to 43 g/day), moderate drinkers (44-87 g/day) and heavy drinkers (88-200 g/day). Moderate and heavy drinkers consumed more meat and meat products, bread and toast, dried vegetables and potatoes than controls but fewer nonalcoholic drinks and less milk, yogurt, cooked vegetables, raw and cooked fruits, pastries and confectioneries. Total energy intake was higher in drinkers than in controls but nonalcoholic energy intake was not significantly different; alcohol was simply added to food intake. Moderate and heavy drinkers consumed significantly less carbohydrates but more fat and protein than controls. Vitamins A and C intakes were lower in the moderate and heavy drinkers than in controls but folate and iron intakes were higher. The differences in dietary habits between controls and drinkers were not related to age nor to socioprofessional status since after adjustment for these two parameters the same relationships were still found.
Adolescent↗