8OHdG levels in brain do not indicate oxidative DNA damage in Alzheimer's disease.

Accumulation of oxidative DNA damage has been proposed to underlie aging and neurodegenerative diseases such as Alzheimer's Disease (AD). The DNA adduct 8-hydroxy-2'-deoxyguanosine (8OHdG) is considered a good indicator of oxidative DNA damage. To investigate whether this type of DNA damage is involved in AD etiology, 8OHdG levels were determined in postmortem human brain tissue of controls and AD patients (in frontal, occipital, and temporal cortex and in hippocampal tissue).

The influence of dietary restriction on the metabolism of theophylline and antipyrine in the ageing female BN/BiRij rat.

The influence of ageing and dietary restriction (DR) on the in vivo activities of different P450 enzymes was studied longitudinally in female BN/BiRij rats. For this purpose, antipyrine (AP) and theophylline (TH) were used as substrates. The metabolic clearances of AP (CIm AP) and TH (CIm TH) were used as indicators for P450 enzyme activities in vivo.

The influence of aging on the metabolism of simultaneously administered hexobarbital enantiomers and antipyrine before and after phenobarbital induction in male rats: a longitudinal study.

The influence of aging on the metabolism of antipyrine (AP) and hexobarbital enantiomers (R-HB and S-HB) with and without phenobarbital (PB) induction was investigated in a longitudinal study in rats aged 6, 12, 24 and 30 months. The metabolic clearances of AP (Clm AP), R-HB (Clm R-HB) and S-HB (Clm S-HB) were used as indicators for P450 enzyme activities in vivo. This also included the assessment of the clearances of formation of three AP metabolites, 3-hydroxymethylantipyrine (Cl-->HMA), 4-hydroxyantipyrine (Cl-->OHA) and norantipyrine (Cl-->NORA).

Cortisol production rate and the urinary excretion of 17-hydroxycorticosteroids, free cortisol, and 6 beta-hydroxycortisol in healthy elderly men and women.

Background: Although many workers have tested adrenal function in the elderly, few have studied the effect of aging on cortisol production rate or urinary free cortisol or 6 beta-hydroxycortisol excretion, and none have published comparisons of these variables between old people of defined health status and young people.

Methods: We have measured cortisol production rate and the urinary excretion of free cortisol, 6 beta-hydroxycortisol, 17-hydroxycorticosteroids (Porter-Silber chromogens) and creatinine in elderly men and women screened by the SENIEUR protocol and in young men; 17-hydroxycorticosteroid and 6 beta-hydroxycortisol excretion were also measured in young women. The period of measurement was 24 h or, usually, 48 h.

The relationship between phenazone (antipyrine) metabolite formation and theophylline metabolism in healthy and frail elderly women.

The influence of aging on the metabolism of phenazone (antipyrine), and the relationship between the formation of 3 phenazone metabolites and the metabolic clearance of theophylline in healthy and frail elderly women, were examined. Whereas the elimination half-life did not change, clearance of phenazone decreased by about 50% with age in healthy women receiving phenazone without theophylline. However, the summation of the urinary recovery of phenazone and the measured metabolites, expressed as percentage of the phenazone dose, was lower in the healthy elderly (37 +/- 9% vs 74 +/- 15%).

Increased sensitivity to the anticonvulsant effect of valproate in aging BN/BiRij rats.

The aim of the present investigations was to study the influence of increasing age on the pharmacodynamics of valproate in BN/BiRij rats, applying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy male BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relationships were determined during a continuous intravenous infusion of sodium valproate at a rate of 5.

Age and the pharmacokinetic-pharmacodynamic relationship of phenobarbital in rats: "pseudo"-longitudinal vs cross-sectional study design.

In a previous study, an apparent age-related increase in brain sensitivity to the anesthetic effect of phenobarbital was observed in BN/BiRij rats. However, since this study was conducted according to a cross-sectional design, the observed change could, in principle, also have been the result of a cohort effect. The purpose of the present investigation was to exclude the role of such a cohort effect by adopting a "pseudo"-longitudinal study design.

Disposition of heptabarbitone in the rat: identification of a new metabolite by tandem mass spectrometry.

The purpose of this study was to elucidate the structure of a metabolite of heptabarbitone, the occurrence of which was reported previously in a number of pharmacokinetic and pharmacodynamic modelling studies. By application of thermospray liquid chromatography (tandem) mass spectrometry, the identity of the metabolite was proposed to be 5-ethyl-5-(1',[3' or 6']-cycloheptadienyl)-barbituric acid. By measuring the ratios between the areas under the concentration time curves of the metabolite and heptabarbitone after administration of three different intravenous dosages of heptabarbitone, it was shown that the exposure to the metabolite is directly correlated with the exposure of heptabarbitone.

Pharmacokinetic-EEG effect relationship of midazolam in aging BN/BiRij rats.

1. The purpose of the present investigations was to determine the influence of increasing age on the pharmacokinetics and pharmacodynamics of midazolam in male BN/BiRij rats as an animal model of aging. 2.

Pharmacodynamics of the anticonvulsant effect of oxazepam in aging BN/BiRij rats.

1. The purpose of this investigation was to examine the influence of increasing age on the pharmacokinetics and the time course of the anticonvulsant response of oxazepam in BN/BiRij rats as an animal model of aging. 2.

Metabolism of simultaneously administered antipyrine and theophylline in male BN/BiRij rats before and after induction with 3-methylcholanthrene.

In order to study the metabolic activities of different P-450 enzymes in male Brown Norway rats, formation rates of antipyrine (AP) metabolites and theophylline (TH) metabolic clearance were determined. Brown Norway rats are often used in studies concerning the influence of age on liver function. Experiments were performed after simultaneous iv administration of the two compounds with and without 3-methylcholanthrene (3-MC) pretreatment.

The effect of age on inducibility of various types of rat liver cytochrome P-450.

1. The content and specific activities of inducible cytochrome P-450 enzymes were determined in liver microsomes of rats of various ages after maximal induction with phenobarbital, isosafrole of 3-methylcholanthrene, and in untreated animals. 2.

Increased sensitivity to the anesthetic effect of phenobarbital in aging BN/BiRij rats.

The purpose of this study was to determine the influence of age on the pharmacokinetic/pharmacodynamic relationship of phenobarbital in male BN/BiRij rats aged 4, 15, 26, 31 and 36 months. The pharmacokinetics were studied on basis of the plasma concentration vs. time profile and the excretion of phenobarbital and parahydroxyphenobarbital in urine and feces after an i.

Effect of the aging process on the gender and phenobarbital dependent expression of glutathione S-transferase subunits in brown Norway rat liver.

The effect of age, gender and phenobarbital treatment on the hepatic cytosolic glutathione S-transferase subunit composition was studied in Brown Norway rats. Affinity chromatography followed by reversed phase HPLC was used in order to separate the various glutathione S-transferase subunits. Corresponding steady-state mRNA levels were measured by Northern Blot analysis using cDNA clones hybridizing to mRNA encoding glutathione S-transferase subunits 1/2, 3/4 and 7, respectively.

The influence of ageing on the induction of the mRNAs of rat liver cytochromes P450IIB1 and P450IIB2.

To investigate the influence of age on the regulation of the cytochromes P450IIB1 and P450IIB2 the levels of the messenger RNAs for these two cytochromes were determined in liver cytoplasmic RNA of rats of various ages after maximal induction with either phenobarbital or isosafrole and in untreated rats. The levels of these mRNAs were determined by solution hybridization with a RNA-probe (riboprobe system) complementary to both mRNAs. This study showed a marked decrease in the maximal induction levels of these mRNAs between the ages of 12 and 36 months irrespective of the type of inducer used.

Hepatic cytosolic glutathione S-transferase activities in ageing brown Norway rats--importance of sex differences and phenobarbital treatment for studies of ageing.

Age-associated alterations of hepatic cytosolic glutathione S-transferase activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene were investigated in Brown Norway rats of both sexes (11-144 weeks old), under control conditions and after administration of phenobarbital. With both substrates, small changes in glutathione S-transferase activities are observed for the control rats (15-53 weeks old). For these specific age groups, male glutathione S-transferase activities are significantly higher than those of their female counterparts, with sex-related differences being most pronounced after 1,2-dichloro-4-nitrobenzene conjugation.

Age-related changes in distribution of cytochrome P-450 in the hepatic lobule of the rat.

The effect of age on distribution of the phenobarbital-inducible forms of cytochrome P-450 IIBI and IIB2 in the hepatic lobule was investigated immunohistochemically by the avidin-biotin-peroxidase complex (ABC) method in male rats of various ages pretreated with phenobarbital. Exposure of liver sections to anti-cytochrome P-450 serum resulted in intense immunostaining in centrilobular hepatocytes but produced staining of weaker intensity in periportal cells in phenobarbital-treated rats, while in livers of nontreated animals, no significant immunoreactivity was detectable. Difference in the intensity of immunostaining between the centrilobular cells and the periportal ones was statistically significant in the liver of 3 and 13 month rats.

Effect of different doses of 3-methylcholanthrene on the localization of the 3-methylcholanthrene-inducible isoenzymes of cytochrome P450 within the centrilobular and periportal zones of the rat liver.

Immunohistochemical staining techniques were used to investigate the localization of the 3-methylcholanthrene inducible isoenzymes (P450 IA1 and IA2) in the rat liver. The rats were induced with different doses of 3-methylcholanthrene, ranging from 2.5 to 25 mg/kg body weight.

The influence of age on the inducibility of rat liver cytochrome P450IA1 (CYPIA1) and P450IA2 (CYPIA2) mRNAs.

The levels of the messenger RNAs for the cytochromes P450IA1 (CYPIA1) and P450IA2 (CYPIA2) were determined in liver cytoplasmic RNA of rats of various ages after maximal induction with either 3-methylcholanthrene or isosafrole and in untreated rats. An increase in the CYPIA1 mRNA levels was observed only after treatment with 3-methylcholanthrene, whereas both 3-methylcholanthrene and isosafrole were able to induce the levels of CYPIA2 mRNA. The study presented here shows that the maximal induction of these 2 mRNAs did not change with age when 3-methylcholanthrene was used as the inducing agent.

The effect of age on the oxidative metabolism of antipyrine by uninduced microsomal fractions of rat liver.

The influence of ageing on the metabolism of antipyrine by different forms of cytochrome P-450 was studied in vitro, by measuring the formation of antipyrine metabolites by microsomes isolated from untreated rats, which were grouped into 5 different ages. Km, Vmax and Vmax/Km values were determined for the metabolites: 3-hydroxymethylantipyrine (HMA), norantipyrine (NORA) and 4-hydroxyantipyrine (OHA). Km values for all metabolites ranged from 2.

Pharmacokinetics of hexobarbital in young and old rats.

Hexobarbital is a drug widely used to study the capacity of the liver to metabolize drugs. The pharmacokinetics of hexobarbital in 3- and 30-month-old male BN/BiRij rats were studied. The half-life of hexobarbital in 30-month-old rats (39.

The effect of age on antipyrine pharmacokinetics and metabolite formation in rats.

The great interindividual variation in drug handling, especially in the elderly, causes a problem in determining the correct individual dose for the administration of a drug. A solution would be the determination of the capacity to metabolize lipophilic drugs in vivo on an individual basis. One approach, as reported in the literature, may be to determine the clearance rates of the antipyrine metabolites, which are formed by different isoenzymes of cytochrome P-450.

The effect of age on antipyrine metabolism by liver microsomes isolated from phenobarbital-treated rats.

A study was performed to test the hypothesis that ageing influences the activities of diverse forms or populations of cytochrome P-450 isoenzymes in different ways. The formation of antipyrine metabolites in induced rats is mediated by such different forms or populations of cytochrome P-450 isoenzymes. To test the hypothesis, the formation rates of antipyrine metabolites by liver microsomes isolated from phenobarbital-treated rats of different ages was determined.

Albumin elimination in female WAG/Rij rats with age: a longitudinal study.

A longitudinal study was performed to examine total albumin elimination and urinary albumin excretion in the female WAG/Rij rat. Complete necropsies were performed following the spontaneous death of the animals. The survival characteristics of this group was similar to that of survival cohorts.