Pharmacokinetic interaction of contraceptive steroids with prednisone and prednisolone

Summary The oestrogenic component of oral contraceptives affects the activity of liver enzymes and the concentrations of plasma proteins implicated in steroid metabolism and transport. The present study was designed to determine these effects on the kinetics of prednisone and prednisolone. After an oral dose of prednisone, women on oral contraceptive steroids (n=10) had higher mean (±SD) area under the plasma concentration versus time curves of total (428±67 µg/ml/min vs 188±28 µg/ml/min, p<0.001) and unbound prednisolone (64±10 µg/ml/min vs 41±10 µg/ml/min, p<0.001) than women not taking oral contraceptive steroids (n=10). The differences were attributable to a lower non-renal clearance of prednisolone and to a higher apparent systemic availability of the drug in contraceptive users than in the controls. The affinity of albumin and transcortin for prednisolone was lower in women on oral contraceptives than in controls (p<0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.     

Binding ofβ-adrenoceptor blocking drugs to human serum albumin,to α1-acid glycoprotein and to human serum

Summary The binding of 8 -adrenergic blocking drugs to human serum albumin, to ₁-acid glycoprotein and to serum from normal volunteers and from patients with rheumatoid arthritis was studied. Protein binding was determined in vitro using equilibrium dialysis of labelled drug at 25° C. Oxprenolol and propranolol were highly bound to serum, alprenolol, pindolol and timolol to a lesser degree, and atenolol, metoprolol and sotalol were negligibly bound. For the five compounds which were appreciably bound, the mean binding was significantly higher in serum from patients with rheumatoid arthritis than in serum from normal volunteers. For those drugs, binding to ₁-acid glycoprotein was higher than to human serum albumin, and binding to a mixture of both proteins approached that to serum from healthy volunteers. For each of these drugs there was a strong correlation between the serum ₁-glycoprotein concentration and the percentage binding.     

Influence of indomethacin on the distribution of cortisol in man

Summary Simultaneous determinations of free and protein bound plasma cortisol and of the concentrations of cortisol in skin biopsies were performed after treatment with indomethacin. Neither after a single dose nor in patients on continuous treatment, were any consistent changes found in the protein binding of plasma cortisol. However, in patients treated for more than 3 weeks a significantly greater number of skin biopsies were observed with very low concentrations of cortisol. No relation between the free fraction of plasma cortisol and the tissue cortisol could be demonstrated.In vitro experiments showed no alteration of the protein binding of cortisol after the addition of indomethacin to plasma. It is concluded that indomethacin does not have antirheumatic activity because of displacement of the protein bound plasma cortisol as proposed by other workers. However, long term treatment with indomethacin does seem to influence the tissue distribution of cortisol. The possible relationship of this observation is discussed in view of reported fatalities after long continued indomethacin treatment.     

Purification and Characterization of DSIP-Like Material From Ovine Pineal Glands: Possible Peptide-Protein Interaction

The nonapeptide delta-sleep-inducing peptide (DSIP) has been isolated from venous blood of rabbits induced to sleep. Numerous reports have described sleep as well as extra-sleep effects. Radiochemical and immunochemical data suggest a relationship of DSIP with the pineal gland supported by interactions of this peptide with pineal functions such as the serotonin N-acetyltransferase activity. In order to demonstrate the natural occurrence of DSIP-like material associated with high Mr proteins in the ovine pineal, organs were water-extracted and fractionated by ultrafiltration and gel filtration. Radioimmunoassay (RIA) for DSIP-like fragments of the fractions revealed considerable amounts of pineal DSIP-like immunoreactivity (DSIP-LI) apparently existing in small as well as large molecular forms. Acidification of large DSIP-LI forms resulted in the elution from Sephadex G-50 of Mr less than or equal to 1,000 DSIP-like material. This free DSIP-LI form coeluted with the synthetic DSIP nonapeptide from microBondapak C18 on high-performance liquid chromatography. The results, therefore, appear to indicate the presence of a (biospecific) noncovalent intermolecular interaction of DSIP (1-9) with proteins (Mr greater than or equal to 10,000) of the ovine pineal gland.     

交泰丸中4种生物碱与人血浆蛋白结合率的测定

目的：研究交泰丸中表小檗碱,盐酸黄连碱,盐酸巴马汀,盐酸小檗碱与人血浆蛋白的结合率。方法：采用平衡透析法测定交泰丸中4种生物碱与人血浆蛋白的结合率,用高效液相色谱（HPLC）法测定透析内、外液中4种成分的质量浓度,计算血浆蛋白结合率。结果：表小檗碱,盐酸黄连碱,盐酸巴马汀和盐酸小檗碱的线性关系、精密度、提取回收率和稳定性均符合方法学要求;交泰丸低、中、高（0.5,1,1.5 mg·mL^-1）浓度中,表小檗碱与人血浆蛋白结合率分别为40.28%±3.02%,42.41%±2.61%,33.76%±2.19%,盐酸黄连碱与人血浆蛋白结合率分别为46.60%±3.47%,58.49%±6.47%,47.00%±1.3%,盐酸巴马汀与人血浆蛋白结合率分别为40.17%±3.26%,33.71%±3.74%,24.05%±1.81%,盐酸小檗碱与人血浆蛋白的结合率分别为29.41%±4.99%,25.35%±1.37%,18.07%±1.61%。结论：交泰丸中表小檗碱,盐酸巴马汀和盐酸小檗碱属于低等结合型成分,盐酸黄连碱属于中等结合型成分。     

MECHANISM OF TOXICITY OF LYSINOALANINE

Free lysinoalanine (LAL) is more toxic than covalently bound LAL in food proteins. This effect may be due to differences in absorption and copper-binding affinity between dietary ll and dl isomers of LAL.     

Inhibition of caspase-8 attenuates neuronal death induced by limbic seizures in a cytochrome c-dependent and Smac/DIABLO-independent way

There is increasing evidence that neuronal cell death induced by seizures occurs via extrinsic (death receptors) and intrinsic (mitochondria) pathways. Caspase-8 cleaves Bid, which releases cytochrome c, bridging the "extrinsic" and "intrinsic" pathways. Cleavage of Bid may amplify caspase-8-induced neuronal cell death following seizures. In the present study, we explored the effect of an inhibitor of caspase-8 (z-IETD-fmk) on the release of Smac/DIABLO and cytochrome c from mitochondria. Rats received intra-amygdaloid injection of kainic acid (KA) to induce seizures for 1 h. The seizures were then terminated by diazepam (30 mg/kg). The damaged and surviving neurons in hippocampus were observed by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and cresyl violet staining, the expression of caspase-8, Bid, XIAP, caspase-9, cytochrome c and Smac/DIABLO were detected with immunofluorescence and Western blot. The cleavage of caspase-8 and Bid increased at 0 h, cytosolic fraction of cytochrome c and Smac/DIABLO increased by 2 h, cleavage of caspase-9 was detected by 4 h, TUNEL-positive neurons appeared at 8 h and reached a maximum at 24 h following administration of diazepam in the ipsilateral CA3 subfield of hippocampus. Inhibition of caspase-8 significantly decreased neuronal cell death, accompanied by reduction of t-Bid, cleaved caspase-9 and cytosol cytochrome c. Smac/DIABLO from mitochondria was not affected. These results suggest that seizures can lead the translocation of cytochrome c into the cytosol, and the activation of caspase-8 occurs upstream the mitochondria release of cytochrome c and Smac/DIABLO. Inhibition of caspase-8 attenuated neuronal cell death following seizures by decreasing mitochondria release of cytochrome c but not Smac/DIABLO.