Background-Several studies suggest a role for an increased circulating pool of tissue factor (TF) in atherothrombotic diseases. Furthermore, certain cardiovascular risk factors, such as diabetes, hyperlipemia, and smoking, are associated with a higher incidence of thrombotic complications. We hypothesized that the observed increased blood thrombogenicity (BT) observed in patients with type 2 diabetes mellitus may be mediated via an increased circulating tissue factor activity. We have extended our study to smokers and hyperlipidemic subjects. Methods and Results-Poorly controlled patients with type 2 diabetes mellitus (nϭ36), smokers (nϭ10), and untreated hyperlipidemic subjects (nϭ10) were studied. Circulating TF was immunocaptured from plasma, relipidated, and quantified by factor Xa (FXa) generation in the presence of factor VIIa. BT was assessed as thrombus formation on the Badimon perfusion chamber.
The effect of molecular structure on the drug disposition and protein binding in plasma, the urinary recovery, and the renal clearance of sulphamerazine (SMR), sulphadiazine (SDZ), and sulphadimidine (SDM) and their N4-acetyl and hydroxy derivatives were studied in pigs. Following IV administration of SDM, SMR and SDZ, their mean elimination half-lives were 12.4 h, 4.3 h and 4.9 h respectively. The plasma concentrations of parent sulphonamide were higher than those of the metabolites, and ran parallel. The acetylated derivatives were the main metabolites; traces of 6-hydroxymethylsulphamerazine and 4-hydroxysulphadiazine were detected in plasma. The urine recovery data showed that in pigs acetylation is the major elimination pathway of SDM, SMR and SDZ; hydroxylation became more important in case of SMR (6-hydroxymethyl and 4-hydroxy derivatives) and SDZ (4-hydroxy derivatives) than in SDM. In pigs methyl substitution of the pyrimidine side chain decreased the renal clearance of the parent drug and made the parent compound less accessible for hydroxylation. Acetylation and hydroxylation speeded up drug elimination, because their renal clearance values were higher than those of the parent drug.
After testosterone pretreatment of castrated goats and during the rutting season of adult entire male goats, the oxidative metabolism of sulphadimidine (SDM) was inhibited markedly compared with the castrated control state of these animals. The oxidation of the 5 position (yielding 5-hydroxysulphadimidine) and of the 6-hydroxymethyl group (yielding 6-carboxysulphadimidine) was decreased equally, with that of the methyl group at the pyrimidine side chain itself being 6-hydroxymethylsulphadimidine (CH2OH), whereas the acetylation pathway was unaffected by testosterone. The consequence of altered metabolism by testosterone was a prolongation of SDM presence in the body. Effects on protein binding of the CH2OH metabolite and on the renal clearance of SDM were also investigated.
SUMMARY The kinetics of sulphamethoxazole (SMZ) in plasma and milk, and its metabolism, protein binding and renal clearance were studied in three newborn calves and two dairy cows after intravenous administration. SMZ was predominantly acetylated; no hydroxy and glucuronide derivatives could be detected in plasma and urine. Age-dependent pharmacokinetics and metabolism of SMZ were observed. The plasma concentration-time curves of the N4-acetyl metabolite in the elimination phase were parallel to those of the parent drug; the No-acetyl metabolite plasma percentage depended on age and ranged between 100% (new-born) to 24.5% (cow). SMZ was rapidly eliminated (elimination half-lives: 2.0-4.7 It) and exhibited a relatively small distribution volume ( f/Darea: 0.44-0.571/kg). SMZ was excreted predominantly by glomerular filtration, while its No-acetyl metabolite was actively eliminated by tubular secretion.
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