Isoniazid acetylatlon rate and development of antinuclear antibodies upon isoniazid treatment

A large proportion of tuberculous patients on isoniazid develop antinuclear antibodies, and an occasional one may also develop overt systemic lupus erythematosus. To determine if the development of antinuclear antibodies in such patients is related to the rate of acetylation of the drug, which is determined phenotypically, we studied both isoniazid acetylation rate and serum antinuclear antibodies in tuberculous patients who had been on isoniazid. Of 153 such patients studied, 78 were phenotypically slow and 75 were phenotypically fast isoniazid acetylators. Antinuclear antibodies to whole nuclei, nucleoprotein, soluble nucleoprotein and isoniazid-altered soluble nucleoprotein were detected by complement fixation tests more frequently in slow than in fast acetylators but this difference was not statistically significant. They also occurred more frequently in females than in males. Antinuclear antibodies that develop after prolonged isoniazid intake may be elicited by in vivo alteration of nucleoprotein by isoniazid and modestly influenced in their frequency by sex and by the pharmacogenetics of isoniazid.     

Effect of L-dopa loading on 5-HTP decarboxylation in rat brain areas

The time course of 5-hydroxytryptophan (5-HTP), serotonin (5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in four rat brain areas (hypothalamus, hippocampus, striatum and olfactory bulbs) were investigated after treatment with L-dopa (125 mg/kg, ip) + benserazide (50 mg/kg, ip). 5-HTP levels increased as early as 0.5 h, showed maximum accumulation at 1.5 h and returned to control levels within 4 h, while 5-HT was markedly decreased in all four structures, with a maximum effect at 1.5 h (approximately -70%) in the four areas. The decrease in 5-HT was not accompanied by changes in 5-HIAA levels. In agreement with previous studies, these data demonstrate that L-dopa loading interferes with serotonin metabolism in the rat brain. However, in addition to the releasing action of newly-synthesized dopamine, the accumulation of 5-HTP and the parallel decrease in 5-HT indicate a reduction in 5-HT synthesis. This inhibition could be explained by a competitive effect of L-dopa for aromatic aminoacid decarboxylase activity.     

Red blood cell survival studies in patients with anti-Cha, anti-Yka, anti-Ge, and anti-Vel

The survival of red blood cells, which were strongly incompatible in vitro, was measured in five patients whose serum contained an antibody to a high-frequency antigen. In the two patients with anti-Cha, and in the patient with anti-Yka, the cells survived normally. In the patient with anti-Ge, a small proportion of the cells was destroyed at an increased rate during the first 24 hours, but the remaining cells survived normally. In the patient with anti-Vel, the injected cells were rapidly destroyed.     

Localization of 13-hydroxyoctadecadienoic acid and the vitronectin receptor in human endothelial cells and endothelial cell/platelet interactions in vitro

Blood/vessel wall cell interactions depend, in part, on the expression of adhesion receptors on cell surfaces, such as expression of the vitronectin receptor (VnR) on the apical surface of endothelial cells (ECs) for platelet/EC adhesion. However, it is unclear how receptor expression is regulated from within cells. In previous studies, we found that ECs metabolize linoleic acid into the lipoxygenase monohydroxide, 13-hydroxyoctadecadienoic acid (13-HODE), and that the intracellular level of 13-HODE correlates inversely with VnR expression and platelet adhesion to the EC apical surface. In this study, we determined the physical associations of 13-HODE and VnR in unstimulated and stimulated ECs, ie, at times when ECs were and were not adhesive for specific ligands and platelets, using double antibody immunofluorescent staining techniques and binding assays. 13-HODE and the VnR were colocalized within unstimulated ECs. When ECs were stimulated, 13-HODE was no longer detectable, either in or outside the ECs, and the VnR was detected on the apical surface of the ECs. These changes were paralleled by increased vitronectin binding and increased platelet adhesion to the ECs. We suggest that colocalization of 13-HODE with VnR reflects a 13-HODE/VnR interaction, confining the VnR in a nonadhesive form inside unstimulated ECs, and, as a result, the ECs are nonadhesive. When the ECs are stimulated, 13-HODE and VnR dissociate, allowing the VnR to relocate on the EC surface, where the VnR undergoes a conformational change resulting in increased EC adhesivity.     

Calcitonin receptor polymorphism is associated with a decreased fracture risk in post-menopausal women

High bone resorption by the osteoclast results in osteoporosis, a disease affecting 40% of women after the menopause. Calcitonin, used to treat osteoporosis, inhibits bone resorption via receptors located on the osteoclasts. Two alleles of the calcitonin receptor gene ( CTR ) exist: a base mutation T-->C in the third intracellular C-terminal domain changes a proline (CCG) at position 447 to a leucine (CTG). We therefore studied the distribution of these alleles in a cohort of 215 post-menopausal Caucasian women suffering or not from osteoporotic fractures. The region of interest within the point mutation was amplified by PCR and screened for single strand conformation polymorphism. This work was followed by DNA sequencing of the fragments amplified. We found that bone mineral density (BMD) at the femoral neck was significantly higher in heterozygous subjects with the Rr genotype compared with the homozygous leucine (RR) and homozygous proline (rr) genotypes. Also, a decreased fracture risk was observed in heterozygote subjects. In conclusion, our results suggest that polymorphism of CTR could be associated with osteoporotic fractures and BMD in a population of post-menopausal women. CTR heterozygotes could produce both alleles of the receptor. The heterozygous advantage effect of Rr subjects could explain their protection against osteoporosis: higher bone density and decreased fracture risk. Establishing the genotype of the CTR gene in post-menopausal women could be of value in evaluating their risk of developing fractures.      

Passage of S-(+)- and R-(-)-ketoprofen across the human isolated perfused placenta

Summary— Ketoprofen is a chiral non-steroidal anti-inflammatory drug (NSAID) available as a racemic (rac) mixture of S -(+)- and R -(-)-isomers. Its inhibitory effect on prostaglandin biosynthesis resides virtually in the S -form. Interestingly, R -ketoprofen does not undergo substantial metabolic inversion in humans. Though contraindicated during the last trimester of pregnancy, NSAIDs, including ketoprofen, are used as tocolytic agents in some cases. The S/R plasma concentration ratio was reported to average 2.3 in premature neonates whose mothers were given rac-ketoprofen and to be close to 1 in the maternal plasma. Thus, we investigated the placental transfer of rac-ketoprofen in vitro using Schneider's perfused human cotyledon model. Glucosed Earle solutions with and without human serum albumin (HSA) were used. Several maternal perfusates were tested with different rac-ketoprofen concentrations together with 20 mg L⁻¹ of antipyrine as a reference substance. Ketoprofen enantiomers were assayed by a specific HPLC method with derivatization procedure. HSA concentrations in maternal perfusate influenced the placental transfer of ketoprofen enantiomers. In the absence of HSA in the maternal perfusate, the S -(+)/ R -(-) concentration ratio was close to 1 in the fetal perfusate. By contrast, this ratio averaged 1.44 after addition of HSA 10 g L⁻¹ on the maternal side. Similar results were found for dialysis experiments using an inert Spectrapor 2 membrane suggesting that the S -(+)-free concentration is superior to the R -(-)-free concentration in the presence of HSA. Direct measurements of the free concentrations by centrifugal ultrafiltration confirmed this hypothesis. Accordingly, the data observed in vivo may result, at least in part, from the stereoselective protein binding of ketoprofen.     

FMC SeaKem HGT Agarose生物学特性的研究

目的：研究ＦＭＣ ＳｅａＫｅｍ ＨＧＴ Ａｇａｒｏｓｅ的生物学特性。方法：急性毒性采用大鼠下腔静脉内直接注射观察法；过敏试验采用豚鼠肌肉、静脉内注射法；吸收试验在兔、鼠皮下及肝内注射后观察。结果：ＦＭＣ ＳｅａＫｅｍ ＨＧＴ Ａｇａｒｏｓｅ无急性毒性、无过敏反应，在兔、鼠皮下及肝内观察３个月均不能被吸收，其溶液能良好地溶解化疗药物卡铂和丝裂霉素。结论：ＦＭＣ ＳｅａＫｅｍ ＨＧＴ Ａｇａｒｏｓｅ有