Serum concentration and protein binding of thioridazine and its metabolites in patients with chronic alcoholism

Summary The blood chemistry and clinical pharmacokinetics of thioridazine and its metabolites, side-chain sulphoxide, side-chain sulphone and ring sulphoxide, were studied in 31 alcoholics and were compared with values in 17 thioridazine-treated controls without alcoholism. Pathological blood chemistry values, including abnormal liver function and protein concentrations, were common among the alcoholics. In relation to dosage, the majority had a low serum concentration of thioridazine and at a given concentration of thioridazine they had high serum concentrations of its metabolites. Positive intercorrelations were found between pathological liver function tests, prolonged serum half-life and increased serum concentration of thioridazine. The free fractions of thioridazine, side-chain sulphoxide and ring sulphoxide were significantly higher and those of the side-chain sulphone lower in the alcoholics than in the controls. The free fractions of side-chain and ring sulphoxide were significantly increased in patients with a low concentration of ₁-acid glycoprotein.     

Influence of acetylator phenotype on the pharmacokinetics of a new vasodilator antihypertensive,endralazine

Summary Five and 10 mg single oral doses of a new vasodilator antihypertensive, endralazine (E) were given on separate occasions to 17 normal male volunteers (8 slow, 7 heterozygous fast and 2 homozygous fast acetylators). The homozygous fast acetylators were excluded from statistical comparisons. Only small differences were observed in the pharmacokinetics of E between the phenotypes and there was no evidence of non-linearity at the 2 dose levels studied. Terminal half-lives ranged from 2.59 to 7.14 h with a mean of 4.30±1.08 h for the 5 mg dose and 4.25±1.09 h for the 10 mg dose. There was no significant difference in half-lives between slow and heterozygous fast acetylators. The mean area under the plasma level-time curve (AUC ₀ ) was 18.2% lower (p<0.05) in the heterozygous fast acetylators than in the slow acetylators following the 5 mg dose and 11.0% lower (p>0.05) following the 10 mg dose. Extremely rapid absorption of the drug precluded accurate estimation of absorption rates. The AUC ₀ of the acetylation metabolite (methyltriazoloendralazine) was small compared to that of E although higher in the heterozygous fast acetylators than in the slow acetylators (p<0.01).     

Regulatory effect of glucagon on its own receptor concentrations and target-cell sensitivity in the rat

Summary To evaluate the role of glucagon on its hepatocyte receptor concentrations, groups of rats were injected with a long-acting glucagon preparation (20 [G-20], 40 [G-40] or 60 [G-60] g/100 g body weight) every 8 h for 4 days. Glucagon receptors in liver plasma membranes of treated animals were decreased in number (control = 1.66±0.20 ng/0.5 mg protein versus G-20=1.24±0.26, G-40=1.03±0.26, G-60 =0.70±0.03 ng/0.5 mg protein; p<0.05, < 0.001, < 0.001, respectively), but they were indistinguishable from receptors of control rats by other criteria including affinity and kinetics of association. Degradation of both glucagon and receptor sites did not account for differences observed in binding. Similar results were obtained with isolated hepatocytes. In relation to controls, isolated hepatocytes of treated rats had a reduced number of receptors (control = 0.70±0.05 versus G-40=0.47±0.04 ng/10⁶ cells; p< 0.02) proportionate to the decreased glucagon-stimulated production of cyclic AMP and glucose. Four to eight hours exposure of cultured hepatocytes of nontreated rats to 4 × 10^-8 mol/l glucagon produced a decreased binding of ¹²⁵I-glucagon to its receptor (p<0.05). In contrast, hormone exposure for shorter periods of time (0–2 h) was without effect. These results suggest (1) an inverse relationship between circulating glucagon levels and hepatocyte glucagon receptor concentration, and (2) a direct relation between receptor number and target-cell response.     

Study of preclinical changes in workers exposed to inorganic mercury in chloralkali plants

Summary The aim of the present work was to clarify the question of preclinical changes of Hg intoxication (micromercurialism) in man. The study to detect these disorders was performed on 39 chloralkali plant workers who had been exposed to mercury for more than 7 years. The ambient air, urine and blood values of the last few years were determined in extensive measurements by various methods and related to one another. The average ambient air concentrations were clearly below the currently applicable threshold limit value (German MAK) of 0.1 mg/m³. For the purpose of clarifying the mentioned question of preclinical changes of intoxication, the exposed persons were subjected to psychomotor-function examinations and compared with a group of nonexposed persons. The blood pressure and pulse frequency values of both groups were also determined and compared with one another. No significant differences between the two groups of persons examined were detectable.Presented at the 18th Congress of the Deutsche Gesellschaft für Arbeitsmedizin in Frankfurt, 24th May 1978     

Cellular uptake and concentrations of tamoxifen upon administration in poly(ε-caprolactone) nanoparticles

Purpose: In an attempt to increase the local concentration of tamoxifen in estrogen receptor positive breast cancer cells, we have prepared and characterized poly (ε-caprolactone) (PCL) nanoparticle formulation. Methods: PCL (mol wt 14,800 daltons) nanoparticles were prepared by the solvent displacement method in acetonewater system in the presence of Pluronic F-68. PCL nanoparticles, labeled with rhodamine 123, were incubated with MCF-7 estrogen receptor positive breast cancer cells to determine uptake, intracellular distribution, and localization as a function of time. Intracellular drug concentrations over a specified period of time using different initial doses were examined using tritiated [³H]-tamoxifen. Results: A significant fraction of the administered rhodamine 123-loaded PCL nanoparticles was found in the perinuclear region of the MCF-7 cells, where estrogen receptors are also localized, after 1 hour of incubation. Measurements of the intracellular concentrations revealed that most of the administered nanoparticle dose was internalized within the first 30 minutes of incubation, and the uptake followed saturable transport kinetics. Conclusion: Results of this study show that PCL nanoparticles were rapidly internalized in MCF-7 cells and intracellular tamoxifen concentrations followed a saturable process. This approach may provide better therapeutic benefit by delivering the drug locally, near the tumor cells, for a longer period of time.     

甘油蔗糖液对哺乳动物桑椹胚的渗透反应及冻存效果研究

为了提供快速冷冻前胚胎发生部分脱水的科学依据，我们观察了家兔桑椹胚在冷冻保护液中的体积变化。当桑椹胚置于仅含３．０ｍｏｌ／Ｌ或４．０ｍｏｌ／Ｌ甘油液中，桑椹胚立即皱缩，２ｍｉｎ时体积为等渗时体积的５８．９％或５９．６＾％，１０ｍｉｎ时桑椹胚体积达到等渗量的９０．８％或７６．９％，将这些桑椹胚接着移入含３．０ｍｏｌ／Ｌ或４．０ｍｏｌ／Ｌ甘油加０．２５ｍｏｌ／Ｌ蔗糖保护液中，桑椹胚再次发生皱缩主膨大变     

中草药提取物的体外抑菌活性研究

目的探讨10种中草药提取物的体外抗菌活性。方法制备10种中草药提取物,采用试管连续稀释法对金黄色葡萄球菌、大肠埃希菌、铜绿假单胞菌和白色念珠菌进行体外抑菌试验。结果10种中草药的提取物对金黄色葡萄球菌、大肠埃希菌、铜绿假单胞菌和白色念珠菌有不同程度的抑制活性;其中尤以赤芍、石榴皮、五味子和黄连的提取物抗耐药菌活性最高,赤芍提取物对上述4种菌的抑制活性均较高,其最低抑菌浓度(MIC)分别为7.80、1.95、1.957、.80 mg/ml。结论赤芍、石榴皮、五味子和黄连提取物呈现广谱抗菌特性,且具有抗耐药菌作用。     

抗生素活性时程的评估指标:靶组织游离药物的浓度

评价抗生素临床疗效的常用参数包括:最低抑菌浓度(MIC)、抗生素后效应(PAE)以及一些基于MIC的药动学/药效学参数,如t>MIC,cmax/MIC,AUC/MIC等。但由于抗生素的蛋白质结合率不同、组织分布不均匀和各种屏障等因素的影响,上述参数都存在一定的局限性。靶组织游离药物浓度是一个重要的药动学/药效学模型参数,能够更好地说明抗生素的临床疗效。近年来,国内外报道的研究靶点药物分布的方法有很多,其常用方法是利用皮肤水疱研究、成像技术和透析技术测定抗生素在靶组织的分布浓度。总之,新技术的介入提供了更多的靶点药物分布的信息。     

The effects of sucrose on stability of human brain natriuretic peptide [hBNP (1–32)] and human parathyroid hormone [hPTH (1–34)]

Abstract: Although the effect of sucrose on the physical stability of proteins has been well documented, its impact on their chemical stability is largely unknown. The aim of this study was to investigate the potential effects of sucrose on the structural conformation of human brain natriuretic peptide [hBNP (1–32)] and the synthetic human parathyroid hormone [hPTH (1–34)], and link these effects to chemical degradation pathways of these peptides. The stability of hBNP (1–32) and hPTH (1–34) was studied at pH 5.5. Aggregation was monitored using size exclusion high‐performance liquid chromatography (SE‐HPLC), whereas oxidation and deamidation products were measured by reversed phase (RP) HPLC. Fourier transform infrared (FT‐IR) spectroscopy was used to study the peptides’ conformation. Sucrose retarded aggregation, deamidation, and oxidation of hBNP (1–32) and hPTH (1–34), with a maximum effect at relatively high concentrations (as much as 1 m ). FT‐IR spectroscopy indicated that sucrose maintained the native conformation of hBNP (1–32) and induced small conformation changes in the hPTH (1–34) structure. Sucrose enhanced the stability of hBNP (1–32) and hPTH (1–34) in liquid formulations. The stabilizing effect of sucrose was due to a large extent to retardation of oxidation and deamidation of hBNP (1–32) and hPTH (1–34).     

远志的化学成分研究Ⅱ

目的 :研究远志的化学成分。方法 :采用多种色谱方法进行分离 ,利用光谱数据结合理化分析进行结构鉴定。结果 :从远志根皮的正丁醇层中分离得到 4个蔗糖酯类化合物 ,分别鉴定为 :sibiricoseA₅(1) ,sibiricoseA₆(2 ) ,tenuifolisideA(3)和 3′ ,6 disinapoylsucrose(4 )。结论 :化合物 1和 2为首次从该植物中分离得到。