Recent advances in preclinical in vitro approaches towards quantitative prediction of hepatic clearance and drug-drug interactions involving organic anion transporting polypeptide (OATP) 1B transporters

Hepatic uptake mediated by organic anion transporting polypeptide (OATP) 1B1 and 1B3 can serve as a major elimination pathway for various anionic drugs and as a site of drug-drug interactions (DDIs). This article provides an overview of the in vitro approaches used to predict human hepatic clearance (CL_h) and the risk of DDIs involving OATP1Bs. On the basis of the so-called extended clearance concept, in vitro–in vivo extrapolation methods using human hepatocytes as in vitro systems have been used to predict the CL_h involving OATP1B-mediated hepatic uptake. CL_h can be quantitatively predicted using human donor lots possessing adequate OATP1B activities. The contribution of OATP1Bs to hepatic uptake can be estimated by the relative activity factor, the relative expression factor, or selective inhibitor approaches, which offer generally consistent outcomes. In OATP1B1 inhibition assays, substantial substrate dependency was observed. The time-dependent inhibition of OATP1B1 was also noted and may be a mechanism underlying the in vitro–in vivo differences in the inhibition constant of cyclosporine A. Although it is still challenging to quantitatively predict CL_h and DDIs involving OATP1Bs from only preclinical data, understanding the utility and limitation of the current in vitro methods will pave the way for better prediction.     

Co-localization of vasoactive intestinal polypeptide, γ-aminobutyric acid and choline acetyltransferase in neocortical interneurons of the adult rat

Interneurons immunoreactive for vasoactive intestinal polypeptide (VIP) are integral elements of columnar organization patterns in the rat cerebral cortex. By application of the sensitive mirror technique, the co-localization of VIP with the classical inhibitory neurotransmitter γ-aminobutyric acid (GABA) and the acetylcholine-synthesizing enzyme, choline acetyltransferase (ChAT), was investigated in neocortical neurons. Furthermore, the frequency of co-localization of ChAT with GABA was determined. In a sample of 118 VIP-immunoreactive neurons, mostly from the primary somatosensory cortex, it was demonstrated that virtually all of them reveal immunoreactivity for GABA and, therefore, are to be GABAergic. Moreover, 34% of mostly bipolar, VIP-positive neurons contained ChAT and are, thus, supposedly cholinergic as well. Co-localization of VIP and ChAT varied according to cortical laminae. Finally, 88% of a total of 60 ChAT-immunoreactive neurons were also immunostained for GABA. It is concluded that almost all VIP-immunoreactive neurons and most of the cholinergic neurons in rat neocortex represent partly overlapping subpopulations of inhibitory interneurons utilizing GABA.     

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Actions on αT3-1 Gonadotrophs Show Desensitization

PACAP is a hypothalamic hypophysiotropic factor that acts upon a number of pituitary cells, including gonadotrophs. In the gonadotroph-derived αT3-1 cell line, PACAP acts via PVR1 receptors to stimulate adenylyl cyclase and phosphoinositidase C. PACAP-stimulated cAMP accumulation is inhibited by protein kinase C-activating phorbol esters in these cells and the current work was undertaken primarily to establish whether it is also subject to homologous regulation. In acute experiments, PACAP27-stimulated cAMP accumulation (intracellular plus extracellular) was measured (in the presence of phosphodiesterase inhibitor) both in intact cells and in cell membranes. The peptide increased cAMP accumulation, but initial rates of PACAP27-stimulated cAMP accumulation were reduced to between 10 and 50% within 10 min of stimulation in both cells and membranes. The initial rate of forskolin-stimulated cAMP accumulation was maintained in membranes but not in intact cells (although the deviation from linearity was less pronounced than with PACAP27). Thus, rapid homologous desensitization to PACAP27 occurs in intact αT3-1 cells, but is not entirely receptor specific. Rapid homologous desensitization of PACAP27-stimulated cAMP accumulation also occurred in the presence of a protein kinase C activating phorbol ester, which inhibited cAMP accumulation without altering the kinetics of the PACAP27 effect. Brief pre-treatment (3 min) with PACAP27 also reduced the ability of PACAP27, but not gonadotrophin-releasing hormone, to cause a spike-type elevation of cytosolic Ca²⁺ concentration (a consequence of phosphoinositidase C activation). In chronic desensitization studies, pre-treatment for 6 h with PACAP27 caused a dose-dependent (IC₅₀ approximately 10 nM) reduction of PACAP-stimulated cAMP accumulation and down regulated cell surface PVR1 receptors (to approximately 50%). Thus, it appears that PACAP27-stimulated (PVR-1 receptor mediated) adenylyl cyclase undergoes rapid homologous desensitization in αT3-1 cells, which is paralleled by homologous desensitization of PACAP27-stimulated phosphoinositidase C activity and involves mechanisms distinct from those underlying heterologous desensitization by phorbol esters. Chronic desensitization of PACAP-stimulated cAMP accumulation and down-regulation of cell surface PVR-1 receptors also occurs in these cells although the receptor loss may not entirely explain the observed desensitization.     

Anatomy and histology of the musk shrew (Suncus murinus) prostate

Gross anatomy and the light and electron microscopic characteristics of the musk shrew (Suncus murinus, Insectivora) prostate are described. The prostate is a pair of compound tubuloalveolar glands with one main excretory duct for each gland. Each gland is divided into ventral and dorsal lobes. The tubuloalveoli are larger in diameter and the secretory cells are lower in the ventral than in the dorsal lobes. Probable spontaneous release of secretory granules and accumulation of secretory material in secretory lumina are only observed in the ventral lobes. Secretory material is often crystallized in the secretory lumina. The epithelium of excretory ducts consists of mucous-type secretory cells and the boundary between this epithelium and the glandular epithelium is complex. The glandular epithelium consists of secretory and clear cells. This report illustrates that the structure of the prostate of musk shrew is unique among mammals.     

蝎毒多肽提取物对肺癌荷瘤裸鼠血流变学的影响

目的观察蝎毒多肽提取物（PESV）对肺癌荷瘤裸鼠血流变学的影响。方法移植肺癌荷瘤裸鼠随机分为PESV组（皮下注射PESV）与对照组（皮下注射生理盐水）。采用FASCO-300型全自动表观黏度快测仪对两组的全血黏度进行检测。结果与对照组相比，PESV组血流变学指标均有不同程度的降低，尤其是全血低切表观黏度、全血高切表观黏度、Casson黏度、Casson屈服应力均明显低于对照组（P〈0．01）。结论PESV可降低荷瘤裸鼠血液黏度，对肺癌荷瘤裸鼠肿瘤转移能力有明显的抑制作用。     

复方麝香注射液联合脑血肿引流术治疗中老年高血压脑出血疗效观察及费用对比

目的:探讨复方麝香注射液联合微创手术治疗中老年高血压脑出血的临床疗效.方法:将78例接受微创治疗的患者随机分组,两组均采用内科综合治疗.手术对照组在综合治疗基础上加用微创手术进行脑血肿引流;中西医结合组在微创手术治疗后加用复方麝香注射液(10～20 ml/d)静脉滴注1周.结果:中西医结合组显效率(66.67%)、有效率(82.05%)均明显高于手术对照组(46.15%和69.23%,P均<0.05),存活患者日常生活能力也明显优于手术对照组(P<0.05),意识恢复时间明显短于手术对照组(P<0.05),并发症的发生率(15.38%)明显低于手术对照组(38.46%,P<0.01),病死率(5.13%)明显低于手术对照组(10.26%,P<0.01),平均住院天数[(18.29±4.93)d]明显少于手术对照组[(26.23±5.82)d,P<0.05],平均住院费用[(5 916.23±826.39)元]明显少于手术对照组[(8 168.35±1 021.21)元,P<0.05].结论:脑血肿引流术后加用复方麝香注射液治疗中老年高血压脑出血,可降低病死率,减少并发症,降低病残程度,提高生存患者的生活质量,缩短住院时间,降低治疗费用.     

老年心功能不全血浆心钠素浓度的变化

采用放射免疫法测定31例老年心功能不全患者血浆心钠素(ANP)浓度,发现老年心功能不全组ANP明显低于对照组(P<0.01)。血浆ANP含量随心功能不全的严重程度而明显减少(P<0.05)。病程与ANP浓度呈负相关 (r=-0.441,P<0.05)。不同病种、不同受累部位及有或无房颤之间ANP差异无显著性(P<0.05)。     

血清TPS浓度在消化道肿瘤中价值的研究

共选择３０例消化道肿瘤病人，其中食管癌，胃癌，大肠癌各１０例，设健康献血者３０例，对两组血清特异型组织多肽抗原浓度进行了检测，结果肿瘤组血清ＴＰＳ浓度明显高于健康人。消化道肿瘤阳性检出经达７０％，其中食管癌８０％，胃癌６０％，大肠癌７０％。消化道肿瘤合并淋巴转移阳性检出率达７６．９％，其中食管癌１００％，胃癌６６．７％，大肠癌７０．０％。随着病程发展，血清ＴＰＳ浓度呈现升高趋势。     

POTASSIUM ACCELERATES URINARY SODIUM EXCRETION DURING SALT LOADING WITHOUT STIMULATING ATRIAL NATRIURETIC POLYPEPTIDE SECRETION

1. Effects of potassium (K) supplementation (100 mEq/day) on urinary sodium (Na) excretion and on the secretion of atrial natriuretic polypeptide (ANP) during salt loading (350 mEq/day) were studied in 12 healthy salt-resistant normotensives under strictly controlled metabolic ward conditions. 2. Urinary volume and Na excretion on the first day of the high salt period (HSP) were significantly greater in the K-supplemented group (KG) than in the control group (CG). 3. There was a significant gain in bodyweight after salt loading in both groups, with a significantly greater gain in CG on the second day of HSP. Haematocrit decreased significantly during salt loading in both groups, the degree of which was significantly greater in CG. 4. Plasma norepinephrine decreased significantly during salt loading in both groups, the degree of which was significantly less in KG than in CG. A significant increase in plasma ANP was observed in CG on and after the second day of HSP, while a significant increase in plasma ANP was observed on the fifth day of HSP in KG. 5. These findings indicate that K supplementation accelerates diuresis and natriuresis, resulting in moderate suppression of volume expansion induced by salt loading and that this accelerated diuresis and natriuresis is not a result of the action of ANP.