Investigation of non-linear Mate1-mediated efflux of trimethoprim in the mouse kidney as the mechanism underlying drug-drug interactions between trimethoprim and organic cations in the kidney

The purpose of this study was to elucidate the involvement of Mate1 in the tubular secretion of trimethoprim and saturation of Mate1-mediated efflux to address the mechanisms underlying the pharmacokinetic drug interactions with trimethoprim. Trimethoprim is a more potent inhibitor of MATE2-K than MATE1 with K_i values (μM) of 0.030–0.28 and 2.4–5.9, respectively. Trimethoprim is a substrate of human MATE1 and MATE2-K with K_m values of 2.3 ± 0.9 and 0.018 ± 0.004 μM, and mouse Mate1, but not human OCT2, mouse Oct1 and Oct2. Pyrimethamine significantly reduced the renal clearance (CL_R) of trimethoprim (mL/min/kg) from 40.0 ± 5.1 to 20.1 ± 3.7 (p < 0.05). Trimethoprim was given to mice at three infusion rates (150, 500, and 1500 nmol/min/kg). Together with an increase in the plasma concentrations of trimethoprim, the CL_R (mL/min/kg) of trimethoprim decreased to 25.9 ± 3.2, 13.5 ± 5.7, and 8.92 ± 1.50 at the respective rates. Trimethoprim decreased the CL_R of rhodamine 123 in an infusion rate-dependent manner: 11.5 ± 1.3 (control), 5.17 ± 1.55, 1.31 ± 0.50, and 0.532 ± 0.180. These results suggest that Mate1 mediates the tubular secretion of trimethoprim, and at therapeutic doses, MATEs-mediated efflux can be saturated, and thereby, cause drug interactions with other MATE substrates.     

腹腔镜胆囊切除术并发症的预防和治疗

目的 探讨腹腔镜胆囊切除术(LC)常见并发症的发生原因及预防措施.方法 回顾性分析本院1998至2007年完成的1126例腹腔镜胆囊切除术患者的临床资料,将患者分为实验组以及对照组,在实验组患者手术过程中采取一系列针对性的措施预防并发症的发生.而对照组采用传统的手术方式及围术期护理.将两组的并发症发生率进行比较.结果 实验组并发症发生率为1.62%,明显低于对照组的3.86%,两组比较,具有统计学意义.结论 腹腔镜胆囊切除术是胆囊切除的最佳选择,但仍存在较严重的并发症,遵循正规的手术原则,及时中转开腹,才能减少并发症,保证手术质量.     

Circular dichroism detection in high-performance liquid chromatography: Evaluation of the anisotropy factor

The application of a circular dichroism (c.d.) detection system in HPLC using a chiral stationary phase is presented. The simultaneous measurement of the absorbance and c.d. signal allows the evaluation of the anisotropy factor (g = Δ/) and thus the determination of the enantiomeric excess (e.e.) of the eluates. When this detection system is used in preparative chiral chromatography the collection of the enantiomeric fractions can be readily optimized.     

中西医结合治疗LC术后胆囊窝积液58例体会

目的:评价中西医结合治疗与纯西医治疗LC术后胆囊窝积液的临床价值。方法:回顾分析中西医结合治疗58例(A组)与纯西医治疗20例(B组)的临床资料,并比较两组的积液吸收时间、疼痛消失时间、腹胀消失时间、体温正常时间、术后住院天数等指标。结果:A组中在积液吸收时间、腹胀消失时间、术后住院天数方面明显优于B组,差异高度显著(P<0.01);疼痛消失时间、体温正常时间优于B组,差异有显著性(P<0.05)。结论:中西医结合治疗LC术后胆囊窝积液比纯西医治疗,具有疗效快、功能恢复好的优点。     

An automated on-line method for simultaneous analysis of phenothiazines in human serum by high-performance liquid chromatography/sonic spray ionization mass spectrometry using backflush column switching

An automated on-line method for simultaneous analysis of five phenothiazine drugs by high-performance liquid chromatography (HPLC)/sonic spray ionization mass spectrometry (SSI-MS) has been established, using backflush column switching. A 400-μl portion of serum sample diluted 81-fold with distilled water was subjected to the on-line system. In the system, an Oasis HLB cartridge was used as the precolumn for extraction; large molecules such as proteins in serum were discarded by use of distilled water containing 0.1% formic acid as a mobile phase. After switching a valve, the analytes trapped in the precolumn were eluted in the backflush mode and separated by a Chromolith Performance RP-18e column, which is composed of C₁₈-bonded monolithic silica. The column effluents were then introduced into the SSI-MS. The present method provided successful separation and determination of six phenothiazines including an internal standard. Satisfactory linearities, reproducibility, and sensitivity were obtained at concentration levels that matched the toxic levels of phenothiazines. All drug peaks appeared within 18 min, and the system could be reequilibrated in only about 8 min for the next run. Because of the simplicity and rapidness of the method, it is likely to be useful in the fields of emergency medicine and forensic toxicology.     

Localization of substance P- and enkephalin-like immunoreactivity in relation to catecholamine-containing cell bodies in the cat dorsolateral pontine tegmentum: an immunofluorescence study

The distribution of tyrosine hydroxylase-, substance P- and enkephalin-immunoreactive neurons in the cat dorsolateral pons was studied using the indirect immunofluorescence method of Coons. To allow for the visualization of substance P- and enkephalin-immunoreactive cell bodies, colchicine was injected either in the ventricular space or in the cerebral tissue. The distribution of the tyrosine hydroxylase-immunoreactive cell bodies corresponded with the well-known distribution of catecholamine cells in this area of the brain. The observation of adjacent sections treated separately with tyrosine hydroxylase- and enkephalin-antiserum revealed that most catecholaminergic cells contain enkephalin-immunoreactivity. In addition to this catecholamine-enkephalin cell population, a moderate number of substance P-immunoreactive cell bodies was found in dorsolateral pons. The peribrachial nuclei were found to be densely supplied with substance P- and enkephalin-immunoreactive fibers, whereas the medial subdivisions, which contain the majority of the catecholamine cells in the dorsolateral pons, display a moderate number of immunoreactive fibers. These results are suggestive of interactions between peptide-containing and catecholaminergic neurons and also between-peptide-containing and non-catecholamine-containing neurons in the cat dorsolateral pons.     

Membrane properties of rat locus coeruleus neurones

Intracellular recordings were made from neurones in the locus coeruleus contained within a slice cut from rat pons and maintained in vitro. Most neurones fired action potentials spontaneously at frequencies of between 1 and 5 Hz; this did not arise from spontaneous synaptic input but appeared to result from endogenous properties of the membrane conductances. Under voltage clamp at potentials near threshold for action potential generation (? 55 mV) there was a persistent inward calcium current. This current became less with membrane hyperpolarization and was abolished at about ?70 mV. Two potassium currents were observed. The first had properties similar to that generally described as the “fast” potassium current (I_K,A); it flowed transiently (for about 200 ms) when the membrane potential passed from about ?65 to ?45 mV, and was blocked by 4-aminopyridine. The second was a calcium-activated potassium current (I_K,Ca); it flowed for several seconds following a burst of calcium action potentials. Spontaneous and evoked action potentials had both tetrodotoxin-sensitive and tetrodotoxin-resistant components. The latter was apparently due to calcium entry. The potential changes occurring during the spontaneous firing of locus coeruleus neurones could be reconstructed qualitatively from the ionic conductances observed. The membrane properties of the locus coeruleus neurones were remarkably uniform; however, about 5% of cells impaled within the region of the locus coeruleus were electrophysiologically distinct. These atypical cells had short duration action potentials, did not fire spontaneously and had large spontaneous depolarizing synaptic potentials.     

Rhythms, synchrony and electrical coupling in the Locus coeruleus

Electrical coupling of neurones is believed to promote synchronized activity. It may, however, also be a requirement for the maintenance of endogenous rhythmic activity in some systems. In en bloc isolated brainstem-spinal cord of the neonatal rat simultaneous whole cell recordings from pairs of LC neurones (n = 47 pairs) disclosed for the most part strongly synchronized activity which could take the form of tonic spiking or phasic bursts. Simultaneous whole cell recording from LC neurones and glia also revealed synchronized waves of depolarization in 7 of 17 pairs. This synchrony was partly due to respiratory-phased synaptic input and partly due to mechanisms, which were not dependent on chemical synapses. The gap junction uncoupler carbenoxolone suppressed non-synaptic rhythmic activity in LC neurones, but did not suppress either respiratory-phased synaptic input to these neurones or their excitatory response to increased CO(2). We give preliminary direct evidence for the existence of a current pathway between LC neurones, which is inhibited by carbenoxolone. Within the LC nucleus carbenoxolone-sensitive electrical coupling, which may involve neurone-glia as well as neurone-neurone interactions, may be required not just for synchronization, but also for the maintenance of rhythm.     

腹腔镜胆囊切除术时中转开腹的临床分析

目的 :探讨腹腔镜胆囊切除术 (LC)时中转开腹手术的原因。方法 :回顾性分析本院 2 10例中 8例中转开腹的临床资料。结果 :LC中转开腹手术的发生率为 3 8%。主要原因是有急性胆囊炎病史 ,近期有急性发作史。B超提示胆囊壁粗糙 ,壁厚大于 0 5cm。术中Colat三角粘连重 ,难以辨认胆囊管。结论 :胆囊病变如有急性胆囊炎发作史 ,近期有急性发作史 ,B超提示胆囊壁厚大于 0 5cm时 ,选择LC应慎重     

电视腹腔镜胆囊切除术胆漏的预防和处理

目的：降低电视腹腔镜胆囊切除术（LC）胆漏的发生率,提高治愈率,防止胆漏对病人的危害。促进愈合。方法：分析1991年12月－1998年12月我院开展LC4000例,出现胆漏29例的原因,用线扎代替钛夹处理胆囊管和胆囊血管,简化了胆囊三角的过多解剖;术中针对性的置放引流管防止胆汁性腹膜炎;特殊情况的胆囊作特殊处理。结果：拓宽了LC的适应范围,大大减少了手术中胆管的损伤、出血。发生胆漏的病人中有41％（12／29）困术中置管引流而未出现胆汁性腹膜炎,并很快康复。术后B超动态观察胆囊窝积液情况,及时引流,胆漏多能自愈。结论：熟练的操作技巧能避免手术损伤,认真线扎处理胆囊管和胆囊血管并针对性置放引流管,能有效防止胆漏和胆汁性腹膜炎;及时发现、及时处理是减少胆漏危害的关键。