聚乙二醇干扰素α序贯联合恩替卡韦治疗慢性乙型肝炎的临床观察

目的观察PegIFN-α序贯联合恩替卡韦治疗慢性乙型肝炎患者的疗效,为临床在单独应用干扰素治疗应答效果不好的慢乙型肝炎提供安全可靠的治疗方法。方法 30例慢性乙型肝炎患者应用PegIFN-α180μg皮下注射每周1次12周后,分两组,单药组(PegIFN-α)和联药组(PegIFN-α序贯联合恩替卡韦)。观察24周后及48周以上的临床疗效。结果两组患者在治疗24周时和48周以上时,在ALT复常率,HBV DNA不可检测率HBeAg阴转率,HBeAg转换率,HBsAg值下降率均存在差异。结论在临床上在单独应用干扰素治疗应答效果不好,PegIFN-α序贯联合恩替卡韦治疗慢性乙型肝炎患者存在疗效显著。值得临床重视。     

恩替卡韦联合苦参素治疗HBeAg阳性慢性乙型肝炎的疗效观察

目的 观察恩替卡韦联合苦参素抗病毒治疗对HBeAg阳性慢性乙型肝炎患者病毒复制指标及T淋巴细胞亚群的影响.方法 将60例慢性乙型肝炎患者随机分为联合组和对照组.联合组30例,给予恩替卡韦联合苦参素治疗;对照组30例,单用恩替卡韦治疗.两组疗程均为48周.结果 疗程结束后,联合组HBVDNA、HBeAg阴转率以及HBeAg/抗HBe转换率显著高于对照组,差异有统计学意义(P均＜0.05);治疗组CD4+以及CD4+/CD8+也较对照组明显升高,差异有统计学意义(P均＜0.05).结论 恩替卡韦联合苦参素抗病毒治疗对HBeAg阳性慢性乙型肝炎患者有较好疗效.     

胸腺肽α1联合恩替卡韦治疗HBeAg阳性慢性乙型肝炎的疗效观察

目的 观察胸腺肽α1联合恩替卡韦治疗HBeAg阳性慢性乙型肝炎的临床疗效,探讨提高HBeAg阳性慢性乙型肝炎临床疗效的治疗方案.方法 选择HBeAg阳性慢性乙型肝炎患者106例,随机分为观察组和对照组,各53例.对照组给予恩替卡韦治疗,观察组给予胸腺肽α1联合恩替卡韦治疗,2组均治疗6个月.比较2组临床疗效和治疗前后丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)水平及不良反应.结果 观察组总有效率为88.7%高于对照组的73.6%,差异有统计学意义(P＜0.05).2组治疗后ALT和AST水平均降低,差异有统计学意义(P＜0.01);且观察组治疗后ALT和AST水平低于对照组,差异有统计学意义(P＜0.05).结论 胸腺肽α1联合恩替卡韦治疗HBeAg阳性慢性乙型肝炎疗效显著,可有效改善患者预后.     

恩替卡韦联合苦参素治疗慢性乙型肝炎的疗效观察

目的 观察恩替卡韦联合苦参素治疗慢性乙型肝炎(乙肝)的临床疗效.方法 选择慢性乙肝患者74例,随机分为两组.观察组40例采用恩替卡韦片0.5 mg/d,口服,联合苦参素600 mg/d,静脉注射治疗；对照组34例仅服用恩替卡韦片0.5 mg/d.从治疗开始后1、3、6、9、12个月及随访期每半年复查血清HBeAg、Anti-HBe及丙氨酸氨荃转移酶(ALT)复常率.结果 治疗开始后1、3、6、9、12个月及随访期每半年,观察组患者血清HBeAg及Anti-HBe转阴率分别为32.5％ 、45.0％、60.0％、60.0％、62.5％、62.5％和62.5％,均高于对照组的5.9％、5.9％、8.8％、11.8％、11.8％、11.8％和11.8％ (x2 =5.46,12.83,25.22,21.68,24.79,24.79,24.79,均P＜0.05).观察组ALT复常率分别为45.0％、67.5％、87.5％、90.0％、90.0％、90.0％和90.0％,均高于对照组的20.6％、32.4％、41.2％、50.0％、52.9％、52.9％和52.9％(x2=4.60,10.36,20.67,14.47,12.08,12.08,12.08,均P＜0.05).结论 恩替卡韦联合苦参素用以治疗慢性乙肝具有协同抗病毒作用,治疗效果好、安全性高、治疗方案简单、值得临床推广使用.     

恩替卡韦与干扰素序贯治疗高病毒载量慢性乙型肝炎的临床疗效

目的观察恩替卡韦与干扰素序贯治疗高病毒载量慢性乙型肝炎的临床疗效。方法选取笔者所在医院2011年1～12月收治的高病毒载量慢性乙型肝炎患者100例,根据不同治疗方法分为治疗组、对照组和空白对照组,在第12、24、48周分别检测HBVDNA、HBeAg定量、HBVYMDD及肝功能等。结果治疗组的HBVDNA及HBeAg阴转率明显高于对照组和空白对照组,且变异率较小,三者比较差异有统计学意义(P<0.05)。结论恩替卡韦与干扰素序贯治疗高病毒载量慢性乙型肝炎疗效显著,值得临床推广应用。     

恩替卡韦治疗HBeAg阳性慢性重度乙型肝炎临床观察

目的:探讨观察恩替卡韦治疗HBeAg阳性慢性重度乙型肝炎(HBV)的临床效果.方法:将我院收治的81例HBeAg阳性慢性重度乙型肝炎患者根据随机综合序贯法分组,对照组(40例)予以拉米夫定治疗,观察组采用恩替卡韦治疗,观察对比两组治疗效果.结果:观察组ALT复常率、HBeAg转阴率、HBV-DNA转阴率均明显优于对照组(P<0.05);观察组不良反应发生率明显低于对照组(P<0.05).结论:恩替卡韦治疗HBeAg阳性慢性重度乙型肝炎的临床效果突出,具有"疗效好、安全性高"等优势,值得推广.     

国产恩替卡韦分散片对慢性乙型肝炎初次抗病毒的疗效分析

目的 比较国产恩替卡韦分散片与进口恩替卡韦及拉米夫定对慢性乙型肝炎初次抗病毒的疗效.方法 168例未接受过抗病毒治疗的慢性乙型肝炎患者完全随机分为3组:国产恩替卡韦组(54例),进口恩替卡韦组(56例),拉米夫定组(58例),治疗1年.观察3组患者治疗第12、24、48周的ALT复常率、HbeAg和HBVdNA的阴转率,平均血清HBVdNA基线水平.结果 治疗第12、24、48周国产思替卡韦组的ALT复常率、HbeAg和HBVdNA的阴转率均明显高于拉米夫定组[第12周分别为74.1％(40例)比51.7％(30例)、24.1％(13例)比8.6％(5例)、77.8％(42例)比55.2％(32例),第24周分别为85.2％(46例)比63.8％(37例)、27.8％(15例)比10.3％(6例)、81,5％(44例)比60.3％(35例),第48周分别为88.9％(48例)比69.0％(40例)、33.3％(18例)比13.8％(8例)、96.3％(52例)比67.2％(39例),均P＜0.05],与进口恩替卡韦组比较,差异均无统计学意义(均P＞0.05).结论 慢性乙型肝炎初次抗病毒治疗国产恩替卡韦分散片疗效明显高于拉米夫定,而与进口恩替卡韦片的疗效差异无统计学意义.     

聚乙二醇干扰素α-2b对慢性乙型肝炎患者的免疫调节及抗病毒效果分析

目的 探讨不同剂量聚乙二醇干扰素α-2b与恩替卡韦联合治疗慢性乙型肝炎的抗病毒效果,及其对免疫调节功能的影响.方法 选择2014年1-12月利川市人民医院收治的慢性乙型肝炎患者180例,按治疗方法分为高剂量组、低剂量组和对照组,每组60例.对照组单纯口服恩替卡韦进行治疗,高剂量组和低剂量组分别在对照组基础上给予聚乙二醇干扰素α-2b 1.5 μg/kg和1.0 μg/kg肌内注射,治疗48周后比较3组近期疗效、乙型肝炎病毒-DNA(HBV-DNA)水平、T淋巴细胞亚群变化、自然杀伤细胞(NK)活性与白介素-2(IL-2)变化及不良反应情况.结果 治疗后,高剂量组与低剂量组的完全应答率与持续应答率均高于对照组(P＜0.05),且高剂量组高于低剂量组(P＜0.05);高剂量组和低剂量组HBV-DNA和CD8+水平低于对照组(P＜0.05),且高剂量组低于低剂量组(P＜0.05);高剂量组和低剂量组NK活性、IL-2、CD3+、CD4+和CD4 +/CD8+水平高于对照组(P＜0.05),且高剂量组高于低剂量组(P＜0.05);高剂量组和低剂量组不良反应总发生率均低于对照组(P＜0.05).结论 高剂量聚乙二醇干扰素α-2b与恩替卡韦联合治疗慢性乙型肝炎,能够有效抑制病毒复制,增强机体免疫力,提高近期疗效,且不良反应少.     

替比夫定与恩替卡韦治疗E抗原阳性慢性乙型肝炎的疗效比较

目的 比较替比夫定与恩替卡韦治疗HBeAg阳性慢性乙型肝炎的临床效果.方法 选取91例HBeAg阳性慢性乙型肝炎患者,采用数字表法随机分组法将患者分为两组,替比夫定治疗组患者46例,恩替卡韦治疗组患者45例,疗程均为60周.分别观察两种药物在治疗24、36、48和60周时的ALT复常率、HBV DNA含量和HBV血清标志物表达情况.结果 两组的ALT复常率、HBV DNA含量在治疗12、24、36、48和60周时差异均无统计学意义（均P＞0.05）;HBeAg血清学转换率在治疗12、24、36周差异均无统计学意义（均P＞0.05）,在治疗48周和60周时替比夫定治疗组要明显优于恩替卡韦治疗组（Х^2=4.589、3.959,均P ＜0.05）.结论 替比夫定与恩替卡韦治疗HBeAg阳性慢性乙型肝炎均具有一定疗效;在治疗48和60周时,替比夫定治疗HBeAg血清学转换率要优于恩替卡韦.     

恩替卡韦联合聚乙二醇干扰素治疗老年慢性乙型肝炎的临床疗效及安全性分析

目的 探讨恩替卡韦联合聚乙二醇干扰素治疗老年慢性乙型肝炎的临床疗效及安全性.方法 选取山东省单县中心医院2020年2月-2021年6月收治的慢性乙肝患者为研究对象,共124例.以随机数字表法将患者分成两组,各62例.其中对照组以聚乙二醇干扰素治疗,观察组以聚乙二醇干扰素联合恩替卡韦治疗,两组患者治疗12周.比较两组患者...     

EDHF: spreading the influence of the endothelium

Our view of the endothelium was transformed around 30 years ago, from one of an inert barrier to that of a key endocrine organ central to cardiovascular function. This dramatic change followed the discoveries that endothelial cells (ECs) elaborate the vasodilators prostacyclin and nitric oxide. The key to these discoveries was the use of the quintessentially pharmacological technique of bioassay. Bioassay also revealed endothelium-derived hyperpolarizing factor (EDHF), particularly important in small arteries and influencing blood pressure and flow distribution. The basic idea of EDHF as a diffusible factor causing smooth muscle hyperpolarization (and thus vasodilatation) has evolved into one of a complex pathway activated by endothelial Ca(2+) opening two Ca(2+) -sensitive K(+) -channels, K(Ca)2.3 and K(Ca)3.1. Combined application of apamin and charybdotoxin blocked EDHF responses, revealing the critical role of these channels as iberiotoxin was unable to substitute for charybdotoxin. We showed these channels are arranged in endothelial microdomains, particularly within projections towards the adjacent smooth muscle, and close to interendothelial gap junctions. Activation of K(Ca) channels hyperpolarizes ECs, and K(+) efflux through them can act as a diffusible 'EDHF' stimulating Na(+) /K(+) -ATPase and inwardly rectifying K-channels. In parallel, hyperpolarizing current can spread from the endothelium to the smooth muscle through myoendothelial gap junctions upon endothelial projections. The resulting radial hyperpolarization mobilized by EDHF is complemented by spread of hyperpolarization along arteries and arterioles, effecting distant dilatation dependent on the endothelium. So the complexity of the endothelium still continues to amaze and, as knowledge evolves, provides considerable potential for novel approaches to modulate blood pressure.     

Opportunities for the replacement of animals in the study of nausea and vomiting

Nausea and vomiting are among the most common symptoms encountered in medicine as either symptoms of disease or side effects of treatments. Developing novel anti-emetics and identifying emetic liability in novel chemical entities rely on models that can recreate the complexity of these multi-system reflexes. Animal models (especially the ferret and dog) are the current gold standard; however, the selection of appropriate models is still a matter of debate, especially when studying the subjective human sensation of nausea. Furthermore, these studies are associated with animal suffering. Here, following a recent workshop held to review the utility of animal models in nausea and vomiting research, we discuss the limitations of some of the current models in the context of basic research, anti-emetic development and emetic liability detection. We provide suggestions for how these limitations may be overcome using non-animal alternatives, including greater use of human volunteers, in silico and in vitro techniques and lower organisms.     

Characteristics of histamine-induced leukocyte rolling in the undisturbed microcirculation of the rat mesentery

1. The main objective of this study was to analyse the role and mode of action of the mast cell mediator histamine in leukocyte-endothelium interactions in small venules in vivo. For this purpose, we used a histological approach (combined with intravital microscopy) that allows studies of rapid mediator-induced venular leukocyte accumulation, reflecting leukocyte rolling, in the undisturbed microcirculation of the rat mesentery where rolling is normally absent.
2. We first examined the relative importance of histamine and 5-hydroxytryptamine (5-HT) in acute mast cell-dependent leukocyte recruitment. The mast cell secretagogue compound 48/80 (i.p. for 15 min) induced a marked venular accumulation of polymorphonuclear leukocytes (PMNL) which was almost abolished by combined histamine₁ (H₁)- and histamine₂ (H₂)-receptor blockade. In contrast, the 5-HT-receptor antagonist methysergide was inactive in this regard. Moreover, exogenous 5-HT was less active than exogenous histamine in evoking venular PMNL accumulation (histamine response dose-dependent; 5-HT response bell shaped). Prostaglandin D₂ did not cause PMNL accumulation.
3. The venular PMNL response to exogenous histamine peaked between 15 min and 1 h, was still significantly elevated at 2 h, and then returned to prechallenge values after 3 h. At all time points, the histamine-induced PMNL accumulation was nearly abolished by i.v. treatment with the polysaccharide fucoidin (which blocks rolling but not firm adhesion per se), suggesting that the PMNL response to histamine was due to rolling rather than firm adhesion over the entire 3 h period. At no time point did histamine trigger accumulation of mononuclear leukocytes (MNL).
4. To examine the role of histamine-receptors in the histamine-induced PMNL accumulation (i.e. rolling), the animals were pretreated with diphenhydramine (H₁-receptor antagonist), cimetidine, or ranitidine (H₂-receptor antagonists). Diphenhydramine alone inhibited the venular PMNL response to histamine by 52%, while both H₂-receptor antagonists were completely inactive. However, the combination of cimetidine and diphenhydramine reduced the histamine-induced PMNL rolling by 82%. Furthermore, in contrast to an H₃-receptor agonist, challenge with either the H₁-receptor agonist 2-thiazolylethylamine or two different H₂-receptor agonists (impromidine, dimaprit) was sufficient to provoke significant venular PMNL accumulation.
5. Treatment with the nitric oxide-synthase inhibitor L-NAME did not affect the histamine-induced PMNL rolling. On the other hand, 3 h pretreatment with dexamethasone reduced the PMNL response to histamine by 73%, and flow cytometric analysis showed that the dexamethasone treatment almost completely inhibited binding of soluble P-selectin to rat isolated PMNLs.
6. We conclude that initial leukocyte recruitment after mast cell activation in the rat mesentery is critically dependent on histamine release. The cellular response to histamine was specifically due to PMNL rolling, involved activation of both H₁- and H₂-receptors, and lasted for 2–3 h. Moreover, the histamine-induced PMNL rolling was not dependent on nitric oxide synthesis, but was sensitive to glucocorticoid treatment, possibly via inhibition of expression or function of leukocytic P-selectin ligand(s).

     

Pharmacological modulation of GABAA receptor-mediated postsynaptic potentials in the CA1 region of the rat hippocampus

1. It is unclear whether GABA_A receptor-mediated hyperpolarizing and depolarizing synaptic potentials (IPSP_As and DPSP_As, respectively) are evoked by (a) the same populations of GABAergic interneurones and (b) exhibit similar regulation by allosteric modulators of GABA_A receptor function. We have attempted to address these questions by investigating the effects of (a) known agonists for presynaptic receptors on GABAergic terminals, and (b) a range of GABA_A receptor ligands, on each response.
2. The GABA uptake inhibitor NNC 05-711 (10 μM) enhanced whereas bicuculline (10 μM) inhibited both IPSP_As and DPSP_As.
3. (−)-Baclofen (5 μM), [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin (DAGO; 0.5 μM), and carbachol (10 μM) caused substantial depressions (up to 99%) of DPSP_As that were reversed by CGP 55845A (1 μM), naloxone (10 μM) and atropine (5 μM), respectively. In contrast, 2-chloroadenosine (CADO; 10 μM) only slightly depressed DPSP_As. Quantitatively, the effect of each agonist was similar to that reported for IPSP_As.
4. The neurosteroid ORG 21465 (1–10 μM), the anaesthetic propofol (50–500 μM), the barbiturate pentobarbitone (100–300 μM) and zinc (50 μM) all enhanced DPSP_As and IPSP_As.
5. The benzodiazepine (BZ) agonist flunitrazepam (10–50 μM) and inverse agonist DMCM (1 μM) caused a respective enhancement and inhibition of both IPSP_As and DPSP_As. The BZω₁ site agonist zolpidem (10–30 μM) produced similar effects to flunitrazepam.
6. The anticonvulsant loreclezole (1–100 μM) did not affect either response.
7. These data demonstrate that similar populations of inhibitory interneurones can generate both IPSP_As and DPSP_As by activating GABA_A receptors that are subject to similar allosteric modulation.

     

Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease

Animal models of Parkinson''s disease (PD) have proved highly effective in the discovery of novel treatments for motor symptoms of PD and in the search for clues to the underlying cause of the illness. Models based on specific pathogenic mechanisms may subsequently lead to the development of neuroprotective agents for PD that stop or slow disease progression. The array of available rodent models is large and ranges from acute pharmacological models, such as the reserpine- or haloperidol-treated rats that display one or more parkinsonian signs, to models exhibiting destruction of the dopaminergic nigro-striatal pathway, such as the classical 6-hydroxydopamine (6-OHDA) rat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models. All of these have provided test beds in which new molecules for treating the motor symptoms of PD can be assessed. In addition, the emergence of abnormal involuntary movements (AIMs) with repeated treatment of 6-OHDA-lesioned rats with L-DOPA has allowed for examination of the mechanisms responsible for treatment-related dyskinesia in PD, and the detection of molecules able to prevent or reverse their appearance. Other toxin-based models of nigro-striatal tract degeneration include the systemic administration of the pesticides rotenone and paraquat, but whilst providing clues to disease pathogenesis, these are not so commonly used for drug development. The MPTP-treated primate model of PD, which closely mimics the clinical features of PD and in which all currently used anti-parkinsonian medications have been shown to be effective, is undoubtedly the most clinically-relevant of all available models. The MPTP-treated primate develops clear dyskinesia when repeatedly exposed to L-DOPA, and these parkinsonian animals have shown responses to novel dopaminergic agents that are highly predictive of their effect in man. Whether non-dopaminergic drugs show the same degree of predictability of response is a matter of debate. As our understanding of the pathogenesis of PD has improved, so new rodent models produced by agents mimicking these mechanisms, including proteasome inhibitors such as PSI, lactacystin and epoximycin or inflammogens like lipopolysaccharide (LPS) have been developed. A further generation of models aimed at mimicking the genetic causes of PD has also sprung up. Whilst these newer models have provided further clues to the disease pathology, they have so far been less commonly used for drug development. There is little doubt that the availability of experimental animal models of PD has dramatically altered dopaminergic drug treatment of the illness and the prevention and reversal of drug-related side effects that emerge with disease progression and chronic medication. However, so far, we have made little progress in moving into other pharmacological areas for the treatment of PD, and we have not developed models that reflect the progressive nature of the illness and its complexity in terms of the extent of pathology and biochemical change. Only when this occurs are we likely to make progress in developing agents to stop or slow the disease progression. The overarching question that draws all of these models together in the quest for better drug treatments for PD is how well do they recapitulate the human condition and how predictive are they of successful translation of drugs into the clinic? This article aims to clarify the current position and highlight the strengths and weaknesses of available models.

LINKED ARTICLES

This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4     

Preclinical studies investigating the neural mechanisms involved in the co‐morbidity of migraine and temporomandibular disorders: the role of CGRP

Background and PurposeTemporomandibular disorders (TMD) and migraine can be co‐morbid. This can be a significant factor in exacerbating and increasing the prevalence of migraine‐like symptoms. However, the underlying mechanisms involved are unknown. Our objective was to investigate these neural mechanisms and the role of CGRP as a key modulator in this co‐morbidity.Experimental ApproachWe combined experimental approaches using CGRP, which triggers a migraine‐like response in patients, with that of masseteric muscle injection of complete Freund''s adjuvant (CFA), to model myofascial TMD‐like inflammation. Using validated electrophysiological methods to assess each of the above approaches independently or in combination, we examined their effects on the response properties of migraine‐like dural‐trigeminocervical neurons.Key ResultsIndependently, in ~2/3 of animals (rats) each approach caused delayed migraine‐like activation and sensitisation of dural‐trigeminocervical neurons. The response to masseteric‐CFA was attenuated by a selective CGRP receptor antagonist. The combination approach caused a migraine‐like neuronal response in all animals tested, with somatosensory‐evoked cranial hypersensitivity significantly exacerbated.Conclusion and ImplicationsThe data demonstrate a neuronal phenotype that translates to the exacerbated clinical co‐morbid phenotype, supporting this combination approach as a relevant model to study the mechanisms involved. It provides a pathophysiological rationale for this exacerbated phenotype, strongly implicating the involvement of CGRP. The results provide support for targeting the CGRP pathway as a novel monotherapy approach for treating this co‐morbid condition. This has key implications into our understanding of this co‐morbid condition, as well as potentially addressing the major unmet need for novel and effective therapeutic approaches.     

A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder

AIMS

To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents.

METHODS

Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays.

RESULTS

Oxybutynin displayed extensive CNS penetration, with brain : plasma ratios (B : P), unbound brain : unbound plasma ratios (Kp,free) and CSF : free plasma ratios each >1. Tolterodine (B : P = 2.95, Kp,free = 0.23 and CSF : free plasma = 0.16) and solifenacin (B : P = 3.04, Kp,free = 0.28 and CSF : free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B : P (0.03–0.16), Kp,free (0.01–0.04) and CSF : free plasma (0.004–0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10⁻⁶ cm s⁻¹), moderate for 5-HMT (11.7 × 10⁻⁶ cm s⁻¹) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5–38.2 × 10⁻⁶ cm s⁻¹). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates.

CONCLUSIONS

Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study.     

依据目前β-内酰胺类抗菌药物交叉过敏反应研究探索相关规范化管理流程

目的：了解国内外关于β-内酰胺类抗菌药物过敏相关的临床研究及处理流程，探索我国对于这一问题的规范化管理流程。方法：对近年来国内外β-内酰胺类抗菌药物过敏相关的作用机制、流行病学数据及处理流程进行汇总分析。结果：β-内酰胺类抗菌药物交叉过敏反应发生率低，经临床相关的过敏风险评估后大部分患者可安全使用侧链结构不同的β-内酰胺类抗菌药物；结合国外相关处理流程建立了对于β-内酰胺类抗菌药物过敏患者可能的规范化管理流程。结论：对某种β-内酰胺类抗菌药物过敏的患者不应该完全排除使用该类抗菌药物的可能性；可通过制定相关管理流程，加强对β-内酰胺类抗菌药物过敏患者的抗菌药物使用管理。     

Circadian variations in the effects of cyclic nucleotides on the thermoregulatory behaviour of a teleost fish

The temperatures selected by white suckers, Catostomus commersoni, placed in a thermal gradient were significantly altered by intraperitoneal injections of cAMP (1 μg/g), cGMP (1 μg/g), caffeine (15 μg/g), and imidazole (5 μg/g). There was an endogenous, circadian, rhythm in the effects of cAMP, cGMP, and caffeine on temperatures selected by individual fish held under constant illumination. Depending on injection time, there was either a significant increase or decrease in temperatures selected by fish injected with cGMP or caffeine. The preferred temperatures selected were elevated by cAMP, though there was a rhythmic variation in the amplitude of the increase. Imidazole consistently decreased the preferred temperatures selected with no apparent rhythmic variation in its actions. These results are considered in relation to the roles of cAMP and cGMP in behavioural and physiological thermoregulation.     

Involvement of a glibenclamide-sensitive mechanism in the nitrergic neurotransmission of the pig intravesical ureter

1. The present study was designed to investigate whether potassium (K⁺) channels are involved in the relaxations to nitric oxide (NO) of pig intravesical ureteral preparations suspended in organ baths for isometric tension recordings. In ureteral strips treated with guanethidine (10⁻⁵ M) and atropine (10⁻⁷ M) to block adrenergic neurotransmission and muscarinic receptors, respectively, NO was either released from nitrergic nerves by electrical field stimulation (EFS, 0.5–10 Hz, 1 ms duration, 20 s trains), or exogenously-applied as an acidified solution of sodium nitrite (NaNO₂, 10⁻⁶–10⁻³ M).
2. Incubation with an inhibitor of guanylate cyclase activation by NO, methylene blue (10⁻⁵ M) did not change the basal tension of intravesical ureteral strips but inhibited the relaxation induced by EFS or exogenous NO on ureteral preparations contracted with the thromboxane analogue U46619 (10⁻⁷ M).
3. Incubation with charybdotoxin (3×10⁻⁸ M) and apamin (5×10⁻⁷ M), which are inhibitors of large and small conductance calcium (Ca²⁺)-activated K⁺ channels, respectively, did not modify basal tension or the relaxations induced by EFS and exogenous NO. Treatment with charybdotoxin or apamin plus methylene blue (10⁻⁵ M) significantly reduced the relaxations to EFS and exogenous NO. However, in both cases the reductions were similar to the inhibition evoked by methylene blue alone. The combined addition of charybdotoxin plus apamin did not change the relaxations to EFS or exogenously added NO of the porcine intravesical ureter.
4. Cromakalim (10⁻⁸–3×10⁻⁶ M), an opener of ATP-sensitive K⁺ channels, evoked a dose-dependent relaxation with a pD₂ of 7.3±0.2 and maximum relaxant effect of a 71.8±4.2% of the contraction induced by U46619 in the pig intravesical ureter. The blocker of ATP-sensitive K⁺ channels, glibenclamide (10⁻⁶ M), inhibited markedly the relaxations to cromakalim.
5. Glibenclamide (10⁻⁶ M) had no effect on the basal tone of ureteral preparations but significantly reduced the relaxations induced by both EFS and exogenous NO. Combined treatment with methylene blue (10⁻⁵ M) and glibenclamide (10⁻⁶ M) did not exert an effect greater than that of methylene blue alone on either EFS- or NO-evoked relaxations of the pig ureter.
6. The present results suggest that NO acts as an inhibitory neurotransmitter in the pig intravesical ureter and relaxes smooth muscle through a guanylate cyclase-dependent mechanism which seems to favour the opening of glibenclamide-sensitive K⁺ channels.