组胺H_1·H_2受体拮抗剂Icotidine·3HCI

组胺对血管的效应与组胺H_1和H_2受体有关。为了抑制组胺对血管的舒张和降压效应,要求组胺拮抗剂对二种受体同时具有阻断作用,曾应用奥美替丁(Oxmetidine)进行组胺H_1受体拮抗剂的构效研究,它也有一些H1受体拮抗活性,以-CH_2-取代-S-,并用取代的嘧啶环代替咪唑和次甲二氧苯基环,希望在增强对H_1受体的拮抗活性时,仍能保留对H_2受体的拮抗活性。当吡啶环上的取代基为甲氧基时(如SK&F-93319),体外测得的抑制二种受体的活性强度相似。合成在回流的四氢呋喃中,2-氯-3-硝基吡啶(Ⅰ)与二乙基2-(2-氰乙基)丙二酸(Ⅱ)借助NaH缩合成1-氰基-3,3-双(乙氧基羰基)-3-(3-硝基-2-吡啶基)丙烷(Ⅲ),     

抗组胺药研究的新进展

新发现的组胺受体分析组胺对人血小板摄入5-羟色胺的作用后,发现血小板上的H_2受体与至今已了解的H_2受体不同。H_2拮抗药抑制组胺对血小板的作用的浓度,为抑制胃酸分泌的浓度的1/10～1/100。即使让组胺作用,血小板的cAMP水平也不变,仅伴有cGMP上升。一般认为这是H_2受体的亚型,称为H_(2h)受体。也有报告认为中枢神经系统中存在着与其他部位效应不同的亚型。     

香肉果的药理Ⅰ—对麻醉状态下大鼠的血压和心率的影响

本文作者测定了香肉果种子的酒精提取物对戊巴比妥麻醉状态下大鼠血压和心率的影响,并与组胺的效应进行比较。提取物引起低血压,高剂量时伴随心动过速。给组胺的大鼠引起的低血压比较短暂,且不伴随心率的改变。各种自律神经拮抗剂的实验揭示,提取物引起的低血压不是通过组胺H_2、蕈毒碱或β-肾上腺素能受体传递的,而是与H_1机制有关。阻断H_1以后,降压反应逆转为升压效应,这是激发了α-肾上腺素能受体刺激所致。心率加速的部分是由于H_1受体的激活,另一部分是由于β-肾上腺素能受体的激活。实验结果提示,所观察到的降压效应可能与咪唑衍生物有关。升压反应则可能由提取物的这些     

组胺H_2受体阻断药的抗肿瘤作用

<正> 组胺H_2受体阻断药(以下简称H_2阻断药)是一类新的抗组胺药,具有多方面的作用。本文综述近年来H_2阻断药抗肿瘤作用的研究概况。 一、组胺与肿瘤生长的关系 组胺在体内有广泛的生物学效应,它与炎症、变态反应、平滑肌舒缩和腺体分泌等功能密切相关。除肥大细胞外,其它细胞也能主动合成组胺,组胺在体内的分布相当广泛。近年发现,实验性肿瘤增殖     

甲氰咪胺

甲氰咪胺为组胺H_2受体拮抗剂,药理研究证明组胺作用于H_1、H_2二种受体。引起气管收缩和毛细血管扩张作用的,是由于兴奋H_1受体,并能被一般习用的抗组胺药物所拮抗,增进胃壁细胞酸分泌的H_2受体,其作用不为一般抗组胺药物所消除。经过化学结构改造与筛选,发现了一类H_2受体拮抗剂,在这类药物中,以氰胍基取代硫脲部分而合成的甲氰咪胺,其毒性较轻。体内作用 1.抑制胃酸分泌:甲氰咪胺能减少胃在静止状态(基础胃酸)及为食物、组胺、五肽胃泌素、胰岛素、咖啡因等刺激后胃酸分泌的容量与浓度,其效能优于抗胆硷能     

雷尼替丁与特非那定联合治疗荨麻疹

慢性荨麻疹的病因是由于组胺的释放并刺激皮肤脉管内的组胺受体而引起的,常规剂量的传统抗组胺药(H_1—受体阻断剂)常常不起反应。由于大多数抗组胺药的副作用是镇静作用,故不断增大剂量通常是不可能的。不久以前已经发现,至少有两类组胺受体称为H_1受体和H_2受体,H_2受体能够使胃中产生胃酸,因此H_2受体阻断剂(西米替丁和雷尼替丁)可用于治疗消化道溃疡。有证据表明,H_2受体也存在于人体皮肤血管内,并且已经发现H_1—和H_2—受体阻断剂的联合使用比单用H_1—受体阻断剂更有效。     

西咪替丁的新用途——免疫调节

抑制性T淋巴细胞(T_s)带有组胺H_2受体,组胺参与T_s细胞功能。近年来的研究发现H_2受体拮抗剂西咪替丁通过阻断T_s细胞的组胺H_2。受体,发挥着调节机体免疫机能的作用,如对混合淋巴细胞反应,白细胞介素-2(IL-2)的生成,NK细胞的活性,抗体形成能力等方面均有影响。动物实验和临床观察都证实了西咪替丁的免疫调节作用。     

H_2——受体拮抗剂的构效关系及Famotidine的试制

<正> 组胺以结合形式存在于体内,因某种刺激游离出来,作用于组胺受体,引起血压降低,毛细血管扩张、平滑肌收缩和腺体分泌增强等一系列生理作用。研究证明,组胺受体有两种,即 H_1—受体和 H_2—受体。H_1—受体为常见的抗组胺药拮抗的受体,H_2—受体是与腺体分泌有关的受体(见表1)。     

西咪替丁对支气管哮喘的应用

西咪替丁(Cimetidime)是抗组胺 H_2型药物,作用强,毒性低,对组胺 H_2受体有选择性阻断作用,是竞争性的对抗药,主要用于治疗胃及十二指肠溃疡,抑制胃酸分泌,促进溃疡愈合。下面主要就西咪替丁在支气管哮喘方面的应用及原理作肤浅的阐述。作用机理1 支气管哮喘 Eyre 认为,支气管舒缩功能虽以 H_2受体主导支配,但 H_2受体亦参与调节。H_2阻滞剂可     

组胺H_2拮抗剂的近期进展

组胺受体的分类与组胺的生理作用组胺受体可分为H_1受体和H_2受体。H_1受体兴奋时,支气管和肠平滑肌收缩,生化机制尚不清楚;H_2受体兴奋则使心率加快、心肌收缩力增强,子宫平滑肌松驰和胃酸分泌,这是由于H_2激动剂兴奋了腺苷酸环化酶使c-AMP增多的结果,这些结果与β受体兴奋相似。血管平滑肌兼有H_1受体和H_2受体,两者都使血管舒张。新安替根能选择性地阻断H_1受体,故称H_1拮抗剂;丁咪胺(Burimamide)、甲硫咪胺(Metiamide)及甲氰咪胍等能选择性地阻断H_2受体,故称H_2拮抗     

Two-step inactivation of bee venom phospholipase A2 by scalaradial

Scalaradial (SLD), a marine natural product isolated from the sponge (Cacospongia sp., possesses anti-inflammatory properties in vivo and in vitro (Pharmacologist 32: 168, 1990). In this study we characterize its effects against bee venom phospholipase A2 (PLA2; EC 3.1.1.4). SLD is a potent inactivator of bee venom PLA2 with an IC50 value of 0.07 microM. Inactivation of bee venom PLA2 occurred in a time-dependent, irreversible manner. The rate of inactivation followed first-order reaction kinetics and was dependent on the concentration of SLD. Kinetic analysis suggested a two-step mechanism of inactivation: an initial apparent noncovalent binding (Ki = 4.5 x 10(-5) M) followed by covalent modification. The rate of inactivation was reduced markedly in the presence of excess phosphatidylcholine, suggesting that modification of the enzyme occurs at or near the substrate binding site.     

Contribution of bee venom phospholipase A2 contamination in melittin fractions to presumed activation of tissue phospholipase A2

Melittin from bee venom has been suggested to activate tissue phospholipase A2 (PLA2) activity, and subsequently has been used as a specific PLA2 probe. The melittin in most cases was obtained commercially and used without further purification or treatment. To test the hypothesis that commercially obtained melittin specifically activates tissue PLA2, we radiolabeled the lipids of immortalized epithelial cells by incubating the cells for 22 hr with 14C-linoleic acid. The cells were then incubated with 2 microM melittin, 2nM bee venom PLA2, 2 microM melittin treated with p-bromophenacyl bromide (p-BPB) or PLA2 plus p-BPB-treated melittin. Lipids were extracted and separated by thin-layer chromatography. The radioactivity in each lipid fraction was then quantitated. The melittin-stimulated PLA2 activity observed in cells was primarily associated with phosphatidylcholine. Fatty acid release was decreased by 75% when the melittin fraction was pretreated with p-BPB to reduce contaminating venom PLA2 activity. Adding PLA2 to the p-BPB-treated melittin at an amount about equal to the original contamination (0.1%) resulted in the same PLA2 activity in cell as observed with the untreated melittin fraction. These findings suggest that bee venom PLA2 contamination, even at very low levels, can account for approximately 75% of the PLA2 activity in cells treated with commercial melittin fractions.     

Involvement of phospholipase A2 in the regulation of [3H]hemicholinium-3 binding

We have examined the effects of exogenous phospholipase A2 (PLA2) on the sodium-dependent high-affinity choline uptake mechanism as assessed by the specific binding of [3H]hemicholinium-3 ([3H]HCh-3). Incubation of striatal synaptic membranes with bee venom PLA2 resulted in a concentration-dependent increase in the specific binding of [3H]HCh-3. The effect of PLA2 on [3H]HCh-3 binding was inhibited by quinacrine, a PLA2 inhibitor, and by removal of calcium. Scatchard analysis revealed that the observed changes in binding reflected a 2-fold increase in both the capacity and affinity of [3H]HCh-3 for its binding site. Choline and N-butylcholine inhibited the specific binding of [3H]HCh-3 in both control and PLA2-treated membranes with similar potency. When a low concentration of PLA2 was incubated with the striatal synaptosomes, a small but significant increase in high-affinity [3H]choline uptake was observed. However, higher concentrations of PLA2, which further increased the specific binding of [3H]HCh-3, caused a reduction of [3H]choline uptake, apparently due to disruption of synaptosomal integrity by PLA2. Finally, potassium depolarization- and PLA2-induced increases in specific [3H]HCh-3 binding were not additive. These results suggest a possible role for endogenous PLA2 in the calcium-dependent regulation of sodium-dependent high-affinity choline uptake.     

Lack of specificity of melittin as a probe for insulin release mediated by endogenous phospholipase A2 or lipoxygenase

The effects of the basic polypeptide melittin on islet phospholipid degradation and insulin release were studied in static incubations of intact rat islets as a possible model of endogenous phospholipase A2 (PLA2) activation. Melittin (2 micrograms/ml) increased [3H]-arachidonic acid [( 3H]-AA) release from prelabeled islets (at 1.7 mM glucose) to 371% of basal values. Concomitantly, melittin induced degradation of islet phospholipids labeled with [3H]-AA or [14C]-stearic acid, and led to the accumulation of stearate-labeled (but not AA-labeled) lysophosphatidylcholine (LPC, 605% of control). These findings suggested, for the first time in intact rat islets, the presence and activation of a PLA2. Under identical conditions, melittin initiated insulin secretion (at 1.7 mM glucose) in a manner that represented stimulation of physiologic exocytosis--that is, it was dose-dependent, reversible (albeit slowly), unassociated with impairment of other physiologic islet processes (i.e. the response to 16.7 mM glucose after removal of the drug) and inhibitable by reduced ambient temperature. The effect of melittin seemed to be independent of extracellular Ca2+ influx or mobilization of intracellular Ca2+ stores but was blocked by nickel or lanthanum, indirectly suggesting that the effects of this cationic amphiphile might involve a superficial pool of Ca2+. Unexpectedly, melittin-induced insulin release (at least at low glucose concentrations) was not greatly or consistently altered by a battery of inhibitors of endogenous PLA2 or of enzymes affecting AA oxygenation. Furthermore, significant contamination by bee venom PLA2 of the commercially-available melittin preparation was found, and insulin release could be induced by pure bee venom PLA2, probably through the generation of lysophospholipids. Although estimates of the amount of PLA2 in the melittin preparation suggested that such contamination was insufficient to explain at least some of the islet phospholipid hydrolysis and insulin release caused by melittin, we conclude that this agent does not serve as a specific probe of the role of endogenous PLA2 or of AA lipoxygenation in hormone release.     

Inactivation of phospholipase A2 by manoalide. Localization of the manoalide binding site on bee venom phospholipase A2

The marine natural product manoalide (MLD), a potent inhibitor of phospholipases, completely inactivates bee venom phospholipase A2 (PLA2) by an irreversible mechanism. It has been proposed [K. B. Glaser and R. S. Jacobs, Biochem. Pharmac. 36, 2079 (1987)] that the reaction of MLD with PLA2 may involve the selective reactivity of MLD to a peptide sequence, possibly a Lys-X-X-Lys peptide. Localization of the MLD binding site on bee venom PLA2 demonstrated that upon MLD modification of bee venom PLA2 the only change in amino acid content was an apparent loss of Lys, corresponding to approximately three of the eleven Lys residues present. Selective chemical modification of Lys residues with [14C]maleic anhydride demonstrated that all eleven Lys residues on bee venom PLA2 were accessible to this reagent (11.6 mol maleyl group incorporated/mol of PLA2). Pretreatment of PLA2 with MLD (less than 0.7% residual activity) resulted in a molar ratio of 8.7, also consistent with the loss of three Lys residues upon modification by MLD. Reverse phase high performance liquid chromatography (RP-HPLC) of the cyanogen bromide (CNBr) digestion product of MLD-treated PLA2 produced three peaks (A280). The second peak showed the most intense absorbance at 434 nm. This material corresponded to residues 81-128, as determined by gas-phase microsequence analysis. Sequencing failure was observed at Lys-88 in the MLD-treated fragment. The control carboxymethylated-PLA2 fragment corresponding to residues 81-128 sequenced beyond Lys-88 without significant change in the expected yield. These data suggest that Lys-88 may correspond to one of the three MLD-modified Lys residues. The minor absorbance at 434 nm of the CNBr fragments containing residues 42-80 and 1-36 as compared to the fragment of residues 81-128 suggests that the major MLD binding fragment residues in residues 81-128.     

Molecular pharmacology of manoalide. Inactivation of bee venom phospholipase A2

The marine natural product manoalide (MLD) was shown to directly inactivate bee venom phospholipase A2 (PLA2). Inactivation was pH dependent (maximum inactivation occurred at pH 8.0), time dependent and concentration dependent. The IC50 was estimated at 0.05 microM and virtually complete inactivation of the enzyme occurred at 4.0 microM. The time-dependent loss of PLA2 activity suggested that inactivation does not follow typical Michaelis-Menten kinetics. Reversibility was studied directly by dilution and dialysis; both methods were ineffective in dissociating the MLD-PLA2 complex. A kinetic plot of initial velocity (v) versus [PLA2] supported our hypothesis that MLD apparently inactivates bee venom PLA2 by an irreversible mechanism.     

Effects of phospholipases A2 from Vipera russelli snake venom on blood pressure, plasma prostacyclin level and renin activity in rats

Vipera russelli venom contains several isoenzymes of phospholipase A2 (PLA2) which were isolated by column chromatography. The effects of PLA2 fractions on blood pressure, plasma prostacyclin level and renin activity were studied in normotensive and renal hypertensive rats. PLA2 fractions II-5, II-7, III-3 and III-6 (0.1 mg/kg) injected i.v. into rats decreased the arterial blood pressure. The hypotensive action of PLA2 fractions was not affected by heat treatment (70-80 degrees C, 30 min, pH 6.8). After indomethacin (30 mg/kg, i.v.), the hypotensive response to PLA2 was markedly reduced. Plasma prostacyclin (PGI2) and thromboxane A2 (TXA2) levels were measured by radioimmunoassays of their degradation products, 6-keto-PGF1 alpha and TXB2, respectively. PLA2 fractions (0.1 mg/kg) induced an increase in plasma PGI2 and TXA2 levels. There was a positive linear correlation between the PLA2-induced hypotensive effect and the ratio of increased 6-keto-PGF1 alpha to TXB2 (r = 0.83) in normotensive rats. In renal hypertensive rats, the increase in PGI2 level was larger than in normotensive rats. Plasma renin activity was also measured by the radioimmunoassay. Plasma renin activity was reduced by PLA2 fractions in renal hypertensive rats, but not in normotensive rats. These results suggest that the hypotensive effect of PLA2 fractions in normotensive rats may be partly due to the increase in plasma prostacyclin and thromboxane A2 levels. In addition to the larger increase in plasma PGI2 level, the reduction in plasma renin activity may also contribute to the greater hypotensive effect of PLA2 fractions in renal hypertensive rats.     

Effect of ranitidine bismuth citrate on the phospholipase A2 activity of Naja naja venom and Helicobacter pylori: a biochemical analysis

BACKGROUND: Helicobacter pylori has become recognized as a fundamental pathogen in the development of gastritis and peptic ulcer disease. Bismuth compounds in combination with antibiotics are widely used to treat H. pylori associated peptic ulcer disease. METHODS: In this study we measured and analysed the inhibitory effect of ranitidine bismuth citrate (RBC, Pylorid, Tritec) on the activity and kinetics of phospholipase A2 (PLA2) (E.C.3.1.1.4) of commercial cobra (Naja naja) venom and H. pylori (French press lysates) using L-alpha-dipalmitoyl-(2[1-14C]palmitoyl)-phosphatidylcholine as substrate. RESULTS: Our data suggest that RBC might exert a dose-dependent uncompetitive inhibition on PLA2 activity of both H. pylori and Naja naja venom. the inhibitory effect of RBC on the PLA2 activity cannot be abolished by the optimal concentration of calcium (10 mM), indicating its mechanism to be unrelated to the displacement of calcium from the activation site of the enzyme. CONCLUSION: Our results suggest that one of the mechanisms by which bismuth compounds are therapeutically effective in the treatment of H. pylori associated gastritis is by inhibiting the activity of the degradative PLA2 enzyme secreted by H. pylori. As a consequence of the inhibitory action of RBC on PLA2 of the bacteria, the extracellular and/or intracellular phospholipid components of the gastric mucosal barrier are preserved.     

Microsphere entrapped bee-venom phospholipase A2 retains specific IgE binding capacity: a possible use for oral specific immunotherapy

The only specific treatments of allergy are long and exacting desensitization by subcutaneous injections of the allergens. While oral administration of allergens could greatly facilitate these treatments, effective delivery systems are needed to prevent allergen degradation in the gastrointestinal tract and to enable their uptake by Peyer's patches. The potential for bee-venom phospholipase A2 (PLA2) to be used in such oral immunotherapy was tested. For this purpose, PLA2 potential alterations were analysed when encapsulated into poly(D,L-lactide-co-glycolide) microspheres by double emulsion solvent evaporation. It was shown that microencapsulation had only limited effects on the integrity of the entrapped PLA2, which retained its fully specific murine IgE binding capacity. Thus, PLA2 loaded microspheres could represent a potential delivery system for bee venom allergy-specific oral immunotherapy.