奥洛他定的合成

目的：合成新型H1受体阻滞剂奥洛他定。方法：以对羟基苯乙酸和苯酞为原料，经取代、环合、维蒂希反应等9步反应合成目标产物。结果与结论：合成了目标产物，其结构经MS和^1H—NMR确定。     

Synthesis, molecular modelling and biological evaluation of 4-amino-2(1H)-quinazolinone and 2,4(1H,3H)-quinazolidone derivatives as antitumor agents

A series of 6-benzoyl-, 6-arylthio- and 6-arylsulfonyl-4-amino-2(1H)-quinazolinones and -2,4(1H,3H)-quinazolinediones were prepared. They were evaluated in vitro for their cytotoxicity against the NCI-60 cancer cell lines.     

Brain histamine H1 receptor occupancy of orally administered antihistamines, bepotastine and diphenhydramine, measured by PET with 11C-doxepin

AIMS

Antihistamines are frequently used for treating various allergic diseases, but often induce sedation. The degree of sedation can be evaluated by measuring histamine H₁ receptor occupancy (H₁RO) in the brain using positron emission tomography (PET). The aim was to measure H₁RO of bepotastine, a new second-generation antihistamine, and to compare it with that of diphenhydramine.

METHODS

Eight healthy male volunteers (mean age ± SD 24.4 ± 3.3 years) were studied after single oral administration of bepotastine (10 mg), diphenhydramine (30 mg) or placebo, by PET imaging with ¹¹C-doxepin in a crossover study design. Binding potential ratio and H₁ROs were calculated using placebo data and were compared between bepotastine and diphenhydramine in the anterior and posterior cingulate gyri (ACG and PCG, respectively), superior and inferior frontal cortices (SFC and IFC, respectively), orbitofrontal cortex (OFC), insular cortex (IC), lateral and medial temporal cortices (LTC and MTC, respectively), parietal cortex (PC), occipital cortex (OC) and sensorimotor cortex (SMC). Plasma concentration of each antihistamine was measured, and its correlation to H₁RO was examined.

RESULTS

H₁RO after bepotastine treatment was significantly lower than that after diphenhydramine treatment in all cortical regions (P < 0.001). Mean H₁ROs of bepotastine and diphenhydramine were 14.7% and 56.4%, respectively. H₁ROs of both bepotastine and diphenhydramine correlated to their respective drug plasma concentration (P < 0.001).

CONCLUSION

Oral bepotastine (10 mg), with its relatively low H₁RO and thus minimal sedation, has the potential for use as a mildly or slightly sedative antihistamine in the treatment of various allergic disorders.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• ‘Bepotastine besilate’ is a novel second-generation antihistamine developed in Japan and its antiallergic effects have already been demonstrated by various studies.
• However, only a few clinical studies regarding its sedative property are available.
• In addition, histamine H₁ receptor occupancy (H₁RO) of this new antihistamine has never been measured by positron emission tomography (PET).

WHAT THIS STUDY ADDS

• This paper provides the first measurement result of cerebral H₁RO of bepotastine besilate (approximately 15%) as determined by PET.
• This result is in accordance with the clinical classification of bepotastine as a second-generation antihistamine.
• In addition, the relationship between subjective sleepiness and cerebral H₁RO of this second-generation antihistamine is demonstrated for the first time using a placebo-controlled crossover study design.

     

Enhanced antinociception by intrathecally-administered morphine in histamine H1 receptor gene knockout mice

We previously reported that histamine H₁ receptor gene knockout mice (H1KO) showed lower spontaneous nociceptive threshold to pain stimuli when compared to wild-type mice. The objective of the present study was to examine the antinociceptive effect of intrathecally-administered morphine in H1KO mice. The antinociceptive effects of morphine were examined using assays for thermal (tail-flick, hot-plate, paw-withdrawal), mechanical (tail-pressure) and chemical nociception (formalin and capsaicin tests) using H1KO and wild-type mice. In these nociceptive assays, intrathecally-administered morphine produced significant antinociceptive effects in wild-type mice. The antinociceptive effect produced by intrathecally administered morphine was enhanced in the knockout mice. We also examined the effect of an histamine H₁ receptor antagonist, an active (d-) isomer of chlorpheniramine, on morphine-induced antinociception in ICR mice. The intrathecal co-administration of d-chlorpheniramine enhanced the effect of morphine in all nociceptive assays examined. The pharmacological experiments using d-chlorpheniramine further substantiate the evidence for the histamine H₁ receptor-mediated suppression of morphine-induced antinociception. These results suggest that existing H₁ receptors play an inhibitory role in morphine-induced antinociception at the spinal cord level.     

Metabotropic glutamate 1 receptor distribution and occupancy in the rat brain: a quantitative autoradiographic study using [3H]R214127

We used the selective metabotropic glutamate (mGlu) 1 receptor antagonist [3H]1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone ([3H]R214127) to investigate the distribution of mGlu1 receptor binding sites in rat brain. We found high mGlu1 receptor binding in the cerebellum, thalamus, dentate gyrus and medial central gray, moderate binding within the CA3 of the hippocampus and hypothalamus, and low mGlu1 receptor binding in the basal ganglia and cortex. The mGlu1 receptor is also present in variable degree in the dorsal lateral septal nucleus, amygdala, interpeduncular nucleus and median raphe nucleus. Additionally, we employed [3H]R214127 autoradiography as a means of investigating the occupancy of central mGlu1 receptors following in vivo administration of mGlu1 receptor antagonists that prevent binding of this radioligand. We found that the mGlu1 receptor antagonist (3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahydro-cyclopenta[c]furan-1-on (BAY 36-7620), administered subcutaneously (s.c.) at 10 mg/kg, only occupied about 30% of cerebellar and thalamic mGlu1 receptors. The mGlu1/5 receptor antagonist 2-quinoxaline-carboxamide-N-adamantan-1-yl (NPS 2390) exhibited a relatively high potency in occupying mGlu1 receptors in rat cerebellum (ED50 = 0.75 mg/kg, s.c.) and thalamus (ED50 = 0.63 mg/kg, s.c). In the future, this method can be employed to gain more insight into the in vivo profile and central activity of potential therapeutic agents that act upon the mGlu1 receptor.     

甲型H1N1流感疫苗不良事件监测及评估

目的:分析甲型H1N1流感疫苗的接种情况,及时总结接种的监测与评估,为开展甲型H1N1流感防控提供参考。方法:对国内外2009年接种甲型H1N1流感疫苗的不良反应监测报告进行分析。结果:甲型H1N1流感疫苗被认为与季节性流感疫苗总体安全性近似。结论:在甲型H1N1流感大流行的背景下,接种该疫苗利大于弊。     

Pharmacological properties of cardiovascular histamine H1 receptor binding sites: characterisation with 2-phenylhistamines

We determined and compared the molecular properties of histamine H₁ receptor binding sites in bovine thoracic aorta smooth muscle and guinea pig myocardial membranes from ventricles with saturation and inhibition binding assay, using ³H-mepyramine to label the receptor and specific and selective H₁ receptor agonists of the 2-phenylhistamine group as displacers of specific ³H-mepyramine binding. ³H-mepyramine binds in a saturable manner to a homogenous population of binding sites with a K _D of 5.6 nM and a B _max of 57 fmol/mg of protein in bovine aorta vascular smooth muscle membranes, whereas in the guinea pig myocardium high and low affinity ³H-mepyramine binding sites exist having the following molecular characteristics: a K _D of 1.6 nM and a B _max of 99 fmol/mg of protein (high affinity site) and a K _D 15.0 nM and a B _max of 466 fmol/mg of protein (low affinity site). Halogenated 2-phenylhistamines: 2-(3-fluoro-) (2-FPH), 2-(3-trifluoromethyl-) (2-triFMPH), 2-(3-chloro-) (2-CPH), 2-(3-bromo-) (2-BPH) and 2-(3-iodophenyl)histamine (2-IPH), which showed high selectivity and potency for H₁ receptors in the functional pharmacological studies, were potent inhibitors of specific radioligand binding in comparison with histamine and parent nonhalogenated 2-phenylhistamine (2-PH). Their rank order of potencies and affinities differ significantly for the vascular and cardiac H₁ receptor binding sites: Specific ³H-mepyramine binding to H₁ receptors in bovine vascular smooth muscle membranes was displaced in a biphasic manner by 2-(3-fluoro-), 2-(3-trifluoromethyl-), 2-(3-chloro-), 2-(3-bromo-), 2-(3-iodophenyl)histamine and histamine. In guinea pig ventricular myocardium the rank order was 2-(3-iodo-), 2-(3-bromo-), histamine, 2-(3-chloro-), and 2-(3-fluorophenyl)histamine showing better correlation with the lipophilicity of the derivatives than in vascular tissue (order of lipophilicity: 2-triFMPH >2-IPH >2-BPH >2-CPH >2-FPH >>2-PH). Displacement of the radioligand binding to myocardial H₁ receptor by the above drugs is (except for 2-(3-fluorophenyl)histamine), better fitted to a two-site model. 2-phenylhistamine, which acted as a moderate agonist in functional studies, displaced the radioligand in a monophasic manner and was the weakest displacer of specific radioligand binding in both model systems (pK _i = 5.76 – vascular and 5.57 – cardiac tissue). The agonistic nature of the halogenated 2-phenylhistamine derivatives was confirmed on the molecular level, since their interaction with the H₁ receptor is regulated by guanine nucleotides. GTP (0.1 mM) significantly lowered the affinities of all tested halogenated 2-phenylhistamines and histamine for H₁ receptor binding site converting biphasic displacement curves, to monophasic ones, whereas GTP had no effect on the affinity of 2-PH. The results of this study support the conclusions that bovine vascular and guinea pig myocardial histamine H₁ receptors differ in their molecular properties. Selective and potent H₁ receptor agonists of 2-phenylhistamine class can discriminate between vascular and cardiac receptor. Received: 3 July 1996 / Accepted: 16 December 1996     

甲流期间469例发热病例血常规分析

目的:了解发热病人的血常规特点,做好甲流期间感染性疾病的预诊断。方法:选取我门诊2009年5月～12月期间发热分诊处接诊的病例469例,分析其体温和血常规的关系。结果:血常规分析显示,甲流期间发热患者随着体温逐渐升高,中性粒细胞百分比(NC)增高的比例显著升高,白细胞计数(WBC)和淋巴细胞百分比(LC)变化无统计学意义。结论:甲流期间,发热患者体温越高,细菌感染的趋势越大,而WBC和LC变化无特异性。     

截短型H1N1神经氨酸酶基因的克隆及其在毕赤酵母中的表达

将密码子优化的截短型H1N1神经氨酸酶基因克隆到载体pPICZαA中,以构建重组质粒pPICZαA-NAS.将线性化的重组质粒pPICZαA-NAS转化毕赤酵母SMD1168,获得了能够分泌表达截短型H1N1神经氨酸酶的重组菌株.结果表明,重组菌株能够分泌表达具有生物活性的截短型神经氨酸酶,该酶受两种已知的神经氨酸酶抑制剂(奥司他韦和扎那米韦)的显著抑制,可用于构建新型神经氨酸酶抑制剂的高通量筛选模型.     

Brain histamine H1 receptor occupancy measured by PET after oral administration of levocetirizine,a non-sedating antihistamine

Objective: Histamine H₁ receptor (H₁R) antagonists often have sedative side effects, which are caused by the blockade of the neural transmission of the histaminergic neurons. We examined the brain H₁R occupancy (H₁RO) and the subjective sleepiness of levocetirizine, a new second-generation antihistamine, comparing fexofenadine, another non-sedating antihistamine, as a negative active control.

Methods: Eight healthy volunteers underwent positron emission tomography (PET) imaging with [¹¹C]doxepin, a PET tracer that specifically binds to H₁Rs, after a single oral administration of levocetirizine (5 mg), fexofenadine (60 mg) or placebo in a double-blind crossover study. Binding potential ratios and H₁ROs in the cerebral cortices regions were calculated using placebo. Subjective sleepiness was assessed with the Line Analogue Rating Scale and the Stanford Sleepiness Scale.

Results: There was no significant difference between the mean brain H₁RO after levocetirizine administration (8.1%; 95% CI: ?9.8 to 26.0%) and fexofenadine administration (?8.0%; 95% CI: ?26.7 to 10.6%). Similarly, subjective sleepiness was not significantly different between the two antihistamines and placebo. Neither subjective sleepiness nor plasma concentrations was significantly correlated with the brain H₁RO of the two antihistamines.

Conclusion: At therapeutic dose, levocetirizine does not bind significantly to the brain H₁Rs and does not induce significant sedation.     

4-Cyclohexyl-1-substituted-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones: novel class of H1-antihistaminic agents

A series of novel 1-substituted-4-cyclohexyl-4H-[1,2,4]triazolo [4,3-a] quinazolin-5-ones were synthesized by the cyclization of 3-cyclohexyl-2-hydrazino-3H-quinazolin-4-one with various one carbon donors. When tested for their in vivo H1-antihistaminic activity on guinea-pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly. The compound 4-cyclohexyl-1-methyl-4H-[1,2,4]triazolo[4,3-a] quinazolin-5-one (II) emerged as the most active compound of the series and it is more potent (72.96% protection) when compared to the reference standard chlorpheniramine maleate (71.00% protection). The compound II shows negligible sedation (9%) when compared to chlorpheniramine maleate (30%). Hence, it could serve as prototype molecule for further development as a new class of H1-antihistamines.     

Blockage of histamine H1 receptor attenuates social isolation-induced disruption of prepulse inhibition: a study in H1 receptor gene knockout mice

Rationale Histaminergic neurotransmission has been implicated in the pathophysiology of stress-related psychiatric diseases. Although several atypical antipsychotics are potent H1 anagonists, the clinical significance of interaction between atypical antipsychotics and H1 receptors is still unknown.Objective In this study, we investigated the effects of H1 receptors blockage on social isolation-induced behavioral changes in H1 receptor gene knockout (H1KO) mice and their wild-type (WT) mice.Methods Both H1KO and their WT mice were subjected to 4-week social isolation rearing after weaning (21 postnatal days). After the 4-week isolation period, mice behavioral changes were evaluated using behavioral tests.Results Locomotor activity in home cages was significantly lower in isolation-reared WT mice than in socially reared WT mice. However, no change in locomotor activity was observed between socially and isolation-reared H1KO mice. Social isolation significantly impaired prepulse inhibition (PPI) of startle response in WT mice but not in H1KO mice. In addition, social isolation significantly impaired spatial learning and memory in WT mice but not in H1KO mice. Furthermore, H1KO mice treated with methamphetamine (METH) showed no enhancement in isolation-induced disruption of PPI. A neurochemical study revealed that isolation-reared WT mice had significantly lower dopamine (DA) levels and slightly increased DA turnover in the cortex than socially reared WT mice. Conversely, isolation-reared H1KO mice showed significantly higher DA contents as compared with socially reared H1KO mice. Conclusion: The results of our study indicate that blockage of H1 receptor-mediated neurotransmission attenuates social isolation-induced behavioral changes and that the therapeutic effects of atypical antipsychotics are mediated, at least in part, by interaction with H1 receptors in the brain.     

Changes in pH differently affect the binding properties of histamine H1 receptor antagonists

We investigated the effect of acidic pH, a condition that can be encountered during inflammation accompanying allergic reaction, on the binding properties of histamine H₁ receptor antagonists, including levocetirizine ((2-{4-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}ethoxy)acetic acid; Xyzal®), fexofenadine (rac-2-[4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl) piperidin-1-yl]butyl]phenyl]-2-methylpropionic acid hydrochloride; Allegra®) and desloratadine (8-Chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine; Clarinex®). Lowering the pH from 7.4 to 5.8 decreased the affinity of [³H]mepyramine for histamine H₁ receptors from 1.7 to 7.5 nM while the opposite was observed with [³H]levocetirizine, whose affinity increased from 4.1 to 1.5 nM. Competition curves with [³H]mepyramine indicated that decreasing the pH from 7.4 to 5.8 led to a 2- to 5-fold increase in the affinity of fexofenadine and levocetirizine, no change in affinity for desloratadine and a 5- to 10-fold decrease in affinity for mepyramine and histamine. Kinetic experiments showed that the increase in affinity of levocetirizine and, to a lesser extent, fexofenadine were totally attributable to a lower dissociation rate at acidic pH (t_1/2 increasing from 77 to 266 min and from 71 to 135 min, respectively). Although the affinity of desloratadine remained unchanged, lowering the pH caused a decrease in its dissociation rate (t_1/2 of 50 and 256 min at pH 7.5 and 5.8, respectively) accompanied by a concomitant 3.5-fold decrease in its association rate constant. The loss of affinity of mepyramine at acidic pH was driven by a decrease in its association rate constant. Interaction between the carboxylic moiety of levocetirizine and Lys¹⁹¹ is responsible for its slow dissociation rate from the receptor. We found that the magnitude of the pH effect on the dissociation rate of levocetirizine was maintained after mutating Lys¹⁹¹ into alanine, suggesting that a tighter interaction of levocetirizine with Lys¹⁹¹ at lower pH is not the cause of its even slower dissociation rate from the receptor. Although these changes may seem limited in amplitude, we show that they may have substantial effects on receptor occupancy in vivo.     

大流行流感与甲型H1N1流感

目的对大流行流感和甲型H1N1进行综述。方法参考国内外近期的有关文献和WHO的相关报道,介绍了流感病毒的基本知识、大流行流感的定义和发展,以及甲型H1N1流感的特点和流行现状等。结果与结论大流行流感具有传播性强、危害大等特点,2009年的甲型H1N1流感为21世纪的第1次大流感,应加以重视。     

Synthesis of new 2-[1(2H)-phthalazinon-2-yl]acetamide and 3-[1(2H)-phthalazinon-2-yl]propanamide derivatives as antinociceptive and anti-inflammatory agents

As a consequence of our ongoing studies on heterocyclic compounds for new antinociceptive and anti-inflammatory agents bearing lactam functional group, new 2-[1(2H)-phthalazinon-2-yl]acetamide and 3-[1(2H)-phthalazinon-2-yl]propanamide derivatives have been synthesized. Among the compounds synthesized, compound (4e) was found the most active derivative in terms of antinociceptive and anti-inflammatory activities, without gastric lesions and bleeding at the given dose.     

重型甲型H1N1流感的早期预测指标

目的寻求重型甲型H1N1流感患者的早期预测指标。方法比较2009年6月~2010年1月南京地区经RT-PCR确诊的183例普通型和64例重型甲型H1N1流感患者的临床特点及实验室参数,分析重型患者的特征。结果重型外周血白细胞绝对数(6.13±4.06)×109/L,较普通型的(4.48±1.44)×109/L明显偏高(P<0.01);而同期淋巴细胞数(1.23±0.76)×109/L,较普通型(1.50±0.59)×109/L明显下降(P<0.01)。结论除已知的重型甲型H1N1流感指征外,淋巴细胞比例和绝对计数下降可作为重型甲型H1N1患者的早期预测指标。     

Conformation and Linkage Studies of Specific Oligosaccharides Related to H1N1, H5N1, and Human Flu for Developing the Second Tamiflu

The interaction between viral HA (hemagglutinin) and oligosaccharide of the host plays an important role in the infection and transmission of avian and human flu viruses. Until now, this interaction has been classified by sialyl(α2-3) or sialyl(α2-6) linkage specificity of oligosaccharide moieties for avian or human virus, respectively. In the case of H5N1 and newly mutated flu viruses, classification based on the linkage type does not correlate with human infection and human-to-human transmission of these viruses. It is newly suggested that flu infection and transmission to humans require high affinity binding to the extended conformation with long length sialyl(α2-6)galactose containing oligosaccharides. On the other hand, the avian flu virus requires folded conformation with sialyl(α2-3) or short length sialyl(α2-6) containing trisaccharides. This suggests a potential future direction for the development of new species-specific antiviral drugs to prevent and treat pandemic flu.     

Brain histamine H receptor occupancy of orally administered antihistamines measured by positron emission tomography with (11)C-doxepin in a placebo-controlled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen

AIMS: The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H(1) receptor (H(1)R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen. METHODS: Eight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with (11)C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H(1)R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H(1)R occupancy was examined. RESULTS: H(1)R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H(1)R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H(1)R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H(1)R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001). CONCLUSION: It is suggested that 5 mg oral olopatadine, with its low H(1)R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H(1) receptor (H(1)R), histamine H(1) receptor occupancy (H(1)RO), dopamine D(2) receptor (D(2)R), positron emission tomography (PET), blood-brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV).     

Use of the H3 receptor antagonist radioligand [3H]-A-349821 to reveal in vivo receptor occupancy of cognition enhancing H3 receptor antagonists

Background and purpose:

The histamine H₃ receptor antagonist radioligand [³H]-A-349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H₃ receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H₃ receptor occupancy to blood levels and efficacy in preclinical models.

Experimental approach:

In vivo cerebral cortical H₃ receptor occupancy by [³H]-A-349821 was determined in rats from differences in [³H]-A-349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H₃ receptors. Comparisons were made to relate antagonist H₃ receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five-trial inhibitory avoidance response in rat pups.

Key results:

In adult rats, [³H]-A-349821, 1.5 µg·kg⁻¹, penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [³H]-A-349821 levels were twofold higher in the latter. With increasing [³H]-A-349821 doses, cortical H₃ receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [³H]-A-349821 doses, ABT-239 and other H₃ receptor antagonists inhibited H₃ receptor occupancy by [³H]-A-349821 in a dose-dependent manner. Blood levels of the antagonists corresponding to H₃ receptor occupancy were consistent with blood levels associated with efficacy in the five-trial inhibitory avoidance response.

Conclusions and implications:

When employed as an occupancy radiotracer, [³H]-A-349821 provided valid measurements of in vivo H₃ receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H₃ receptor antagonists.