Characterization of etoricoxib,a novel,selective COX-2 inhibitor

Etoricoxib is a potent selective COX-2 inhibitor in man. Ex vivo whole-blood assays assessed COX-2 inhibition after oral administration of etoricoxib in single (5-500 mg) and multiple (25-150 mg) once-daily doses to healthy human subjects. A separate study examined ex vivo gastric mucosal PGE2 synthesis after etoricoxib (120 mg qd), naproxen (500 mg bid), or placebo for 5 days. The effect of etoricoxib 120 mg qd on the COX-1-mediated antiplatelet effects of low-dose aspirin (ASA) was also assessed. The mean (time)-weighted average inhibition (WAI) of lipopolysaccharide (LPS)-stimulated PGE2 (COX-2 assay) vcrsus placebo was dose related after single (range: 3.1%-99.1%) and multiple doses (range: 52.5%-96.7%). PGE2 remained significantly inhibited 24 hours postdose at steady state. Inhibition of LPS-stimulated PGE2 showed a strong relationship with etoricoxib plasma concentrations; ex vivo, IC50 was almost identical to in vitro. Multiple dosing of etoricoxib (up to 150 mg qd) showed no important effects on serum TXB2, bleeding time, or platelet aggregation (COX-1-mediated effects). The nonselective nonsteroidal anti-inflammatory (NSAID) naproxen significantly inhibited (approximately 78%) ex vivo prostaglandin synthesis in gastric mucosa; etoricoxib had no effect. Etoricoxib did not interfere with the antiplatelet effects of low-dose ASA, as assessed by serum TXB2 and platelet aggregation. Etoricoxib was generally well tolerated, even at doses above the clinical dose range. Based on these results, etoricoxib is a potent selective inhibitor of COX-2 after single and multiple dosing regimens and does not inhibit prostaglandin synthesis in the gastric mucosa, even at doses above the clinical dose range of 60 to 120 mg.     

Endocannabinoid modulation of hyperaemia evoked by physiologically relevant stimuli in the rat primary somatosensory cortex

Background and purpose:

In vitro studies demonstrate that cannabinoid CB₁ receptors subserve activity-dependent suppression of inhibition in the neocortex. To examine this mechanism in vivo, we assessed the effects of local changes in CB₁ receptor activity on somatosensory cortex neuronal activation by whisker movement in rats.

Experimental approach:

Laser Doppler flowmetry and c-Fos immunohistochemistry were used to measure changes in local blood flow and neuronal activation, respectively. All drugs were applied directly to the cranium above the whisker barrel fields of the primary somatosensory cortex.

Key results:

The CB₁ receptor agonist WIN55212-2 potentiated the hyperaemia induced by whisker movement and this potentiation was occluded by bicuculline. The CB₁ receptor antagonists, rimonabant and AM251, inhibited hyperaemic responses to whisker movement; indicating that activation of endogenous CB₁ receptors increased during whisker movement. Whisker movement-induced expression of c-Fos protein in neurons of the whisker barrel cortex was inhibited by rimonabant. Movement of the whiskers increased the 2-arachidonoylglycerol content in the contralateral, compared to the ipsilateral, sensory cortex.

Conclusions and implications:

These results support the hypothesis that endocannabinoid signalling is recruited during physiologically relevant activation of the sensory cortex. These data support the hypothesis that the primary effect of CB₁ receptor activation within the activated whisker barrel cortex is to inhibit GABA release, resulting in disinhibition of neuronal activation. These studies provide physiological data involving endocannabinoid signalling in activity-dependent regulation of neuronal activation and provide a mechanistic basis for the effects of cannabis use on sensory processing in humans.This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476-5381.2010.00831.x     

Education,Postgraduate Training,Board Certification,and Experience Requirements in Advertisements for Clinical Faculty Positions

Objectives

To compare requirements for pharmacy practice faculty positions in advertisements from 2002 through 2006 to those reported from 1990 through 1994.

Methods

Positions advertised from January 2002 through December 2006 in 3 newsletters and journals were evaluated for required or preferred degree, completion of residencies and/or fellowships, years of work experience, board certification, and other postgraduate training and education. Advertisements were separated by tenure-eligibility and rank.

Results

Of 426 advertisements for faculty members, 77% required additional training, including residencies and fellowships or their equivalent in experience. Board certification was required in only 0.9% but preferred in 11%. Advertisements for tenure-eligible positions did not have more extensive requirements than nontenured, nor did upper vs. lower rank.

Conclusions

Compared to 1996, the number of advertisements requiring postgraduate training to secure a faculty position almost doubled. Whether the qualifications of faculty members recruited match the requirements is unknown.     

Ranitidine bismuth citrate: a novel anti-ulcer agent with different physico-chemical characteristics and improved biological activity to a bismuth citrate-ranitidine admixture.

BACKGROUND: Ranitidine bismuth citrate (RBC) is a new chemical entity for the treatment of peptic ulcer disease. RESULTS: RBC is freely soluble in water (more than 600 mg/mL at pH 4.6), whereas an equimolar admixture of its component molecules, bismuth citrate and ranitidine, formed an almost totally insoluble suspension. Even at very low pH values (around 2.0), the solubility of bismuth in ranitidine bismuth citrate was at least two-fold better than in the admixture. Comparison of several physico-chemical characteristics indicated that RBC possessed significantly different melting point properties, X-ray powder diffraction patterns, infra-red spectra and 13C-NMR solid-state spectra to the admixture. Ranitidine bismuth citrate inhibited human pepsin isoenzymes 1, 2, 3 and 5 but the admixture was inactive. RBC showed approximately two-fold greater anti-Helicobacter pylori activity in vitro than the admixture (geometric mean minimum inhibitory concentrations of 12.5 and 25.7 mg/L, respectively) and was more rapidly bactericidal. In a mouse model of gastric H. pylori colonization, 200 mg/kg of bismuth, given as RBC, eradicated the organism from all mice while only 10% of infections were eradicated by equivalent levels of bismuth in admixture form. CONCLUSION: It is believed that the significantly greater solubility of RBC, especially at lower pH values, is highly relevant to its better antipepsin and anti-H. pylori action compared to the insoluble admixture of bismuth citrate and ranitidine.     

Consuming broccoli does not induce genes associated with xenobiotic metabolism and cell cycle control in human gastric mucosa

Epidemiological studies suggest that a diet rich in broccoli can reduce the risk of cancer at several sites. The anticarcinogenic activity has been largely attributed to the biological activity of sulforaphane (SF), the isothiocyanate derived from 4-methylsulphinylbutyl glucosinolate, which accumulates in broccoli. SF induces xenobiotic metabolizing genes in both cell cultures and animal models and induces genes associated with cell cycle arrest and apoptosis. However, it is not known whether these genes are induced in humans after consumption of broccoli. Sixteen subjects were recruited into a randomized, 3-phase crossover dietary trial of standard broccoli, high glucosinolate broccoli, and water. Global changes in gene expression that occurred 6 h after consuming broccoli soups or water were quantified in gastric mucosal tissue, using Affymetrix whole genome microarrays (n = 4), and in selected genes by real-time RT-PCR in the other individuals. Consumption of high glucosinolate broccoli resulted in up-regulation of several xenobiotic metabolizing genes, including thioredoxin reductase, aldoketoreductases, and glutamate cysteine ligase modifier subunit, which have previously been reported to be induced in cell and animal models after exposure to SF. Only 1 such gene was significantly up-regulated after consumption of standard broccoli. The consequences of these results in relation to the potential anticarcinogenic action of broccoli are discussed.     

Effect in man of aspirin, standard indomethacin, and sustained release indomethacin preparations on gastric bleeding.

1. We have compared acute gastric bleeding caused by a new slow release preparation of indomethacin (indomethacin Continus) with that caused by aspirin and other indomethacin preparations. 2. In a randomized crossover study, blood loss into timed gastric aspirates was determined in 20 healthy volunteers after receiving, over 96 h, either placebo, aspirin (600 mg four times daily; 17 doses) indomethacin BP (50 mg three times daily; 13 doses), Indocid-R (75 mg twice daily; 9 doses) or indomethacin Continus (75 mg twice daily; 9 doses). A venous blood sample was also taken during each treatment period for subsequent determination of alpha 1-glycoprotein, and for drug assay. 3. Gastric bleeding on placebo was 1.4 (0.7-2.8) microliters 10 min-1 (mean, 95% confidence interval). Both aspirin and the indomethacin preparations caused significantly more bleeding (P less than 0.05). Rates of bleeding after aspirin, indomethacin BP, Indocid-R, and indomethacin Continus were respectively 22.0 (10.7-47.2) microliters 10 min-1, 4.4 (2.2-9.1) microliters 10 min-1, 10.8 (5.3-22.3) microliters 10 min-1, and 5.1 (3.0-10.6) microliters 10 min-1. 4. Rates of bleeding after indomethacin BP and indomethacin Continus, but not Indocid-R, were significantly less than after aspirin (P less than 0.01). 5. Salicylate or indomethacin was detectable in the plasma of all subjects after the active treatment periods, except for one instance involving a subject allocated indomethacin BP. Indomethacin levels were significantly higher 2 h after Indocid-R than with indomethacin BP or indomethacin Continus. 6. alpha 1-acid glycoprotein levels were not significantly affected by prior treatment with aspirin or indomethacin.     

兴安升麻酚性甙成分的研究

从中药兴安升麻[Cimicifuga dahurica(Turcz.)Maxim.]的根茎中分得三个新结构的酚甙类,即异升麻酰胺(isocimicifugamide,I)、北升麻瑞(cimidahurine,II)和北升麻宁(cimidahurinine,III),其中I为升麻酰胺(cimicifugamide,IV)的几何异构体,而II和III则分别为3,4-二羟基-β-苯乙醇-3-O-β-D-吡哺半乳糖甙和3,4-二羟基-β-苯乙醇-3-O-β-D-吡喃葡萄糖甙。由光谱数据(IR,MS,¹H和¹³C-NMR及NOE差谱)阐明了它们的化学结构。另外还分得蔗糖(V)。     

尿中麻黄碱类药物的HPLC定量分析

以甲基苯丙胺为内标,在C₁₈柱上,用高效液相色谱技术分离并同时测定了尿中6种麻黄碱类药物。在25min内,麻黄碱、伪麻黄碱、去甲麻黄碱、去甲伪麻黄碱、甲基麻黄碱、乙基麻黄碱和内标均达到基线分离,分离度大于1.80,且尿中其它杂质不干扰。方法回收率高,重现性好,在1.5～25μg/ml的浓度范围内有很好的线性关系,相关系数大于0.999。