Role of prostanoid EP receptors in mechanisms of emesis and defaecation in ferrets.

Prostanoid EP receptor agonists are used for a number of clinical indications but may be associated with gastric disturbance. In the present studies we used the ferret and sulprostone (30µg/kg, i.p.

Mechanism of the prostanoid TP receptor agonist U46619 for inducing emesis in the ferret.

U46619 is a potent thromboxane A(2) mimetic with emesis-inducing actions that are mediated via prostanoid TP receptors. We investigated its emetic mechanism of action in more detail using the ferret as model animal. The emesis induced by U46619 (30 microg/kg, intraperitoneal) was antagonized significantly by (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine hydrochloride (CP-99,994; 1 and 10 mg/kg; P < 0.

The physicochemical properties and the in vivo AChE inhibition of two potential anti-Alzheimer agents, bis(12)-hupyridone and bis(7)-tacrine.

The lipophilicity and solubility profiles of bis(12)-hupyridone (B12H) and bis(7)-tacrine (B7T), two novel acetylcholinesterase inhibitors dimerized from huperzine A fragments and tacrine, respectively, were investigated over a broad pH range. Lipophilicity was assessed by both shake flask method with 1-octanol-water system and a reverse-phase HPLC system with methanol-water as mobile phase. The former method was used for determining the lipophilicities of the ionized forms (log D) of the dimers while the latter method was used for that of the neutral forms (log P).

Development of a high performance liquid chromatography-tandem mass method for determination of bis(7)-tacrine, a promising anti-Alzheimer's dimer, in rat blood.

An analytical method using on-line high performance liquid chromatography-tandem mass spectrometry with electrospray ionization was developed and applied for the quantification of bis(7)-tacrine (B7T) in rat blood. B7T and pimozide (internal standard, IS) were extracted in a single step from 100 microl of alkalized blood with ethyl acetate. Analytes were separated using an Extend C-18 column at 25 degrees C.

Synergistic neuroprotection by bis(7)-tacrine via concurrent blockade of N-methyl-D-aspartate receptors and neuronal nitric-oxide synthase.

The excessive activation of the N-methyl-D-aspartate receptor (NMDAR)/nitric oxide (NO) pathway has been proposed to be involved in the neuropathology of various neurodegenerative disorders. In this study, NO was found to mediate glutamate-induced excitotoxicity in primary cultured neurons. Compared with the NO synthase (NOS) inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), and the NMDAR antagonist memantine, bis(7)-tacrine was found to be more potent in reducing NO-mediated excitotoxicity and the release of NO caused by glutamate.

Alkylene tether-length dependent gamma-aminobutyric acid type A receptor competitive antagonism by tacrine dimers.

Bis(7)-tacrine was previously demonstrated as an antagonist of gamma-aminobutyric acid type A (GABA(A)) receptors. In this study, the effects of a series of alkylene-linked tacrine dimers on GABA(A) receptors were examined. In radioligand binding assay, the analogues differed in binding affinity for GABA(A) receptors, and potency monotonically increased as the tether was shortened from nine to two methylenes.

Differential action of anti-emetic drugs on defecation and emesis induced by prostaglandin E2 in the ferret.

In the present studies we investigated the mechanism of action of prostaglandin E2 (1 mg/kg, i.p.) to induce emesis and defecation and/or tenesmus in the ferret.

Bis(7)-tacrine attenuates beta amyloid-induced neuronal apoptosis by regulating L-type calcium channels.

Beta amyloid protein (Abeta) and acetylcholinesterase (AChE) have been shown to be closely implicated in the pathogenesis of Alzheimer's disease. In the current study, we investigated the effects of bis(7)-tacrine, a novel dimeric AChE inhibitor, on Abeta-induced neurotoxicity in primary cortical neurons. Bis(7)-tacrine, but not other AChE inhibitors, elicited a marked reduction of both fibrillar and soluble oligomeric forms of Abeta-induced apoptosis as evidenced by chromatin condensation and DNA specific fragmentation.

Neuroprotection via inhibition of nitric oxide synthase by bis(7)-tacrine.

Here we report that bis(7)-tacrine, a novel acetylcholinesterase inhibitor, exerts neuroprotective effects by inhibition of nitric oxide synthase. In cortical neurons at 12 days in vitro, bis(7)-tacrine concentration-dependently reduced cell death induced by glutamate, beta-amyloid and L-arginine, but not by nitric sodium nitroprusside. N-monomethyl-L-arginine, a nitric oxide synthase inhibitor, also prevented the former three types but not the last type of the cytotoxicity; however, nitric oxide scavengers blocked all of these insults, indicating that nitric oxide mediated these neuronal injuries.

Optimization of pressurized liquid extraction for Z-ligustilide, Z-butylidenephthalide and ferulic acid in Angelica sinensis.

Pressurized liquid extraction, one of the most promising and recent sample preparation techniques, offers the advantages of reducing solvent consumption and allowing for automated sample handling. It is being exploited in diverse areas because of its distinct advantages. However, because the extraction is performed at elevated temperatures using PLE, thermal degradation could be a concern.

Action of ondansetron and CP-99,994 to modify behavior and antagonize cisplatin-induced emesis in the ferret.

The action of ondansetron (1 mg/kg, i.p.) and (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994; 10 mg/kg, i.

Simultaneous determination of ergosterol, nucleosides and their bases from natural and cultured Cordyceps by pressurised liquid extraction and high-performance liquid chromatography.

A simple method is described for the simultaneous determination of ergosterol, nucleosides and their bases in Cordyceps. The samples were extracted by using pressurised liquid extraction (PLE). The effects of experimental variables, such as solvent, temperature, static extraction time and cycles, on PLE efficiency have been studied.

Excitatory action of prostanoids on the ferret isolated vagus nerve preparation.

We have investigated the actions of various prostanoid receptor agonists on an isolated preparation of the ferret cervical vagus using a grease-gap extracellular recording technique. The potency ranking for depolarization was BW245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin; DP-selective, EC50=0.14 microM)>prostaglandin E2 (nonselective EP agonist)>U-46619 (11alpha, 9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid; TP agonist)>prostaglandin F2alpha (FP receptor agonist).

Emetic action of the prostanoid TP receptor agonist, U46619, in Suncus murinus (house musk shrew).

The emetic action of the prostanoid TP receptor agonist, 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619; 300 microg/kg, i.p.), was investigated in Suncus murinus.

Action of prostanoids on the emetic reflex of Suncus murinus (the house musk shrew).

Several prostanoids were investigated for a potential to induce emesis in Suncus murinus. The TP receptor agonist 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619) induced emesis at doses as low as 3 microg/kg, i.p.

Action of 5-HT3 receptor antagonists and dexamethasone to modify cisplatin-induced emesis in Suncus murinus (house musk shrew).

Ondansetron (1-3 mg/kg), granisetron (0.3-1 mg/kg) and dexamethasone (0.3-1 mg/kg), administered at 12-h intervals, were investigated for their potential to prevent cisplatin (30 mg/kg, i.

Action of metyrapone and tetracosactrin to modify cisplatin-induced acute and delayed emesis in the ferret.

Cisplatin 5 mg/kg, i.p., induced an acute (day 1) and delayed (days 2 and 3) emetic response in the ferret that was used to investigate the potential anti-emetic activity of metyrapone and tetracosactrin and their potential interaction.

Actions of prostanoids to induce emesis and defecation in the ferret.

Several prostanoids were investigated for their ability to induce emesis and/or defecation and tenesmus in the ferret. The rank order of emetic potency (dose producing four episodes, D4) was: sulprostone (5 microg/kg)>11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619; 8 microg/kg)>misoprostol (27 microg/kg)>17-phenyl-omega-trinor prostaglandin E2 (53 microg/kg)>prostaglandin E2 (94 microg/kg)>5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin (BW245C; 148 microg/kg)>>prostaglandin F(2alpha) (13,500 microg/kg). Emesis was also induced by iloprost (D4 not determined) and prostaglandin E2 methyl ester (D4=350 microg/kg).