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PubMed2004

Delta9-tetrahydrocannabinol-induced conditioned place preference and intracerebroventricular self-administration in rats.

On the basis of contradictory findings on the rewarding effects of Delta9-tetrahydrocannabinol (Delta9-THC) in laboratory animals, the effect of the compound on conditioned place preference and intracerebroventricular (i.c.v.) self-administration in a free-choice procedure, using a wide range of doses (0.015-6 mg/kg for conditioned place preference test and 0.01-1 microg/2 microl/infusion for i.c.v. self-administration), was studied in Wistar rats. The present results showed that Delta9-THC induced reward in both tests, but only at the lowest tested doses (0.075-0.75 mg/kg i.p. for conditioned place preference test and 0.01-0.02 microg/infusion for i.c.v. self-administration). This effect was fully antagonised by i.p. pretreatment with the cannabinoid CB1 receptor antagonist, SR 141716A [N-piperidino-5-(4-chlorophenyl)1-(2,4-dichlorophenyl)-4 methyl pyrazole 3-carboxamide] (0.25-1 mg/kg), and the opiate receptor antagonist, naloxone (0.5-2 mg/kg), suggesting the involvement of both endocannabinoid and opioid systems. In conclusion, these findings demonstrate, for the first time, that low doses of Delta9-THC can act as an effective reinforcer in Wistar rats providing a reliable animal model of human marijuana abuse.

Animals↗

PubMed2004

Formation of 8-isoprostaglandin F2alpha and prostaglandin E2 in carrageenan-induced air pouch model in rats.

To investigate a possible role of 8-isoprostaglandin F2alpha in inflammation, 8-isoprostaglandin F2alpha and prostaglandin E2 levels were determined by enzyme immunoassay (EIA) in carrageenan-induced air pouch model in rats. In this model, 8-isoprostaglandin F2alpha and prostaglandin E2 levels were found to be increased significantly. To evaluate whether this increase was due to the development of inflammation or solely to cyclooxygenase-2 induction, a lipopolysaccharide-induced air pouch model, in which only cyclooxygenase-2 induction occurs without inflammation, was used. In this model, 8-isoprostaglandin F2alpha was also found to be increased parallel to the increase in prostaglandin E2 level. Cyclooxygenase-dependent formation of 8-isoprostaglandin F2alpha was investigated in carrageenan-induced air pouch model by administrating nonselective cyclooxygenase inhibitor indomethacin, selective cyclooxygenase-1 inhibitor valeryl salicylate or selective cyclooxygenase-2 inhibitor SC-582368 (4-(5-(4-chlorophenyl)-3-3-trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonanmide) 1 h before carrageenan injection. All these inhibitors significantly inhibited the production of 8-isoprostaglandin F2alpha and prostaglandin E2. These findings show that 8-isoprostaglandin F2alpha can be formed in carrageenan-induced air pouch model in rats. The formation of 8-isoprostaglandin F2alpha in lipopolysaccharide-induced air pouch model and the inhibition of its production by various cyclooxygenase inhibitors provide evidence for cyclooxygenase-dependent formation of isoprostanes in this model.

Air↗

PubMed2005

Blocking cannabinoid activation of FAK and ERK1/2 compromises synaptic integrity in hippocampus.

The cannabinoid CB1 receptor allows endocannabinoids to act as intercellular and retrograde messengers in the central nervous system. Endocannabinoid actions have been implicated in both synaptic plasticity and neuroprotection. Here, cannabinergic activation of extracellular signal regulated-kinase (ERK) and focal adhesion kinase (FAK) occurred correspondingly in long-term hippocampal slice cultures. The stable endocannabinoid analogue R-methanandamide activated ERK1/ERK2 subtypes of mitogen-activated protein kinase (MAPK) through the upstream activator MAPK kinase (MEK). R-methanandamide also promoted FAK signaling, but in a MEK-independent manner. Both events of ERK and FAK activation were selectively blocked by N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281), a cannabinoid CB1 receptor antagonist, and the blockage was associated with a gradual decline in synaptic markers. Interestingly, the integrin antagonist Gly-Arg-Gly-Asp-Ser-Pro also caused the disruption of R-methanandamide-mediated ERK and FAK responses and upset the integrity of excitatory synapses. These results suggest that the endocannabinoid system supports synaptic maintenance through linkages with MAPK pathways and integrin-related FAK signaling.

Animals↗

PubMed2005

Relaxations to oestrogen receptor subtype selective agonists in rat and mouse arteries.

It has been recently reported that the oestrogen receptor alpha agonist PPT (4,4',4"-(4-propyl-[1H]-pyrazole-1,3,5-triyl) tris-phenol) is more potent than the oestrogen receptor beta agonist DPN (2,3-bis(4-hydroxyphenyl)-propionitrile) at producing relaxations in rat mesenteric artery. We have investigated the relaxant actions of PPT and DPN in rat and mouse aorta and mesenteric artery. In rat aortic rings contracted with KCl (40 mM), the oestrogen receptor beta agonist DPN produced significantly greater relaxations than the oestrogen receptor alpha agonist PPT. In wild-type (WT) mouse aorta, the same result was found, but in WT mouse mesenteric artery, as in rat mesenteric artery, DPN was significantly less potent than PPT in females but had similar potency to PPT in males. Relaxations to DPN also occurred in aorta from nitric oxide synthase-3-knockout (NOS-3-KO) mice, and in denuded aorta from both mouse and rat. Hence, in the mouse mesenteric artery, as in the rat mesenteric artery, PPT is at least as potent as DPN at producing relaxations; however, DPN was much more potent than PPT in the rat and mouse aorta. Effects of oestrogen receptor subtype selective agonists are tissue dependent. In addition, actions are largely endothelium-independent.

Animals↗

PubMed2005

Interaction between gamma-aminobutyric acid GABAB and cannabinoid CB1 receptors in spinal pain pathways in rat.

Antinociceptive effects of cannabinoids are mediated, in part, at the spinal level. Cannabinoid CB1 receptors are co-localized with dorsal horn interneurons containing gamma-aminobutyric acid (GABA). In this study, we investigated the interaction between intrathecally administered cannabinoid and GABA(B) receptor agonists and antagonists in the modulation of formalin-induced pain at the spinal level. Intrathecal pretreatment of rats with a cannabinoid receptor antagonist [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1-H-pyrazole-3-carboxamide] (SR141716A, 30 microg) decreased the analgesic effect of the intrathecal administration of the GABA(B) receptor agonist, baclofen (0.125 microg and 0.25 microg). Intrathecal administration of the GABA(B) receptor antagonist, saclofen (30 microg), 10 min before administration of the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)-cyclohexano (CP55940), did not affect the analgesia produced by the cannabinoid receptor agonist. Our results confirm that intrathecal administration of cannabinoid and GABA(B) receptor agonists have analgesic effects and that spinal antinociceptive effects of GABA(B) receptor agonists are likely through endocannabinoid modulation.

Analysis of Variance↗

PubMed2005

CC 05, a novel anti-inflammatory compound, exerts its effect by inhibition of cyclooxygenase-2 activity.

In the present study, we examined the anti-inflammation of a novel compound, 4-[5-(3-amino-4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (CC 05) in vitro and in vivo. In an in vitro cell-based assay, CC 05 inhibited cyclooxygenase (COX)-2-derived prostaglandin E(2) (PGE(2)) synthesis with an IC(50) value of 0.328+/-0.04 microM compared with an IC(50) value of 14.34+/-0.05 microM for the inhibition of COX-1-derived PGE(2) synthesis. In two in vivo rodent models, CC 05 (12.5, 25 and 50 mg/kg, i.g.) is a moderate potential and selective inhibitor of COX-2. It can reduce carrageenan-induced paw edema and PGE(2) production in the inflamed pouch dose-dependently without affecting the PGE(2) production in stomachs. Furthermore, CC 05 had no effect on COX-2 mRNA and protein expression in phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 human macrophages stimulated with lipopolysaccharide (LPS). These results demonstrate that CC 05 is a novel COX-2 inhibitor and the anti-inflammatory action is not directed towards the transcription or translation of the COX-2 gene but only to the enzymatic activity of the protein.

Animals↗

PubMed2005

Involvement of cannabinoid CB(2) receptor-mediated response and efficacy of cannabinoid CB(2) receptor inverse agonist, JTE-907, in cutaneous inflammation in mice.

Involvement of cannabinoid CB(2) receptor and effect of cannabinoid CB(2) receptor antagonist/inverse agonists on cutaneous inflammation were investigated. Mice ears topically exposed to an ether-linked analogue of 2-arachidonoylglycerol (2-AG-E) or selective cannabinoid CB(2) receptor agonist, {4-[4-(1,1-dimethylheptyl)-2,6-dimethoxy-phenyl]-6.6-dimethyl-bicyclo[3.1.1]hept-2-en-2-yl}-methanol (HU-308), had early and late ear swelling (0--24 h and 1--8 days after exposure, respectively). Both types of responses induced by 2-AG-E were significantly suppressed by oral administration of cannabinoid CB(2) receptor antagonist/inverse agonists, [N-(benzo[1,3]dioxol-5-ylmethyl)-7-methoxy-2-oxo-8-pentyloxy-1,2-dihydroquinoline-3-carboxamide] (JTE-907) and {N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2 yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide}} (SR 144528). In contrast, JTE-907 did not affect arachidonic acid-induced swelling. Orally administered JTE-907 (0.1-10 mg/kg) and SR 144528 (1 mg/kg) also produced significant inhibition of dinitrofluorobenzene-induced ear swelling, with increased cannabinoid CB(2) receptor mRNA expression observed in the inflamed ear. These results suggest that cannabinoid CB(2) receptor is partially involved in local inflammatory responses and cannabinoid CB(2) receptor antagonist/inverse agonist has beneficial effects on ear swelling.

Animals↗

PubMed2005

Modulation of ATP-mediated contractions of the rat vas deferens through presynaptic cannabinoid receptors.

The effect of R-(+)-[2,3-dihydro-5-methyl-3-[(morpholiny)methyl]pyrolol[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate (WIN 55,212-2; a cannabinoid receptor agonist) was investigated on contractions of the bisected (epididymal and prostatic portions) rat vas deferens to assess the role of cannabinoid receptors in sympathetic ATP neurotransmission. WIN 55,212-2 inhibited the electrically induced contractions in both portions of the rat vas deferens. In the presence of the alpha1-adrenoreceptor antagonist prazosin, electrical stimulation produces a contraction mediated exclusively by ATP. In this condition, WIN 55,212-2 in the prostatic portion elicited a concentration-dependent inhibition that was antagonized by N-piperidinyl-[8-chloro-1-(2,4-dichlorophenyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxamide] (NESS 0327), a selective cannabinoid CB1 receptor antagonist. NESS 0327 caused a parallel dextral displacement of the WIN 55,212-2 concentration-response curve. It is suggested that activation of pre-junctional cannabinoid receptors on sympathetic nerves of the vas deferens modulates ATP neurotransmission.

Adenosine Triphosphate↗

PubMed2006

Activation of cannabinoid CB1 receptors induces glucose intolerance in rats.

Recent reports have described the presence of cannabinoid CB1 receptors in pancreatic islets. Here we show that administration of the endogenous cannabinoid anandamide or the selective cannabinoid CB1 receptor agonist Arachidonyl-2'-chloroethylamide (ACEA) results in glucose intolerance after a glucose load. This effect is reversed by the selective cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). These results suggest that targeting cannabinoid CB1 receptors may serve as new therapeutic alternatives for metabolic disorders such as diabetes.

Animals↗

PubMed2006

Systemic effect of cannabinoids on the spontaneous firing rate of locus coeruleus neurons in rats.

Previous reports have described modulation of noradrenergic activity by cannabinoid receptors. The aim of the present research was to examine the effect of two synthetic cannabinoid CB1/CB2 receptor agonists, R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolol-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone (WIN 55212-2) and (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl) cyclohexanol (CP 55940), on the spontaneous activity of locus coeruleus noradrenergic neurons by single-unit extracellular recordings in vivo and in vitro. In anaesthetized rats, intravenous administrations of WIN 55212-2 (31.3-500 microg/kg) or CP 55940 (31.3-500 microg/kg) increased the firing rate of locus coeruleus neurons in a dose-dependent manner. The stimulatory effect of WIN 55212-2 was blocked by pretreatment with the cannabinoid CB1 receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR 141716A; 2 mg/kg). Paradoxically, local administration of WIN 55212-2 (8.3-31.3 pmol) into the locus coeruleus and intracerebroventricular injections of WIN 55212-2 (10-20 microg) or CP 55940 (20-40 microg) failed to change the spontaneous firing rate of locus coeruleus neurons. Likewise, in rat brain slice preparations perfusion with WIN 55212-2 (10 microM) or CP 55940 (10-30 microM) did not specifically affect the spontaneous firing rate of locus coeruleus cells. Therefore, we conclude that synthetic cannabinoids increase the spontaneous firing activity of noradrenergic neurons in the rat locus coeruleus through cannabinoid CB1 receptors. This stimulation appears to be indirectly induced via a receptor mechanism probably located at the peripheral level.

Action Potentials↗

PubMed2006

Evaluation of the role of nicotinic acetylcholine receptor subtypes and cannabinoid system in the discriminative stimulus effects of nicotine in rats.

Male Wistar rats were trained to discriminate (-)-nicotine (0.4 mg/kg) from saline under a two-lever, fixed-ratio 10 schedule of water reinforcement. During test sessions the following drugs were coadministered with saline (substitution studies) or nicotine (0.025-0.4 mg/kg; combination studies): the alpha4beta2 nicotinic acetylcholine receptor subtype antagonist dihydro-beta-erythroidine (DHbetaE), the non-selective nicotinic acetylcholine receptor subtype antagonist mecamylamine, the alpha7 nicotinic acetylcholine receptor subtype antagonist methyllycaconitine (MLA), the alpha4beta2 nicotinic acetylcholine receptor subtype agonist 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5-IA), the cannabinoid CB1 receptor antagonist/partial agonist rimonabant, the cannabinoid CB2 receptor antagonist N-[(1S)-endo-1,3,3-trimethylbicyclo-[2.2.1]heptan-2-yl]5-(4-chloro-3-methyl-phenyl)-1-(4-methybenzyl)pyrazole-3-carboxamide (SR 144528), the cannabinoid CB1/2 receptor agonists (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)-phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol (CP 55,940) or R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]-pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl)-methanone mesylate (WIN 55,212-2), the endogenous cannabinoid agonist and non-competitive alpha7 nicotinic acetylcholine receptor subtype antagonist anandamide, the anandamide uptake and fatty acid amide hydrolase inhibitor N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM-404), the fatty acid amide hydrolase inhibitor cyclohexylcarbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB 597), AM-404+anandamide or URB 597+anandamide. 5-IA (0.01 mg/kg) fully substituted for nicotine, while other drugs were inactive. In combination studies, DHbetaE and mecamylamine dose-dependently attenuated the discriminative stimulus effects of nicotine and the full substitution of 5-IA, while MLA, rimonabant, SR 144528, CP 55,940, WIN 55,212-2, and URB 597 did not alter the nicotine cue. Pretreatment with AM-404+anandamide or URB 597+anandamide weakly enhanced nicotine-lever responding. Our pharmacological analyses demonstrates that the expression of nicotine discrimination is under the control of nicotinic acetylcholine receptor subtypes composed of alpha4beta2 (but not of alpha7) subunits. Furthermore, we excluded the involvement of either cannabinoid CB1 and CB2 receptors or increases in the endocannabinoid tone in the nicotine discrimination.

Aconitine↗

PubMed2006

Roles of stretch-activated cation channel and Rho-kinase in the spontaneous contraction of airway smooth muscle.

In guinea pigs, it is well-known that mechanical stretch of airway smooth muscle exhibits spontaneous tone which is mediated by cyclooxygenase (COX) activation. We tested the hypothesis that this spontaneous contraction of airway smooth muscle is mediated by stretch-activated non-selective cation channels and the Rho/Rho-kinase pathway, as well as COX-2 using a pharmacological approach. Isometric force and intracellular Ca(2+) concentrations ([Ca(2+)](i)) were assessed in isolated guinea pig tracheal smooth muscle tissues. The samples were stretched to a given level and the muscle behavior was monitored under isometric conditions. We observed an increase in [Ca(2+)](i) and subsequent force generation over a 15-min period. The augmented [Ca(2+)](i) and spontaneous contraction due to the stretch were markedly attenuated by application of Gd(3+), an inhibitor of stretch-activated channels, and removal of extracellular Ca(2+). In contrast, nifedipine only had a mild inhibitory effect on the contraction. (R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexane-carboxamide (Y-27632; a Rho-kinase inhibitor) abolished the spontaneous contraction with no changes in [Ca(2+)](i). Simvastatin, which down-regulates Rho activity, also significantly inhibited the contraction. Moreover, indomethacin, an inhibitor of COX-1 and -2, and N-[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398; a COX-2 inhibitor) abolished the stretch-induced contraction without affecting [Ca(2+)](i), whereas the inhibitory effect of 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC560; a COX-1 inhibitor) on the contraction was much less. These findings demonstrated that Ca(2+) entry via stretch-activated channels, the Rho/Rho-kinase pathway, and COX-2 are involved in the mechanotransduction in guinea pig tracheal smooth muscle. Additionally, while the Rho/Rho-kinase pathway and COX-2 regulate the spontaneous contraction independently of [Ca(2+)](i), COX-1 is not involved in the stretch-induced force generation.

Amides↗

PubMed2006

Antidepressant-induced undesirable weight gain: prevention with rimonabant without interference with behavioral effectiveness.

Antidepressant pharmacotherapy has dramatically improved the quality of life for many patients. However, prolonged use may induce weight gain, resulting in enhanced risk for treatment noncompliance. Cannabinoid CB(1) receptor antagonists decrease food intake and body weight, but may also affect mood. We investigated in female Sabra mice first, whether acute treatment with the cannabinoid receptor antagonist rimonabant (5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide, SR141716, 5 mg/kg) interfered with the tricyclic antidepressant desipramine (15 mg/kg) or the selective serotonin reuptake inhibitor fluoxetine (20 mg/kg) in the Porsolt forced swimming test. Second, whether chronic treatment (3 months) with desipramine (5 mg/kg) enhanced weight gain and whether cotreatment with rimonabant (2 mg/kg), prevented the excessive weight gain, while retaining antidepressant effectiveness. Motor activity and anxiety-like behavior were also investigated. The acute studies indicated that rimonabant did not influence 'antidepressant' activity of desipramine or fluoxetine. In the chronic studies, desipramine enhanced weight gain, despite the observation that the injection procedure reduced weight gain. The enhanced weight gain continued at least 35 days after treatment ended. Rimonabant reduced weight gain to which no tolerance developed and which persisted at least 30 days beyond treatment. Mice cotreated with rimonabant and desipramine had body weights closer to controls or to those receiving rimonabant alone than to those treated with desipramine alone. The antidepressant effects of desipramine were maintained throughout treatment; this was not altered by the chronic rimonabant treatment at any time, although rimonabant together with desipramine transiently enhanced anxiety-like behavior. These observations suggest that combined treatment with antidepressants and cannabinoid CB(1) receptor antagonist to prevent undesirable weight gain, should be further investigated.

Analysis of Variance↗

PubMed2004

Enantiomeric separation of cizolirtine and metabolites on amylose tris (3,5-dimethylphenyl carbamate) chiral stationary phase.

The enantiomeric resolution of (+/-)-cizolirtine, (+/-)-cizolirtine-N-oxide, (+/-)-N-desmethylcizolirtine and (+/-)-5(alpha-hydroxybenzyl)-1-methylpyrazole was achieved on amylose tris (3,5-dimethylphenyl carbamate) chiral stationary phase known as Chiralpak AD using hexane/2-propanol/triethylamine (80:20:0.05, v/v/v) as the mobile phase. The flow rate of the mobile phase used was 1.0 ml/min with UV detection at 230 nm. The values of R(s) of the resolved enantiomers of (+/-)-cizolirtine, (+/-)-cizolirtine-N-oxide, (+/-)-N-desmethylcizolirtine and (+/-)-5(alpha-hydroxybenzyl)-1-methyl pyrazole were 1.20, 0.60, 1.16 and 1.15, respectively.

Amylose↗

PubMed2004

1-Phenyl-3-toluyl-4-[ortho-1'-(N-ethyl-2'-methylpropylamine)]phenylpyrazole, synthesis and evaluation of the in vitro antifungal activity against Botrytis cinerea and Fusarium oxysporum.

A novel antifungal pyrazole derivative was synthesized. Designated 1-phenyl-3-toluyl-4-[ortho-1'-(N-ethyl-2'-methylpropylamine)]phenylpyrazole, the compound exerted an antifungal effect toward Botrytis cinerea and Fusarium oxysporum. In fact, our results clearly show that mycelial growth and conidial germination of both fungi were blocked by the compound. Indeed, a 96-well microbioassay procedure was used for fast and easy evaluation of minimal inhibitory concentration (MIC). The MIC values for B. cinerea and F. oxysporum were 25 and 36 microg/ml, respectively.

Antifungal Agents↗

PubMedDate not supplied

Study on the inclusion complex between beta-cyclodextrin and celecoxib by spectrofluorimetry and its analytical application.

The supramolecular interaction of celecoxib (chemically 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzene sulfonamide) and beta-cyclodextrin (beta-CD) has been studied by spectrofluorimetry. The results showed that beta-CD reacted with celecoxib to form an inclusion complex. 1:1 stoichiometry for beta-CD-celecoxib complex was established and its association constant at different temperatures was calculated by applying a non-linear regression method to the change in the fluorescence of celecoxib that brought about by the presence of beta-CD. The thermodynamic parameters (DeltaH degrees, DeltaS degrees and DeltaG degrees) associated with the inclusion process were also determined. Based on the significant enhancement of the fluorescence intensity of celecoxib produced through complex formation, a simple, rapid and highly sensitive spectrofluorimetric method for the determination of celecoxib in aqueous solution in the presence of beta-CD was developed. The measurement of relative fluorescence intensity was carried out at 390 nm with excitation at 270 nm. A linear relationship between the fluorescence intensity and celecoxib concentration was obtained in the range of 0.1-4.0 microg ml-1, with a correlation coefficient of 0.9996. The detection limit was 7.29 ng ml-1 and the relative standard deviation was 1.28%. The method was successfully applied to the determination of celecoxib in pharmaceutical preparations.

Algorithms↗

PubMed2006

Cannabinoid derivatives induce cell death in pancreatic MIA PaCa-2 cells via a receptor-independent mechanism.

Cannabinoids (CBs) are implicated in the control of cell survival in different types of tumors, but little is known about the role of CB system in pancreatic cancer. Herein, we investigated the in vitro antitumor activity of CBs and the potential role of their receptors in human pancreatic cancer cells MIA PaCa-2. Characterization tools used for this study included growth inhibition/cell viability analyses, caspase 3/7 induction, DNA fragmentation, microarray analysis and combination index-isobologram method. Our results demonstrate that CBs produce a significant cytotoxic effect via a receptor-independent mechanism. The CB1 antagonist N-(piperidin-1-1yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) was the most active compound with an IC50 of 8.6 +/- 1.3 microM after 72 h. AM251 induces apoptosis, causes transcriptional changes of genes in janus kinase/signal transducers and activators of transcription signaling network and synergistically interacts with the pyrimidine analogue, 5-fluorouracil. These findings exclude the involvement of CB receptors in the regulation of MIA PaCa-2 cell growth and put AM251 forward as a candidate for the development of novel compounds worthy to be tested in this type of neoplasia.

Antineoplastic Agents↗

PubMed2005

Effects of the very late adhesion molecule 4 antagonist WAY103 on human peripheral blood eosinophil vascular cell adhesion molecule 1-dependent functions.

BACKGROUND: Eosinophil infiltration to the lung in allergic inflammation can be initiated by the tethering of circulating cells through very late adhesion molecule 4 (VLA-4; alpha4beta1, CD49d/CD29) to vascular cell adhesion molecule 1 (VCAM-1) expressed on pulmonary vascular endothelium. Small-molecule VLA-4 antagonists have been proposed as a therapeutic mechanism to prevent eosinophil infiltration in asthma; however, they might affect other eosinophil functions. OBJECTIVE: The small-molecule VLA-4 antagonist (2S)-3-(4-Dimethylcarbamoyloxyphenyl)-2-{[(4R)-5,5-dimethyl-3-(1-methyl-1H-pyrazole-4 sulfonyl)thiazolidine-4-carbonyl]amino}propionic acid (WAY103) was assessed for its effects on eosinophil VLA-4-dependent functions, including adhesion, migration, respiratory burst, and degranulation. METHODS: Human peripheral blood eosinophils were preincubated with WAY103, anti-alpha4, and/or anti-beta2 integrin mAbs and then assessed for adhesion to recombinant VCAM-1, intercellular adhesion molecule 1, and endothelial cell monolayers. Transmigration was measured by using human pulmonary microvascular endothelial cell monolayers and Transwell filters. Superoxide anion generation was determined by means of cytochrome C reduction and degranulation by means of eosinophil-derived neurotoxin release. RESULTS: WAY103 inhibition of eosinophil adhesion to recombinant VCAM-1 was dose dependent (63% inhibition with 100 nM WAY103, P < .04) and comparable with inhibition caused by anti-alpha4 mAb (60.1% inhibition). Although pretreatment with WAY103 also decreased eosinophil adhesion to TNF-alpha plus IL-4-activated human pulmonary microvascular endothelial cell monolayers, it did not prevent eosinophil transendothelial migration in response to RANTES. Finally, WAY103 inhibited VCAM-1-stimulated superoxide generation but enhanced cytokine-activated eosinophil-derived neurotoxin degranulation. CONCLUSION: Although small-molecule VLA-4 antagonists, such as WAY103, might reduce eosinophil adhesion, this approach might not be sufficient to eliminate this cell from in vivo allergic airway inflammatory participation and could even promote specific cell activation.

Adolescent↗