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I.p. Administration (i.p + administration)
Selected AbstractsEffects of repeated injections of fibroblast-stimulating lipopeptide-1 on fever, formation of cytokines, and on the responsiveness to endotoxin in guinea-pigsACTA PHYSIOLOGICA, Issue 1 2009A. Greis Abstract Aims:, We investigated, whether the Toll-like receptors (TLRs)-2/6-agonist fibroblast-stimulating lipopeptide-1 (FSL-1), like the TLR-4 agonist lipopolysaccharide (LPS), induces a state of tolerance. We further tested the influence of repeated pre-treatment with FSL-1 on the animals' responsiveness to LPS. Methods:, Abdominal temperature was recorded in unrestrained guinea-pigs with intra-abdominally implanted radiotransmitters. Circulating concentrations of tumour necrosis factor (TNF) and interleukin-6 (IL-6) were measured with specific bioassays. We tested the effects of intra-arterial (i.a.) or intraperitoneal (i.p.) injections of 100 ,g kg,1 FSL-1, repeated five times at intervals of 3 days. The animals' responses to i.a. or i.p. injections of 10 ,g kg,1 LPS were determined another 3 days later and compared to those of naïve guinea-pigs. Results:, The FSL-1-induced TNF peak was significantly attenuated starting with the third i.a. administration, while fever was unimpaired and the IL-6-peak just tended to decrease. Fever and IL-6 in response to i.a. injections of LPS were identical in both groups, while circulating TNF was higher in naïve compared to FSL-1 pre-treated animals. The effects of repeated i.p. injections of FSL-1 were more pronounced resulting in attenuation of fever as well as circulating TNF and IL-6, the strongest reduction observed after the third stimulation with FSL-1. Repeated i.p. pre-treatment with FSL-1 induced hyporesponsiveness to i.p. administration of LPS compared to naïve animals with regard to fever and especially with regard to LPS-induced formation of cytokines. Conclusions:, There is a development of tolerance to FSL-1 and cross-tolerance between FSL-1 and LPS depending on the route of administration of the respective TLR-2/6 and TLR-4 agonists. [source] Anticonvulsant profile and teratogenicity of 3,3-dimethylbutanoylurea: A potential for a second generation drug to valproic acidEPILEPSIA, Issue 7 2008Jakob Avi Shimshoni Summary Purpose: The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3-dimethylbutanoylurea (DBU), as potential second-generation drugs to valproic acid (VPA). Methods: The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical-, or chemical-induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA-induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats. Results: DBU emerged as the most potent compound having an MES-ED50of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet-ED50of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED50= 35 mg/kg), the psychomotor 6 Hz mouse model (ED50= 80 mg/kg at 32 mA and ED50= 133 mg/kg at 44 mA), the bicuculline- and picrotoxin-induced seizure mouse model (ED50= 205 mg/kg and 167 mg/kg, respectively). In contrast to VPA, DBU, IVU, and PVU did not induce a significant increase in NTDs as compared to control. DBU was eliminated by metabolism with a half-life of 4.5 h. Conclusions: DBU's broad spectrum and potent anticonvulsant activity, along with its high safety margin and favorable pharmacokinetic profile, make it an attractive candidate to become a new, potent, and safe AED. [source] Anticonvulsant Profile and Teratogenicity of N -methyl-tetramethylcyclopropyl Carboxamide: A New Antiepileptic DrugEPILEPSIA, Issue 2 2002Nina Isoherranen Summary: ,Purpose: The studies presented here represent our efforts to investigate the anticonvulsant activity of N -methyl-tetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite tetramethylcyclopropyl carboxamide (TMCD) in various animal (rodent) models of human epilepsy, and to evaluate their ability to induce neural tube defects (NTDs) and neurotoxicity. Methods: The anticonvulsant activity of M-TMCD and TMCD was determined after intraperitoneal (i.p.) administration to CF#1 mice, and either oral or i.p. administration to Sprague,Dawley rats. The ability of M-TMCD and TMCD to block electrical-, chemical-, or sensory-induced seizures was examined in eight animal models of epilepsy. The plasma and brain concentrations of M-TMCD and TMCD were determined in the CF#1 mice after i.p. administration. The induction of NTDs by M-TMCD and TMCD was evaluated after a single i.p. administration at day 8.5 of gestation in a highly inbred mouse strain (SWV) that is susceptible to valproic acid,induced neural tube defects. Results: In mice, M-TMCD afforded protection against maximal electroshock (MES)-induced, pentylenetetrazol (Metrazol)-induced, and bicuculline-induced seizures, as well as against 6-Hz "psychomotor" seizures and sound-induced seizures with ED50 values of 99, 39, 81, 51, and 10 mg/kg, respectively. In rats, M-TMCD effectively prevented MES- and Metrazol-induced seizures and secondarily generalized seizures in hippocampal kindled rats (ED50 values of 82, 45, and 39 mg/kg, respectively). Unlike M-TMCD, TMCD was active only against Metrazol-induced seizures in mice and rats (ED50 values of 57 and 52 mg/kg, respectively). Neither M-TMCD nor TMCD was found to induce NTDs in SWV mice. Conclusions: The results obtained in this study show that M-TMCD is a broad-spectrum anticonvulsant drug that does not induce NTDs and support additional studies to evaluate its full therapeutic potential. [source] Effect of Dipotassium Clorazepate on Ainygdaloid-Kiiidling and Comparison Between Amygdaloid- and Hippocampal-Kindled Seizures in RatsEPILEPSIA, Issue 2000Kouichiro Amano Purpose: We reportcd previously that dipotassium clorazcpate (potassium 7-chloro-2, 3-dihydro-2-oxo-S-phcnyI- l H- l, 4-bcnzodiazepinc-3-carboxylate potassium hydroxide: DC), an antianxiety drug, suppressed hippocampel kindled scizures in rats i n a dose-dependent manner (Amano et al. Psychiatry Clin Neuroscienccs 1998; 52: 459,462). Its effect on kindling, howcver, has not been evaluated. Moreover, differcnces in the anticonvulsive effccts of conventional anticonvulsants bctween amygdaloid-and hippocampal-kindlcd seizures have becn reportcd (Kamci et al. Arch. Int. Pharmacodyn I98 1; 249: 164,176). To clarify the anticonvulsive propcrties of DC, we examined its effects on amygdaloid kindling and compared it for 7 succcssive days against amygdaloid- and hippocampal-kindled seizures using thc rat kindling model of epilcpsy. Methods: Adult inale Wistar rata weighing 220,330 g werc used. Electrodes were implanted stereotaxically into thc left basoiatcfiil amygdala or the left dorsal hippocampus under pcntobarhital ancsthesia. Expcriment 1: Anticonvulsive effect on amygdaloid-kindled seizurcs. Rats having >5 consecutive stage-5 seimrcs were htimulated at the generalizcd seizure-triggering threshold (GST) intensity 30 minutes after i.p. administration or DC or saline. Experiment 2: Effect on amygdala kindling. In other groups of Tiits, the amygdala was stimulated once daily following 30 minutes i.p. administration or DC at 5 mg/kg or saline until the first stage-5 seizure was attained. Experimcnt 3: Comparison of anticonvulsive effect bctween amygdaloid- and hippocampal-kindled scizures. In other groups of rats having 5 consecutive stage-5 seizures, the GST was determined. Furthermorc, rats having >I0 stage-5 scizures induced at thc GST intensity were testcd once a day for 7 consecutive days. Thc stimulation was delivercd 30 minutes aftcr i.p. administration of DC or saline. Results: Expcriment I: DC suppresscd amygdaloid-kindled scizures in a dose-depcndent manner. Significant reduction of aftcr-discharge duration compared with the control group was observed at dosagcs of 2 mg/kg or more, hut complete suppression of after-discharges was observed in only I of 7 sessions at the highcst dose. Expcriment 2: Thc number of stimulations rcquired for the first stage-5 seiiurc in the 5 mg/kg dosage group was 14.1+1.4 stimulations, which was significantly greater than the 10.2+1.7 stimulations in the control group (P4.01). The contralateral cortical afterdischarge duration i n the DC treated group was signilicantly shortcr than thc afterdischarge duration in the amygdala at the first 7 stimulations, whereas it was significantly shorter only the first 3 stimulations i n the control group. Experiment 3: DC suppressed amygdaloid-kindled seizures at 2 and 5 mg/kg, whcreas I mg/kg or morc suppresscd hippocampal-kindlcd seizures. Conclusions: Thc result of the present study suggcst that thc principal anticonvulsive cffect of DC is likely to be relatcd mainly to attenuation of propagation of scizure activity rather than to an elevatcd seizure threshold, which may support our previously findings that increased stimulus intensity could not complctcly reverse thc anticonvulsive effects of DC. Thus, differences in effective dosages in both amygdaloid- and hippocampal-kindled seizures may suggcst a difference in the neuronal mechanisms that arc cvolved in this kindling. The present study dcmonstratcd that DC has a modest anticonvulsive effect without serious adverse effccts, which indicates thc clinical uscfulness of DC for treatment intractable epilepsy. [source] Retinoid metabolism in the small intestine during development of liver cirrhosisJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 5 2009Sathish Kumar Natarajan Abstract Background and Aims:, Retinoids are important mediators of cellular differentiation and proliferation in various epithelia of the body including the small intestine. Though alterations in intestinal epithelial cell proliferation have been noted in liver cirrhosis, mechanisms involved in the process are not well understood. This study examined the levels of various retinoids and retinoid-metabolizing enzymes in the small intestine during development of liver cirrhosis. Methods:, Four groups of animals were used (control, phenobarbitone control, thioacetamide and carbon tetrachloride treatment). Twice-weekly intragastric or i.p. administration of carbon tetrachloride or thioacetamide, respectively, produced liver cirrhosis after 3 months, which was confirmed through histology and serum markers. Retinoid levels were measured by high-performance liquid chromatography. Results:, A decrease in the levels of retinal, retinoic acid and retinol was evident in the intestine by 3 months, when cirrhosis was evident histologically, and these remained low until 6 months. A decrease in the activities of retinaldehyde oxidase, retinaldehyde reductase and retinol dehydrogenase was also seen in intestine from cirrhotic rats. Conclusion:, These results suggest that altered retinoid metabolism in the intestine of cirrhotic rats might have an influence on changes in intestinal epithelial cell differentiation, seen in liver cirrhosis. [source] Effects of lipopolysaccharide on vascular reactivity and mortality in ratsAUTONOMIC & AUTACOID PHARMACOLOGY, Issue 5-6 2002J. P. L. Nunes Summary 1 The effects of intraperitoneal (i.p.) lipopolysaccharide on vascular reactivity to noradrenaline in rat aorta under different conditions of passive tension, as well as on mortality in normotensive and hypertensive rats, were studied. 2 Concentration,response curves to noradrenaline were obtained in aorta rings, at two levels of passive tension: 3 and 0.5 g, from control and lipopolysaccharide-treated Wistar rats. Contractile responses were expressed as percentage of the maximal response to noradrenaline obtained in the beginning of the experiment at a resting tension of 2 g. The maxima were significantly larger (P < 0.05) at 3 g than at 0.5 g in both groups of rats: 117.8 vs. 62.3%, respectively, for control animals; 85.8 vs. 32.5%, respectively, for lipopolysaccharide-treated rats. 3 The 24-h mortality after the i.p. administration of lipopolysaccharide was lower in spontaneously hypertensive rats (1/12; 8%), when compared with control Wistar,Kyoto rats (5/11; 45%). However, mortality was higher in Wistar,Kyoto made hypertensive by 8-day administration of corticosterone (6/6; 100%). 4 We conclude that a differential sensitivity to noradrenaline of aortic smooth muscle at two different levels of passive tension is still present in lipopolysaccharide-treated animals. Chronic hypertension in SHR rats is associated with resistance to the lethal effects of lipopolysaccharide, whereas abrupt-onset hypertension induced by corticosterone leads to an increased mortality. 5 These results are compatible with the myofibrillary hypothesis, which explains vascular hyper-reactivity in chronic arterial hypertension, by postulating that a more favourable relative position (and/or proportion) for actin and myosin occurs, whereas in states of vascular hypo-reactivity, such as vasodilatory shock, the opposite phenomenon may exist. [source] A comparative study on the acute and long-term effects of MDMA and 3,4-dihydroxymethamphetamine (HHMA) on brain monoamine levels after i.p. or striatal administration in miceBRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2005Isabel Escobedo 1This study investigated whether the immediate and long-term effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in mouse brain are due to the parent compound and the possible contribution of a major reactive metabolite, 3,4-dihydroxymethamphetamine (HHMA), to these changes. The acute effect of each compound on rectal temperature was also determined. 2MDMA given i.p. (30 mg kg,1, three times at 3-h intervals), but not into the striatum (1, 10 and 100 ,g, three times at 3-h intervals), produced a reduction in striatal dopamine content and modest 5-HT reduction 1 h after the last dose. MDMA does not therefore appear to be responsible for the acute monoamine release that follows its peripheral injection. 3HHMA does not contribute to the acute MDMA-induced dopamine depletion as the acute central effects of MDMA and HHMA differed following i.p. injection. Both compounds induced hyperthermia, confirming that the acute dopamine depletion is not responsible for the temperature changes. 4Peripheral administration of MDMA produced dopamine depletion 7 days later. Intrastriatal MDMA administration only produced a long-term loss of dopamine at much higher concentrations than those reached after the i.p. dose and therefore bears little relevance to the neurotoxicity. This indicates that the long-term effect is not attributable to the parent compound. HHMA also appeared not to be responsible as i.p. administration failed to alter the striatal dopamine concentration 7 days later. 5HHMA was detected in plasma, but not in brain, following MDMA (i.p.), but it can cross the blood,brain barrier as it was detected in the brain following its peripheral injection. 6The fact that the acute changes induced by i.p. or intrastriatal HHMA administration differed indicates that HHMA is metabolised to other compounds which are responsible for changes observed after i.p. administration. British Journal of Pharmacology (2005) 144, 231,241. doi:10.1038/sj.bjp.0706071 [source] Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodentsBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Nina Isoherranen Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer,enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P<0.05) more potent (ED50 values 11 mg kg,1, 46 mg kg,1 and 57 mg kg,1 at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED50 values 20 mg kg,1, 73 mg kg,1 and 81 mg kg,1 at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED50 values 16 mg kg,1, 20 mg kg,1 and 19 mg kg,1 respectively). In the hippocampal kindled rat a dose of 40 mg kg,1 of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg,1. Racemic PID also significantly increased the seizure threshold in this model. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer,enantiomer interaction. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer,enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture. British Journal of Pharmacology (2003) 138, 602,613. doi:10.1038/sj.bjp.0705076 [source] Direct inhibition of EGF receptor activation in vascular endothelial cells by gefitinib (,Iressa', ZD1839)CANCER SCIENCE, Issue 7 2004Akira Hirata The development of gefitinib (,Iressa', ZD1839) by targeting the EGFR tyrosine kinase is a recent therapeutic highlight. We have reported that gefitinib is antiangiogenic in vitro, as well as in vivo. In this study, we asked if the anti-angiogenic action of gefitinib is due to a direct effect on activation of vascular endothelial cells by EGF. EGF, as well as VEGF, caused pronounced angiogene-sis in an avascular area of the mouse cornea, and i.p. administration of gefitinib almost completely blocked the response to EGF, but not to VEGF. Immunohistochemical analysis demonstrated phosphorylation of EGFR by EGF in the neovasculature, and gefitinib markedly reduced this effect. Gefitinib also inhibited downstream activation of ERK 1/2 via EGFR in cultured microvascular endothelial (HMVE) cells. These findings suggest that the anti-angiogenic effect of gefitinib in the vascular endothelial cells of neo-vasculature is partly attributable to direct inhibition of EGFR activation, and that endothelial cells in malignant tumors play a critical role in the cancer therapeutic efficacy of gefitinib. [source] Synthesis of Conformationally Constrained Glutamic Acid Homologues and Investigation of Their Pharmacological ProfilesCHEMMEDCHEM, Issue 11 2007Paola Conti Prof. Abstract Homologation of the glutamic acid chain together with conformational constraint is a commonly used strategy to achieve selectivity towards different types of glutamate receptors. We investigated the effects of a further increase in the distance between the amino acid moiety and the distal carboxylate group of model compounds (±)- 1 and (±)- 2 on their activity/selectivity profiles. We therefore synthesized new derivatives (±)- 3,(±)- 6, which are homologues of glutamic acid containing three additional carbon units. Moreover, because the potency of NMDA antagonists can be markedly increased by replacing the distal carboxylate with the bioisosteric phosphonate group, we also prepared the corresponding phosphonate derivatives (±)- 7,(±)- 10. All new compounds were submitted to binding assays with iGluRs, and derivatives (±)- 3,(±)- 6 were also tested in second messenger assays at representative mGluR subtypes. All the applied structural modifications were detrimental to the interaction with NMDA receptors. Conversely, structural variation of the nonselective mGluR ligand (±)- 2 led to derivative (±)- 5, which behaved as a selective group,I metabotropic receptor antagonist. Notably, upon i.c.v. administration in DBA/2 mice, amino acid (±)- 5 produced a significant protection against audiogenic seizures, whereas it was inactive after i.p. administration. [source] Inhibitory effect of magnolol on tumour metastasis in micePHYTOTHERAPY RESEARCH, Issue 8 2003Koji Ikeda Abstract It has previously been reported that magnolol, a phenolic compound isolated from Magnolia obovata, inhibited tumour cell invasion in vitro. The purpose of this study was to investigate the antimetastatic effect of magnolol on tumour metastasis in vivo with experimental and spontaneous metastasis models and to clarify the mechanism. The antimetastatic effects of magnolol were evaluated by an experimental liver and spleen metastasis model using L5178Y-ML25 lymphoma, or an experimental and spontaneous lung metastasis model using B16-BL6 melanoma. Intraperitoneal (i.p.) administration of 2 or 10 mg/kg of magnolol signi,cantly suppressed liver and spleen metastasis or lung metastasis. As for the spontaneous lung metastasis model using B16-BL6 melanoma, multiple i.p. administrations of 10 mg/kg of magnolol after and before tumour inoculation signi,cantly suppressed lung metastasis and primary tumour growth. In addition, magnolol signi,cantly inhibited B16-BL6 cell invasion of the reconstituted basement membrane (Matrigel, MG) without affecting cell growth. These data from the in vivo experiments suggest that magnolol possesses strong antimetastatic ability and that it may be a lead compound for drug development. The antimetastatic action of magnolol is considered to be due to its ability to inhibit tumour cell invasion. Copyright © 2003 John Wiley & Sons, Ltd. [source] | ||||||||||