Antinociceptive effects of nefopam activating descending serotonergic modulation via 5-HT2 receptors in the nucleus raphe magnus.

BACKGROUND: Nefopam is a centrally acting antinociceptive drug; however, the underlying mechanisms are not fully understood. This study investigated the supraspinal mechanisms of nefopam. METHODS: The effects of intraperitoneally administered nefopam were assessed in rats using the formalin test, and the mechanisms were investigated by intrathecal or intra-nucleus raphe magnus (NRM) pre-treatment with the serotonin (5-HT) receptor antagonist or 5-HT2 receptor antagonist. The change in extracellular 5-HT levels was measured by spinal cord microdialysis. RESULTS: Intraperitoneally administered nefopam showed antinociceptive effects in the rat formalin test, which were reversed by intrathecal pre-treatment with 5-HT receptor antagonist dihydroergocristine. Microdialysis study revealed that systemic nefopam significantly increased 5-HT level in the spinal dorsal horn. Pretreatment of cinanserin, a 5-HT2 receptor antagonist, into the NRM blocked the antinociceptive effects of intraperitoneally delivered nefopam. Direct injection of nefopam into the NRM mimicked the effects of systemic nefopam, and this effect was reversed by intra-NRM cinanserin pre-treatment. The increase in spinal level of 5-HT by systemic nefopam was attenuated by intra-NRM cinanserin pre-treatment. CONCLUSION: The antinociceptive effects of systemically administered nefopam are mediated by 5-HT2 receptors in the NRM, which recruit the descending serotonergic fibres to increase the release of 5-HT into the spinal dorsal horn. SIGNIFICANCE: This study revealed supraspinal mechanisms of nefopam-produced analgesia mediated by 5-HT2 receptors in the NRM recruiting the descending serotonergic fibres to increase the release of 5-HT into the spinal dorsal horn. These observations support a potential role for nefopam in multimodal analgesia based on its distinct mechanisms of action that are not shared by the other analgesics.

[Cinacalcet in the treatment of secondary hyperparathyreoidism in a child with chronic kidney disease--case report]. / Zastosowanie cinakalcetu w leczeniu wtónej nadczynnosci przytarczyc u dziecka z przewlekla niewydoinoscia nerek--opis przypadku.

UNLABELLED: The medical history and treatment of 2.5 years old girl with chronic kidney disease and heavy hyperparathyreoidism was presented in this case report. This girl was treated by peritoneal dialysis (APD) due to chronic kidney disease and congenital nephrotic syndrome. The secondary paraidothyreoidism was a reason of the epiphysial of the upper end of the femur, which appeared despite of the treatment by the Vitamin D3 (Calciphediol and Alphacalcidol) and phosphate binding drugs like Calcium Carbonate and Sevelamer. The primary laboratory tests were: Ca 9.32 mg/dl, Ca jon. 1.21 mmol/l, PO4 7.29 mg/dl, BE +4.9 mmol/l, ALP 1425 U/l, PTH 3774 pg/ml, Albumins 3.23 g/l, Hgb 8.2 g/l. The treatment of cinacalcet (Mimpara, 30 mg, Amgen) in dose of 15 mg was started because of lack of the standard therapy results. The laboratory tests were controlled after 2 weeks and then every week to 5th and every 2 weeks to the end. This therapy was finished after 30 weeks and only the standard therapy of hyperphosphatemia was continued. The laboratory tests 3 month after stopped the treatment were: Ca 10.5 mg/dl, Ca jon. 1.36 mmol/l, PO4 4.0 mg/dl, BE +4.9 mmol/l, ALP 312 U/l, PTH 134 pg/ml, Albumins 3.23 g/l, Hgb 9.9 g/l. There were any adverse events observed during the treatment. CONCLUSION: It seems, the cinacalcet may be an alternate treatment to paraidectomy in children with chronic kidney disease and heavy secondary hyperparathyreoidism.

Cinitaprida

cinitaprida, principio activo de la especialidad Cidine, es una ortopramida procinetica a nivel del tracto gastrointestinal que posee una marcada actividad procolinergica. Asimismo, mediante su bloqueo de los receptores presinapticos para la serotonina, aumenta la liberacion de la misma resultando en una mayor actividad serotoninergica. Su actividad antidopaminergica, aunque discreta, contribuye al efecto terapeutico. Todo ello le confiere a cinitaprida el papel de sincronizador de la motilidad del esofago, estomago e intestino. (AU)

Efficacy of drug regimen exceeds electrostimulation in treatment of avian muscular dystrophy.

Autosomal-recessive dystrophic chickens were treated in three experimental groups with an intraperitoneal multicomponent drug mixture (50 mg/kg Ep475, 20 mg/kg Cinanserin, 10 mg/kg stanazolol, 100 mg/kg leucine, 0.1 mg/kg insulin, 100 mg/kg glucose, and 50 mg/kg carnitine), percutaneous high-frequency electrostimulation of the pectoralis muscle, or a combination of both drug and electrostimulation treatments. Therapeutic efficacy was determined in each group by measurements of strength, righting ability, and histomorphometric analyses of the pectoralis musculature. Drug treatment alone was found to significantly improve muscular strength, function, and relative myofiber necrosis compared with sham-injected controls. The efficacy of drug treatment was found to be equal to or better than singular electrostimulation treatment; there was no apparent additive effect of electrostimulation. As a result, these findings support the use of drug treatment as a useful nongenetic approach to the management of human muscular dystrophy where there is the potential risk of injury from exercise usage.

Protective effect of serotonin (5-HT2) receptor antagonists in ischemic rat hearts.

Serotonin (5-HT) may play a role in exacerbating thrombosis and coronary spasm during myocardial ischemia, but its role in mediating myocardial damage directly is not clear. We determined the effect of the 5-HT2 receptor antagonists cinanserin (0.1-10 microM), ketanserin (0.3-10 microM), and LY 53857 (1-10 microM) on time to contracture, recovery of contractile function, and lactate dehydrogenase (LDH) release after 25-min global ischemia and 30-min reperfusion in isolated rat heart. All 5-HT2 antagonists significantly increased time to contracture in a concentration-dependent manner (EC25 = 1.6, 5.5, and 6.1 microM for cinanserin, ketanserin, and LY 53857, respectively). These compounds also significantly reduced LDH release and improved recovery of contractile function during reperfusion. 5-HT > or = 30 microM significantly reduced time to contracture, indicating a proischemic effect. The proischemic effect of 5-HT was abolished by ketanserin and cinanserin. Inhibition of 5-HT synthesis by parachlorophenylalanine resulted in significant cardioprotection, further indicating the involvement of 5-HT in the pathogenesis of ischemia in this model. Although cinanserin and ketanserin had alpha 1-adrenoceptor blocking effects, LY 53857 was devoid of this activity at concentrations exhibiting cardioprotection. Therefore, 5-HT may exacerbate ischemic injury in rat heart, and this exacerbation appears to be mediated specifically by 5-HT2 receptors.

Arabinogalactan- and dextran-induced ear inflammation in mice: differential inhibition by H1-antihistamines, 5-HT-serotonin antagonists and lipoxygenase blockers.

Intravenous injection of arabinogalactan or dextran together with pontamine sky-blue dye into mice increased vascular permeability and led to marked blueing of the ears. Arabinogalactan caused a rapidly progressing ear blueing (maximal coloration 20-30 min after injection). This response was suppressed by pretreating the animals with the histamine H1-antihistamines levocabastine and loratadine. In contrast, dextran induced a slowly evolving ear inflammation (maximal coloration 60-90 min after injection), which was blocked by the 5-HT-serotonin antagonists cinanserin, metergoline and ritanserin. Furthermore, the dextran reaction was inhibited by the lipoxygenase (LO)/cyclooxygenase (CO) inhibitors BW540C, BW755C and phenidone and by the specific 5-LO inhibitor AA-861. Both arabinogalactan and dextran responses were inhibited by aprotinin, a kallikrein inhibitor, and the mixed H1/5-HT antagonists astemizole and azatadine. The inflammogenic activity of the polysaccharides was not affected by administration of the CO inhibitors indomethacin and suprofen, the thromboxane synthetase inhibitor dazoxiben, the H2-antihistamines cimetidine and ranitidine, the anticholinergics isopropamide or the PAF-antagonist L-652, 731. These data indicate the existence of distinctive endogenous molecules that mediate the pinnal extravasation reaction to both polysaccharides: histamine for arabinogalactan, serotonin and lipoxygenase-derived arachidonic acid metabolites for dextran.

Antimyoclonic properties of S2 serotonin receptor antagonists in the rat.

The capacity of the putative S2 serotonin receptor antagonists, pirenperone, pipamperone, ketanserin and cinanserin, to block the myoclonic syndrome produced by 30 mg/kg of L-5-hydroxytryptophan (5-HTP) [after lesioning 5-hydroxytryptamine (serotonin, 5-HT)-containing neurons with 5,7-dihydroxytryptamine (DHT)] or 15 mg/kg of fenfluramine (FF) or p-chloroamphetamine (PCA) was tested in adult male Sprague-Dawley rats. S2 antagonists inhibited limb (arrhythmic and asynchronous) and axial (truncal) myoclonus in a dose-dependent manner in the rank order of potency: pirenperone greater than pipamperone greater than ketanserin = cinanserin. Abnormal movements (myoclonus, lateral head weaving) of the myoclonic syndromes were better antagonized than postural abnormalities (hindlimb abduction, hunching of back). Centrally acting drugs, selective for S2 receptors (pirenperone, pipamperone), exhibited greater antimyoclonic properties than the non-selective 5-HT antagonist methysergide, which was as effective as ketanserin and cinanserin. Significant non-specific reduction in myoclonus without the improvement of other behavioral responses followed treatment with sedative/neuroleptic drugs, such as haloperidol (but not the non-neuroleptic dopamine antagonist sulpiride), clonazepam and diazepam. The anticonvulsants valproic acid (100 and 300 mg/kg), adrenocorticotrophic hormone (ACTH; 100 and 300 U/kg), diphenylhydantoin (15 mg/kg), and phenobarbital (20 mg/kg) and drugs which do not act principally at S2 receptors were ineffective in these models. These data support the hypothesis that myoclonus in behavioral models induced by 5-HT is S2 receptor mediated. S2 antagonists could have a role in the treatment of human myoclonus.

Delayed functional disability in dystrophic chickens receiving chemotherapy.

Line 413 early-onset, genetically homozygous dystrophic chickens were given twice-daily intraperitoneal injections of the antiserotoninergic drug cinanserin, alone or in combination with methysergide. Other trials consisted of penicillamine treatment in combination with either methysergide or cyproheptadine. Chemotherapy significantly prolonged the righting ability of treated dystrophic chickens, as measured by a periodic standardized flip-test procedure. Plasma creatine kinase activities were not affected by any of the various drug treatments. However, the blood serotonin levels of the dystrophic chickens (grand mean 1.47 microgram serotonin/ml blood) were found to be significantly higher (p less than 0.001) than those in the corresponding normal chickens (0.99 microgram/ml). This finding may partially account for the antiserotoninergic drug enhancement in righting ability that was demonstrated in the drug-treated dystrophic chickens.