scholarly journals ANTICONVULSANT EFFECTS OF NIMODIPINE ALONE AND COMBINATION WITH PHENYTOIN ON MES INDUCED SEIZURES

2018 ◽  
Vol 10 (3) ◽  
pp. 44
Author(s):  
Jain Raina ◽  
Jain Ashish
Keyword(s):  
Synergistic Effect ◽  
Calcium Channel Blockers ◽  
Anticonvulsant Activity ◽  
Channel Blockers ◽  
Dependent Manner ◽  
The Novel ◽  
Antiepileptic Activity ◽  
Effective Doses ◽  
Dose Dependent ◽  
Anticonvulsant Effects

Objective: To evaluate the anticonvulsant activity of Nimodipine alone and in combination with Phenytoin, in MES induced seizures.Methods: The study was conducted in mice and MES seizure was induced by Techno electro-convulsometer. In the first part of the study, animals were treated with Nimodipine (20 mg/kg i. p. and 40 mg/kg i. p.) and Phenytoin (0.5 mg/100g i. p. and 1.0 mg/100g i. p.), MES was induced and durations of various phases were noted. Duration of Tonic hindlimb extension (THLE) was taken as an index for antiepileptic activity. In the second part, the animals were treated with a combination of sub effective doses of Nimodipine (20 mg/kg i. p.) and Phenytoin (0.5 mg/100g i. p.), MES was induced and durations of various phases were noted.Results: Nimodipine produced significant antiepileptic activity, in a dose-dependent manner. Phenytoin produced a significant antiepileptic effect in dose of 1.0 mg/100g, but failed to produce any such effect in a dose of 0.5 mg/100g, when administered alone. But when sub-effective doses. Of Nimodipine and Phenytoin were combined, a synergistic effect was seen.Conclusion: Nimodipine posses significant antiepileptic activity, alone, as well as it potentiates the antiepileptic effect of Phenytoin, suggesting the novel application of already proven safe and efficacious calcium channel blockers.

scholarly journals Anticonvulsant effects of nimodipine alone and combination with phenytoin on MES induced seizures

2018 ◽  
Vol 7 (6) ◽  
pp. 1160
Author(s):  
Raina Jain ◽  
Ashish Jain
Keyword(s):  
Synergistic Effect ◽  
Anticonvulsant Activity ◽  
Hind Limb ◽  
Channel Blockers ◽  
Dependent Manner ◽  
The Novel ◽  
Antiepileptic Activity ◽  
Effective Doses ◽  
Dose Dependent ◽  
Anticonvulsant Effects

Background: To evaluate the anticonvulsant activity of Nimodipine alone and in combination with Phenytoin, in MES induced seizures.Methods: The study was conducted in mice and MES seizure was induced by Techno electroconvulsometer. In first part of study, animals were treated with Nimodipine (20mg/kg i.p. and 40mg/kg i.p.) and Phenytoin (0.5 mg/100g i.p. and 1.0mg/100g i.p.), MES was induced and durations of various phases were noted. Duration of Tonic hind limb extension (THLE) was taken as index for antiepileptic activity. In second part, the animals were treated with combination of sub effective doses of Nimodipine (20mg/kg i.p.) and Phenytoin (0.5mg/100g i.p.), MES was induced and durations of various phases were noted.Results: Nimodipine produced significant antiepileptic activity, in dose dependent manner. Phenytoin produced significant antiepileptic effect in dose of 1.0mg/100g but failed to produce any such effect in dose of 0.5mg/100g, when administered alone. But when sub effective doses.Of Nimodipine and Phenytoin were combined, a synergistic effect was seen.Conclusions: Nimodipine possess significant antiepileptic activity, alone, as well as it potentiates the antiepileptic effect of Phenytoin, suggesting the novel application of already proven safe and efficacious calcium channel blockers.

p-Nitrophenylphosphatase Activity Catalyzed by Plasma Membrane (Ca2++Mg2+)ATPase: Correlation with Structural Changes Modulated by Glycerol and Ca2+

2001 ◽  
Vol 21 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Gutemberg G. Alves ◽  
Luis Maurício T. R. Lima ◽  
Maely P. Fávero-Retto ◽  
Adriana P. Lemos ◽  
Carlos E. Peres-Sampaio ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Synergistic Effect ◽  
Phosphatase Activity ◽  
Structural Changes ◽  
Center Of Mass ◽  
Binding Domain ◽  
Dependent Manner ◽  
Dose Dependent ◽  
Substrate Binding Domain

The plasma membrane (Ca2++Mg2+)ATPase hydrolyzes pseudo-substrates such as p-nitrophenylphosphate. Except when calmodulin is present, Ca2+ ions inhibit the p-nitrophenylphosphatase activity. In this report it is shown that, in the presence of glycerol, Ca2+ strongly stimulates phosphatase activity in a dose-dependent manner. The glycerol- and Ca2+-induced increase in activity is correlated with modifications in the spectral center of mass (average emission wavenumber) of the intrinsic fluorescence of the enzyme. It is concluded that the synergistic effect of glycerol and Ca2+ is related to opposite long-term hydration effects on the substrate binding domain and the Ca2+ binding domain.

scholarly journals Antinociceptive Interaction and Pharmacokinetics of the Combination Treatments of Methyleugenol Plus Diclofenac or Ketorolac

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5106
Author(s):  
Héctor Isaac Rocha-González ◽  
María Elena Sánchez-Mendoza ◽  
Leticia Cruz-Antonio ◽  
Francisco Javier Flores-Murrieta ◽  
Xochilt Itzel Cornelio-Huerta ◽  
...  
Keyword(s):  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Dependent Manner ◽  
Analgesic Drugs ◽  
Isobolographic Analysis ◽  
Combination Treatments ◽  
Significant Difference ◽  
Effective Doses ◽  
Inflammatory Drugs ◽  
Dose Dependent

Although nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the main types of drugs used to treat pain, they have several adverse effects, and such effects can be reduced by combining two analgesic drugs. The aim of this study was to evaluate the nociceptive activity of methyleugenol combined with either diclofenac or ketorolac, and determine certain parameters of pharmacokinetics. For the isobolographic analysis, the experimental effective dose 30 (ED30) was calculated for the drugs applied individually. With these effective doses, the peak plasma concentration (Cmax) was found and the other parameters of pharmacokinetics were established. Methyleugenol plus diclofenac and methyleugenol plus ketorolac decreased licking behavior in a dose-dependent manner in phase II, with an efficacy of 32.9 ± 9.3 and 39.8 ± 9.6%, respectively. According to the isobolographic analysis, the experimental and theoretical ED30 values were similar for methyleugenol plus diclofenac, suggesting an additive effect, but significantly different for methyleugenol plus ketorolac (3.6 ± 0.5 vs. 7.7 ± 0.6 mg/kg, respectively), indicating a probable synergistic interaction. Regarding pharmacokinetics, the only parameter showing a significant difference was Cmax for the methyleugenol plus diclofenac combination. Even with this difference, the combinations studied may be advantageous for treating inflammatory pain, especially for the combination methyleugenol plus ketorolac.

Rapamycin inhibits the growth of cholangiocarcinoma cells in vitro

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15153-15153 ◽  
Author(s):  
T. Sawada ◽  
T. Okada ◽  
K. Kubota
Keyword(s):  
Synergistic Effect ◽  
Cell Lines ◽  
Mtt Assay ◽  
Mrna Level ◽  
Dependent Manner ◽  
In Vitro Methods ◽  
Proliferative Effect ◽  
Cholangiocarcinoma Cell ◽  
Dose Dependent

15153 Background: In the present study, anti-neoplastic effect of rapamycin against cholangiocarcinoma was studied in vitro. Methods: Expression of mTOR in 4 cholangiocarcinoma cell lines, TFK1, HuCCT1, NOZW, and OZ was evaluated by real-time PCR. Then, the four cholangiocarcinoma cell lines were cultured with rapamycin (0, 25, 50, 100, 200 nM), gemcitabine (0, 0.5, 1, 2 μM), or both, and anti-proliferative effect was evaluated by MTT assay. Results: All the four cholangiocarcinoma cell lines expressed endogenous mTOR- mRNA. Level of expression was the highest in HuCCT1 (65.8), and the lowest in TFK1 (17.6). Then, rapamycin significantly inhibited the growth of all the four cholangiocarcinoma cell lines, in dose-dependent manner. Gemcitabine inhibited the growth of NOZW (48.4%) and HuCCT1 (48.9%), but less efficiently in TFK1 (5.9%) and OZ (27.4%). Furthermore, synergistic anti-proliferative effect of rapamycin and gemcitabine was observed in TFK1 (39.1%), NOZW (38.9%), and OZ (47.1%), not in HuCCT1 (18.9%). Conclusion: Rapamycin effectively inhibited the growth of the cholangiocarcinoma cell lines, and synergistic effect with gemcitabine was observed in three of the four cell lines. No significant financial relationships to disclose.

scholarly journals Nesfatin-1 Suppresses Cardiac L-type Ca2+ Channels Through Melanocortin Type 4 Receptor and the Novel Protein Kinase C Theta Isoform Pathway

2015 ◽  
Vol 36 (2) ◽  
pp. 555-568 ◽  
Author(s):  
Jiaoqian Ying ◽  
Yuan Zhang ◽  
Shan Gong ◽  
Zhigang Chang ◽  
Xiaofeng Zhou ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Ventricular Myocytes ◽  
Dependent Manner ◽  
The Novel ◽  
Inotropic Effects ◽  
Kinase C ◽  
Melanocortin 4 Receptor ◽  
Dose Dependent ◽  
Ca2 Channels

Background/Aims: Nesfatin-1 (NF-1), an anorexic nucleobindin-2 (NUCB2)-derived hypothalamic peptide, acts as a peripheral cardiac modulator and it can induce negative inotropic effects. However, the mechanisms underlying these effects in cardiomyocytes remain unclear. Methods: Using patch clamp, protein kinase assays, and western blot analysis, we studied the effect of NF-1 on L-type Ca2+ currents (ICa,L) and to explore the regulatory mechanisms of this effect in adult ventricular myocytes. Results: NF-1 reversibly decreased ICa,L in a dose-dependent manner. This effect was mediated by melanocortin 4 receptor (MC4-R) and was associated with a hyperpolarizing shift in the voltage-dependence of inactivation. Dialysis of cells with GDP-β-S or anti-Gβ antibody as well as pertussis toxin pretreatment abolished the inhibitory effects of NF-1 on ICa,L. Protein kinase C (PKC) antagonists abolished NF-1-induced responses, whereas inhibition of PKA activity or intracellular application of the fast Ca2+-chelator BAPTA elicited no such effects. Application of NF-1 increased membrane abundance of PKC theta isoform (PKCθ), and PKCθ inhibition abolished the decrease in ICa,L induced by NF-1. Conclusion: These data suggest that NF-1 suppresses L-type Ca2+ channels via the MC4-R that couples sequentially to the βγ subunits of Gi/o-protein and the novel PKCθ isoform in adult ventricular myocytes.

scholarly journals Diabetes induces and calcium channel blockers prevent cardiac expression of proapoptotic thioredoxin-interacting protein

2009 ◽  
Vol 296 (5) ◽  
pp. E1133-E1139 ◽  
Author(s):  
Junqin Chen ◽  
Hyunjoo Cha-Molstad ◽  
Anna Szabo ◽  
Anath Shalev
Keyword(s):  
Calcium Channel ◽  
Diabetic Cardiomyopathy ◽  
Calcium Channel Blockers ◽  
Caspase 3 ◽  
Critical Role ◽  
Cardiomyocyte Apoptosis ◽  
Channel Blockers ◽  
Dependent Manner ◽  
Interacting Protein ◽  
Thioredoxin Interacting Protein

Cardiomyocyte apoptosis is a critical process in the pathogenesis of ischemic and diabetic cardiomyopathy, but the mechanisms are not fully understood. Thioredoxin-interacting protein (TXNIP) has recently been shown to have deleterious effects in the cardiovascular system and we therefore investigated whether it may also play a role in diabetes-associated cardiomyocyte apoptosis. In fact, TXNIP expression was increased in H9C2 cardiomyocytes incubated at high glucose, and cardiac expression of TXNIP and cleaved caspase-3 were also elevated in vivo in streptozotocin- and obesity-induced diabetic mice. Together, these findings not only suggest that TXNIP is involved in diabetic cardiomyopathy but also that it may represent a novel therapeutic target. Surprisingly, testing putative TXNIP modulators revealed that calcium channel blockers reduce cardiomyocyte TXNIP transcription and protein levels in a dose-dependent manner. Oral administration of verapamil for 3 wk also reduced cardiac TXNIP expression in mice even in the face of severe diabetes, and these reduced TXNIP levels were associated with decreased apoptosis. To determine whether lack of TXNIP can mimic the verapamil-induced decrease in apoptosis, we used TXNIP-deficient HcB-19 mice, harboring a natural nonsense mutation in the TXNIP gene. Interestingly, we found significantly reduced cleaved caspase-3 levels in HcB-19 hearts, suggesting that TXNIP plays a critical role in cardiac apoptosis and that the verapamil effects were mediated by TXNIP reduction. Thus our results suggest that TXNIP reduction is a powerful target to enhance cardiomyocyte survival and that agents such as calcium channel blockers may be useful in trying to achieve this goal and prevent diabetic cardiomyopathy.

Swelling-activated efflux of taurine and other organic osmolytes in endothelial cells

1997 ◽  
Vol 273 (1) ◽  
pp. C214-C222 ◽  
Author(s):  
V. G. Manolopoulos ◽  
T. Voets ◽  
P. E. Declercq ◽  
G. Droogmans ◽  
B. Nilius
Keyword(s):  
Endothelial Cells ◽  
Anion Channel ◽  
Disulfonic Acid ◽  
Channel Blockers ◽  
Organic Osmolytes ◽  
Dependent Manner ◽  
Anion Channels ◽  
Whole Cell Patch Clamp ◽  
Osmolyte Efflux ◽  
Dose Dependent

We used a combined biochemical, pharmacological, and electrophysiological approach to study the effects of hyposmotic swelling on organic osmolyte efflux in endothelial cells (EC). In [3H]taurine-loaded monolayers of calf pulmonary artery EC (CPAEC), hyposmolality activated time- and dose-dependent effluxes of [3H]taurine. Swelling-activated [3H]taurine efflux (Jtau swell)in CPAEC was inhibited by the anion channel blockers tamoxifen, 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB), 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), fenamates, and also quinine (in a pH-dependent manner), ATP, and the phospholipase A2 inhibitor 4-bromophenacyl bromide. In contrast, Jtau swell was partly or totally insensitive to bumetanide, forskolin, phorbol 12-myristate 13-acetate, and staurosporine. Swelling also activated myo-[3H]inositol efflux that was blocked by tamoxifen, NPPB, DIDS, and niflumic acid. Moreover, the cellular content of taurine and other amino acids was significantly reduced in osmotically activated CPAEC. Finally, in whole cell patch-clamp experiments, taurine, glycine, aspartate, and glutamate exhibited significant permeability for swelling-activated anion channels. In conclusion, hyposmotic swelling activates efflux of taurine and other organic osmolytes in EC. In addition, our results suggest that anion channels may provide a pathway for swelling-activated efflux of organic osmolytes in EC.

Effect of aminophylline-Ca2+ blocker interaction on membrane potential of rat diaphragm fibers

1993 ◽  
Vol 74 (6) ◽  
pp. 2745-2749 ◽  
Author(s):  
O. Delbono ◽  
B. A. Kotsias
Keyword(s):  
Membrane Potential ◽  
Calcium Channel ◽  
Calcium Channel Blockers ◽  
Intrinsic Activity ◽  
Resting Membrane Potential ◽  
Maximum Effect ◽  
Channel Blockers ◽  
Dependent Manner ◽  
Rat Diaphragm

We studied the antagonism between aminophylline and two calcium channel blockers, nifedipine and verapamil, and its effect on the resting membrane potential of rat diaphragm fibers in vitro at 25 degrees C. Aminophylline hyperpolarizes the fibers in a dose-dependent manner, and the maximum effect is reached with 1 mM of the drug, approximately 9 mV compared with normal values. Both nifedipine and verapamil (1–5 microM) decreased the amount of hyperpolarization induced by aminophylline, and this is partially reversed when the xanthine concentration in the bath is increased. From the Hill equation we obtained a value of 2 for the slope, suggesting that two molecules of aminophylline bind to the receptor. Nifedipine modifies the affinity and the intrinsic activity of aminophylline, whereas verapamil reduces its intrinsic activity. The effect of nifedipine and verapamil is explained on the basis of the changed action of aminophylline on its site as a result of the interaction of the calcium channel blockers with their interdependent receptors.

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