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Sample records for nicardipine

  1. Nicardipine

    MedlinePlus

    ... heart disease, a heart attack, heart failure, stroke, kidney failure, loss of vision, and other problems. In addition ... if you have or have ever had heart failure, or heart, liver, or kidney disease.tell your doctor if you are pregnant, ...

  2. Effects of nicardipine on ventriculo-arterial coupling in humans.

    PubMed

    Tanaka, K; Oshita, S; Kitahata, H; Kimura, H; Kawahito, S; Park, Y C; Sakabe, T

    1998-08-01

    The ratio of effective arterial elastance (Ea) to left ventricular elastance (Ees) is an indicator of the coupling between ventricular properties and arterial load properties. Another criterion for the coupling between an energy source and its load is the principle of economical fuel consumption, or mechanical efficiency, which is defined as the ratio of stroke work (SW) to myocardial oxygen consumption per beat (MVO2). It has been revealed that SW of ventricular contraction is maximized when Ea/Ees = 1, while mechanical efficiency is maximized when Ea/Ees = 0.5. The purpose of the present study was to investigate the ventriculo-arterial coupling during hypertension, and the effects of nicardipine on this relationship in surgical patients using Ea/Ees and SW/MVO2 as indicators. Anaesthesia was maintained with isoflurane, nitrous oxide, and fentanyl. Radial artery pressure was displayed on a polygraph, and left ventricular end-systolic and end-diastolic volumes were determined by use of transoesophageal echocardiography. Ees was calculated as MAP/(ESVI-4), where MAP is mean arterial pressure and ESVI is end-systolic volume index. Ea was calculated as the ratio of MAP to stroke volume index (SVI). Stroke work index (SWI) was calculated as the product of MAP and SVI. MVO2 was assessed by estimating the ventricular pressure-volume area index (PVAI), which is expressed as the sum of SWI and the end-systolic potential energy index. Before (baseline), and 3, 10, 20, and 30 min after i.v. nicardipine (30 micrograms kg-1), Ea/Ees and SWI/PVAI were determined in 14 surgical patients with intraoperative hypertension. Before nicardipine (during hypertension), Ea was almost equal to Ees, whereas Ea/Ees was significantly reduced to about 0.5-0.6 at 3, 10, and 20 min after nicardipine. SWI/PVAI was maximized and significantly greater than the baseline value at 3 min after nicardipine. These results suggest that, during hypertension, ventricular and arterial properties were so

  3. The Optimal Dose of Nicardipine for Enhancement of Indirect Portography

    SciTech Connect

    Inoue, Yutaka; Nakamura, Hironobu; Akaji, Hideyo

    1998-01-15

    Purpose: To determine the optimal dose of nicardipine (NCR) for enhancement of indirect portography. Methods: Forty-eight patients underwent conventional film indirect portography via the superior mesenteric artery (SMA) first without and then with preinjection of 1/64-2 mg of NCR into the SMA. Results: NCR (1/8-2 mg) shortened the arterial phase to 50% and the portal appearance time to 60% of control without reflux of contrast medium into the aorta. Portal enhancement was excellent at doses of 1/32 mg or more. Blood pressures and pulse rate showed no significant change at 1/4 mg or less. Conclusion: NCR (1/8-1/4 mg) into the SMA is the optimal dose for achieving sufficient contrast enhancement on indirect portography while reducing the transit time of contrast medium and minimizing effects on the systemic circulation.

  4. Treatment with nicardipine protects brain in an animal model of hypertension-induced damage.

    PubMed

    Amenta, Francesco; Tomassoni, Daniele

    2004-05-01

    Control of blood pressure protects from the development of cerebrovascular lesions and vascular dementia (VaD). This study has assessed the influence of treatment with the dihydropyridine-type Ca2+ antagonist nicardipine on brain microanatomical changes in spontaneously hypertensive rats (SHR). SHR were treated from 16th to 26th week of age with hypotensive (3 mg/Kg/day) or non-hypotensive (0.1 mg/Kg/day) doses of nicardipine, with the non-dihydropyridine-type vasodilator hydralazine (10 mg/kg/day) or with vehicle (control group). Untreated age-matched Wistar Kyoto (WKY) rats were used as a normotensive reference group. Brain volume, number of neurons, glial fibrillary-acidic protein (GFAP)-immunoreactive astrocytes and neurofilament 200 KDa (NFP)-immunoreactivity (IR) were assessed in frontal and occipital cortex, hippocampus and striatum. A decrease of volume and number of nerve cells and a loss of NFP-IR was found in the frontal and occipital cortex and in the CA1 subfield of hippocampus and in the striatum of SHR. Treatment with nicardipine countered microanatomical changes occurring in SHR, whereas hydralazine displayed a less pronounced effect. Comparatively, the non-hypotensive dose of nicardipine was less active than the hypotensive one. The observation that equihypotensive doses of nicardipine or hydralazine did not protect brain in the same way from hypertensive brain damage suggests that lowering blood pressure is per se not enough for affording neuroprotection. The demonstration of neuroprotective effect of nicardipine suggests an use of the compound in situations in which hypertension is accompanied by the risk of brain damage.

  5. Nicardipine in the treatment of Raynaud's phenomenon. Dissociation of platelet activation from vasospasm.

    PubMed

    Wigley, F M; Wise, R A; Malamet, R; Scott, T E

    1987-03-01

    A new calcium channel blocker, nicardipine, was studied for treatment of Raynaud's phenomenon in a double-blind, placebo-controlled, crossover trial during the winter months. Clinical response was assessed by a patient-kept diary of symptoms and finger systolic pressure that was measured at room temperature and during cold challenge. In vivo platelet activation was determined by measuring plasma levels of the platelet-specific proteins, beta-thromboglobulin and platelet factor 4. When treatment with placebo was compared with treatment with nicardipine, no significant differences were found in the number of Raynaud's attacks per day, the severity of attacks, change in character in Raynaud's phenomenon, use of hands in winter months, patient assessment of medication or objective measurements of finger systolic pressure, and critical closing temperature. There was a reduction of plasma levels of beta-thromboglobulin and platelet factor 4 in the overall study group while taking nicardipine compared with that during the placebo period (mean change 5.0 +/- 2.4 ng/ml, P = 0.054, and 1.4 +/- 0.6 ng/ml, P less than 0.01, respectively). These results demonstrate that while nicardipine was not effective in reducing the episodes of Raynaud's phenomenon, it did inhibit in vivo platelet activation. These findings suggest that platelet activation is not the primary event in the pathogenesis of acute vasospasm in Raynaud's phenomenon, since reduction of platelet activation by the drug did not change the severity of vasospasm.

  6. The effect of nicardipine on glucose and drug-stimulated insulin secretion in normal volunteers

    PubMed Central

    Dow, R. J.; Baty, J.; Isles, T. E.

    1985-01-01

    1 The effect of nicardipine on insulin secretion was examined in two double-blind, randomised, cross-over, placebo-controlled studies in normal volunteers. 2 In the first study, the effect of acute dosing (via an intravenous infusion of 5 mg h-1 for 3 h) on the glucose, insulin, hormonal, and intermediary metabolite responses to an intravenous glucose tolerance test was determined in six healthy male volunteers. 3 In the second study, the glucose, insulin, and C-peptide responses to intravenous tolbutamide (200 mg) was determined in another six male volunteers after oral dosing with nicardipine 30 mg three times daily for 1 week. 4 A relative increase in insulin secretion was the principal finding of the first study. No other response was affected significantly. 5 No significant differences between the nicardipine- and placebo-treated groups were noted in the insulin, glucose, and C-peptide measurements of the second study. 6 In conclusion, treatment with nicardipine does not appear to impair insulin secretion in response either to an intravenous glucose load or intravenously administered tolbutamide. PMID:3896283

  7. Nicardipine-induced acute pulmonary edema: a rare but severe complication of tocolysis.

    PubMed

    Serena, Claire; Begot, Emmanuelle; Cros, Jérôme; Hodler, Charles; Fedou, Anne Laure; Nathan-Denizot, Nathalie; Clavel, Marc

    2014-01-01

    We report four cases of acute pulmonary edema that occurred during treatment by intravenous tocolysis using nicardipine in pregnancy patients with no previous heart problems. Clinical severity justified hospitalization in intensive care unit (ICU) each time. Acute dyspnea has begun at an average of 63 hours after initiation of treatment. For all patients, the first diagnosis suspected was pulmonary embolism. The patients' condition improved rapidly with appropriate diuretic treatment and by modifying the tocolysis. The use of intravenous nicardipine is widely used for tocolysis in France even if its prescription does not have a marketing authorization. The pathophysiological mechanisms of this complication remain unclear. The main reported risk factors are spontaneous preterm labor, multiple pregnancy, concomitant obstetrical disease, association with beta-agonists, and fetal lung maturation corticotherapy. A better knowledge of this rare but serious adverse event should improve the management of patients. Nifedipine or atosiban, the efficiency of which tocolysis was also studied, could be an alternative. PMID:25215245

  8. Identification of Possible Binding Sites for Morphine and Nicardipine on the Multidrug Transporter P-Glycoprotein Using Umbrella Sampling Techniques.

    PubMed

    Subramanian, Nandhitha; Condic-Jurkic, Karmen; Mark, Alan E; O'Mara, Megan L

    2015-06-22

    The multidrug transporter P-glycoprotein (P-gp) is central to the development of multidrug resistance in cancer. While residues essential for transport and binding have been identified, the location, composition, and specificity of potential drug binding sites are uncertain. Here molecular dynamics simulations are used to calculate the free energy profile for the binding of morphine and nicardipine to P-gp. We show that morphine and nicardipine primarily interact with key residues implicated in binding and transport from mutational studies, binding at different but overlapping sites within the transmembrane pore. Their permeation pathways were distinct but involved overlapping sets of residues. The results indicate that the binding location and permeation pathways of morphine and nicardipine are not well separated and cannot be considered as unique. This has important implications for our understanding of substrate uptake and transport by P-gp. Our results are independent of the choice of starting structure and consistent with a range of experimental studies.

  9. Characterization of nicardipine hydrochloride-induced cell injury in human vascular endothelial cells.

    PubMed

    Ochi, Masanori; Kawai, Yoshiko; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2015-02-01

    Nicardipine hydrochloride (NIC), a dihydropyridine calcium-channel blocking agent, has been widely used for the treatment of hypertension. Especially, nicardipine hydrochloride injection is used as first-line therapy for emergency treatment of abnormally high blood pressure. Although NIC has an attractive pharmacological profile, one of the dose-limiting factors of NIC is severe peripheral vascular injury after intravenous injection. The goal of this study was to better understand and thereby reduce NIC-mediated vascular injury. Here, we investigated the mechanism of NIC-induced vascular injury using human dermal microvascular endothelial cells (HMVECs). NIC decreased cell viability and increased percent of dead cells in a dose-dependent manner (10-30 μg/mL). Although cell membrane injury was not significant over 9 hr exposure, significant changes of cell morphology and increases in vacuoles in HMVECs were observed within 30 min of NIC exposure (30 μg/mL). Autophagosome labeling with monodansylcadaverine revealed increased autophagosomes in the NIC-treated cells, whereas caspase 3/7 activity was not increased in the NIC-treated cells (30 μg/mL). Additionally, NIC-induced reduction of cell viability was inhibited by 3-methyladenine, an inhibitor of autophagosome formation. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy could contribute to the reduction of NIC-induced vascular injury.

  10. Cardio-ankle vascular index (CAVI) differentiates pharmacological properties of vasodilators nicardipine and nitroglycerin in anesthetized rabbits.

    PubMed

    Chiba, Tatsuo; Yamanaka, Mari; Takagi, Sachie; Shimizu, Kazuhiro; Takahashi, Mao; Shirai, Kohji; Takahara, Akira

    2015-08-01

    Cardio-ankle vascular index (CAVI) has been developed for measurement of vascular stiffness from the aorta to tibial artery, which is clinically utilized for assessing the progress of arteriosclerosis. In this study, we established measuring system of the CAVI in rabbits, and assessed whether the index could reflect different pharmacological actions of nitroglycerin and nicardipine on the systemic vasculature. Rabbits were anesthetized with halothane, and the CAVI was calculated from the well-established basic equations with variables obtained from brachial and tibial blood pressure and phonocardiogram. Nicardipine (1, 3 and 10 μg/kg, i.v.) decreased the blood pressure, femoral vascular resistance, and heart-ankle pulse wave velocity (haPWV). Meanwhile, no significant change was detected in the CAVI at the low or middle dose, which reflects the defining feature of the CAVI that is independent of blood pressure. The index increased at the high dose. Nitroglycerin (2, 4 and 8 μg/kg, i.v.) decreased the blood pressure, femoral vascular resistance, and haPWV. Meanwhile, the CAVI was decreased during the nitroglycerin infusion, which may reflect its well-known pharmacological action dilating conduit arteries. These results suggest that the CAVI differentiates the properties of these vasodilators in vivo. PMID:26238254

  11. Epileptogenic activity induced by combined treatment with antiinflammatory drugs and enoxacin and its inhibition by a calcium antagonist, nicardipine.

    PubMed

    Kamei, C; Sugimoto, Y; Ohishi, H; Okumura, Y; Kitazumi, K

    1996-11-01

    Epileptogenic activity induced by combined treatment with antiinflammatory drugs and enoxacin was investigated in chronic electrode-implanted rats. Ferubinac ethyl and aspirin DL-lysine showed a spike and wave complex in EEG without showing remarkable behavioral changes when they were injected intraventricularly, although a relatively high dose was needed. Enoxacin, on the other hand, elicited potent epileptogenic activity characterized by uninterrupted high voltage spike and wave complex at doses of 50 and 100 micrograms. At the same time, rats showed hyperactivity, jumping and violent convulsion. Combined treatment with enoxacin (p.o.) and ferubinac ethyl (i.v.) caused potent epileptogenic activity characterized by uninterrupted burst of high voltage spike and wave complex. Behaviorally, animals showed forelimb clonus, head nodding and generalized convulsion. High voltage spike and wave complex was also observed after combined treatment with enoxacin (i. vent.) and ferubinac ethyl (i.v. or i. vent.) in association with hyperactivity and jumping and violent convulsion. Nicardipine remarkably inhibited epileptic seizures induced by combined treatment with enoxacin (p.o.) and ferubinac ethyl (i.v.). It is concluded that simultaneous treatment with enoxacin and ferubinac ethyl produced epileptogenic activity when injected intraventricularly, and nicardipine inhibited convulsions induced by combined use of enoxacin (p.o.) and ferubinac ethyl (i.v.).

  12. Quantitative determination of amorphous nicardipine hydrochloride in long acting formula (NIC-LA) using light anhydrous silicic acid.

    PubMed

    Kohinata, Takeru; Fujii, Mitsuo; Nakamura, Souichiro; Hamada, Noritaka; Yonemochi, Etsuo; Terada, Katsuhide

    2004-12-01

    We investigated a method to quantitatively determine amorphous nicardipine hydrochloride (NIC) in the NIC-long acting formula (LA) model formulas prepared using NIC, light anhydrous silicic acid (LASA) and carboxymethylethylcellulose (CMEC). Consequently, since the quantity of total NIC in the formula can be determined by means of HPLC and crystal NIC can be determined by the differential scanning calorimetry (DSC) method because the heat of fusion (85.08 J/g) of NIC is constant and unaffected by excipients, we developed the HPLC-DSC method by which the quantity of amorphous NIC is calculated as the difference between the quantity of total NIC determined by HPLC and the quantity of crystal NIC determined by DSC. This practical HPLC-DSC method was confirmed to have good accuracy and reproducibility.

  13. Protective effect of N-acetylcysteine against nicardipine hydrochloride-induced autophagic cell death of human vascular endothelial cells.

    PubMed

    Ochi, Masanori; Tanaka, Yoshiyuki; Toyoda, Hiromu

    2015-01-01

    Nicardipine hydrochloride (NIC) injection has been widely used for emergency treatment of abnormally high blood pressure. However, NIC injection often causes severe peripheral vascular injury. The purpose of the present study was to reduce the NIC-induced cell injury in human vascular endothelial cells by use of clinical agents. The mechanism of NIC-induced cell injury was evaluated by time-lapse microscopic imaging, autophagosome staining with monodansylcadaverine, immunostaining of light chain 3 isoform B (LC-3B) and assessment of cell viability after exposure to NIC with or without an inhibitor of autophagosome formation (3-methyladenine, 3-MA). Results from autophagosome labeling and immunostaining of LC-3B revealed an increase of autophagosomes and LC-3B in NIC-treated cells. NIC-mediated reduction of cell viability was inhibited by 3-methyladenine. Moreover, we found that N-acetylcysteine (NAC) reduced NIC-induced cell injury in human vascular endothelial cells. These findings suggest that NIC causes severe peripheral venous irritation via induction of autophagic cell death and that inhibition of autophagy with NAC could contribute to the reduction of NIC-induced vascular injury.

  14. Ranolazine enhances nicardipine-induced relaxation of alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta.

    PubMed

    Malavaki, Christina; Hatziefthimiou, Apostolia; Daskalopoulou, Stella S; Stefanidis, Ioannis; Karatzaferi, Christina; Aidonidis, Isaac

    2015-04-01

    Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the combination of these agents against adrenergic vasoconstriction has not been tested. The present study aimed at investigating the vasorelaxing effect by the combination of the two agents on alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta. Aortic rings were mounted for isometric tension recording in organ baths containing Krebs-Henseleit solution. Concentration-response curves of RAN (10(-9) to 10(-4) M), NIC (10(-1) to 10(-5) M), and RAN + NIC (3 x 10(-6) M) were obtained in a cumulative manner using phenylephrine (PE, 2 x 10(-6) M) as constrictor agent. The effective concentration (EC)50 values for RAN and NIC were 6.5 x 10(-6) M and 1.4 x 10(-5) M, respectively. The treatment of PE-precontracted aortic rings with either RAN or NIC up to 65 min revealed that both agents displayed a biphasic pattern of initial rising and late sustained phases of relaxation. At 35 min of incubation, RAN and NIC induced relaxation by 23 +/- 3% and 14 +/- 4%, respectively (N = 7, P=NS, RAN vs. NIC); their combination resulted in a 34 +/- 4% relaxation (N=7; P < 0.01, RAN + NIC vs. NIC). At 65 min the effect of NIC prevailed and tended to be closer to the values of the combination treatment (P < 0.01, RAN + NIC vs. RAN). The results indicate that RAN at therapeutic concentrations exerts a significant additive vasorelaxing effect when combined with NIC in rabbit aorta.

  15. Ranolazine enhances nicardipine-induced relaxation of alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta.

    PubMed

    Malavaki, Christina; Hatziefthimiou, Apostolia; Daskalopoulou, Stella S; Stefanidis, Ioannis; Karatzaferi, Christina; Aidonidis, Isaac

    2015-04-01

    Ranolazine (RAN) and nicardipine (NIC) have been studied for their vasorelaxing effects but the combination of these agents against adrenergic vasoconstriction has not been tested. The present study aimed at investigating the vasorelaxing effect by the combination of the two agents on alpha1-adrenoceptor-mediated contraction on isolated rabbit aorta. Aortic rings were mounted for isometric tension recording in organ baths containing Krebs-Henseleit solution. Concentration-response curves of RAN (10(-9) to 10(-4) M), NIC (10(-1) to 10(-5) M), and RAN + NIC (3 x 10(-6) M) were obtained in a cumulative manner using phenylephrine (PE, 2 x 10(-6) M) as constrictor agent. The effective concentration (EC)50 values for RAN and NIC were 6.5 x 10(-6) M and 1.4 x 10(-5) M, respectively. The treatment of PE-precontracted aortic rings with either RAN or NIC up to 65 min revealed that both agents displayed a biphasic pattern of initial rising and late sustained phases of relaxation. At 35 min of incubation, RAN and NIC induced relaxation by 23 +/- 3% and 14 +/- 4%, respectively (N = 7, P=NS, RAN vs. NIC); their combination resulted in a 34 +/- 4% relaxation (N=7; P < 0.01, RAN + NIC vs. NIC). At 65 min the effect of NIC prevailed and tended to be closer to the values of the combination treatment (P < 0.01, RAN + NIC vs. RAN). The results indicate that RAN at therapeutic concentrations exerts a significant additive vasorelaxing effect when combined with NIC in rabbit aorta. PMID:26148375

  16. [Effects of intravenous nicardipine on blood pressure, hemorheology platelet function in arterial hypertension. Dose-effect relations].

    PubMed

    Zannad, F; Voisin, P; Sadoul, N; Marchal, C; Donetti, C; Stoltz, J F; Gilgenkrantz, J M

    1987-06-01

    In arterial hypertension, hyperviscosity with hemorheological disturbances and platelet dysfunction may play a role in the prognosis and complications of the disease. We studied the effects of Nicardipine (NIC) on these blood disturbances in a group of 21 untreated patients with essential hypertension, aged 25 to 70 years (SBP/DBP = 185 +/- 28/105 +/- 17 mmHg). During one hour before and 4 hours after the IV injection of single doses of 5, 7.5 or 10 mg NIC over 5 min, blood pressure was recorded automatically (Dinamap). Hemorheological variables and platelet function were studied before and 30 min, 3 h and 24 hours after the injection. NIC lowered blood pressure and increased heart rate significantly (At 5 min, SBP = -24 mmHg; DBP = -18 mmHg; HR = +22 b/min). These effects were dose-dependent with rapid onset and short duration (less than 2 hrs). NIC decreased plasma viscosity from 1.36 +/- 0.08 to 1.30 +/- 0.07 Cst; p less than 0.01, whole blood viscosity from 22.4 +/- 2.8 to 20.7 +/- 1.5 mPas; p less than 0.05 for gamma = 0.512 s-1, and erythrocyte filterability with the Ca++ ionophore A 23187 from 16.3 +/- 3.8 to 13.5 +/- 3.1; p less than 0.01. Platelet aggregation with ADP was unchanged, but aggregation with A 23187 decreased from 46.9 +/- 21.2 to 31.3 +/- 25.6; p less than 0.05, as well as plasma levels of beta-thromboglobulin (71.2 +/- 29.8 to 55.4 +/- 24.3 ng/ml; p less than 0.02) and platelet generated malonaldehyde (7.2 +/- 1.8 to 6.7 +/- 1.4 nM/10(9) platelets; NS).(ABSTRACT TRUNCATED AT 250 WORDS)

  17. Hemodynamic, renal, and humoral effects of the calcium entry blocker nicardipine and converting enzyme inhibitor captopril in hypertensive type II diabetic patients with nephropathy.

    PubMed

    Stornello, M; Valvo, E V; Scapellato, L

    1989-12-01

    We compared the effect of nicardipine, a dihydropiridine derivative calcium entry blocker (CEB), with that of captopril (CAP), a converting-enzyme inhibitor (CEI), and that of the two drugs combined, on blood pressure (BP), heart rate (HR), and renal function in 12 hypertensive type II diabetic outpatients with nephropathy (persistent proteinuria greater than 500 mg/24 h) according to a 2 x 2 factorial design. For 4-week treatments, the patients received nicardipine (NIC) 20 mg t.i.d., CAP 50 mg b.i.d., NIC plus CAP, and matched placebo. Each active treatment significantly reduced BP, with an additive effect of NIC and CAP combined versus either drug alone. HR did not change. Effective renal plasma flow (RPF) and glomerular filtration rate (GRF) were unmodified, but renal vascular resistances (RVRs) were significantly reduced by the three active treatments. Filtration fraction (FF) did not change with NIC or with NIC plus CAP and was significantly reduced with CAP. Urinary albumin excretion (UAE) was significantly reduced by each active treatment to a similar extent. Plasma renin activity (PRA) increased significantly with NIC plus CAP only and did not change when the drugs were administered singly. Plasma aldosterone, glucose, potassium, fructosamine, and urinary sodium and volume did not change during the trial. We conclude that the two drugs singly and combined are useful for treatment of hypertensive non-insulin-dependent diabetes (NIDD) patients with persistent proteinuria.

  18. Augmentation of 3-methylcholanthrene-induced bioactivation in the human hepatoma cell line HepG2 by the calcium channel blocker nicardipine.

    PubMed

    Hosaka, Takuomi; Sekimoto, Masashi; Nemoto, Kiyomitsu; Degawa, Masakuni

    2010-03-01

    The abilities of the dihydropyridine calcium channel blocker nicardipine (Nic) to induce cytochrome P450 1 family enzymes (CYP1s) and to enhance the 3-methylcholanthrene (MC)-mediated induction of CYP1s and formation of MC-DNA adduct were examined in the human hepatoma cell line HepG2. The results from real time RT-PCR analysis demonstrated that Nic could induce CYP1 mRNAs and enhance the MC-mediated induction of the CYP1 mRNAs. The luciferase-reporter gene assay using the HepG2-A10 cell line, which has been previously established for the screening of aryl hydrocarbon receptor (AhR) activators, also indicated the augmentation of MC-mediated activation of AhR (induction of luciferase) by Nic, although Nic showed limited capacity for the activation of AhR. Furthermore, the results from the Western blot analysis of CYP1s, the enzyme activity assay, and the assay for MC-DNA adduct formation indicated that Nic could enhance the MC-mediated induction of CYP1s, especially CYP1A1. Furthermore, the intracellular accumulation level of [(3)H]MC after treatment of HepG2 cells with [(3)H]MC significantly increased in the presence of Nic. The present findings demonstrate that Nic can enhance the MC-mediated induction of CYP1s, especially CYP1A1, and the formation of MC-DNA adduct in HepG2 cells. Furthermore, the augmentation of the MC-mediated bioactivation by Nic is demonstrated to occur mainly through an increase in intracellular accumulation of MC. PMID:20067464

  19. Clevidipine for Perioperative Blood Pressure Control in Infants and Children

    PubMed Central

    Tobias, Joseph D.; Tulman, David B.; Bergese, Sergio D.

    2013-01-01

    Various pharmacologic agents have been used for perioperative BP control in pediatric patients, including sodium nitroprusside, nitroglycerin, β-adrenergic antagonists, fenoldopam, and calcium channel antagonists. Of the calcium antagonists, the majority of the clinical experience remains with the dihydropyridine nicardipine. Clevidipine is a short-acting, intravenous calcium channel antagonist of the dihydropyridine class. It undergoes rapid metabolism by non-specific blood and tissue esterases with a half-life of less than 1 minute. As a dihydropyridine, its cellular and end-organ effects parallel those of nicardipine. The clevidipine trials in the adult population have demonstrated efficacy in rapidly controlling BP in various clinical scenarios with a favorable adverse effect profile similar to nicardipine. Data from large clinical trials regarding the safety and efficacy of clevidipine in children is lacking. This manuscript aims to review the commonly used pharmacologic agents for perioperative BP control in children, discuss the role of calcium channel antagonists such as nicardipine, and outline the preliminary data regarding clevidipine in the pediatric population. PMID:24275788

  20. Critical care guidelines on the endovascular management of cerebral vasospasm.

    PubMed

    Kimball, Matthew M; Velat, Gregory J; Hoh, Brian L

    2011-09-01

    Cerebral vasospasm and delayed cerebral ischemia account for significant morbidity and mortality after aneurysmal subarachnoid hemorrhage. While most patients are managed with triple-H therapy, endovascular treatments have been used when triple-H treatment cannot be used or is ineffective. An electronic literature search was conducted to identify English language articles published through October 2010 that addressed endovascular management of vasospasm. A total of 49 articles were identified, addressing endovascular treatment timing, intra-arterial treatments, and balloon angioplasty. Most of the available studies investigated intra-arterial papaverine or balloon angioplasty. Both have generally been shown to successfully treat vasospasm and improve neurological condition, with no clear benefit from one treatment compared with another. There are reports of complications with both therapies including vessel rupture during angioplasty, intracranial hypertension, and possible neurotoxicity associated with papaverine. Limited data are available evaluating nicardipine or verapamil, with positive benefits reported with nicardipine and inconsistent benefits with verapamil. PMID:21761272

  1. Calcium channel antagonists and cyclosporine metabolism: in vitro studies with human liver microsomes.

    PubMed Central

    Tjia, J F; Back, D J; Breckenridge, A M

    1989-01-01

    The effects of four Ca2+ channel antagonists on the metabolism of cyclosporine (CsA) by human liver microsomes (n = 4) in vitro have been examined. Nicardipine produced marked inhibition of both M17 and M21 (IC50 = 7.0 microM) formation. In contrast nifedipine produced less than 20% inhibition of M17 and M21 even at the highest concentration examined (50 microM). Diltiazem data were comparable to those for nifedipine. Verapamil (50 microM) produced 30 and 28% inhibition of M17 and M21 formation, respectively. These findings give a basis to the increase in CsA blood concentrations seen in transplant patients who are also given nicardipine. PMID:2789931

  2. Effect of pinaverium and other calcium channel blockers on contraction of isolated gastric antral smooth muscle cells caused by gastrointestinal hormones.

    PubMed

    Bobo, M H; Magous, R; Christen, M O; Bali, J P

    1994-01-01

    Gastrointestinal hormones, gastrin, cholecystokinin (CCK), and motilin, are known to induce contraction of digestive smooth muscle cells from various species. In this paper, we studied the effect of calcium channel blockers, diltiazem, nicardipine, and pinaverium on the hormone-dependent contraction of smooth muscle cells isolated from rabbit antrum. Gastrin, CCK-8, and motilin caused dose-dependent contraction with EC-50 values in the physiological range (10-100 pM). This contractile effect was dependent upon extracellular calcium for gastrin and CCK-8 but not for motilin. When used alone, calcium channel blockers diltiazem, nicardipine, but not pinaverium, caused a weak but significant contraction of the cells. Pinaverium inhibited both gastrin- and CCK-8-induced contractions with IC-50 values of 1 nM and it was much less potent in the inhibition of motilin-induced contractions (IC-50 = 25 nM). The effect of pinaverium was equivalent to that of diltiazem in the inhibition of CCK-8- or gastrin-induced contractions. Both drugs were slightly more potent than nicardipine (IC-50 = 10 nM versus 1 nM for pineaverium and 5 nM for diltiazem). In contrast, diltiazem and pinaverium were less potent against motilin stimulation, diltiazem being 5 times more potent than pinaverium. In conclusion, it appears that since Ca2+ antagonists pinaverium, diltiazem and nicardipine inhibited contraction of smooth muscle cells stimulated by gastrointestinal hormones, "L-type" calcium channels of the plasma membrane might also be regulated through occupation of gastrin or CCK receptors. PMID:8201843

  3. Effects of calcium entry blockers on calcium-dependent contractions of rat portal vein.

    PubMed Central

    Dacquet, C.; Mironneau, C.; Mironneau, J.

    1987-01-01

    1 The effects of six calcium entry blockers belonging to the dihydropyridine (isradipine or PN 200-110, nifedipine, nicardipine), verapamil (D888 or desmethoxyverapamil, D600 or gallopamil) and diltiazem classes were investigated on isometric spontaneous contractions and contractions induced by high-K+ solutions, noradrenaline, acetylcholine and caffeine. 2 The rank order of potency was PN 200-110 greater than nicardipine = nifedipine = D888 greater than D600 greater than diltiazem from experiments on spontaneous contractions and high-K+ induced contractions. With depolarized preparations, the concentration-response curves for nicardipine, PN 200-110, nifedipine and D600 were significantly shifted to the left indicating that the calcium entry blockers show voltage-dependent inhibitory properties. This effect was not significant with D888 and diltiazem. 3 All the calcium entry blockers strongly reduced the noradrenaline (NA)- and acetylcholine (ACh)-induced contractions at concentrations which produced complete inhibition of spontaneous contractions. They had a slight effect on caffeine-induced contractions. 4 In Ca2+-free, EGTA-containing solutions, both ACh, NA and caffeine produced transient contractions, the amplitude of which could be taken as a measurement of the amount of internal calcium present in a drug-sensitive calcium store. The filling of the calcium store was maximal after 10-12 min of calcium loading in 2.1 mM Ca2+, while the depletion was complete after 4-6 min of perfusion in Ca2+-free solution. 5 At concentrations which abolished spontaneous contractions, PN 200-110, nifedipine, D888 and D600 had no appreciable effect on contractions evoked in Ca2+-free solutions by ACh, NA and caffeine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2959345

  4. Nifedipine and nimodipine protect dopaminergic substantia nigra neurons against axotomy-induced cell death in rat vibrosections via modulating inflammatory responses.

    PubMed

    Daschil, Nina; Humpel, Christian

    2014-09-18

    Neurodegeneration of cholinergic and dopaminergic neurons is a major hallmark in Alzheimer's or Parkinson's disease, respectively. A dysregulation in calcium homeostasis may be part of this process and counteracting calcium influx may have neuroprotective properties in both diseases. Therefore, we investigated the putative neuroprotective or neurotoxic activity of L-type calcium channel (LTCC) inhibitors on cholinergic and dopaminergic neurons in a rat organotypic vibrosection model. Sagittal or coronal vibrosections (200 μm thick) of postnatal day 10 rats were cultured on 0.4 μm semipermeable membranes for 2 weeks with 10 ng/ml nerve growth factor (NGF) and/or glial-cell line derived neurotrophic factor (GDNF) to maintain survival of cholinergic or dopaminergic neurons, respectively. Thereafter, sections were incubated with 0.1, 1 or 10 μM isradipine, nicardipine or verapamil for 2 weeks to explore cytotoxicity. Alternatively, in order to explore neuroprotective activity, vibrosections were incubated without growth factors but with isradipine or verapamil or with nicardipine, nimodipine or nifedipine from the beginning for 4 weeks. Our data show that all LTCC inhibitors exhibited no neurotoxic effect on cholinergic and dopaminergic neurons. Further, LTCC inhibitors did not have any neuroprotective activity on cholinergic neurons. However, nimodipine and nifedipine significantly enhanced the survival of dopaminergic substantia nigra (SN) but not ventral tegmental area (VTA) neurons, while nicardipine, isradipine and verapamil had no effect. Nifedipine (and more potently GDNF) reduced inflammatory cytokines (macrophage inflammatory protein-2, tumor necrosis factor-α), but did not influence oxidative stress or caspase-3 activity and did not interfere with iron-mediated overload. Our data show that nifedipine and nimodipine are very potent to enhance the survival of axotomized SN neurons, possibly influencing inflammatory processes.

  5. Altered L-type Ca2+ channel activity contributes to exacerbated hypoperfusion and mortality in smooth muscle cell BK channel-deficient septic mice.

    PubMed

    Xu, Hui; Garver, Hannah; Fernandes, Roxanne; Galligan, James J; Fink, Gregory D

    2014-07-15

    We determined the contribution of vascular large conductance Ca2+-activated K+ (BK) and L-type Ca2+ channel dysregulation to exaggerated mortality in cecal ligation/puncture (CLP)-induced septic BK channel β1-subunit knockout (BK β1-KO, smooth muscle specific) mice. CLP-induced hemodynamic changes and mortality were assessed over 7 days in wild-type (WT) and BK β1-KO mice that were either untreated, given volume resuscitation (saline), or saline + calcium channel blocker nicardipine. Some mice were euthanized 24 h post-CLP to measure tissue injury and vascular and immune responses. CLP-induced hypotension was similar in untreated WT and BK β1-KO mice, but BK β1-KO mice died sooner. At 24 h post-CLP (mortality latency in BK β1-KO mice), untreated CLP-BK β1-KO mice showed more severe hypothermia, lower tissue perfusion, polymorphonuclear neutrophil infiltration-independent severe intestinal necrosis, and higher serum cytokine levels than CLP-WT mice. Saline resuscitation improved survival in CLP-WT but not CLP-BK β1-KO mice. Saline + nicardipine-treated CLP-BK β1-KO mice exhibited longer survival times, higher tissue perfusion, less intestinal injury, and lower cytokines versus untreated CLP-BK β1-KO mice. These improvements were absent in treated CLP-WT mice, although saline + nicardipine improved blood pressure similarly in both septic mice. At 24 h post-CLP, BK and L-type Ca2+ channel functions in vitro were maintained in mesenteric arteries from WT mice. Mesenteric arteries from BK β1-KO mice had blunted BK/enhanced L-type Ca2+ channel function. We conclude that vascular BK channel deficiency exaggerates mortality in septic BK β1-KO mice by activating L-type Ca2+ channels leading to blood pressure-independent tissue ischemia.

  6. Antianxiety actions of Ca2+ channel antagonists with Vogel-type conflict test in rats.

    PubMed

    Matsumoto, Y; Kataoka, Y; Watanabe, Y; Miyazaki, A; Taniyama, K

    1994-10-13

    We examined the effects of various derivatives of Ca2+ channel antagonists in a modified rat Vogel-type conflict model. Flunarizine (10 and 20 mg/kg), nicardipine (20 mg/kg), and verapamil (20 mg/kg), given as single i.p. injections, significantly increased punished lickings by 50-110%. Chronic administration of diltiazem, at 20 mg/kg i.p. for 8 days, a dose ineffective with a single i.p. injection, produced a significant anticonflict action. The possibility that Ca2+ channel antagonists have anxiolytic action should be considered.

  7. The effect of ionizing radiation of 1,4-dihydropyridine derivatives in the solid state

    NASA Astrophysics Data System (ADS)

    Naskrent, Marek; Mielcarek, Jadwiga

    2007-05-01

    Electron paramagnetic resonance (EPR) spectroscopy was used to investigate the gamma-radiation damage in the crystalline powder form of nine calcium channel blockers from the 1,4-dihydropyridine derivatives, which are in clinical use for treatment of arteria hypertension and ischemic heart disease. EPR studies have been carried out, showing the influence of irradiation and storage parameters on the nature and concentration of the free radicals trapped. EPR spectra of isardipine and felodipine showed single EPR line. EPR spectra of nifedipine, nisoldipine, nitrendipine, nimodipine, nicardipine and nilvadipine reveal a broad anisotropic signal of hyperfine interaction. No EPR signal was observed from amlodipine.

  8. Evaluation of the long-lasting antihypertensive action of 7-O-ethylfangchinoline.

    PubMed

    Kato, T; Noguchi, K; Sakanashi, M

    1994-09-01

    The antihypertensive effect of 7-O-ethylfangchinoline (TJN-220) was analyzed in an experimental model of hypertensive rats under the conscious condition. Single oral administration of TJN-220 (25 and 50 mg/kg) produced a progressive and long-lasting fall of mean blood pressure in spontaneously hypertensive rats (SHRs), deoxycorticosterone acetate (DOCA)-salt hypertensive rats and renal hypertensive rats until 72 hr after the drug administration, but affected neither the heart rate in these hypertensive rats nor the hemodynamic parameters in normotensive rats. In SHRs implanted with a telemetry transmitter, TJN-220 (50 mg/kg, p.o.) produced falls of systolic and diastolic blood pressures and diminished the difference in blood pressure between the dark period and the light period for 3 days, particularly by suppressing the increasing phase of blood pressure during the dark period without influencing heart rate or locomotor activity. On the other hand, nicardipine (10 mg/kg, p.o.) produced a transient fall of blood pressure associated with a tachycardia during the light period on the first day alone. Clonidine (0.3 mg/kg, p.o.) diminished the increasing phases of blood pressure and heart rate during the dark period on the first day alone. Thus, the antihypertensive action of TJN-220 was much longer than those of nicardipine and clonidine. The present results suggest that TJN-220 may have potential for use as a beneficial antihypertensive drug. PMID:7861666

  9. Stoichiometry and Physical Chemistry of Promiscuous Aggregate-Based Inhibitors

    PubMed Central

    Coan, Kristin E. D.

    2009-01-01

    Many false positives in early drug discovery owe to nonspecific inhibition by colloid-like aggregates of organic molecules. Despite their prevalence, little is known about aggregate concentration, structure, or dynamic equilibrium; the binding mechanism, stoichiometry with, and affinity for enzymes remain uncertain. To investigate the elementary question of concentration, we counted aggregate particles using flow cytometry. For seven aggregate-forming molecules, aggregates were not observed until the concentration of monomer crossed a threshold, indicating a “critical aggregation concentration” (CAC). Above the CAC, aggregate count increased linearly with added organic material, while the particles dispersed when diluted below the CAC. The concentration of monomeric organic molecule is constant above the CAC, as is the size of the aggregate particles. For two compounds that form large aggregates, nicardipine and miconazole, we measured particle numbers directly by flow cytometry, determining that the aggregate concentration just above the CAC ranged from 5 to 30 fM. By correlating inhibition of an enzyme with aggregate count for these two drugs, we determined that the stoichiometry of binding is about 10 000 enzyme molecules per aggregate particle. Using measured volumes for nicardipine and miconazole aggregate particles (2.1 × 1011 and 4.7 × 1010 Å3, respectively), computed monomer volumes, and the observation that past the CAC all additional monomer forms aggregate particles, we find that aggregates are densely packed particles. Finally, given their size and enzyme stoichiometry, all sequestered enzyme can be comfortably accommodated on the surface of the aggregate. PMID:18588298

  10. Cyclodextrin-polyhydrazine degradable gels for hydrophobic drug delivery.

    PubMed

    Jalalvandi, Esmat; Cabral, Jaydee; Hanton, Lyall R; Moratti, Stephen C

    2016-12-01

    An injectable and biocompatible hydrogel system was designed for hydrophobic drug delivery. This hydrogel consisted of degradable polymers with cyclodextrin (CD) moieties. CD groups were used to increase the solubility of a hydrophobic molecule (nicardipine) in an aqueous solution through the formation of the inclusion complex. Two sets of gels were prepared by mixing oxidized dextran (DA) and CD functionalized polyhydrazine (PH) at physiological conditions and different level of crosslinking via hydrazone bonds. Cytotoxicity studies on the gels and their components confirmed the biocompatibility of these materials. Gel-30 with higher crosslinking density showed a two week degradation period whereas this period was 10days for gel-10, with lower crosslinking density, to complete degradation. The results from swelling tests and rheological measurements were also found to be dependent on crosslinking density of the hydrogels. Release profile of the hydrogel displayed a sustained release of nicardipin up to 6days for gel-30 and a 4day release with initial burst release for gel-10. PMID:27612699

  11. Calcium balance in pea root statocytes under both clinorotation and Ca2+ channel blockers' influence

    NASA Astrophysics Data System (ADS)

    Belyavskaya, Ninel A.; Tsarik, Nina P.

    We have previously demonstrated that space flight and clinorotation conditions increase cytoplasmic Ca^2+ level in pea root statocytes. A rise in [Ca^2+]_i may be a serious problem for plants in microgravity environment. It is hypothesized that involvement of Ca^2+ channel blockers in the growth medium may rescue a plant from abundance of Ca^2+ ions. Indeed, combination of clinorotation (2 rpm, 5 days) and any Ca^2+ channel blocker (1 μm D600 or nicardipine, 12 hr) causes decreasing the Ca^2+ concentration in pea root statocytes in comparison with clinorotation alone. Redistribution of Ca^2+-ATPase activities observed under clinorotation comes to normal after D600 application whereas following by nicardipine action the pattern of the cytochemical staining is intermediate between those in stationary control and under clinorotation. Our data support the hypothesis that Ca^2+ channel blockers may act as protectors for plants against rise in [Ca^2+]i. The role for Ca^2+ channels in graviperception and in microgravity effects as well as ways for stabilization of Ca^2+ balance in plant cells in space flights are discussed.

  12. [Hypertensive crisis in children and adolescents].

    PubMed

    Skrzypczyk, Piotr; Roszkowska-Blaim, Maria; Daniel, Maria

    2013-12-01

    Hypertensive crisis is a sudden rise in blood pressure above 99 c. for sex, age and height +5 mm Hg. Depending on patient's symptoms, hypertensive crisis can be divided into hypertensive emergency severe arterial hypertension with target organ insufficiency and/r damage (central nervous system, heart, kidney, eye), and hypertensive urgency - severe arterial hypertension without target organ insufficiency and damage with non-specific symptoms like: headaches, vertigo, nasal bleeding, nausea, and vomiting. The most common causes of hypertensive crisis in neonates and infants are renal artery thrombosis, broncho-pulmonary dysplasia, and coarctation of aorta; in older children - kidney diseases and renal artery stenosis. In neonates and infants symptoms of cardiac failure predominate, whereas in older children symptoms from central nervous system (headaches, nausea, vomiting, changes in level of consciousness, seizures, focal deficits). Hypertensive crisis is treated with fast- and short-acting medications; 25% reduction of blood pressure within first 8 hours is recommended, with complete normalization within 24-48 hours. Hypertensive emergency should be treated with intravenous agents (labetalol, hydralazine, nicardipine, and sodium nitroprusside), hypertensive urgency with intravenous or oral agents like nifedipine, isradipine, clonidine and minoxidil. Nicardipine is a first-choice medication in neonates. PMID:24490470

  13. Intracellular calcium store filling by an L-type calcium current in the basolateral amygdala at subthreshold membrane potentials.

    PubMed

    Power, John M; Sah, Pankaj

    2005-01-15

    The long-term changes that underlie learning and memory are activated by rises in intracellular Ca2+ that activate a number of signalling pathways and trigger changes in gene transcription. Ca2+ rises due to influx via L-type voltage-dependent Ca2+ channels (L-VDCCs) and release from intracellular Ca2+ stores have been consistently implicated in the biochemical cascades that underlie the final changes in memory formation. Here, we show that pyramidal neurones in the basolateral amygdala express an L-VDCC that is active at resting membrane potentials. Subthreshold depolarization of neurones either by current injection or summating synaptic potentials led to a sustained rise in cytosolic Ca2+ that was blocked by the dihydropyridine nicardipine. Activation of metabotropic receptors released Ca2+ from intracellular Ca2+ stores. At hyperpolarized potentials, metabotropic-evoked store release ran down with repeated stimulation. Depolarization of cells to -50 mV, or maintaining them at the resting membrane potential, restored release from intracellular Ca2+ stores, an effect that was blocked by nicardipine. These results show that Ca2+ influx via a low-voltage-activated L-type Ca2+ current refills inositol 1,4,5-trisphosphate (IP(3))-sensitive intracellular Ca2+ stores, and maintains Ca2+ release and wave generation by metabotropic receptor activation.

  14. Investigation of calcium antagonist-L-type calcium channel interactions by a vascular smooth muscle cell membrane chromatography method.

    PubMed

    Du, Hui; He, Jianyu; Wang, Sicen; He, Langchong

    2010-07-01

    The dissociation equilibrium constant (K(D)) is an important affinity parameter for studying drug-receptor interactions. A vascular smooth muscle (VSM) cell membrane chromatography (CMC) method was developed for determination of the K(D) values for calcium antagonist-L-type calcium channel (L-CC) interactions. VSM cells, by means of primary culture with rat thoracic aortas, were used for preparation of the cell membrane stationary phase in the VSM/CMC model. All measurements were performed with spectrophotometric detection (237 nm) at 37 degrees C. The K(D) values obtained using frontal analysis were 3.36 x 10(-6) M for nifedipine, 1.34 x 10(-6) M for nimodipine, 6.83 x 10(-7) M for nitrendipine, 1.23 x 10(-7) M for nicardipine, 1.09 x 10(-7) M for amlodipine, and 8.51 x 10(-8) M for verapamil. This affinity rank order obtained from the VSM/CMC method had a strong positive correlation with that obtained from radioligand binding assay. The location of the binding region was examined by displacement experiments using nitrendipine as a mobile-phase additive. It was found that verapamil occupied a class of binding sites on L-CCs different from those occupied by nitrendipine. In addition, nicardipine, amlodipine, and nitrendipine had direct competition at a single common binding site. The studies showed that CMC can be applied to the investigation of drug-receptor interactions.

  15. Intracellular calcium store filling by an L-type calcium current in the basolateral amygdala at subthreshold membrane potentials

    PubMed Central

    Power, John M; Sah, Pankaj

    2005-01-01

    The long-term changes that underlie learning and memory are activated by rises in intracellular Ca2+ that activate a number of signalling pathways and trigger changes in gene transcription. Ca2+ rises due to influx via L-type voltage-dependent Ca2+ channels (L-VDCCs) and release from intracellular Ca2+ stores have been consistently implicated in the biochemical cascades that underlie the final changes in memory formation. Here, we show that pyramidal neurones in the basolateral amygdala express an L-VDCC that is active at resting membrane potentials. Subthreshold depolarization of neurones either by current injection or summating synaptic potentials led to a sustained rise in cytosolic Ca2+ that was blocked by the dihydropyridine nicardipine. Activation of metabotropic receptors released Ca2+ from intracellular Ca2+ stores. At hyperpolarized potentials, metabotropic-evoked store release ran down with repeated stimulation. Depolarization of cells to −50 mV, or maintaining them at the resting membrane potential, restored release from intracellular Ca2+ stores, an effect that was blocked by nicardipine. These results show that Ca2+ influx via a low-voltage-activated L-type Ca2+ current refills inositol 1,4,5-trisphosphate (IP3)-sensitive intracellular Ca2+ stores, and maintains Ca2+ release and wave generation by metabotropic receptor activation. PMID:15550460

  16. [Hypertensive crisis in children and adolescents].

    PubMed

    Skrzypczyk, Piotr; Roszkowska-Blaim, Maria; Daniel, Maria

    2013-12-01

    Hypertensive crisis is a sudden rise in blood pressure above 99 c. for sex, age and height +5 mm Hg. Depending on patient's symptoms, hypertensive crisis can be divided into hypertensive emergency severe arterial hypertension with target organ insufficiency and/r damage (central nervous system, heart, kidney, eye), and hypertensive urgency - severe arterial hypertension without target organ insufficiency and damage with non-specific symptoms like: headaches, vertigo, nasal bleeding, nausea, and vomiting. The most common causes of hypertensive crisis in neonates and infants are renal artery thrombosis, broncho-pulmonary dysplasia, and coarctation of aorta; in older children - kidney diseases and renal artery stenosis. In neonates and infants symptoms of cardiac failure predominate, whereas in older children symptoms from central nervous system (headaches, nausea, vomiting, changes in level of consciousness, seizures, focal deficits). Hypertensive crisis is treated with fast- and short-acting medications; 25% reduction of blood pressure within first 8 hours is recommended, with complete normalization within 24-48 hours. Hypertensive emergency should be treated with intravenous agents (labetalol, hydralazine, nicardipine, and sodium nitroprusside), hypertensive urgency with intravenous or oral agents like nifedipine, isradipine, clonidine and minoxidil. Nicardipine is a first-choice medication in neonates.

  17. Natural abundance (14)N and (15)N solid-state NMR of pharmaceuticals and their polymorphs.

    PubMed

    Veinberg, Stanislav L; Johnston, Karen E; Jaroszewicz, Michael J; Kispal, Brianna M; Mireault, Christopher R; Kobayashi, Takeshi; Pruski, Marek; Schurko, Robert W

    2016-06-29

    (14)N ultra-wideline (UW), (1)H{(15)N} indirectly-detected HETCOR (idHETCOR) and (15)N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of (14)N EFG tensors, were utilized to characterize a series of nitrogen-containing active pharmaceutical ingredients (APIs), including HCl salts of scopolamine, alprenolol, isoprenaline, acebutolol, dibucaine, nicardipine, and ranitidine. A case study applying these methods for the differentiation of polymorphs of bupivacaine HCl is also presented. All experiments were conducted upon samples with naturally-abundant nitrogen isotopes. For most of the APIs, it was possible to acquire frequency-stepped UW (14)N SSNMR spectra of stationary samples, which display powder patterns corresponding to pseudo-tetrahedral (i.e., RR'R''NH(+) and RR'NH2(+)) or other (i.e., RNH2 and RNO2) nitrogen environments. Directly-excited (14)N NMR spectra were acquired using the WURST-CPMG pulse sequence, which incorporates WURST (wideband, uniform rate, and smooth truncation) pulses and a CPMG (Carr-Purcell Meiboom-Gill) refocusing protocol. In certain cases, spectra were acquired using (1)H → (14)N broadband cross-polarization, via the BRAIN-CP (broadband adiabatic inversion - cross polarization) pulse sequence. These spectra provide (14)N electric field gradient (EFG) tensor parameters and orientations that are particularly sensitive to variations in local structure and intermolecular hydrogen-bonding interactions. The (1)H{(15)N} idHETCOR spectra, acquired under conditions of fast magic-angle spinning (MAS), used CP transfers to provide (1)H-(15)N chemical shift correlations for all nitrogen environments, except for two sites in acebutolol and nicardipine. One of these two sites (RR'NH2(+) in acebutolol) was successfully detected using the DNP-enhanced (15)N{(1)H} CP/MAS measurement, and one (RNO2 in nicardipine) remained elusive due to the absence of

  18. The effects of terpene enhancers on the percutaneous permeation of drugs with different lipophilicities.

    PubMed

    El-Kattan, A F; Asbill, C S; Kim, N; Michniak, B B

    2001-03-14

    Four model drugs were selected based on their lipophilicity denoted as log P (nicardipine hydrochloride log P -0.99 +/- 0.1, hydrocortisone log P 1.43 +/- 0.47, carbamazepine log P 2.67 +/- 0.38, and tamoxifen log P 7.87 +/- 0.75). The enhancing activities of four terpene enhancers (fenchone log P 2.13 +/- 0.30, thymol log P 3.28 +/- 0.20, D-limonene log P 4.58 +/- 0.23, and nerolidol log P 5.36 +/- 0.38) were tested in vitro across full thickness hairless mouse skin with each of the evaluated drugs formulated in hydroxypropyl cellulose gel formulations. The relationships between lipophilicity (log P) of the terpene enhancers and model drugs and efficacy (represented by the enhancement ratio of flux ER(flux)) of the drugs when coadministered with the enhancers were examined using linear regression. Terpene enhancers had significant effect on the percutaneous permeation of the model drugs. Nerolidol (highest lipophilicity) provided the highest increase in the flux of the evaluated model drugs. The flux of nicardipine hydrochloride increased by approximately 135-fold, hydrocortisone by 33-fold, carbamazepine 8-fold, and tamoxifen 2-fold. The lowest increase in the flux was observed with fenchone. Linear relationships were generated between the ER(flux) of nicardipine hydrochloride, hydrocortisone, carbamazepine, and tamoxifen and the log P of the terpene enhancers [r = 0.951, (P = 0.049), r = 0.977, (P = 0.023), r = 0.942, (P = 0.057), and r = 0.874, (P = 0.126), respectively]. Furthermore, the four terpene enhancers produced linear relationships, indicating that they were more effective at enhancing the penetration of hydrophilic drugs rather than lipophilic drugs r=-0.824 (P=0.176) for fenchone, r = -0.891 (P = 0.109) for thymol, r = -0.846 (P = 0.154) for limonene, and r = -0.769 (P = 0.232) for nerolidol. PMID:11250108

  19. Minimally invasive treatment of Peyronie's disease: evidence-based progress.

    PubMed

    Jordan, Gerald H; Carson, Culley C; Lipshultz, Larry I

    2014-07-01

    Peyronie's disease (PD) is often physically and psychologically devastating for patients, and the goal of treatment is to improve symptoms and sexual function without adding treatment-related morbidity. The potential for treatment-related morbidity after more invasive interventions, e.g. surgery, creates a need for effective minimally invasive treatments. We critically examined the available literature using levels of evidence to determine the reported support for each treatment. Most available minimally invasive treatments lack critical support for effectiveness due to the absence of randomised, placebo-controlled trials (RCTs) or non-significant results after RCTs. Iontophoresis, oral therapies (vitamin E, potassium para-aminobenzoate, tamoxifen, carnitine, and colchicine), extracorporeal shockwave therapy, and intralesional injection with verapamil or nicardipine have shown mixed or negative results. Treatments that have decreased penile curvature deformity in Level 1 or Level 2 evidence-based, placebo-controlled studies include intralesional injection with interferon α-2b or collagenase clostridium histolyticum.

  20. Effects of isradipine and other calcium antagonists on arteriovenous-shunt flow in anesthetized rabbits and cats

    SciTech Connect

    Hof, R.P.

    1989-04-17

    The effects of vasodilators on arteriovenous (AV)-shunt flow was investigated in anesthetized cats and rabbits, using the tracer microsphere method. In cats, the calcium antagonist isradipine reduced AV-shunt flow; verapamil showed a similar tendency and nicardipine was without effect. Dihydralazine strongly increased, but nitroglycerin and dipyridamole decreased AV-shunt flow. In rabbits, the effects of isradipine and verapamil were similar to those seen in cats. Sodium nitroprusside had no effect, whereas prazosin, minoxidil, and the potassium-channel activator cromakalim increased AV-shunt flow. The contrasting effects of drugs sharing the same mechanism of action suggest that target-tissue selectivity is more important than the mechanism of action. An increase of AV-shunt flow is unlikely to be beneficial but could be associated with a number of undesirable side effects. It might negatively affect migraine sufferers and, if AV-shunt dilatation shows no tolerance development, it represents an unnecessary hemodynamic burden for the heart.

  1. Rational use of calcium-channel antagonists in Raynaud's phenomenon.

    PubMed

    Sturgill, M G; Seibold, J R

    1998-11-01

    Raynaud's phenomenon (RP) is a peripheral circulatory disorder characterized by sudden episodes of digital artery spasm, often precipitated by cold temperature or emotional stress. Although the cause of RP is not fully known, it appears to involve inappropriate adrenergic response to cold stimuli. Treatment of RP is conservative in most patients, but in patients with severe disease includes the use of agents that promote digital vasodilation. The calcium-channel antagonists, particularly the dihydropyridine derivative nifedipine, are the most thoroughly studied drug class for the treatment of RP. Approximately two thirds of patients respond favorably, with significant reductions in the frequency and severity of vasospastic attacks. Nifedipine use is often limited by the appearance of adverse vasodilatory effects such as headache or peripheral edema. The newer second-generation dihydropyridines such as amlodipine, isradipine, nicardipine, and felodipine also appear to be effective in patients with RP and may be associated with fewer adverse effects.

  2. [Management of arterial hypertension before 20weeks gestation in pregnant women].

    PubMed

    Seguro, Florent; Duly Bouhanick, Béatrice; Chamontin, Bernard; Amar, Jacques

    2016-01-01

    In the first 6 months of pregnancy, the primary goal of antihypertensive treatment is to prevent the complications of severe hypertension. Initiation of antihypertensive drug treatment is recommended in pregnant women with severe hypertension (blood pressure>160/110mmHg). Initiation of antihypertensive drug treatment should also be considered in pregnant women at high cardiovascular risk (diabetes, chronic kidney disease, personal history of cardiovascular disease) with moderate hypertension (blood pressure between 140-159/90-109mmHg). A systolic blood pressure goal<160 and a diastolic blood pressure goal between 85 and 100mmHg is recommended in pregnancy. Labetalol, nifedipine, nicardipine and alphamethyldopa should be considered preferential antihypertensive drugs in pregnancy. Salt restriction, physical exercise and weight loss have not demonstrated any effect in the prevention of preeclampsia and serious maternal complications of hypertension. PMID:27554460

  3. Stability and Compatibility of Ceftazidime Administered by Continuous Infusion to Intensive Care Patients

    PubMed Central

    Servais, Hélène; Tulkens, Paul M.

    2001-01-01

    The stability and compatibility of ceftazidime have been examined in the context of its potential use in concentrated solutions for continuous infusion in patients suffering from severe nosocomial pneumonia and receiving other intravenous medications by the same route. Ceftazidime stability in 4 to 12% solutions was found satisfactory (<10% degradation) for 24 h if kept at a temperature of 25°C (77°F) maximum. Studies mimicking the simultaneous administration of ceftazidime and other drugs as done in clinics showed physical incompatibilities with vancomycin, nicardipine, midazolam, and propofol and a chemical incompatibility with N-acetylcystein. Concentrated solutions (50 mg/ml) of erythromycin or clarithromycin caused the appearance of a precipitate, whereas gentamicin, tobramycin, amikacin, isepamicin, fluconazole, ketamine, sufentanil, valproic acid, furosemide, uradipil, and a standard amino acid solution were physically and chemically compatible. PMID:11502544

  4. Sensitizing effect of lysophosphatidic acid on mechanoreceptor-linked response in cytosolic free Ca2+ concentration in cultured smooth muscle cells.

    PubMed

    Ohata, H; Seito, N; Aizawa, H; Nobe, K; Momose, K

    1995-03-01

    We found that lysophosphatidic acid (LPA) sensitizes response in cytosolic free Ca2+ concentration ([Ca2+]i) to mechanical stimulation in cultured longitudinal muscle cells from guinea pig ileum. [Ca2+]i was transiently increased by spritzing of bath solution onto cells as mechanical stimulation in the presence of LPA, but not in absence of LPA. The effect was reversible and concentration-dependent (1-30 nM). Ga3+ but not nicardipine inhibited the [Ca2+]i transient in the presence of LPA. Phosphatidic acid also induced the sensitization, but the effective concentration was more than 10 times higher than in LPA. Histamine and carbachol did not have any sensitizing effect to mechanical stimulation. These results show that LPA sensitizes mechanoreceptor-linked response, suggesting that LPA may play an important role in mechanotransduction mechanisms as an endogenous regulatory factor.

  5. Natural abundance 14N and 15N solid-state NMR of pharmaceuticals and their polymorphs

    DOE PAGESBeta

    Veinberg, Stanislav L.; Johnston, Karen E.; Jaroszewicz, Michael J.; Kispal, Brianna M.; Mireault, Christopher R.; Kobayashi, Takeshi; Pruski, Marek; Schurko, Robert W.

    2016-06-08

    14N ultra-wideline (UW), 1H{15N} indirectly-detected HETCOR (idHETCOR) and 15N dynamic nuclear polarization (DNP) solid-state NMR (SSNMR) experiments, in combination with plane-wave density functional theory (DFT) calculations of 14N EFG tensors, were utilized to characterize a series of nitrogen-containing active pharmaceutical ingredients (APIs), including HCl salts of scopolamine, alprenolol, isoprenaline, acebutolol, dibucaine, nicardipine, and ranitidine. Here, a case study applying these methods for the differentiation of polymorphs of bupivacaine HCl is also presented. All experiments were conducted upon samples with naturally-abundant nitrogen isotopes. For most of the APIs, it was possible to acquire frequency-stepped UW 14N SSNMR spectra of stationarymore » samples, which display powder patterns corresponding to pseudo-tetrahedral (i.e., RR'R"NH+ and RR'NH2+) or other (i.e., RNH2 and RNO2) nitrogen environments.« less

  6. Hypertensive crisis in children.

    PubMed

    Chandar, Jayanthi; Zilleruelo, Gastón

    2012-05-01

    Hypertensive crisis is rare in children and is usually secondary to an underlying disease. There is strong evidence that the renin-angiotensin system plays an important role in the genesis of hypertensive crisis. An important principle in the management of children with hypertensive crisis is to determine if severe hypertension is chronic, acute, or acute-on-chronic. When it is associated with signs of end-organ damage such as encephalopathy, congestive cardiac failure or renal failure, there is an emergent need to lower blood pressures to 25-30% of the original value and then accomplish a gradual reduction in blood pressure. Precipitous drops in blood pressure can result in impairment of perfusion of vital organs. Medications commonly used to treat hypertensive crisis in children are nicardipine, labetalol and sodium nitroprusside. In this review, we discuss the pathophysiology, differential diagnosis and recent developments in management of hypertensive crisis in children.

  7. [Drugs during preeclampsia. Fetal risks and pharmacology].

    PubMed

    Serreau, R

    2010-04-01

    During pregnancy, the maternal, placental and fetal physiological characteristics constantly evolve and thereby constantly alter drug bioavailability in the mother and feto-placental unit. Gastric emptying time is increased and bowel movements are reduced. Distribution in the maternal body is mainly influenced by body mass variations, water content and fat stores. Metabolic capacity of the liver appears unchanged but renal clearance of drugs is gradually increased. The placental transfer of most drugs mainly consists of passive diffusion between the maternal and fetal circulations, along their respective concentration gradients. Only the free, unbound and non-ionized fraction of the drug readily crosses the membranes. Four anti-hypertensive drugs have been granted a license for the treatment of PE since the year 2000: these are Clonidine (Catapressan), Nicardipine (Loxen+), Labetalol (Trandate), Dihydralazine (Nepressol). Dihydralazine, Labetalol and Nicardipine are not contraindicated in the breast feeding mother. The administration of a long acting Benzodiazepine during pregnancy can lead to new born intoxication of variable severity and duration. These symptoms may precede a withdrawal syndrome (hyper-excitability, tremor, gastro-intestinal upset, such as diarrhea or vomiting). Breast feeding by mothers using benzodiazepines (Nitrazepam and Midazolam) is not recommended. In France, the use of low molecular weight heparins is not recommended during pregnancy whereas in the United States, they are recommended as a prophylactic measure. Their high molecular weight prevents their diffusion across the placental membrane and therefore prevents any fetal or neonatal risk. Bromocriptine is used as an inhibitor of lactation. During the post-partum period, serious accidents have been described: these consist of systemic hypertension, fits, infarcts (cardiac and neurological). It is contraindicated in case of systemic hypertension.

  8. Effects of bradykinin B2 receptor antagonism on the hypotensive effects of ACE inhibition.

    PubMed Central

    Bouaziz, H; Joulin, Y; Safar, M; Benetos, A

    1994-01-01

    1. The aim of this study was to determine the participation of endogenous bradykinin (BK) in the antihypertensive effects of the angiotensin converting enzyme inhibitor (ACEI), perindoprilat, in the spontaneously hypertensive rat (SHR) on different salt diets. 2. Conscious SHRs receiving either a low or a high NaCl diet were used in order to evaluate the respective roles of angiotensin II suppression and bradykinin stimulation in the acute hypotensive effects of perindoprilat. Two different B2 receptor antagonists (B 4146 and Hoe 140) were used after bolus administration of 7 mg kg-1 of the ACEI, perindoprilat. In separate animals, Hoe 140 was administered before the injection of perindoprilat. In other experiments, the effects of Hoe 140 on the hypotensive effects of the calcium antagonist, nicardipine, were tested. 3. The different NaCl diets had no effect on baseline blood pressure. Hoe 140 injection before ACE inhibition did not modify blood pressure. Perindoprilat caused more marked hypotension in the low salt-fed rats than in the high salt animals (P < 0.01). Administration of Hoe 140 or B4146 after perindoprilat significantly reduced the antihypertensive effects of perindoprilat in the different groups, but this effect was more pronounced in high salt-fed rats. However, in SHRs receiving Hoe 140 before perindoprilat, the antihypertensive effect of perindoprilat was completely abolished in both high or low salt diet rats. In separate experiments we confirmed that Hoe 140 did not affect the hypotensive efficacy of the calcium antagonist, nicardipine. 4. Our study shows that inhibition of endogenous bradykinin degradation participates in the acute antihypertensive effects of perindoprilat in SHRs. The role of bradykinin is more pronounced following exposure to a high salt diet i.e., when the renin-angiotensin system is suppressed.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7858859

  9. [Intracellular recording of myotonia in mdx mouse and the effect of Ca antagonist in myotonia].

    PubMed

    Kishi, M; Kurihara, T; Uchida, H; Kinoshita, M

    1989-05-01

    Bulfield and others found X-linked muscular dystrophic (mdx) mouse by screening C57 BL/10 mice. The serum CK and PK are high in mdx mice, and they develop muscle degeneration 10-15 days after birth. The regeneration is vigorous in mdx mice and almost all the muscle fibers are replaced by regenerated fibers by 60 days after birth. Although mdx mice have been developed as a model for X-linked muscular dystrophy we have found that myotonic bursts are recorded when a glass microelectrode is inserted into the muscle fibers of hemidiaphragm preparations of mdx mice. Insertion myotonia is ceased by addition of the Na channel blocker tetrotoxin. Myotonia is not reduced, nor ceased by lowering the extracellular Ca to 1/15 of the volume of ordinary Tyrode's solution. Calcium antagonist, nicardipine at the dose of 10(-7), and 10(-6)M/L do not reduce myotonic bursts. Higher dose of nicardipine up to 2 x 10(-5)M/L abolished myotonic bursts. These results indicate that myotonic bursts are related to muscle membrane abnormalities, and each action potential occurs through Na channel, but not through Ca channel Higher dose of calcium antagonist can abolish myotonia by affecting Na channel in addition to their primary effects of Ca channel. The clinical effects of the Ca antagonist for myotonia was reported in one study. Since previous medications for myotonia including quinine HCl, procaine amide, diphenylhydantoin, and carbamazepine have some side effects such as tinnitus, headache, nausea, cardiac blocks, and bone marrow suppression, Ca antagonist may be used as a safe therapeutic drug for myotonia.

  10. Mechanisms of the antihypertensive effects of Nigella sativa oil in L-NAME-induced hypertensive rats

    PubMed Central

    Jaarin, Kamsiah; Foong, Wai Dic; Yeoh, Min Hui; Kamarul, Zaman Yusoff Nik; Qodriyah, Haji Mohd Saad; Azman, Abdullah; Zuhair, Japar Sidik Fadhlullah; Juliana, Abdul Hamid; Kamisah, Yusof

    2015-01-01

    OBJECTIVES This study was conducted to determine whether the blood pressure-lowering effect of Nigella sativa might be mediated by its effects on nitric oxide, angiotensin-converting enzyme, heme oxygenase and oxidative stress markers. METHODS: Twenty-four adult male Sprague-Dawley rats were divided equally into 4 groups. One group served as the control (group 1), whereas the other three groups (groups 2-4) were administered L-NAME (25 mg/kg, intraperitoneally). Groups 3 and 4 were given oral nicardipine daily at a dose of 3 mg/kg and Nigella sativa oil at a dose of 2.5 mg/kg for 8 weeks, respectively, concomitantly with L-NAME administration. RESULTS Nigella sativa oil prevented the increase in systolic blood pressure in the L-NAME-treated rats. The blood pressure reduction was associated with a reduction in cardiac lipid peroxidation product, NADPH oxidase, angiotensin-converting enzyme activity and plasma nitric oxide, as well as with an increase in heme oxygenase-1 activity in the heart. The effects of Nigella sativa on blood pressure, lipid peroxidation product, nicotinamide adenine dinucleotide phosphate oxidase and angiotensin-converting enzyme were similar to those of nicardipine. In contrast, L-NAME had opposite effects on lipid peroxidation, angiotensin-converting enzyme and NO. CONCLUSION: The antihypertensive effect of Nigella sativa oil appears to be mediated by a reduction in cardiac oxidative stress and angiotensin-converting enzyme activity, an increase in cardiac heme oxygenase-1 activity and a prevention of plasma nitric oxide loss. Thus, Nigella sativa oil might be beneficial for controlling hypertension. PMID:26602523

  11. Ca2+ entry in gonadotrophs and alpha T3-1 cells: does store-dependent Ca2+ influx mediate gonadotrophin-releasing hormone action?

    PubMed

    McArdle, C A; Forrest-Owen, W; Davidson, J S; Fowkes, R; Bunting, R; Mason, W T; Poch, A; Kratzmeier, M

    1996-04-01

    thapsigargin augmented the increase in [Ca2+]i seen on return to Ca(2+)-containing medium (to two- to threefold higher than that seen in control cells) indicating the activation of SDCI, whereas pool depletion by GnRH pretreatment had no such effect. To ensure maintained pool depletion after Ca2+ re-addition, similar studies were performed in which the thapsigargin and GnRH treatments were not washed off, but were retained through the period of return to Ca(2+)-containing medium. Return of GnRH-treated cells to Ca(2+)-containing medium caused an increase in [Ca2+]i which was inhibited by nicardipine, whereas the increase seen on return of thapsigargin-treated cells to Ca(2+)-containing medium was not reduced by nicardipine. The quench of fura-2 fluorescence by MnCl2 (used as a reporter of Ca2+ influx) was increased by GnRH and thapsigargin, indicating that both stimulate Ca2+ influx via Mn2+ permeant channels. The GnRH effect was abolished by nicardipine whereas that of thapsigargin was not. Finally, depletion of intracellular Ca2+ pools by pretreatment of superfused rat pituitary cells with GnRH or thapsigargin in Ca(2+)-free medium did not enhance LH release on return to Ca(2+)-containing medium. The results indicate that (a) thapsigargin stimulates SDCI in alpha T3-1 cells via nicardipine-insensitive Ca2+ channels, (b) in spite of the fact that GnRH depletes the hormone-mobilizable Ca2+ pool, it fails to stimulate SDCI, (c) GnRH stimulates Ca2+ entry predominantly via nicardipine-sensitive channels, a route not activated by SDCI and (d) in rat gonadotrophs, GnRH-stimulated LH release is not mediated by SDCI.

  12. Hydrogen sulfide-induced enhancement of gastric fundus smooth muscle tone is mediated by voltage-dependent potassium and calcium channels in mice

    PubMed Central

    Meng, Xiang-Min; Huang, Xu; Zhang, Chun-Mei; Liu, Dong-Hai; Lu, Hong-Li; Kim, Young-chul; Xu, Wen-Xie

    2015-01-01

    AIM: To investigate the effect of hydrogen sulfide (H2S) on smooth muscle motility in the gastric fundus. METHODS: The expression of cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE) in cultured smooth muscle cells from the gastric fundus was examined by the immunocytochemistry technique. The tension of the gastric fundus smooth muscle was recorded by an isometric force transducer under the condition of isometric contraction with each end of the smooth muscle strip tied with a silk thread. Intracellular recording was used to identify whether hydrogen sulfide affects the resting membrane potential of the gastric fundus in vitro. Cells were freshly separated from the gastric fundus of mice using a variety of enzyme digestion methods and whole-cell patch-clamp technique was used to find the effects of hydrogen sulfide on voltage-dependent potassium channel and calcium channel. Calcium imaging with fura-3AM loading was used to investigate the mechanism by which hydrogen sulfide regulates gastric fundus motility in cultured smooth muscle cells. RESULTS: We found that both CBS and CSE were expressed in the cultured smooth muscle cells from the gastric fundus and that H2S increased the smooth muscle tension of the gastric fundus in mice at low concentrations. In addition, nicardipine and aminooxyacetic acid (AOAA), a CBS inhibitor, reduced the tension, whereas Nω-nitro-L-arginine methyl ester, a nonspecific nitric oxide synthase, increased the tension. The AOAA-induced relaxation was significantly recovered by H2S, and the NaHS-induced increase in tonic contraction was blocked by 5 mmol/L 4-aminopyridine and 1 μmol/L nicardipine. NaHS significantly depolarized the membrane potential and inhibited the voltage-dependent potassium currents. Moreover, NaHS increased L-type Ca2+ currents and caused an elevation in intracellular calcium ([Ca2+]i). CONCLUSION: These findings suggest that H2S may be an excitatory modulator in the gastric fundus in mice. The

  13. Effect of KC399, a newly synthesized K+ channel opener, on acetylcholine-induced electrical and mechanical activities in rabbit tracheal smooth muscle.

    PubMed

    Kamei, K; Nabata, H; Kuriyama, H; Watanabe, Y; Itoh, T

    1995-08-01

    1. Effects of KC399, an opener of ATP-sensitive K+ channels were investigated on membrane potential, isometric force and intracellular Ca2+ ([Ca2+]i) mobilization induced by acetylcholine (ACh) in smooth muscle from the rabbit trachea. 2. In these smooth muscle cells, ACh (0.1 and 1 microM) depolarized the membrane in a concentration-dependent manner, KC399 (1-100 nM) hyperpolarized the membrane whether in the presence or absence of ACh. When the concentration of ACh was increased, the absolute values of the membrane potential induced by the maximum concentration of KC399 were less negative. 3. ACh (0.1 to 10 microM) concentration-dependently produced a phasic, followed by a tonic increase in both [Ca2+]i and force. KC399 (above 3 nM) lowered the resting [Ca2+]i and attenuated the ACh-induced phasic and tonic increases in [Ca2+]i and force, in a concentration-dependent manner. The magnitude of the inhibition was greater for the ACh-induced tonic responses than for the phasic ones. Nicardipine (0.3 microM), a blocker of the L-type Ca2+ channel, attenuated the ACh-induced tonic, but not phasic, increases in [Ca2+]i and force. KC399 further attenuated the ACh-induced tonic responses in the presence of nicardipine. 4. In beta-escin-skinned strips, Ca2+ (0.3-10 microM) produced a contraction in a concentration-dependent manner. KC399 (0.1 microM) had no effect on the Ca(2+)-force relationship in the presence or absence of ATP with GTP. However, at a very high concentration (1 microM), this agent slightly shifted the relationship to the right and attenuated the maximum Ca(2+)-induced contraction. 5. We conclude that, in rabbit tracheal smooth muscle, the membrane hyperpolarization induced byKC399 attenuates the ACh-induced tonic increase in [Ca2+], through an inhibition of nicardipinesensitive and -insensitive Ca2+-influxes, thus causing an inhibition of the ACh-induced tonic contraction. The ACh-induced phasic increase in [Ca2+]i and force are also inhibited, but less

  14. Potentiation of sulfonylurea action by an EPAC-selective cAMP analog in INS-1 cells: comparison of tolbutamide and gliclazide and a potential role for EPAC activation of a 2-APB-sensitive Ca2+ influx.

    PubMed

    Jarrard, Rachel E; Wang, Yuchen; Salyer, Amy E; Pratt, Evan P S; Soderling, Ian M; Guerra, Marcy L; Lange, Allison M; Broderick, Hilary J; Hockerman, Gregory H

    2013-01-01

    Tolbutamide and gliclazide block the K(ATP) channel K(ir)6.2/Sur1, causing membrane depolarization and stimulating insulin secretion in pancreatic beta cells. We examined the ability of the EPAC-selective cAMP analog 8-pCPT-2'-O-Me-cAMP-AM to potentiate the action of these drugs and the mechanism that might account for it. Insulin secretion stimulated by both 200 μM tolbutamide and 20 μM gliclazide, concentrations that had equivalent effects on membrane potential, was inhibited by thapsigargin (1 μM) or the L-type Ca(2+) channel blocker nicardipine (2 μM) and was potentiated by 8-pCPT-2'-O-Me-cAMP-AM at concentrations ≥2 μM in INS-1 cells. Ca(2+) transients stimulated by either tolbutamide or gliclazide were inhibited by thapsigargin or nicardipine and were significantly potentiated by 8-pCPT-2'-O-Me-cAMP-AM at 5 μM but not 1 μM. Both tolbutamide and gliclazide stimulated phospholipase C activity; however, only gliclazide did so independently of its activity at K(ATP) channels, and this activity was partially inhibited by pertussis toxin. 8-pCPT-2'-O-Me-cAMP-AM alone (5 μM) did not stimulate insulin secretion, but did increase intracellular Ca(2+) concentration significantly, and this activity was inhibited by 25 μM 2-aminoethoxydiphenylborate (2-APB) or the removal of extracellular Ca(2+). 8-pCPT-2'-O-Me-cAMP-AM potentiation of insulin secretion stimulated by tolbutamide was markedly inhibited by 2-APB (25 μM) and enhanced by the PKC inhibitor bisindolylmaleimide I (1 μM). Our data demonstrate that the actions of both tolbutamide and gliclazide are strongly potentiated by 8-pCPT-2'-O-Me-cAMP-AM, that gliclazide can stimulate phospholipase C activity via a partially pertussis toxin-sensitive mechanism, and that 8-pCPT-2'-O-Me-cAMP-AM potentiation of tolbutamide action may involve activation of a 2-APB-sensitive Ca(2+) influx. PMID:23071106

  15. Suppression of cytochrome P450 3A protein levels by proteasome inhibitors.

    SciTech Connect

    Zangar, Richard C. ); Kocarek, Thomas A.; Shen, Shang; Bollinger, Nikki ); Dahn, Michael S.; Lee, Donna W.

    2003-06-01

    We have previously reported that CYP3A cross-links with polyubiquitinated proteins in microsomes from nicardipine-treated rats in a process that is distinct from classical polyubiquitination. To further examine the role of the proteasome in CYP3A degradation, we investigated the effects of proteasome inhibitors lactacystin, MG132, proteasome inhibitor 1, and hemin in primary cultures of rat and human hepatocytes. With the exception of hemin, these agents increased the total pool of ubiquitinated proteins in microsomes isolated from rat hepatocytes, indicating that lactacystin, MG132, and proteasome inhibitor 1 effectively inhibited the proteasome in these cells. All four agents caused a reduction in the amount of the major approximately 55-kDa CYP3A band, opposite to what would be expected if the ubiquitin-proteasome pathway degraded CYP3A. Only hemin treatment caused an increase in high molecular mass (HMM) CYP3A bands. Because hemin treatment did not alter levels of ubiquitin in CYP3 A immunoprecipitates, the HMM CYP3A bands formed in response to hemin treatment clearly were not due to proteasome inhibition. Rather, because hemin treatment also caused an increase in HMM CYP3A in the detergent-insoluble fraction of the 10,000g pellet, the HMM CYP3A seems to represent a large protein complex that is unlikely to primarily represent ubiquitination.

  16. Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization.

    PubMed

    Lee, Hyang-Ae; Hyun, Sung-Ae; Park, Sung-Gurl; Kim, Ki-Suk; Kim, Sung Joon

    2016-01-01

    Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca(2+) channel current (I Ca) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K(+) channel currents (I Kr, I Ks) and voltage-gated Na(+) channel current (I Na). The concentration-dependent inhibition of Ca(2+) channel currents (I Ca) was examined in rat cardiomyocytes; these CCBs have similar potency on I Ca channel blocking with IC50 (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD50 and APD90 already at 1 µM whereas NIC and AML shortened APD50 but not APD90 up to 30 µM. According to ion channel studies, NIC and AML concentration-dependently inhibited I Kr and I Ks while ISR had only partial inhibitory effects (<50% at 30 µM). Inhibition of I Na was similarly observed in the three CCBs. Since the I Kr and I Ks mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of I Ca.

  17. Interactions of phospholipase D and cytochrome P450 protein stability

    SciTech Connect

    Zangar, Richard C.; Fan, Yang-Yi; Chapkin, Robert S.

    2004-08-01

    Previous studies have suggested a relationship between cytochrome P450 (P450) 3A (CYP3A) conformation and the phospholipid composition of the associated membrane. In this study, we utilized a novel microsomal incubation system that mimics many of the characteristics of CYP3A degradation pathway that have been observed in vivo and in cultured cells to study the effects of phospholipid composition on protein stability. We found that addition of phosphatidylcholine-specific phospholipase D (PLD) stabilized CYP3A in this system, but that phosphatidylinositol-specific phospholipase C (PLC) was without effect. Addition of phosphatidic acid also stabilized CYP3A protein in the microsomes. The use of 1,10-phenanthroline (phenanthroline), an inhibitor of PLD activity, decreased CYP3A stability in incubated microsomes. Similarly, 6-h treatment of primary cultures of rat hepatocytes with phenanthroline resulted in nearly complete loss of CYP3A protein. Treatment of rats with nicardipine or dimethylsulfoxide (DMSO), which have been shown to affect CYP3A stability, altered the phospholipid composition of hepatic microsomes. It did not appear, though, that the changes in phospholipid composition that resulted from these in vivo treatments accounted for the change in CYP3A stability observed in hepatic microsomes from these animals.

  18. Contractile properties of synthetic cationic polypeptides in guinea-pig isolated trachea.

    PubMed Central

    Spina, D.; Goldie, R. G.

    1994-01-01

    1. The synthetic polypeptides, poly-L-arginine, poly-L-lysine and poly-D-lysine contract guinea-pig isolated trachea in a concentration-dependent, epithelium-independent manner. Indomethacin augmented the contractile response to poly-L-arginine. 2. The contractile response to poly-L-arginine was not significantly inhibited by nicardipine, a selective L-type calcium channel blocker or by the histamine H1-receptor antagonist, mepyramine nor significantly augmented by the neutral endopeptidase inhibitor, phosphoramidon. 3. The contractile response to poly-L-arginine was inhibited in a concentration-dependent manner by prior incubation of guinea-pig tracheal rings with a number of anionic polypeptides including, low molecular weight heparin, poly-L-aspartic acid and bovine serum albumin. 4. In vitro capsaicin-induced desensitization failed to attenuate the contractile response to poly-L-arginine, suggesting little, if any role for sensory neuropeptides in the functional response in the guinea-pig. 5. Synthetic polypeptides induce an epithelium-independent, charge-dependent contraction of guinea-pig isolated trachea. PMID:8012709

  19. Interactions of ethanol on the acute toxicity of cocaine in the rat

    SciTech Connect

    Trouve, R. ); Latour, C ); Nahas, G.G. Columbia Univ., New York, NY )

    1992-02-26

    Administration of 65 mg/kg in the awake rate, restrained and instrumented, is associated with cardiovascular toxicity, convulsions and lethality within 9 feet 44 inches {plus minus} 4 feet 56 inches. Such an outcome is prevented if selected Ca{sup 2+} antagonists are administered intraarterially 5 minutes following cocaine. Four additional groups of Sprague Dawley rats were studied. The first was administered I.P. ethanol 1.5-2.0 gr. Such doses were well tolerated only producing hypertension of 50 minutes duration and all animals survived without apparent ill effects. Second and third groups were first administered the same doses of ethanol and 15 minutes later 65 mg/kg of cocaine. Survival time was 5 feet 49 inches with 1.5 mg/kg ethanol and 5 feet 57 inches {plus minus} 1 foot 26 inches with 2 mg/kg, significantly less than after cocaine administration alone. In a fourth group, animals were treated intraarterially with nicardipine or flunarizine, 2 minutes after cocaine. Survival time was not different from saline control. Ethanol enhances significantly cocaine lethal toxicity in the rate and prevents the protective effects of antidotes to this alkaloid.

  20. A novel rapid quantitative analysis of drug migration on tablets using laser induced breakdown spectroscopy.

    PubMed

    Yokoyama, Makoto; Tourigny, Martine; Moroshima, Kenji; Suzuki, Junsuke; Sakai, Miyako; Iwamoto, Kiyoshi; Takeuchi, Hirofumi

    2010-11-01

    There have been few reports wherein drug migration from the interior to the surface of a tablet has been analyzed quantitatively until now. In this paper, we propose a novel, rapid, quantitative analysis of drug migration in tablets using laser induced breakdown spectroscopy (LIBS). To evaluate drug migration, model tablets containing nicardipine hydrochloride as active pharmaceutical ingredient (API) were prepared by a conventional wet granulation method. Since the color of this API is pale yellow and all excipients are white, we can observe the degree of drug migration by visual inspection in these model tablets. In order to prepare tablets with different degrees of drug migration, the temperature of the drying process after tableting was varied between 50 to 80 °C. Using these manifold tablets, visual inspection, Fourier transform (FT)-IR mapping and LIBS analysis were carried out to evaluate the drug migration in the tablets. While drug migration could be observed using all methods, only LIBS analysis could provide quantitative analysis wherein the average LIBS intensity was correlated with the degree of drug migration obtained from the drying temperature. Moreover, in this work, we compared the sample preparation, data analysis process and measurement time for visual inspection, FT-IR mapping and LIBS analysis. The results of the comparison between these methods demonstrated that LIBS analysis is the simplest and the fastest method for migration monitoring. From the results obtained, we conclude that LIBS analysis is one of most useful process analytical technology (PAT) tools to solve the universal migration problem.

  1. Calcium channels responsible for potassium-induced transmitter release at rat cerebellar synapses.

    PubMed

    Momiyama, A; Takahashi, T

    1994-04-15

    The effects of calcium channel blockers on potassium-induced transmitter release were studied in thin slices of cerebellum from neonatal rats using whole-cell patch clamp methods. Miniature inhibitory postsynaptic currents (mIPSCs) mediated by gamma-aminobutyric acid (GABA) were recorded from deep cerebellar nuclear neurones in the presence of tetrodotoxin. The frequency of mIPSCs was reproducibly increased by a brief application of high-potassium solution. In the presence of the L-type Ca2+ channel blocker nicardipine (10 microM), the potassium-induced increase in mIPSC frequency was suppressed by 49%. Neither the mean amplitude nor the time course of mIPSCs was affected by the blocker. The N-type Ca2+ channel blocker omega-conotoxin GVIA (omega-CgTX, 3 microM) had no effect on the frequency of potassium-induced mIPSCs. The P-type Ca2+ channel blocker omega-Aga-IVA (200 nM) suppressed the potassium-induced increase in mIPSC frequency by 83% without affecting the mean amplitude or time course of mIPSCs. Comparing these data with previous studies of neurally evoked transmission, it is concluded that the Ca2+ channel subtypes responsible for potassium-induced transmitter release may be different from those mediating fast synaptic transmission.

  2. Suppression of cytochrome P450 3A protein levels by proteasome inhibitors.

    PubMed

    Zangar, Richard C; Kocarek, Thomas A; Shen, Shang; Bollinger, Nikki; Dahn, Michael S; Lee, Donna W

    2003-06-01

    We have previously reported that CYP3A cross-links with polyubiquitinated proteins in microsomes from nicardipine-treated rats in a process that is distinct from classical polyubiquitination. To further examine the role of the proteasome in CYP3A degradation, we investigated the effects of proteasome inhibitors lactacystin, MG132, proteasome inhibitor 1, and hemin in primary cultures of rat and human hepatocytes. With the exception of hemin, these agents increased the total pool of ubiquitinated proteins in microsomes isolated from rat hepatocytes, indicating that lactacystin, MG132, and proteasome inhibitor 1 effectively inhibited the proteasome in these cells. All four agents caused a reduction in the amount of the major approximately 55-kDa CYP3A band, opposite to what would be expected if the ubiquitin-proteasome pathway degraded CYP3A. Only hemin treatment caused an increase in high molecular mass (HMM) CYP3A bands. Because hemin treatment did not alter levels of ubiquitin in CYP3A immunoprecipitates, the HMM CYP3A bands formed in response to hemin treatment clearly were not due to proteasome inhibition. Rather, because hemin treatment also caused an increase in HMM CYP3A in the detergent-insoluble fraction of the 10,000g pellet, the HMM CYP3A seems to represent a large protein complex that is unlikely to primarily represent ubiquitination.

  3. [Anesthetic Management of a Parturient with Eclampsia, Posterior Reversible Encephalopathy Syndrome and Pulmonary Edema due to Pregnancy-induced Hypertension].

    PubMed

    Aida, Junko; Okutani, Hiroai; Oda, Yutaka; Okutani, Ryu

    2015-08-01

    A 27-year-old woman with mental retardation was admitted to a nearby hospital for an abrupt onset of seizure. Physical examination revealed remarkable hypertension and pregnancy with estimated gestational age of 28th week. Severe pulmonary edema and hypoxia led to a diagnosis of pregnancy-induced hypertension (PIH) accompanied by eclampsia. She was orotracheally intubated because of refractory seizure and hypoxemia, and transferred to our hospital for further treatment. Besides severe hypoxia and hypercapnea, an enhanced lesion was detected in the left posterior cerebrum by brain MRI. No abnormal findings were detected in the fetus, with heart rate of 150 beats x min. She was diagnosed with posterior reversible encephalopathy syndrome (PRES) caused by PIH and emergency cesarean section under general anesthesia was scheduled. A male newborn was delivered with Apgar score of 1/4 (1/5 min), followed by starting continuous infusion of nicardipine for controlling hypertension. Chest X-P on completion of surgery revealed remarkably alleviated pulmonary edema. She received intensive treatment and continued positive pressure ventilation for four days after delivery. She recovered with no neurological deficits and her child was well without any complications. PMID:26442424

  4. Characterizing the binding interactions between P-glycoprotein and eight known cardiovascular transport substrates

    PubMed Central

    Jagodinsky, Justin C; Akgun, Ugur

    2015-01-01

    The multidrug efflux pump P-glycoprotein (Pgp) is upregulated in cardiomyocytes following chronic ischemia from infarction and hypoxia caused by sleep apnea. This report summarizes the molecular dynamic studies performed on eight cardiovascular drugs to determine their corresponding binding sites on mouse Pgp. Selected Pgp transport ligands include: Amiodarone, Bepridil, Diltiazem, Dipyridamole, Nicardipine, Nifedipine, Propranolol, and Quinidine. Extensive molecular dynamic equilibration simulations were performed to determine drug docking interactions. Distinct binding sites were not observed, but rather a binding belt was seen with multiple residues playing a role in each studied drug's stable docking. Three key drug–protein interactions were identified: hydrogen bonding, hydrophobic packing, and the formation of a “cage” of aromatic residues around the drug. After drug stabilization, water molecules were observed to leak into the binding belt and condense around the drug. Water influx into the binding domain of Pgp may play a role in catalytic transition and drug expulsion. The cytoplasmic recruitment theory was also tested, and the drugs were observed to interact with conserved loops of residues with a strong affinity. A free energy change of astronomical value is required to recruit the drug from the cytoplasm to the binding belt within the transmembrane domain of Pgp. PMID:25729581

  5. Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

    PubMed Central

    Lee, Hyang-Ae; Hyun, Sung-Ae; Park, Sung-Gurl

    2016-01-01

    Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca2+ channel current (ICa) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K+ channel currents (IKr, IKs) and voltage-gated Na+ channel current (INa). The concentration-dependent inhibition of Ca2+ channel currents (ICa) was examined in rat cardiomyocytes; these CCBs have similar potency on ICa channel blocking with IC50 (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD50 and APD90 already at 1 µM whereas NIC and AML shortened APD50 but not APD90 up to 30 µM. According to ion channel studies, NIC and AML concentration-dependently inhibited IKr and IKs while ISR had only partial inhibitory effects (<50% at 30 µM). Inhibition of INa was similarly observed in the three CCBs. Since the IKr and IKs mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of ICa. PMID:26807031

  6. Mycophenolate-Induced Posterior Reversible Encephalopathy Syndrome.

    PubMed

    Khajuria, Bhavik; Khajuria, Mansi; Agrawal, Yashwant

    2016-01-01

    A 29-year-old woman presented with diffuse anasarca and shortness of breath. Workup revealed a creatinine of 3.3 and a glomerular filtration rate of 17. The patient was also found to be pancytopenic with evidence of hemolytic anemia. A renal biopsy showed evidence of stage IV lupus nephritis with rapidly progressive glomerulonephritis. Her lupus was further classified as ANA negative and anti-dsDNA positive. Mycophenolate and triweekly hemodialysis were started along with a steroid burst of methylprednisolone 1 g for 3 days followed by prednisone 60 mg daily. Four days after discharge, the patient represented with a witnessed 3-minute seizure involving bowel incontinence, altered mental status, and tongue biting. She was given 2 mg intravenous lorazepam and loaded with 1000 mg levetiracetam for seizure prophylaxis. Magnetic resonance imaging of the head revealed bilateral posterior hemispheric subcortical edema, and the diagnosis of posterior reversible encephalopathy syndrome was made. Mycophenolate was immediately discontinued and replaced with cyclophosphamide. Strict blood pressure control below 140/90 mm Hg was maintained initially with intravenous nicardipine drip and then transitioned to oral nifedipine, clonidine, losartan, and minoxidil. A repeat head magnetic resonance imaging 8 days later showed resolved subcortical edema consistent with the patient's improved mental status. No permanent neurologic sequelae were recorded as a result of this hospital episode. PMID:25933141

  7. Safrole-induced Ca2+ mobilization and cytotoxicity in human PC3 prostate cancer cells.

    PubMed

    Chang, H C; Cheng, H H; Huang, C J; Chen, W C; Chen, I S; Liu, S I; Hsu, S S; Chang, H T; Wang, J K; Lu, Y C; Chou, C T; Jan, C R

    2006-01-01

    The effect of the carcinogen safrole on intracellular Ca2+ mobilization and on viability of human PC3 prostate cancer cells was examined. Cytosolic free Ca2+ levels ([Ca2+]i) were measured by using fura-2 as a probe. Safrole at concentrations above 10 microM increased [Ca2+]i in a concentration-dependent manner with an EC50 value of 350 microM. The Ca2+ signal was reduced by more than half after removing extracellular Ca2+ but was unaffected by nifedipine, nicardipine, nimodipine, diltiazem, or verapamil. In Ca2+-free medium, after treatment with 650 microM safrole, 1 microM thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) failed to release Ca2+. Neither inhibition of phospholipase C with U73122 nor modulation of protein kinase C activity affected safrole-induced Ca2+ release. Overnight incubation with 0.65-65 microM safrole did not affect cell viability, but incubation with 325-625 microM safrole decreased viability. Collectively, the data suggest that in PC3 cells, safrole induced a [Ca2+]i increase by causing Ca2+ release from the endoplasmic reticulum in a phospholipase C- and protein kinase C-independent fashion, and by inducing Ca2+ influx. Safrole can decrease cell viability in a concentration-dependent manner.

  8. Micellar electrokinetic chromatography as a fast screening method for the determination of 1,4-dihydropyridine calcium antagonists.

    PubMed

    Martínez, V; López, J A; Alonso, R M; Jiménez, R M

    1999-03-19

    A micellar electrokinetic chromatographic method (MEKC) was optimized for the separation of six calcium antagonists. The effects of the buffer (concentration and pH), concentration of sodium dodecyl sulphate (SDS), the organic modifier, the injection time, and the voltage applied were studied. A final appropriate electrolyte of 50 mM borate buffer, pH 8.2, containing 20 mM SDS and 15% (v/v) acetonitrile was found to provide the optimum separation with respect to resolution and migration time. The samples were introduced hydrostatically for 4 s at 50 mbar injection pressure and the applied voltage was +25 kV. The screening of the six compounds was achieved in less than 15 min: nifedipine (migration time, tm = 6.9 min), nimodipine (tm = 10.1 min), felodipine (tm = 12.2 min), nicardipine hydrochloride (tm = 12.7 min), lacidipine (tm = 13.5 min) and amlodipine besylate (tm = 14.1 min, tm = 8 min). The method developed showed to be linear at least up to 70 micrograms/ml with a detection limit of about 5 micrograms/ml for each compound. The within-day and inter-day area reproducibility (R.S.D.) were, respectively, lower than 4.8 and 8.6% for six replicate samples.

  9. Intrathecal application of the nimodipine slow-release microparticle system eg-1962 for prevention of delayed cerebral ischemia and improvement of outcome after aneurysmal subarachnoid hemorrhage.

    PubMed

    Etminan, Nima; Macdonald, R Loch; Davis, Cara; Burton, Kevin; Steiger, Hans-Jakob; Hänggi, Daniel

    2015-01-01

    The effective reduction of delayed cerebral ischemia (DCI), a main contributor for poor outcome following aneurysmal subarachnoid hemorrhage (SAH), remains challenging. Previous clinical trials on systemic pharmaceutical treatment of SAH mostly failed to improve outcome, probably because of insensitive pharmaceutical targets and outcome measures, small sample size, insufficient subarachnoid drug concentrations and also detrimental, systemic effects of the experimental treatment per se. Interestingly, in studies that are more recent, intrathecal administration of nicardipine pellets following surgical aneurysm repair was suggested to have a beneficial effect on DCI and neurological outcome. However, this positive effect remained restricted to patients who were treated surgically for a ruptured aneurysm. Because of the favorable results of the preclinical data on DCI and neurological outcome in the absence of neurotoxicity or systemic side effects, we are initiating clinical trials. The PROMISE (Prolonged Release nimOdipine MIcro particles after Subarachnoid hemorrhage) trial is designed as an unblinded, nonrandomized, single-center, single-dose, dose-escalation safety and tolerability phase 1 study in patients surgically treated for aSAH and will investigate the effect of intracisternal EG-1962 administration. The NEWTON (Nimodipine microparticles to Enhance recovery While reducing TOxicity after subarachNoid hemorrhage) trial is a phase 1/2a multicenter, controlled, randomized, open-label, dose-escalation, safety, tolerability, and pharmacokinetic study comparing EG-1962 and nimodipine in patients with aneurysmal SAH.

  10. Phenotypic profiling of Raf inhibitors and mitochondrial toxicity in 3D tissue using biodynamic imaging.

    PubMed

    An, Ran; Merrill, Dan; Avramova, Larisa; Sturgis, Jennifer; Tsiper, Maria; Robinson, J Paul; Turek, John; Nolte, David D

    2014-04-01

    The existence of phenotypic differences in the drug responses of 3D tissue relative to 2D cell culture is a concern in high-content drug screening. Biodynamic imaging is an emerging technology that probes 3D tissue using short-coherence dynamic light scattering to measure the intracellular motions inside tissues in their natural microenvironments. The information content of biodynamic imaging is displayed through tissue dynamics spectroscopy (TDS) but has not previously been correlated against morphological image analysis of 2D cell culture. In this article, a set of mitochondria-affecting compounds (FCCP, valinomycin, nicardipine, ionomycin) and Raf kinase inhibitors (PLX4032, PLX4720, GDC, and sorafenib) are applied to multicellular tumor spheroids from two colon adenocarcinoma cell lines (HT-29 and DLD-1). These were screened by TDS and then compared against conventional image-based high-content analysis (HCA). The responses to the Raf inhibitors PLX4032 and PLX4720 are grouped separately by cell line, reflecting the Braf/Kras difference in these cell lines. There is a correlation between TDS and HCA phenotypic clustering for most cases, which demonstrates the ability of dynamic measurements to capture phenotypic responses to drugs. However, there are significant 2D versus 3D phenotypic differences exhibited by several of the drugs/cell lines.

  11. Phenotypic Profiling of Raf Inhibitors and Mitochondrial Toxicity in 3D Tissue Using Biodynamic Imaging

    PubMed Central

    An, Ran; Merrill, Dan; Avramova, Larisa; Sturgis, Jennifer; Tsiper, Maria; Robinson, J. Paul; Turek, John; Nolte, David D.

    2014-01-01

    The existence of phenotypic differences in the drug responses of 3D tissue relative to 2D cell culture is a concern in high-content drug screening. Biodynamic imaging is an emerging technology that probes 3D tissue using short-coherence dynamic light scattering to measure the intracellular motions inside tissues in their natural microenvironments. The information content of biodynamic imaging is displayed through tissue dynamics spectroscopy (TDS) but has not previously been correlated against morphological image analysis of 2D cell culture. In this article, a set of mitochondria-affecting compounds (FCCP, valinomycin, nicardipine, ionomycin) and Raf kinase inhibitors (PLX4032, PLX4720, GDC, and sorafenib) are applied to multicellular tumor spheroids from two colon adenocarcinoma cell lines (HT-29 and DLD-1). These were screened by TDS and then compared against conventional image-based high-content analysis (HCA). The responses to the Raf inhibitors PLX4032 and PLX4720 are grouped separately by cell line, reflecting the Braf/Kras difference in these cell lines. There is a correlation between TDS and HCA phenotypic clustering for most cases, which demonstrates the ability of dynamic measurements to capture phenotypic responses to drugs. However, there are significant 2D versus 3D phenotypic differences exhibited by several of the drugs/cell lines. PMID:24361645

  12. Pre-surgical regional blocks in orthognathic surgery: prospective study evaluating their influence on the intraoperative use of anaesthetics and blood pressure control.

    PubMed

    Chen, Y A; Rivera-Serrano, C M; Chen, C; Chen, Y R

    2016-06-01

    In orthognathic surgery, maxillary (CNV2) and mandibular (CNV3) divisions of the trigeminal nerve can be blocked successfully prior to surgery. In this study, it was hypothesized that regional blocks (nerve block over a particular region: bilateral CNV2 and CNV3 divisions of the trigeminal nerve) would decrease the total requirement for intraoperative anaesthetic agents and facilitate the process of hypotensive anaesthesia. Local anaesthesia containing 1/100,000 epinephrine and 10ml 0.5% levobupivacaine was injected into the planned incisions in 50 patients. Twenty-five patients (group A) underwent orthognathic surgery without regional blocks and another 25 patients (group B) underwent surgery with regional blocks. The anaesthetic protocol was the same in both groups and administered by a single anaesthesiologist. The mean arterial pressure was recorded at several points throughout the operation, as well as all the medications used. The blood loss and the amounts of medications administered were lower in group B than in group A. In patients receiving regional blocks, the amounts of fentanyl and nicardipine required were significantly lower. The use of pre-emptive anaesthesia in orthognathic surgery may reduce the overall amounts of medications required for hypotensive anaesthesia, facilitate the intraoperative control of blood pressure, and decrease intraoperative blood loss.

  13. Cardiovascular Pharmacology of Sinomenine: The Mechanical and Electropharmacological Actions

    PubMed Central

    Nishida, Seiichiro; Satoh, Hiroyasu

    2007-01-01

    Sinomenine is one of the alkaloids extracted from Chinese medical plant, Sinomenium acutum Rehder et Wilson. Sinomenine has been used for Rheumatoid arthritis as an anti-inflammatory and immunomodulative drugs. We have so far been investigated the cardiovascular pharmacological actions of sinomenine. Sinomenine dilated NE (5 μM)-, KCl (60 mM)- and PDB (300 nM)-induced vasoconstrictions. The pretreatment with nicardipine (0.1 μM), staurosporine (30 nM), L-NMMA (100 μM), indomethacin (10 μM) or propranolol significantly attenuated the sinomenine-induced vasorelaxation. Therefore, these results indicate that sinomenine causes the vasorelaxation by the involvement with the inhibitions of Ca2+ current (ICa) and PK-C, β-adrenoceptor stimulation, and the activation of NO and PGI2 syntheses in endothelium. On the other hand, in the ventricular cardiomyocytes of guinea pig, sinomenine inhibits ICa and simultaneously decreases the delayed rectifier K+ current (IK), resulting in the prolongation of action potential duration. Sinomenine also suppresses the dysrhysmias induced by triggered activities under the Ca2+ overload condition. Therefore, sinomenine may be expected as one of effective therapeutic drugs for heart failure and dysrhythmias, and may maintain the cardiovascular functions due to modulation of cardiac ionic channels and blood vessels. PMID:21901066

  14. The existence of a highly tetrodotoxin sensitive Na channel in freshly dispersed smooth muscle cells of the rabbit main pulmonary artery.

    PubMed

    Okabe, K; Kitamura, K; Kuriyama, H

    1988-04-01

    To characterize the inward current recorded from single smooth muscle cells of the rabbit main pulmonary artery, a voltage clamp procedure using patch pipettes filled with high Cs solution to inhibit K currents was employed. Under superfusion with normal physiological salt solution, application of a command potential to -10 mV from the holding potential of -80 mV elicited an inward current comprising fast and slow components. In Ca-free solution containing 2.5 mM Mn and 134 mM Na, the major part of the slow inwart current (Islow) ceased, but a transient fast inward current (Ifast) remained. A reduction in the Na concentration in the bath solution inhibited the amplitude of Ifast. Both nicardipine (30 nM) and diltiazem (1-10 microM) inhibited Islow but had no effect on Ifast. Application of tetrodotoxin (greater than 1 nM) in Ca free solution inhibited the amplitude of Ifast in a dose-dependent manner with a dissociation constant of 8.7 nM. Chloramine-T (0.3 mM) increased the peak amplitude and reduced the rate of decay of Ifast and completely inhibited Islow. These results suggest that the inward curent generated in the smooth muscle cells of the rabbit main pulmonary artery is associated with activation of a voltage-dependent Ca channel and a tetrodotoxin-sensitive Na channel. PMID:2456516

  15. [Medical therapy for intracranial hemorrhage: update blood pressure management for prevention and acute treatment].

    PubMed

    Koga, Masatoshi; Toyoda, Kazunori

    2012-01-01

    Intracerebral hemorrhage (ICH) is a common stroke subtype in Japan. Hypertension is the leading cause. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) revealed that blood pressure (BP) lowering could reduce stroke recurrence by 28% (ICH recurrence by 49%). The guideline for the management of hypertension (JSH2009) recommends BP control of ≤ 140/90 mm Hg for patients with prior stroke. BP is frequently elevated in acute ICH, although BP management strategy is controversial. The guideline from the American Stroke Association suggests if systolic BP (SBP) >180 mm Hg and there is no evidence of elevated intracranial pressure, then consider a modest reduction of BP. A nationwide survey revealed that SBP lowering to ≤ 160 mm Hg using intravenous nicardipine in acute ICH is a major strategy in Japan, and the safety was confirmed by a multicenter, prospective, observational study. Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT) and Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) showed the feasibility and safety of early rapid BP lowering to 140 mm Hg. INTERACT2 and ATACH II are the randomized trials to compare the guideline-based control (<180 mm Hg) and strict control (<140 mm Hg). We have just started to enroll patients to ATACH II from Japan on February 2012.

  16. Blood pressure control in acute cerebrovascular disease.

    PubMed

    Owens, William B

    2011-03-01

    Acute cerebrovascular diseases (ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage) affect 780,000 Americans each year. Physicians who care for patients with these conditions must be able to recognize when acute hypertension requires treatment and should understand the principles of cerebral autoregulation and perfusion. Physicians should also be familiar with the various pharmacologic agents used in the treatment of cerebrovascular emergencies. Acute ischemic stroke frequently presents with hypertension, but the systemic blood pressure should not be treated unless the systolic pressure exceeds 220 mm Hg or the diastolic pressure exceeds 120 mm Hg. Overly aggressive treatment of hypertension can compromise collateral perfusion of the ischemic penumbra. Hypertension associated with intracerebral hemorrhage can be treated more aggressively to minimize hematoma expansion during the first 3 to 6 hours of illness. Subarachnoid hemorrhage is usually due to aneurysmal rupture; systolic blood pressure should be kept <150 mm Hg to prevent re-rupture of the aneurysm. Nicardipine and labetalol are recommended for rapidly treating hypertension during cerebrovascular emergencies. Sodium nitroprusside is not recommended due to its adverse effects on cerebral autoregulation and intracranial pressure. Hypoperfusion of the injured brain should be avoided at all costs.

  17. [A Case of Undiagnosed Extra-adrenal Pheochromocytoma in an Adult Patient with Single Ventricle Circulation after the Bidirectional Glenn Operation].

    PubMed

    Kohno, Masaki; Nagamine, Yusuke; Goto, Takahisa

    2015-09-01

    We experienced a case of undiagnosed extra-adrenal pheochromocytoma in an adult patient with single ventricle circulation after the bidirectional Glenn operation. A 32-year-old woman was scheduled for open abdominal surgery for incidental retroperitoneal tumor. She had undergone the bidirectional Glenn operation for complex congenital heart disease consisting of double outlet right ventricle, ventricular septal defect, and pulmonary artery stenosis. She had not undergone the Fontan operation because of insufficient development of pulmonary circulation. Her physical status was New York Heart Association (NYHA) functional class II, and her oxygen saturation was 80% in room air. She reported no symptoms for the abdominal tumor preoperatively. The surgery was performed under general and epidural anesthesia. After induction of general anesthesia, she developed hypertension and tachycardia, and the manipulation of the tumor worsened them. Landiolol, a short acting beta blocker, and nicardipine were administrated. After the resection of the tumor, hypotension refractory to volume replacement emerged, and we administrated low dose noradrenaline. She was extubated in'the operating room and was transferred to the intensive care unit. The histopathological examination of the tumor revealed extra-adrenal pheochromocytoma (paraganglioma). Catecholamine release from pheochromocytoma can be dangerous in patients with single ventricular circulation because it may elevate pulmonary resistance and thereby decrease cardiac output. Thorough preoperative examination is desirable. PMID:26466501

  18. Cholesterol reduces the sensitivity to platinum-based chemotherapy via upregulating ABCG2 in lung adenocarcinoma.

    PubMed

    Wu, Yufeng; Si, Ruirui; Tang, Hong; He, Zhen; Zhu, Hui; Wang, Lili; Fan, Yingchao; Xia, Suhua; He, Zelai; Wang, Qiming

    2015-02-20

    Inoperable lung adenocarcinoma is currently treated with platinum-based chemotherapy. However, the effectiveness of these chemotherapeutic agents is not the same for all patients. Patients either show quick chemoresistance (QCR) or delayed chemoresistance (DCR), which are defined by 87 and 242 days of progression-free survival (PFS) after initial platinum-based treatment, respectively. We found that QCR patients displayed an elevated level of serum cholesterol and that their tumors showed upregulated ABCG2 expression. We propose that chemoresistance may be attributed to cholesterol-induced ABCG2 expression and hypothesize that blocking ABCG2 may increase the efficacy of platinum-based chemotherapeutic agents. Using the MTT cell viability assay, we observed that cotreatment with ABCG2 blocker Nicardipine and platinum-based drugs Cisplatin, Oxaliplatin or Carboplatin significantly decreased cell viability of tumor cells. Importantly, our results also showed that incubating cells with cholesterol prior to chemotherapy treatment or cotreatment increased cell viability of tumor cells relative to the controls.

  19. Dutch guideline for the management of hypertensive crisis -- 2010 revision.

    PubMed

    van den Born, B J H; Beutler, J J; Gaillard, C A J M; de Gooijer, A; van den Meiracker, A H; Kroon, A A

    2011-05-01

    Hypertensive crises are divided into hypertensive urgencies and emergencies. Together they form a heterogeneous group of acute hypertensive disorders depending on the presence or type of target organs involved. Despite better treatment options for hypertension, hypertensive crisis and its associated complications remain relatively common. In the Netherlands the number of patients starting renal replacement therapy because of 'malignant hypertension' has increased in the past two decades. In 2003, the first Dutch guideline on hypertensive crisis was released to allow a standardised evidence-based approach for patients presenting with a hypertensive crisis. In this paper we give an overview of the current management of hypertensive crisis and discuss several important changes incorporated in the 2010 revision. These changes include a modification in terminology replacing 'malignant hypertension' with 'hypertensive crisis with retinopathy and reclassification of hypertensive crisis with retinopathy under hypertensive emergencies instead of urgencies. With regard to the treatment of hypertensive emergencies, nicardipine instead of nitroprusside or labetalol is favoured for the management of perioperative hypertension, whereas labetalol has become the drug of choice for the treatment of hypertension associated with pre-eclampsia. For the treatment of hypertensive urgencies, oral administration of nifedipine retard instead of captopril is recommended as first-line therapy. In addition, a section on the management of hypertensive emergencies according to the type of target organ involved has been added. Efforts to increase the awareness and treatment of hypertension in the population at large may lower the incidence of hypertensive crisis and its complications.

  20. Use of Continuous Infusion Hydralazine in a Pediatric Patient on Mechanical Circulatory Support.

    PubMed

    Dillman, Nicholas O; Anders, Marc M; Moffett, Brady S

    2016-01-01

    Hydralazine is a direct peripheral arterial vasodilator used for acute hypertension. Usually administered as a bolus dose, continuous infusion has been described during pregnancy for preeclampsia and eclampsia and in limited reports in cardiac surgeries for afterload reduction. This case describes the use of continuous infusion hydralazine for afterload reduction in an infant receiving extracorporeal membrane oxygenation (ECMO) post-cardiac surgery. Postsurgery, the patient's mean arterial pressures (MAPs) could not be controlled despite escalating doses of vasodilatory medications including nitroprusside, nicardipine, and milrinone; hence, continuous infusion hydralazine was initiated. Although the initiation of a hydralazine infusion produced a decrease in MAP, the response was unsustainable. This case highlights an alternative method for managing systemic vascular resistance and cardiac output to allow for myocardial recovery after cardiac surgery and use of extracorporeal support. At the time of this writing, this is the first published case describing hydralazine administration via continuous infusion in pediatric patients. The use of continuous infusion hydralazine for afterload reduction provided a brief, non-sustained reduction in MAP in a post-cardiac surgery infant managed on ECMO support.

  1. Use of Continuous Infusion Hydralazine in a Pediatric Patient on Mechanical Circulatory Support

    PubMed Central

    Dillman, Nicholas O.; Anders, Marc M.

    2016-01-01

    Hydralazine is a direct peripheral arterial vasodilator used for acute hypertension. Usually administered as a bolus dose, continuous infusion has been described during pregnancy for preeclampsia and eclampsia and in limited reports in cardiac surgeries for afterload reduction. This case describes the use of continuous infusion hydralazine for afterload reduction in an infant receiving extracorporeal membrane oxygenation (ECMO) post–cardiac surgery. Postsurgery, the patient's mean arterial pressures (MAPs) could not be controlled despite escalating doses of vasodilatory medications including nitroprusside, nicardipine, and milrinone; hence, continuous infusion hydralazine was initiated. Although the initiation of a hydralazine infusion produced a decrease in MAP, the response was unsustainable. This case highlights an alternative method for managing systemic vascular resistance and cardiac output to allow for myocardial recovery after cardiac surgery and use of extracorporeal support. At the time of this writing, this is the first published case describing hydralazine administration via continuous infusion in pediatric patients. The use of continuous infusion hydralazine for afterload reduction provided a brief, non-sustained reduction in MAP in a post–cardiac surgery infant managed on ECMO support. PMID:27453704

  2. Hypertensive crisis during pregnancy and postpartum period.

    PubMed

    Too, Gloria T; Hill, James B

    2013-08-01

    Hypertension affects 10% of pregnancies, many with underlying chronic hypertension, and approximately 1-2% will undergo a hypertensive crisis at some point during their lives. Hypertensive crisis includes hypertensive urgency and emergency; the American College of Obstetricians and Gynecologists describes a hypertensive emergency in pregnancy as persistent (lasting 15 min or more), acute-onset, severe hypertension, defined as systolic BP greater than 160 mmHg or diastolic BP >110 mmHg in the setting of pre-eclampsia or eclampsia. Pregnancy may be complicated by hypertensive crisis, with lower blood pressure threshold for end-organ damage than non-pregnant patients. Maternal assessment should include a thorough history. Fetal assessment should include heart rate tracing, ultrasound for growth and amniotic assessment, and Doppler evaluation if growth restriction is suspected. Initial management of hypertensive emergency (systolic BP >160 mmHg or diastolic BP >110 mmHg in the setting of pre-eclampsia or eclampsia) generally includes the rapid reduction of blood pressure through the use of intravenous antihypertensive medications, with goal systolic blood pressure between 140 mmHg and 150 mmHg and diastolic pressure between 90 mmHg and 100 mmHg. First-line intravenous drugs include labetalol and hydralazine, but other agents may be used, including esmolol, nicardipine, nifedipine, and, as a last resort, sodium nitroprusside. Among patients with hypertensive urgency, slower blood pressure reduction can be provided with oral agents. The objective of this article is to review the current understanding, diagnosis, and management of hypertensive crisis during pregnancy and the postpartum period.

  3. LIM Kinase, a Newly Identified Regulator of Presynaptic Remodeling by Rod Photoreceptors After Injury

    PubMed Central

    Wang, Weiwei; Townes-Anderson, Ellen

    2015-01-01

    Purpose Rod photoreceptors retract their axon terminals and develop neuritic sprouts in response to retinal detachment and reattachment, respectively. This study examines the role of LIM kinase (LIMK), a component of RhoA and Rac pathways, in the presynaptic structural remodeling of rod photoreceptors. Methods Phosphorylated LIMK (p-LIMK), the active form of LIMK, was examined in salamander retina with Western blot and confocal microscopy. Axon length within the first 7 hours and process growth after 3 days of culture were assessed in isolated rod photoreceptors treated with inhibitors of upstream regulators ROCK and p21-activated kinase (Pak) (Y27632 and IPA-3) and a direct LIMK inhibitor (BMS-5). Porcine retinal explants were also treated with BMS-5 and analyzed 24 hours after detachment. Because Ca2+ influx contributes to axonal retraction, L-type channels were blocked in some experiments with nicardipine. Results Phosphorylated LIMK is present in rod terminals during retraction and in newly formed processes. Axonal retraction over 7 hours was significantly reduced by inhibition of LIMK or its regulators, ROCK and Pak. Process growth was reduced by LIMK or Pak inhibition especially at the basal (axon-bearing) region of the rod cells. Combining Ca2+ channel and LIMK inhibition had no additional effect on retraction but did further inhibit sprouting after 3 days. In detached porcine retina, LIMK inhibition reduced rod axonal retraction and improved retinal morphology. Conclusions Thus structural remodeling, in the form of either axonal retraction or neuritic growth, requires LIMK activity. LIM kinase inhibition may have therapeutic potential for reducing pathologic rod terminal plasticity after retinal injury. PMID:26658506

  4. Method development and validation for the simultaneous determination of cinnarizine and co-formulated drugs in pharmaceutical preparations by capillary electrophoresis.

    PubMed

    Abdelal, A A; Kitagawa, S; Ohtani, H; El-Enany, N; Belal, F; Walash, M I

    2008-02-13

    Rapid and simple capillary electrophoresis (CE) methods were developed for the simultaneous determinations of cinnarizine and domperidone (CN/DOM) and cinnarizine and nicergoline (CN/NIC) in their co-formulated tablets. The optimized CE conditions were as follows: running buffer, methanol-acetate buffer (pH 3.0, 10 mM) (80:20 and 85:15 (v/v) for CN/DOM and CN/NIC, respectively); applied voltage, 20 kV; UV detection wavelengths, 215 and 227 nm for CN/DOM and CN/NIC, respectively; hydrodynamic injection was performed at a height of 25 mm for 30 s. Quinine hydrochloride and nicardipine hydrochloride were used as internal standards for the determination of CN/DOM and CN/NIC, respectively. Calibration curves were linear over the ranges 0.25-20/0.375-15 microg/ml (CN/DOM) and 0.25-25/0.4-10 microg/ml (CN/NIC) in each optimized condition. Detection limits were 0.074/0.119 microg/ml and 0.072/0.116 microg/ml for CN/DOM and CN/NIC, respectively. The proposed methods were successfully applied for the simultaneous determination of both CN/DOM and CN/NIC in their co-formulated tablets without interfering peaks due to the excipients present in the pharmaceutical tablets. The estimated amounts of CN/DOM and CN/NIC were almost identical with the certified values, and their percentage relative standard deviation values (%R.S.D.) were found to be < or =2.34% (n=3). PMID:18164891

  5. Anti-hypertensive treatment in pheochromocytoma and paraganglioma: current management and therapeutic features.

    PubMed

    Mazza, Alberto; Armigliato, Michela; Marzola, Maria Cristina; Schiavon, Laura; Montemurro, Domenico; Vescovo, Giorgio; Zuin, Marco; Chondrogiannis, Sotirios; Ravenni, Roberta; Opocher, Giuseppe; Colletti, Patrick M; Rubello, Domenico

    2014-04-01

    Pheochromocytoma (PH) and paraganglioma (PG) are neuroendocrine neoplasms arising from chromaffin cells of the adrenal medulla and the sympathetic ganglia, respectively. Although are unusual cause of hypertension (HT) accounting for at most 0.1-0.2 % of cases, they may lead to severe and potentially lethal hypertensive crisis due to the effects of the released catecholamines. However, both PH and PG may be asymptomatic as ~30 % of subjects are normotensive or have orthostatic hypotension and in these cases the 24 h ambulatory blood pressure (BP) monitoring is an important toll to diagnose and treat HT. HT treatment may be difficult when PH or PG occurs in pregnancy or in the elderly subjects and in these cases a multidisciplinary team is required. When surgical excision is mandatory the perioperative management requires the administration of selective α1-adrenergic blocking agents (i.e., doxazosin, prazosin or terazosin) followed by a β-adrenergic blockade (i.e., propranolol, atenolol). This latter should never be started first because blockade of vasodilatory peripheral β-adrenergic receptors with unopposed α-adrenergic receptor stimulation can lead to a further elevation of BP. Although labetalol is traditionally considered the ideal agent due to its α- and β-adrenergic antagonism, experimental studies do not support its use in this clinical setting. As second regimen, the administration of vasodilators as calcium channel blockers (i.e., nicardipine, nifedipine) may be required to control BP. Oral and sublingual short-acting nifedipine are potentially dangerous in patients with hypertensive emergencies and are not recommend. The latest evidences into the diagnosis and treatment of hypertensive crisis due to PH and PG are reviewed here.

  6. Does the use of thiopental provide added cerebral protection during deep hypothermic circulatory arrest?

    PubMed

    Al-Hashimi, Sara; Zaman, Mahvash; Waterworth, Paul; Bilal, Haris

    2013-08-01

    A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: Does the use of thiopental provide added cerebral protection during deep hypothermic circulatory arrest (DHCA)? Altogether, more than 62 papers were found using the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Four of the seven papers used thiopental alongside other neuroprotective methods and agents. The methods included the use of ice packs to the head and core systemic hypothermia. Agents used alongside thiopental included nicardipine and mannitol. Thiopental was found to have the ability to lower oxygen consumption, where oxygen consumption was measured using the phosphocreatinine and adenosine triphosphate ratio. The neuroprotective effect of thiopental was evaluated by assessing the electrical activity of the brain during circulatory arrest, by which it was shown to be advantageous. However, other trials suggested that adding thiopental during circulatory arrest did not provide any extra protection to the brain. The timing of thiopental administration is of importance in order to gain positive outcomes, as it's ability to lower the cerebral energy state may result in unfavourable results if added before hypothermic circulatory arrest, where this may lead to an ischaemic event. We conclude that the use of thiopental during deep hypothermic circulatory arrest is beneficial, but if administered too early, it may replete the cerebral energy state before arrest and prove to be detrimental. PMID:23644730

  7. Perioperative Use of Dexmedetomidine is Associated with Decreased Incidence of Ventricular and Supraventricular Tachyarrhythmias after Congenital Cardiac Surgery

    PubMed Central

    Chrysostomou, Constantinos; Sanchez-de-Toledo, Joan; Wearden, Peter; Jooste, Edmund H; Lichtenstein, Steven E; Callahan, Patrick M; Suresh, Tunga; O’Malley, Elizabeth; Shiderly, Dana; Haney, Jamie; Yoshida, Masahiro; Orr, Richard; Munoz, Ricardo; Morell, Victor O

    2012-01-01

    Background Postoperative tachyarrhythmias remain a common complication after congenital cardiac surgery. A recent case-series has shown that dexmedetomidine, an alpha-2 adrenoreceptor agonist can have a therapeutic role in supraventricular tachyarrhythmias for either cardioversion to sinus rhythm or heart rate control. The present study was performed to determine if routine perioperative use of dexmedetomidine can decrease the incidence of supraventricular and ventricular tachyarrhythmias. Methods Prospective cohort study of pediatric patients undergoing cardiothoracic surgery. Thirty-two patients who were initiated on dexmedetomidine infusion (DEX-group) before surgery were compared with 20 patients who did not receive dexmedetomidine (control-group). Results Dexmedetomidine was started after anesthesia induction and continued through surgery and postoperative period for 38±4 hours at a mean dose of 0.76 ±0.04 mcg/kg/hr. Ten patients in control-group and 2 in DEX-group (p=0.001) had a total of 16 episodes of tachyarrhythmias. The incidence of ventricular tachycardia was 25% vs.0% (p=0.01) and of supraventricular arrhythmias 25% vs. 6% (p=0.05) in the control and DEX-group respectively. Two patients in the control-group and 1 in the Dex-group had transient complete heart block. Control-group had a higher heart rate 141 ± 5 vs.127 ±3 bpm (p=0.03), more sinus tachycardia episodes 40% vs. 6% (p=0.008), required more antihypertensives with nitroprusside 20 ± 7 vs.4 ± 1 mcg/kg (p=0.004) and nicardipine 13 ± 5 vs.2 ± 1 mcg/kg (p=0.02) and required more fentanyl 39 ± 8 vs.19 ± 3 mcg/kg (p=0.005). Conclusions Perioperative use of dexmedetomidine is associated with significantly decreased incidence of ventricular and supraventricular tachyarrhythmias without significant adverse effects. PMID:21871284

  8. Sodium-calcium exchanger and R-type Ca(2+) channels mediate spontaneous [Ca(2+)]i oscillations in magnocellular neurones of the rat supraoptic nucleus.

    PubMed

    Kortus, Stepan; Srinivasan, Chinnapaiyan; Forostyak, Oksana; Zapotocky, Martin; Ueta, Yoichi; Sykova, Eva; Chvatal, Alexandr; Verkhratsky, Alexei; Dayanithi, Govindan

    2016-06-01

    Isolated supraoptic neurones generate spontaneous [Ca(2+)]i oscillations in isolated conditions. Here we report in depth analysis of the contribution of plasmalemmal ion channels (Ca(2+), Na(+)), Na(+)/Ca(2+) exchanger (NCX), intracellular Ca(2+) release channels (InsP3Rs and RyRs), Ca(2+) storage organelles, plasma membrane Ca(2+) pump and intracellular signal transduction cascades into spontaneous Ca(2+) activity. While removal of extracellular Ca(2+) or incubation with non-specific voltage-gated Ca(2+) channel (VGCC) blocker Cd(2+) suppressed the oscillations, neither Ni(2+) nor TTA-P2, the T-type VGCC blockers, had an effect. Inhibitors of VGCC nicardipine, ω-conotoxin GVIA, ω-conotoxin MVIIC, ω-agatoxin IVA (for L-, N-, P and P/Q-type channels, respectively) did not affect [Ca(2+)]i oscillations. In contrast, a specific R-type VGCC blocker SNX-482 attenuated [Ca(2+)]i oscillations. Incubation with TTX had no effect, whereas removal of the extracellular Na(+) or application of an inhibitor of the reverse operation mode of Na(+)/Ca(2+) exchanger KB-R7943 blocked the oscillations. The mitochondrial uncoupler CCCP irreversibly blocked spontaneous [Ca(2+)]i activity. Exposure of neurones to Ca(2+) mobilisers (thapsigargin, cyclopiazonic acid, caffeine and ryanodine); 4-aminopyridine (A-type K(+) current blocker); phospholipase C and adenylyl cyclase pathways blockers U-73122, Rp-cAMP, SQ-22536 and H-89 had no effect. Oscillations were blocked by GABA, but not by glutamate, apamin or dynorphin. In conclusion, spontaneous oscillations in magnocellular neurones are mediated by a concerted action of R-type Ca(2+) channels and the NCX fluctuating between forward and reverse modes. PMID:27052156

  9. Quantitative prediction of intestinal metabolism in humans from a simplified intestinal availability model and empirical scaling factor.

    PubMed

    Kadono, Keitaro; Akabane, Takafumi; Tabata, Kenji; Gato, Katsuhiko; Terashita, Shigeyuki; Teramura, Toshio

    2010-07-01

    This study aimed to establish a practical and convenient method of predicting intestinal availability (F(g)) in humans for highly permeable compounds at the drug discovery stage, with a focus on CYP3A4-mediated metabolism. We constructed a "simplified F(g) model," described using only metabolic parameters, assuming that passive diffusion is dominant when permeability is high and that the effect of transporters in epithelial cells is negligible. Five substrates for CYP3A4 (alprazolam, amlodipine, clonazepam, midazolam, and nifedipine) and four for both CYP3A4 and P-glycoprotein (P-gp) (nicardipine, quinidine, tacrolimus, and verapamil) were used as model compounds. Observed fraction of drug absorbed (F(a)F(g)) values for these compounds were calculated from in vivo pharmacokinetic (PK) parameters, whereas in vitro intestinal intrinsic clearance (CL(int,intestine)) was determined using human intestinal microsomes. The CL(int,intestine) for the model compounds corrected with that of midazolam was defined as CL(m,index) and incorporated into a simplified F(g) model with empirical scaling factor. Regardless of whether the compound was a P-gp substrate, the F(a)F(g) could be reasonably fitted by the simplified F(g) model, and the value of the empirical scaling factor was well estimated. These results suggest that the effects of P-gp on F(a) and F(g) are substantially minor, at least in the case of highly permeable compounds. Furthermore, liver intrinsic clearance (CL(int,liver)) can be used as a surrogate index of intestinal metabolism based on the relationship between CL(int,liver) and CL(m,index). F(g) can be easily predicted using a simplified F(g) model with the empirical scaling factor, enabling more confident selection of drug candidates with desirable PK profiles in humans. PMID:20354105

  10. pH-Dependent Liquid-Liquid Phase Separation of Highly Supersaturated Solutions of Weakly Basic Drugs.

    PubMed

    Indulkar, Anura S; Box, Karl J; Taylor, Robert; Ruiz, Rebeca; Taylor, Lynne S

    2015-07-01

    Supersaturated solutions of poorly aqueous soluble drugs can be formed both in vivo and in vitro. For example, increases in pH during gastrointestinal transit can decrease the aqueous solubility of weakly basic drugs resulting in supersaturation, in particular when exiting the acidic stomach environment. Recently, it has been observed that highly supersaturated solutions of drugs with low aqueous solubility can undergo liquid-liquid phase separation (LLPS) prior to crystallization, forming a turbid solution such that the concentration of the drug in the continuous solution phase corresponds to the amorphous solubility while the colloidal phase is composed of a disordered drug-rich phase. Although it is well established that the equilibrium solubility of crystalline weakly basic drugs follows the Henderson-Hasselbalch relationship, the impact of pH on the LLPS phenomenon or the amorphous solubility has not been explored. In this work, the LLPS concentration of three weakly basic compounds-clotrimazole, nicardipine, and atazanavir-was determined as a function of pH using three different methods and was compared to the predicted amorphous solubility, which was calculated from the pH-dependent crystalline solubility and by estimating the free energy difference between the amorphous and crystalline forms. It was observed that, similar to crystalline solubility, the experimental amorphous solubility at any pH follows the Henderson-Hasselbalch relation and can be predicted if the amorphous solubility of the free base is known. Excellent agreement between the LLPS concentration and the predicted amorphous solubility was observed. Dissolution studies of amorphous drugs showed that the solution concentration can reach the corresponding LLPS concentration at that pH. Solid-state analysis of the precipitated material confirmed the amorphous nature. This work provides insight into the pH-dependent precipitation behavior of poorly water-soluble compounds and provides a

  11. G(o) transduces GABAB-receptor modulation of N-type calcium channels in cultured dorsal root ganglion neurons.

    PubMed

    Menon-Johansson, A S; Berrow, N; Dolphin, A C

    1993-11-01

    High-voltage-activated (HVA) calcium channel currents (IBa) were recorded from acutely replated cultured dorsal root ganglion (DRG) neurons. IBa was irreversibly inhibited by 56.9 +/- 2.7% by 1 microM omega-conotoxin-GVIA (omega-CTx-GVIA), whereas the 1,4-dihydropyridine antagonist nicardipine was ineffective. The selective gamma-aminobutyric acidB (GABAB) agonist, (-)-baclofen (50 microM), inhibited the HVA IBa by 30.7 +/- 5.4%. Prior application of omega-CTx-GVIA completely occluded inhibition of the HVA IBa by (-)-baclofen, indicating that in this preparation (-)-baclofen inhibits N-type current. To investigate which G protein subtype was involved, cells were replated in the presence of anti-G protein antisera. Under these conditions the antibodies were shown to enter the cells through transient pores created during the replating procedure. Replating DRGs in the presence of anti-G(o) antiserum, raised against the C-terminal decapeptide of the G alpha o subunit, reduced (-)-baclofen inhibition of the HVA IBa, whereas replating DRGs in the presence of the anti-Gi antiserum did not. Using anti-G alpha o antisera (1:2000) and confocal laser microscopy, G alpha o localisation was investigated in both unreplated and replated neurons. G alpha o immunoreactivity was observed at the plasma membrane, neurites, attachment plaques and perinuclear region, and was particularly pronounced at points of cell-to-cell contact. The plasma membrane G alpha o immunoreactivity was completely blocked by preincubation with the immunising G alpha o undecapeptide (1 microgram.ml-1) for 1 h at 37 degrees C. A similar treatment also blocked recognition of G alpha o in brain membranes on immunoblots.(ABSTRACT TRUNCATED AT 250 WORDS)

  12. Deltamethrin, a type II pyrethroid insecticide, has neurotrophic effects on neurons with continuous activation of the Bdnf promoter.

    PubMed

    Ihara, Daisuke; Fukuchi, Mamoru; Honma, Daisuke; Takasaki, Ichiro; Ishikawa, Mitsuru; Tabuchi, Akiko; Tsuda, Masaaki

    2012-02-01

    Pyrethroids, widely used insecticides with low acute toxicity in mammals, affect sodium channels in neurons. In a primary culture of rat cortical neurons, deltamethrin (DM), a type II pyrethroid, markedly enhanced the expression of brain-derived neurotrophic factor (BDNF) exon IV-IX (Bdnf eIV-IX) mRNA. In this study, we found that DM has a neurotrophic effect on cultured neurons and investigated the mechanisms responsible for it. One μM DM increased cell survival, neurite complexity and length. Neurite complexity and length were reduced not only by a blockade of cellular excitation with GABA or Ca(2+) influx via L-type voltage-dependent calcium channels with nicardipine, but also by a blockade of TrkB, a specific receptor for BDNF, with TrkB/Fc. These data indicate DM has neurotrophic actions. DM-induced Bdnf eIV-IX mRNA expression through the calcineurin and ERK/MAPK pathways, the increase of which was reduced by GABA(A) receptor activation. Using a promoter assay, we found that Ca(2+)-responsive elements including a CRE are involved in the DM-induced activation of the Bdnf promoter IV (Bdnf-pIV). The intracellular concentration of Ca(2+) and activation of Bdnf-pIV remained elevated for, at least, 1 and 24 h, respectively. Moreover, GABA(A) receptor activation or a blockade of Ca(2+) influx even after starting the incubation with DM reduced the elevated activity of Bdnf-pIV. These data demonstrated that the prolonged activation of Bdnf-pIV occurred because of this continuous increase in the intracellular Ca(2+) concentration. Thus, DM has neurotrophic effects on neurons, likely due to prolonged activation of Bdnf promoter in neurons. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

  13. G(o) transduces GABAB-receptor modulation of N-type calcium channels in cultured dorsal root ganglion neurons.

    PubMed

    Menon-Johansson, A S; Berrow, N; Dolphin, A C

    1993-11-01

    High-voltage-activated (HVA) calcium channel currents (IBa) were recorded from acutely replated cultured dorsal root ganglion (DRG) neurons. IBa was irreversibly inhibited by 56.9 +/- 2.7% by 1 microM omega-conotoxin-GVIA (omega-CTx-GVIA), whereas the 1,4-dihydropyridine antagonist nicardipine was ineffective. The selective gamma-aminobutyric acidB (GABAB) agonist, (-)-baclofen (50 microM), inhibited the HVA IBa by 30.7 +/- 5.4%. Prior application of omega-CTx-GVIA completely occluded inhibition of the HVA IBa by (-)-baclofen, indicating that in this preparation (-)-baclofen inhibits N-type current. To investigate which G protein subtype was involved, cells were replated in the presence of anti-G protein antisera. Under these conditions the antibodies were shown to enter the cells through transient pores created during the replating procedure. Replating DRGs in the presence of anti-G(o) antiserum, raised against the C-terminal decapeptide of the G alpha o subunit, reduced (-)-baclofen inhibition of the HVA IBa, whereas replating DRGs in the presence of the anti-Gi antiserum did not. Using anti-G alpha o antisera (1:2000) and confocal laser microscopy, G alpha o localisation was investigated in both unreplated and replated neurons. G alpha o immunoreactivity was observed at the plasma membrane, neurites, attachment plaques and perinuclear region, and was particularly pronounced at points of cell-to-cell contact. The plasma membrane G alpha o immunoreactivity was completely blocked by preincubation with the immunising G alpha o undecapeptide (1 microgram.ml-1) for 1 h at 37 degrees C. A similar treatment also blocked recognition of G alpha o in brain membranes on immunoblots.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8309795

  14. [Central effect of Ca2+ channel blockers: multiple sites of action].

    PubMed

    Shibuya, T; Watanabe, Y

    1992-09-01

    To develop a new concept of central acting drugs, the modulation of brain Ca2+ flux must be considered as one of the important factors. This is because excessive Ca2+ influx to neuronal cells damages or kills these cells, and also because abnormal intracellular Ca2+ concentrations induce several types of mental disorders. Recently, both pre-clinical and clinical studies indicated that some Ca2+ channel blockers (Ca antagonists) will be useful for the treatment of grand mal, manic depressive insanity, panic disorder and anxiety. Furthermore, it has been estimated by animal studies and clinical pharmacology that ischemia-induced neuronal death can be prevented by the treatment with a Ca antagonist. However, the latter data, especially, has been mainly explained by pharmacological effects on the cerebrovascular system, not because of possible direct central actions. To invoke the notion of direct central action, it must be assumed that Ca antagonists might pass the blood-brain barrier (BBB). This potentiality that some Ca antagonists (i.e., flunarizine, nicardipine, nimodipine, etc.) can pass the BBB has been initially explored. If substantiated, such direct central effects of Ca antagonists may explain both the psychotropic effects and neuronal protection by these agents. To investigate the actual therapeutic effects of Ca2+ antagonists on psychotropic disorders and neuronal death, a suitable animal model and reasonable methods and criteria must be established. Then, both preclinical and clinical studies can be expected to relate to atypical central acting drugs modulating the brain Ca2+ channels, and also to the development of new pharmacological properties of Ca2+ antagonists.

  15. Smooth muscle NOS, colocalized with caveolin-1, modulates contraction in mouse small intestine

    PubMed Central

    El-Yazbi, Ahmed F; Cho, Woo Jung; Cena, Jonathan; Schulz, Richard; Daniel, Edwin E

    2008-01-01

    Neuronal nitric oxide synthase (nNOS) in myenteric neurons is activated during peristalsis to produce nitric oxide which relaxes intestinal smooth muscle. A putative nNOS is also found in the membrane of intestinal smooth muscle cells in mouse and dog. In this study we studied the possible functions of this nNOS expressed in mouse small intestinal smooth muscle colocalized with caveolin-1(Cav-1). Cav-1 knockout mice lacked nNOS in smooth muscle and provided control tissues. 60 mM KCl was used to increase intracellular [Ca2+] through L-type Ca2+ channel opening and stimulate smooth muscle NOS activity in intestinal tissue segments. An additional contractile response to LNNA (100 μM, NOS inhibitor) was observed in KCl-contracted tissues from control mice and was almost absent in tissues from Cav-1 knockout mice. Disruption of caveolae with 40 mM methyl-β cyclodextrin in tissues from control mice led to the loss of Cav-1 and nNOS immunoreactivity from smooth muscle as shown by immunohistochemistry and a reduction in the response of these tissues to N-ω-nitro-L-arginine (LNNA). Reconstitution of membrane cholesterol using water soluble cholesterol in the depleted segments restored the immunoreactivity and the response to LNNA added after KCl. Nicardipine (1 μM) blocked the responses to KCl and LNNA confirming the role of L-type Ca2+ channels. ODQ (1 μM, soluble guanylate cyclase inhibitor) had the same effect as inhibition of NOS following KCl. We conclude that the activation of nNOS, localized in smooth muscle caveolae, by calcium entering through L-type calcium channels triggers nitric oxide production which modulates muscle contraction by a cGMP-dependent mechanism. PMID:18400048

  16. Designing an extended release waxy matrix tablet containing nicardipine–hydroxy propyl β cyclodextrin complex

    PubMed Central

    Al-Zein, Hind; Sakeer, Khalil; Alanazi, Fars K.

    2011-01-01

    Aim The current study aimed to prepare a sustained release tablet for a drug which has poor solubility in alkaline medium using complexation with cyclodextrin. Nicardipine hydrochloride (NC) a weak basic drug was chosen as a model drug for this study. Method Firstly the most suitable binary system NC-HPβCD was selected in order to improve drug solubility in the intestinal media and then embedding the complexed drug into a plastic matrix, by fusion method, consists of glycerol monostearate (GMS) as an inert waxy substance and polyethylene glycol 4000 (PEG4000) as a channeling agent, after that the final solid dispersion [(NC:HPβCD):GMS:PEG4000] which was prepared at different ratios was mixed with other excipients, avicel PH101, lactose, and talc, to get a tablet owning dissolution profile complying with the FDA and USP requirements for the extended release solid dosage forms. Results Infrared spectroscopy (IR), differential scanning colorimetry (DSC), polarized microscopy and X-ray diffractometry proved that the coevaporation technique was effective in preparing amorphous cyclodextrin complexes with NC and trapping of NC within the HPβCD cavity by dissolving both in ethanol and evaporate the solvent using a rotavapor at 65 °C. Dissolution profile of NC enhanced significantly in pH 6.8 from NC:HPβCD inclusion complex prepared by the rotavapor (t-test Student p < 0.05). The release of NC from tablet containing [(NC:HPβCD):GMS:PEG4000] [(1):0.75:0.5] (w/w/w) solid dispersion (F8) was complying with the FDA dissolution requirements for extended release dosage forms, and studying the kinetics of the release showed that the diffusional contribution is the major factor controlling the drug release from that formula. Conclusion The prepared waxy matrix tablet containing NC complexes with CD shows promising results as extended release tablets. PMID:23960765

  17. Osteoclast cytosolic calcium, regulated by voltage-gated calcium channels and extracellular calcium, controls podosome assembly and bone resorption

    NASA Technical Reports Server (NTRS)

    Miyauchi, A.; Hruska, K. A.; Greenfield, E. M.; Duncan, R.; Alvarez, J.; Barattolo, R.; Colucci, S.; Zambonin-Zallone, A.; Teitelbaum, S. L.; Teti, A.

    1990-01-01

    The mechanisms of Ca2+ entry and their effects on cell function were investigated in cultured chicken osteoclasts and putative osteoclasts produced by fusion of mononuclear cell precursors. Voltage-gated Ca2+ channels (VGCC) were detected by the effects of membrane depolarization with K+, BAY K 8644, and dihydropyridine antagonists. K+ produced dose-dependent increases of cytosolic calcium ([Ca2+]i) in osteoclasts on glass coverslips. Half-maximal effects were achieved at 70 mM K+. The effects of K+ were completely inhibited by dihydropyridine derivative Ca2+ channel blocking agents. BAY K 8644 (5 X 10(-6) M), a VGCC agonist, stimulated Ca2+ entry which was inhibited by nicardipine. VGCCs were inactivated by the attachment of osteoclasts to bone, indicating a rapid phenotypic change in Ca2+ entry mechanisms associated with adhesion of osteoclasts to their resorption substrate. Increasing extracellular Ca2+ ([Ca2+]e) induced Ca2+ release from intracellular stores and Ca2+ influx. The Ca2+ release was blocked by dantrolene (10(-5) M), and the influx by La3+. The effects of [Ca2+]e on [Ca2+]i suggests the presence of a Ca2+ receptor on the osteoclast cell membrane that could be coupled to mechanisms regulating cell function. Expression of the [Ca2+]e effect on [Ca2+]i was similar in the presence or absence of bone matrix substrate. Each of the mechanisms producing increases in [Ca2+]i, (membrane depolarization, BAY K 8644, and [Ca2+]e) reduced expression of the osteoclast-specific adhesion structure, the podosome. The decrease in podosome expression was mirrored by a 50% decrease in bone resorptive activity. Thus, stimulated increases of osteoclast [Ca2+]i lead to cytoskeletal changes affecting cell adhesion and decreasing bone resorptive activity.

  18. Efficacy of Raynaud's phenomenon and digital ulcer pharmacological treatment in systemic sclerosis patients: a systematic literature review.

    PubMed

    García de la Peña Lefebvre, Paloma; Nishishinya, María Betina; Pereda, Claudia Alejandra; Loza, Estíbaliz; Sifuentes Giraldo, Walter Alberto; Román Ivorra, José Andrés; Carreira, Patricia; Rúa-Figueroa, Iñigo; Pego-Reigosa, Jose María; Muñoz-Fernández, Santiago

    2015-09-01

    To evaluate the efficacy of current treatments for the Raynaud phenomenon (RP) in patients with systemic sclerosis (SSc), a systematic literature search was performed using Medline, EMBASE, and Cochrane Central Register of Controlled Trials (from 1961 to October 2011). We included meta-analyses, systematic reviews, clinical trials, and high-quality cohort studies published in English or Spanish. Patient populations had to include adults diagnosed with limited cutaneous or diffuse SSc who had associated RP and/or digital ulcers under pharmacological treatment. Efficacy of treatments was evaluated based on: number of RP episodes, RP severity, episode-free time, ulcer improvement/healing, and appearance of new ulcers. We used the Jadad scale of methodological quality to evaluate the quality of randomized clinical trials, and the 2009 Oxford Centre for Evidence-Based Medicine classification for other studies. Of a total of 1617 studies identified, only 27 fulfilled inclusion criteria. Drugs received the following grade recommendations: Grade A for nifedipine, nicardipine, quinapril, IV iloprost, bosentan, tadalafil, and MQx-503; Grade B for beraprost, cicaprost, DMSO, cyclofenil, and atorvastatin; and Grade C for misoprostol, prazosin, OPC-2826, enalapril, sildenafil, antioxidant, and stanazolol. Calcium channel blockers, prostanoids, tadalafil, and bosentan received the highest recommendation level for their effectiveness. However, most systematic reviews reviewed just a handful of studies with small sample sizes and short follow-ups. Our review shows that the existing evidence on the efficacy of RP treatment in SSc patients is inconclusive which calls for further research, especially in the form of prospective studies of high quality with long-term follow-ups.

  19. Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine.

    PubMed

    Zheng, Haifeng; Park, Kyung Sik; Koh, Sang Don; Sanders, Kenton M

    2014-04-01

    Interstitial cells of Cajal (ICC) generate slow waves in gastrointestinal (GI) muscles. Previous studies have suggested that slow wave generation and propagation depends on a voltage-dependent Ca(2+) entry mechanism with the signature of a T-type Ca(2+) conductance. We studied voltage-dependent inward currents in isolated ICC. ICC displayed two phases of inward current upon depolarization: a low voltage-activated inward current and a high voltage-activated current. The latter was of smaller current density and blocked by nicardipine. Ni(2+) (30 μM) or mibefradil (1 μM) blocked the low voltage-activated current. Replacement of extracellular Ca(2+) with Ba(2+) did not affect the current, suggesting that either charge carrier was equally permeable. Half-activation and half-inactivation occurred at -36 and -59 mV, respectively. Temperature sensitivity of the Ca(2+) current was also characterized. Increasing temperature (20-30°C) augmented peak current from -7 to -19 pA and decreased the activation time from 20.6 to 7.5 ms [temperature coefficient (Q10) = 3.0]. Molecular studies showed expression of Cacna1g (Cav3.1) and Cacna1h (Cav3.2) in ICC. The temperature dependence of slow waves in intact jejunal muscles of wild-type and Cacna1h(-/-) mice was tested. Reducing temperature decreased the upstroke velocity significantly. Upstroke velocity was also reduced in muscles of Cacna1h(-/-) mice, and Ni(2+) or reduced temperature had little effect on these muscles. Our data show that a T-type conductance is expressed and functional in ICC. With previous studies our data suggest that T-type current is required for entrainment of pacemaker activity within ICC and for active propagation of slow waves in ICC networks. PMID:24477235

  20. Efficacy and safety of intravenous nimodipine administration for treatment of hypertension in patients with intracerebral hemorrhage

    PubMed Central

    Li, Yuqian; Fang, Wei; Tao, Lei; Li, Min; Yang, Yanlong; Gao, Yafei; Ge, Shunnan; Gao, Li; Zhang, Bin; Li, Zhihong; Zhou, Wei; Wang, Boliang; Li, Lihong

    2015-01-01

    Background Nicardipine (NC) is the most commonly used antihypertensive drug in neurological patients with hypertension. Although nimodipine (NM) is widely used to treat cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage, trials exploring its antihypertensive effect after intravenous administration in subjects with intracerebral hemorrhage (ICH) are scarce. Methods A retrospective study was carried out to compare the safety and efficacy of NC and NM administered intravenously in patients with ICH. Therapeutic responses were assessed by achievement of goal blood pressure (BP); use of additional medications for BP control; proportion of time spent within goal; variability in BP; time to goal BP; number of dose adjustments; variability in ICH volume, Glasgow Coma Scale score, and intracranial pressure; and drug-related complications. Results A total of 87 patients were eligible for analysis (n=46 [NC]; n=41 [NM]), and baseline characteristics between groups were similar. Both agents were effective in achieving goal BP during infusion, with 93.5% and 87.8% patients in the NC and NM groups achieving goal, respectively. Fewer additional medications were needed to control BP in the NC group. BP variability was similar and no differences were observed in the mean time to goal BP and mean numbers of dose adjustments between both groups. Interestingly, intracranial pressure declined (P=0.048) during NC administration but increased (P=0.066) after NM treatment. Finally, the incidences of hematoma expansion, neurological deterioration, and adverse drug events were similar in both groups. Conclusion NM is effective and safe for BP control in patients with ICH. PMID:26056454

  1. Therapeutic Interchange of Clevidipine For Sodium Nitroprusside in Cardiac Surgery

    PubMed Central

    Cruz, Joseph E.; Thomas, Zachariah; Lee, David; Moskowitz, David M.; Nemeth, Jeff

    2016-01-01

    Background: Generic price inflation has resulted in rising acquisition costs for sodium nitroprusside (SNP), an agent historically described as the drug of choice for the treatment of perioperative hypertension in cardiac surgery. Purpose: To describe the implementation and cost avoidance achieved by utilizing clevidipine as an alternative to SNP in cardiac surgery patients at a 520-bed community teaching hospital that performs more than 300 cardiac surgeries each year. Methods: A multidisciplinary team inclusive of anesthesiologists, intensivists, pharmacists, and surgeons collaborated to develop a therapeutic interchange for SNP in cardiac surgery patients. Consistent with current guidelines for therapeutic interchange, the goal was to encourage a less expensive alternative that was demonstrated to be at least therapeutically equivalent to SNP based on data derived from clinical trials published in peer-reviewed literature. A comprehensive literature review identified clevidipine as an alternative to SNP for perioperative hypertension in cardiac surgery. Nicardipine was considered as well, but was not chosen as a substitute due to lack of strong evidence and comparative data with SNP. Results: Clevidipine was implemented successfully in our cardiac surgery patients and will result in a net cost avoidance of approximately $300,000 in 2016. This is thought to be driven largely by the difference in acquisition cost between clevidipine and SNP. The operating room in our institution no longer keeps SNP stocked in anesthesia trays as a result of the success of our interchange. No requests have been made to return to the SNP standard. Conclusion: Through effective communication and multidisciplinary collaboration, our institution was able to develop an evidence-based and effective therapeutic interchange program for SNP. PMID:27757002

  2. Cytochrome P450 3A Conjugation to Ubiquitin in a Process Distinct from Classical Ubiquitination Pathway

    SciTech Connect

    Zangar, Richard C. ); Kimzey, Amy L.; Okita, Janice R.; Wunschel, David S. ); Edwards, Robert J.; Kim, Hyesook; Okita, Richard T.

    2001-12-01

    We characterize a novel microsome system that forms high-molecular-mass (HMM) CYP3A, CYP2E1, and ubiquitin conjugates, but does not alter CYP4A or most other microsomal proteins. The formation of the HMM bands was observed in hepatic microsomes isolated from rats treated 1 week or more with high doses (50 mg/kg/day) of nicardipine, clotrimazole, or pregnenolone 16alpha-carbonitrile, but not microsomes from control, dexamethasone-, nifedipine-, or diltiazem-treated rats. Extensive washing of the microsomes to remove loosely attached proteins or cytosolic contaminants did not prevent the conjugation reaction. In contrast to prototypical ubiquitination pathways, this reaction did not require addition of ubiquitin, ATP, Mg(2+), or cytosol. Addition of cytosol did result in the degradation of the HMM CYP3A bands in a process that was not blocked by proteasome inhibitors. Immunoprecipitated CYP3A contained HMM ubiquitin. Even so, mass spectrometric analysis of tryptic peptides indicated that the HMM CYP3A was in molar excess to ubiquitin, suggesting that the formation of the HMM CYP3A may have resulted from conjugation to itself or a diffuse pool of ubiquitinated proteins already present in the microsomes. Addition of CYP3A substrates inhibited the formation of the HMM CYP3A and the cytosol-dependent degradation of HMM CYP3A. These results suggest that after extended periods of elevated CYP3A expression, microsomal factors are induced that catalyze the formation of HMM CYP3A conjugates that contain ubiquitin. This conjugation reaction, however, seems to be distinct from the classical ubiquitination pathway but may be related to the substrate-dependent stabilization of CYP3A observed in vivo.

  3. Involvement of IP3-receptor activation in endothelin-1-induced Ca(2+) influx in rat pulmonary small artery.

    PubMed

    Kato, K; Okamura, K; Hatta, M; Morita, H; Kajioka, S; Naito, S; Yamazaki, J

    2013-11-15

    We examined the endothelin-1 (ET-1)-induced increase in the intracellular free Ca(2+) concentration ([Ca(2+)]i) in fura-2-loaded rat pulmonary small arteries. ET-1 (30 nM) elicited a long-lasting increase in [Ca(2+)]i in physiological salt solution (PSS). In subsequent experiments, arteries were pretreated with BQ-788, an ETB-specific blocker, to allow us to focus on responses mediated via the ETA receptor, the existence of which was confirmed by immunohistochemistry. In Ca(2+)-free PSS, ET-1 evoked a small transient increase in [Ca(2+)]i, indicating Ca(2+) release from the SR (sarcoplasmic reticulum). After a switch to PSS (containing 2mM CaCl2), ET-1 elicited a long-lasting increase in [Ca(2+)]i that was not inhibited by 1 μM nicardipine, an L-type Ca(2+)-channel inhibitor, suggesting involvement of a Ca(2+)-influx pathway independent of that channel. In arteries preincubated with 30 μM cyclopiazonic acid (CPA) or 2 μM thapsigargin (TG), the ET-1-induced Ca(2+)-release was greatly reduced, and the induced Ca(2+)-influx was attenuated. U-73122, a phospholipase C (PLC) inhibitor, had inhibitory effects similar to those of CPA and TG on the ET-1-induced Ca(2+)-release and Ca(2+)-influx, whereas U-73343, an inactive analogue of U-73122, had no such effects. Two putative membrane-permeable IP3-receptor blockers, 2-aminoethoxydiphenyl borate (2APB, 50 μM) and Xestospongin C (20 μM), (a) almost completely inhibited the ET-1-induced Ca(2+)-release and Ca(2+)-influx, and (b) reduced the ET-1-induced contraction. These results indicate that in rat pulmonary small arteries, ET-1 induces receptor-operated Ca(2+) influx via the ETA receptor, and that this influx interacts with InsP3-receptor activation. PMID:24157978

  4. Infiltrating basal cell carcinoma in the setting of a venous ulcer.

    PubMed

    Lutz, M E; Davis, M D; Otley, C C

    2000-07-01

    A 77-year-old man was referred with a 5-year history of an intermittently painful, nonhealing right medial ankle ulcer. The ulcer had not responded to multiple treatment modalities, including Unna boots, compression therapy, sclerotherapy, and split-thickness skin grafting. The past medical history was significant for a deep venous thrombosis in the right leg 30 years earlier (treated with warfarin for 3 months) and a history of greater saphenous vein harvesting for coronary bypass grafting 28 years previously. After the vein stripping, the patient had suffered from increasing right leg edema and stasis changes in the right leg. His history was also remarkable for coronary artery disease, dyslipidemia, and lymphoma treated with chemotherapy 8 years before presentation, with no evidence of recurrence. He had stopped smoking approximately 20 years earlier. Medications included atenolol, simvastatin, nicardipine, nitroglycerin, and aspirin. Skin examination revealed a 3.0 x 3.5-cm ulcer adjacent to the medial malleolus. The edges of the ulcer appeared raised and rolled (Fig. 1). Centrally, there was granulation tissue, which appeared healthy. There were surrounding dermatitic changes. Dorsalis pedis and the posterior tibial pulses were normal. Noninvasive vascular studies revealed severe venous incompetence of the right popliteal and superficial veins. Arterial studies and transcutaneous oximetry were normal. Computed tomographic scan of the pelvis did not reveal any adenopathy, and radiographic imaging did not reveal any bony changes suggestive of osteomyelitis. Biopsy of the ulcer edge and base showed infiltrating basal cell carcinoma (Fig. 2). Mohs' micrographic surgery required three layers; the final extent of the ulcer was 7.8 x 6.9 cm. A split-thickness skin graft was placed.

  5. [Peroperative risks in cerebral aneurysm surgery].

    PubMed

    Mustaki, J P; Bissonnette, B; Archer, D; Boulard, G; Ravussin, P

    1996-01-01

    The perioperative complications associated with cerebral aneurysm surgery require a specific anaesthetic management. Four major perioperative accidents are discussed in this review. The anaesthetic and surgical management in case of rebleeding subsequent to the re-rupture of the aneurysm is mainly prophylactic. It includes haemodynamic stability assurance, maintenance of mean arterial pressure (MAP) between 80-90 mmHg during stimulation of the patient such as endotracheal intubation, application of the skull-pin head-holder, incision, and craniotomy. The aneurysmal transmural pressure should be adequately maintained by avoiding an aggressive decrease of intracranial pressure. Once the skull is open, the brain must be kept slack in order to decrease pressure under the retractors and avoid the risks of stretching and tearing of the adjacent vessels. If, despite these precautions, the aneurysm ruptures again. MAP should be decreased to 60 mmHg and the brain rendered more slack, in order to allow direct clipping of the aneurysm, or temporary clipping of the adjacent vessels. The optimal agents in this situation are isoflurane (which decreases CMRO2), intravenous anaesthetic agents (inspite their negative inotropic effect, they may potentially protect the brain) and sodium nitroprusside. Vasospasm occurs usually between the 3rd and the 7th day after subarachnoid haemorrhage. It may be seen peroperatively. The optimal treatment, as well as prophylaxis, is moderate controlled hypertension (MAP > 100 mmHg), associated with hypervolaemia and haemodilution, the so-called triple H therapy, with strict control of the filling pressures. Other beneficial therapies are calcium antagonists (nimodipine and nicardipine), the removal of the blood accumulated around the brain and in the cisternae, and possibly local administration of papaverine. Abrupt MAP increases are controlled in order to maintain adequate aneurysmal transmural pressure. Beta-blockers, local anaesthetics

  6. ISH AHA-1 A CASE OF REFRACTORY HYPERTENSION CONTROLLED BY REPEATED RENAL DENERVATION AND CELIAC PLEXUS BLOCK: A CASE OF REFRACTORY SYMPATHETIC OVERLOAD.

    PubMed

    Lee, Chan Joo; Woo, Yeongmin; Kim, Byeong-Keuk; Yoon, Kyung Bong; Lee, Hae-Young; Park, Sungha

    2016-09-01

    A 30-year-old woman was referred to our hospital due to high blood pressure, dizziness, headache and blurred vision. She had past history of preeclampsia and gestational hypertension 4 years ago but she had not taken antihypertensive medication in spite of remained hypertension after delivery. She was hospitalized for fever due to urinary tract infection and severe hypertension which was above 210/140 mmHg. Despite maximal medical treatment with telmisartan 80 mg, nifedipine 120 mg, carvedilol 50 mg, doxazocin 8 mg, chlorthalidone 50 mg, spironolactone 50 mg#2, isosorbide dinitrate 80 mg and intermittent intravenous administration of nicardipine and labetalol, her systolic blood pressure remained above 160 mmHg and repeatedly measured above 200 mmHg. Her blood pressure was even refractory to combination of isosorbide dinitrate and sildenafil. Repeated evaluation for secondary cause of hypertension was negative. White coat effect was ruled out by repeated ambulatory blood pressure monitoring. Due to the blood pressure being uncontrolled over the next 3 months, renal denervation was carried out without any significant improvement in her blood pressure. She was referred to another tertiary hospital for a second opinion and suprapubic cystostomy was performed because neurogenic bladder was considered as a possible cause for the refractory hypertension. However, it failed to control the blood pressure. Three months later redo renal denervation was performed but its effect did not last for two days. She was referred to the department of anesthesiology and pain center to determine whether or not celiac plexus block would be effective in reducing the blood pressure. Initially, a temporary celiac plexus block was performed with local anesthetics. Two hours after procedure, blood pressure declined to 110/60 mmHg which was sustained for three days. Based on the efficacy of celiac plexus block, permanent celiac plexus block was perfomed using dehydrated alcohol and

  7. Novel ipriflavone receptors coupled to calcium influx regulate osteoclast differentiation and function.

    PubMed

    Miyauchi, A; Notoya, K; Taketomi, S; Takagi, Y; Fujii, Y; Jinnai, K; Takahashi, K; Chihara, K; Fujita, T

    1996-08-01

    Ipriflavone (7-isopropoxyisoflavone) is an effective antiresorptive agent used to treat osteoporosis. However, the mechanism of its action on osteoclasts and their precursor cells is not well understood. To determine whether the mechanism involves direct effects on osteoclasts or their precursors, we examined the effects of ipriflavone on cytosolic free calcium ([Ca2+]i) in osteoclasts and their precursors and measured specific binding of 3H-labeled ipriflavone. Highly purified chicken osteoclast precursors, which spontaneously differentiate into multinucleated osteoclasts in 3-6 days, were loaded with fura-2, and the subcellular [Ca2+]i distribution was monitored by videoimaging. Ipriflavone induced a rapid increase in [Ca2+]i followed by a sustained elevation [EC50 = 5 x 10(-7) M, 263 +/- 74 nM (SE) (n = 8) above basal levels, by 10(-6) M ipriflavone, sustained phase]. The responses were the same in differentiated chicken osteoclasts and isolated rabbit osteoclasts. An influx of extracellular Ca2+ is likely to be responsible for the ipriflavone-induced change in [Ca2+]i because the response was abolished by 0.5 mM LaCl3, or by Ca-free medium containing EGTA. Moreover, high [Ca2+]i levels were detected adjacent to the cell membrane after ipriflavone addition. Ipriflavone induced Ca influx mainly through dihydropyridine-insensitive Ca2+ channels, because nicardipine (10(-7)M) and verapamil (10(-7)M) had no effects on ipriflavone-induced [Ca2+]i responses. [3H]Ipriflavone binding studies indicated the presence of specific ipriflavone binding sites (two classes), both in precursor cells [dissociation constant (Kd), 7.60 x 10(-8)M, 2.67 x 10(-6)M] and in mature osteoclasts (Kd, 4.98 x 10(-8)M, 3.70 x 10(-6)M). Specific ipriflavone binding was not displaced by various modulators of avian osteoclast function, such as estradiol (10(-8)M) or retinoic acid (10(-6)M), indicating that ipriflavone receptors differ from the receptors for these Ca-regulating hormones. The

  8. Hormone release from isolated nerve endings of the rat neurohypophysis.

    PubMed Central

    Cazalis, M; Dayanithi, G; Nordmann, J J

    1987-01-01

    1. Isolated neurosecretory nerve endings were prepared from rat neurohypophyses. The amount of vasopressin (AVP) and oxytocin released was measured by radioimmunoassay. 2. The amount of hormone release under resting conditions was not affected by external calcium (Ca2+o). Secretion decreased by ca. 50% when external sodium (Na+o) was replaced by choline or sucrose. 3. Ouabain did not modify the basal AVP release. 4. The Na+ ionophore monensin increased the release of AVP only in the presence of Na+o. This increase was maintained during prolonged exposure to the ionophore and occurred in the presence of Ca2+o only. 5. In the presence of Ca2+o, the amount of evoked hormone release was dependent on the external K+ concentration. Half-maximal activation was achieved with ca. 40 mM-K+. The K+-induced secretion was potentiated in Na+-free solution. 6. Prolonged 100 mM-K+-induced depolarization in the presence of Ca2+o gave rise to a large increase in hormone secretion which decreased with time (t1/2 = 2.5 min). The release could be reactivated after permeabilization of the nerve terminals in the presence of micromolar concentrations of Ca2+. 7. A stepwise paradigm in which Ko+ is incrementally increased to 25, 50, 75 and then 100 mM released more AVP than a prolonged exposure to 100 mM-K+. 8. Veratridine increased the amount of AVP released. This effect was considerably reduced in the absence of Nao+ and abolished in the presence of D600. 9. The depolarization-induced AVP release was blocked by different Ca2+-antagonists. Their effectiveness was nitrendipine = nicardipine greater than Cd2+ greater than Gd3+ greater than Co2+ = Mn2+. 10. The dihydropyridine Bay K 8644 potentiated both the basal and the K+-evoked AVP release. Its maximal effect was obtained with 25-50 mM-Ko+. 11. In conclusion, the isolated neurohypophysial terminals which have both Na+ and Ca2+ channels and release AVP and oxytocin upon depolarization might be an excellent system to study further the

  9. Management of Landau-Kleffner syndrome.

    PubMed

    Mikati, Mohamad A; Shamseddine, Alhan N

    2005-01-01

    Landau-Kleffner syndrome (LKS) is an acquired epileptic aphasia disorder in which children, usually 3-8 years of age who have developed age-appropriate speech, experience language regression with verbal auditory agnosia, abnormal epileptiform activity, behavioral disturbances, and sometimes overt seizures. There are no controlled clinical trials investigating the therapeutic options for LKS. Only open-label data are available. Early diagnosis and initiation of prompt medical treatment appear to be important to achieving better long-term prognosis.Several antiepileptic drugs have been reported to be beneficial in treating this syndrome. These include valproic acid (valproate sodium), diazepam, ethosuximide, clobazam, and clonazepam. Reports on the efficacy of lamotrigine, sultiame, felbamate, nicardipine, vigabatrin, levetiracetam, vagal nerve stimulation, and a ketogenic diet are few and more experience is needed. Carbamazepine and possibly phenobarbital and phenytoin have been reported to occasionally exacerbate the syndrome. As initial therapy, valproic acid or diazepam is often empirically chosen. Subsequently, other antiepileptic drugs, corticosteroids, or intravenous immunoglobulin (IVIG) therapy are often used. Corticosteroid therapy should probably not be delayed more than 1-2 months after the initial diagnosis. Various corticosteroid regimens including oral prednisone and, recently, high doses of intravenous pulse corticosteroids, as well as corticotropin (adrenocorticotropic hormone) have been reported to be effective in LKS. Oral corticosteroids are used more often and usually need to be maintained for a long period of time to prevent relapses. The use of IVIG has been associated with an initial dramatic response in only a few patients. In our experience, a long-term worthwhile improvement has been noted in only 2 of 11 patients. These two patients had an immediate response to IVIG initially and after relapses before eventually achieving a long

  10. Effects of extracellular pH on receptor-mediated Ca2+ influx in A7r5 rat smooth muscle cells: involvement of two different types of channel.

    PubMed Central

    Iwasawa, K; Nakajima, T; Hazama, H; Goto, A; Shin, W S; Toyo-oka, T; Omata, M

    1997-01-01

    1. The effects of extracellular pH (pHo) on receptor (vasopressin or endothelin-1)-mediated Ca2- entry and Ca(2+)-permeable channels were investigated in aortic smooth muscle cells (A7r5) from rat embryonic thoracic aorta. Intracellular Ca2+ ([Ca2+]i) was measured using fura-2 AM and whole-cell voltage clamp techniques were employed. 2. Vasopressin and endothelin-1 (100 nM) in the presence of nicardipine (10 microM) evoked a sustained rise in [Ca2+]i due to calcium entry. Extracellular acidosis decreased receptor (vasopressin or endothelin-1)-mediated Ca2+ entry, while extracellular alkalosis potentiated it. 3. Depletion of intracellular Ca2+ stores with thapsigargin (1 microM) also evoked Ca2+ entry activated by emptying of intracellular Ca2+ stores (capacitative Ca2+ entry). Extracellular acidosis decreased this capacitative Ca2+ entry, while extracellular alkalosis potentiated it. 4. Under voltage-clamp conditions with Ca+ internal solution, vasopressin and endothelin-1 activated non-selective cation currents (ICAT). Ba2+ or Ca2+ were also charge carriers of ICAT. Reducing the pHo inhibited ICAT, while increasing pHo potentiated it in a reversible manner. 5. Intracellular pH (pHi) changes did not cause the same marked effects as pHo changes, and a high concentration of Hepes (50 mM) in the patch pipette did not inhibit the effects of pHo on ICAT. 6. Similar results were obtained when ICAT was activated by GTP gamma S (1 mM) applied through the patch pipette, even in the absence of agonists, probably because of direct activation of GTP-binding proteins coupled to the receptors. 7. In cells treated with thapsigargin, addition of Ca2+ to the bath solution induced Ca(2+)-dependent K+ currents activated by capacitative Ca2+ entry. However, no measurable ionic currents activated by capacitative Ca2+ entry (ICRAC) were observed under conditions with Cs+ internal solution and EGTA (5 mM), although vasopressin still activated ICAT. 8. These results suggest that the

  11. Trichosporin-B-III, an alpha-aminoisobutyric acid-containing peptide, causes Ca(2+)-dependent catecholamine secretion from adrenal medullary chromaffin cells.

    PubMed

    Tachikawa, E; Takahashi, S; Furumachi, K; Kashimoto, T; Iida, A; Nagaoka, Y; Fujita, T; Takaishi, Y

    1991-11-01

    We examined the effect of trichosporin-B-III, an alpha-aminoisobutyric acid-containing antibiotic peptide consisting of 19 amino acid residues and a phenylalaninol, on catecholamine secretion from cultured bovine adrenal chromaffin cells. Incubation of the cells with trichosporin-B-III (3-20 microM) caused an increase in the secretion of catecholamines. The secretion induced by trichosporin-B-III at low concentrations (3 and 5 microM) was completely dependent on external Ca2+, whereas that induced by higher concentrations (10 and 20 microM) was partly independent of Ca2+. Trichosporin-B-III at low concentration (5 microM) did not increase the release of lactate dehydrogenase, a marker enzyme of cytoplasm, from the cells. In contrast, the peptide at higher concentration (10 microM) increased the release of the enzyme. Trichosporin-B-III also caused both 45Ca2+ influx into the cells and an increase in the intracellular free Ca2+ concentration. The increases in catecholamine secretion and 45Ca2+ influx behaved similarly in relation to trichosporin-B-III concentration (3-10 microM). The time courses of the increases in secretion, 45Ca2+ influx, and intracellular free Ca2+ concentration induced by trichosporin-B-III were also quite similar. Trichosporin-B-III-induced (at 5 microM) secretion was not affected by the elimination of Na+ from the incubation medium or by the addition of tetrodotoxin, a blocker of highly selective voltage-dependent Na+ channels, or hexamethonium, a blocker of nicotinic acetylcholine receptors. On the other hand, both diltiazem (2-200 microM) and nicardipine (1-200 microM), blockers of voltage-dependent Ca2+ channels, inhibited the secretion induced by trichosporin-B-III (5 microM) in a concentration-dependent manner. Trichosporin-B-III-induced (at 5 microM) secretion also was suppressed by the addition of Mn2+ (5 mM) to the medium. The diltiazem (20 microM) inhibition of trichosporin-B-III-induced (at 5 microM) secretion was reversed by

  12. SAHIT Investigators--on the outcome of some subarachnoid hemorrhage clinical trials.

    PubMed

    Macdonald, R Loch; Jaja, Blessing; Cusimano, Michael D; Etminan, Nima; Hanggi, Daniel; Hasan, David; Ilodigwe, Don; Lantigua, Hector; Le Roux, Peter; Lo, Benjamin; Louffat-Olivares, Ada; Mayer, Stephan; Molyneux, Andrew; Quinn, Audrey; Schweizer, Tom A; Schenk, Thomas; Spears, Julian; Todd, Michael; Torner, James; Vergouwen, Mervyn D I; Wong, George K C; Singh, Jeff

    2013-06-01

    Outcome of patients with aneurysmal subarachnoid hemorrhage (SAH) has improved over the last decades. Yet, case fatality remains nearly 40% and survivors often have permanent neurological, cognitive and/or behavioural sequelae. Other than nimodipine drug or clinical trials have not consistently improved outcome. We formed a collaboration of SAH investigators to create a resource for prognostic analysis and for studies aimed at optimizing the design and analysis of phase 3 trials in aneurysmal SAH. We identified investigators with data from randomized, clinical trials of patients with aneurysmal SAH or prospectively collected single- or multicentre databases of aneurysmal SAH patients. Data are being collected and proposals to use the data and to design future phase 3 clinical trials are being discussed. This paper reviews some issues discussed at the first meeting of the SAH international trialists (SAHIT) repository meeting. Investigators contributed or have agreed to contribute data from several phase 3 trials including the tirilazad trials, intraoperative hypothermia for aneurysmal SAH trial, nicardipine clinical trials, international subarachnoid aneurysm trial, intravenous magnesium sulphate for aneurysmal SAH, magnesium for aneurysmal SAH and from prospectively-collected data from four institutions. The number of patients should reach 15,000. Some industry investigators refused to provide data and others reported that their institutional research ethics boards would not permit even deidentified or anonymized data to be included. Others reported conflict of interest that prevented them from submitting data. The problems with merging data were related to lack of common definitions and coding of variables, differences in outcome scales used, and times of assessment. Some questions for investigation that arose are discussed. SAHIT demonstrates the possibility of SAH investigators to contribute data for collaborative research. The problems are similar to those

  13. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage.

    PubMed

    Qureshi, Adnan I; Palesch, Yuko Y; Barsan, William G; Hanley, Daniel F; Hsu, Chung Y; Martin, Renee L; Moy, Claudia S; Silbergleit, Robert; Steiner, Thorsten; Suarez, Jose I; Toyoda, Kazunori; Wang, Yongjun; Yamamoto, Haruko; Yoon, Byung-Woo

    2016-09-15

    Background Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. Methods We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. Results Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events

  14. [Historical sketch of modern pharmaceutical science and technology (Part 4). Post World War II 50 years].

    PubMed

    Yamakawa, K

    1995-01-01

    ethical drugs and re-evaluation of drugs. Many facilities were built for the purpose of ensuring efficacy and safety, as shwon in Table 1. 6. Problems of Intellectual Property and followed the revisionist line of research and development for new ethical drugs. In 1976, Japanese pharmaceutical companies ceased to be an imitation industry, and increased research for the development of new drugs. 7. Pharmaceutical science and technology innovation (After 1985). Many of the pharmaceutical innovations during this period were as follows: 7.1) Technology innovation for evaluation of drug efficacy; 7.2) 1st to 3rd medical diagnostic technology innovations; 7.3) medical analytical methods and spectrometry technologies; 7.4) Computer-aided drug-design technology and drug information technology innovation; and 7.5) Drug delivery system and treatment drugs. 8. Recent research and development of new ethical drugs in Japan (1970 to 1995). Cephalosporine type beta-lactams (cefazolin, cefametazole, furomoxef, cefdinir), new quinolones (norfloxcin, ofloxacin, tosfloxcin), H1-Blockers (famotidine), Ca-antagonists (diltiazem, nicardipine), and other new drugs (pravastatine, taclolimus, leuprine) etc. came onto the market. 9. International Harmonization Age and Review toward 21 century. The rapid development and globalization of the pharmaceutical market has promoted international harmonization and rationalization of pharmaceutical regulatory affairs. In 1990, the Japan Pharmaceutical Manufacturers Association published a report toward 21 century, which described practical plans.

  15. Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage.

    PubMed

    Qureshi, Adnan I; Palesch, Yuko Y; Barsan, William G; Hanley, Daniel F; Hsu, Chung Y; Martin, Renee L; Moy, Claudia S; Silbergleit, Robert; Steiner, Thorsten; Suarez, Jose I; Toyoda, Kazunori; Wang, Yongjun; Yamamoto, Haruko; Yoon, Byung-Woo

    2016-09-15

    Background Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. Methods We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. Results Among 1000 participants with a mean (±SD) systolic blood pressure of 200.6±27.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events

  16. Treatment for calcium channel blocker poisoning: A systematic review

    PubMed Central

    Dubé, P.-A.; Gosselin, S.; Guimont, C.; Godwin, J.; Archambault, P. M.; Chauny, J.-M.; Frenette, A. J.; Darveau, M.; Le sage, N.; Poitras, J.; Provencher, J.; Juurlink, D. N.; Blais, R.

    2014-01-01

    Context Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. Objective To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. Methods Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in

  17. Mechanisms of bradykinin-induced contraction of the guinea-pig gallbladder in vitro.

    PubMed

    Cabrini, D A; Silva, A M; Calixto, J B

    1995-04-01

    1. The mechanisms underlying bradykinin (BK)-mediated contractions in strips of guinea-pig gallbladder (GPG) were examined by use of selective bradykinin (BK) receptor agonists and antagonists. 2. Addition of BK and related kinins (0.1 pM-10 microM) after 2 h of equilibration of the preparation caused graded contractions characterized by two distinct phases: high affinity (0.1 pM-1 nM) and low affinity (3 nM-10 microM). The rank order of potency for the first phase (mean EC50, pM) was: BK (1.36) = Hyp3-BK (1.44) = Lys-BK (1.54) > Tyr8-BK (2.72) > Met-Lys-BK (4.30). The rank order of potency for the second phase (mean EC50, nM, at concentration producing 50% of the contraction caused by 80 mM KCl) was: Hyp3-BK (8.95) > Met-Lys-BK (12.78) > Tyr8-BK (33.75) > Lys-BK caused by 80 mM KCl) was: Hyp3-BK (8.95) > Met-Lys-BK (12.78) > Tyr8-BK (33.75) > Lys-BK (60.92) > BK (77.35). The contractile responses (g of tension) to 3 microM of BK (the highest concentration tested) were: Hyp3-BK, 1.76 +/- 0.09; BK, 1.65 +/- 0.12; Lys-BK, 1.45 +/- 0.13; Tyr8-BK, 1.36 +/- 0.15 and Met-Lys-BK, 1.36 +/- 0.15. The selective B1 agonist, des-Arg9-BK, caused only a weak contraction with maximal response (0.21 +/- 0.05 g), which corresponded to approximately 10% of that induced by BK. 3. BK-induced contraction in GPG was inhibited by indomethacin (3 microM) or ibuprofen (30 microM), and was partially reduced by phenidone (30 microM), but was not affected by atropine (1 JM), nicardipine (1 gM),Ca2+-free medium plus EGTA, dazoxiben (30 nM), L-655,240 (10 nM, a selective receptor antagonist ofthromboxane A2), MK-571 (0.1 microM, a selective leukotriene D4 receptor antagonist), tetrodotoxin(0.3microM), CP 96,345 (0.3 microM, a NK1 receptor antagonist), mepyramine (1 microM), glibenclamide (1 microM), H-7(3 microM), staurosporine (100 nM), or phorbol 12-myristate 13-acetate (1 microM). However, BK-induced contractions in GPG maintained in Ca2+-free medium were markedly attenuated by ryanodine (10