These data indicate that applying transdermal verapamil gel to the penile shaft results in a small amount of systemic absorption but the gel does not infiltrate the tunica albuginea. Based on these findings the use of transdermal verapamil for Peyronie's disease has no scientific basis.
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Verapamil was instituted, resulting in prompt and sustained resolution of symptoms.
Syl611 is an effective and potential agent in reversing multidrug resistance (MDR) by multiple actions, which attributed to p-glycoprotein inhibition and drug permeability enhancement.
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Rhodamine (Rh123) efflux was used to study ABCB1 activity, with or without the addition of the ABCB1 inhibitor verapamil. Intracellular interleukin (IL) 2 production in T cells was used to measure the pharmacodynamic effect of tacrolimus after phorbol-12-myristate-13-acetate/ionomycin stimulation of whole blood. In addition, the ABCB1 genotype of 36 tacrolimus-treated renal transplant patients was related to ABCB1 activity and tacrolimus efficacy.
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Ca2+ plays an essential role in pituitary adenylate cyclase-activating polypeptide (PACAP)-stimulated growth hormone (GH) secretion from porcine somatotropes. Here, Indo-1 microfluorimetry was used to investigate the dynamics of free cytosolic Ca2+ concentration ([Ca2+]i) in single porcine somatotropes in response to PACAP38 and PACAP27. We also evaluated the relative contributions of extra- and intracellular Ca2+ sources and of cAMP-dependent protein kinase (PKA) and phospholipase C (PLC). A high proportion of somatotropes responded to PACAP38 (79.4%) and PACAP27 (68.4%) with [Ca2+]i rises that could be followed by a refractory plateau (type 1 response), or by a decrease in [Ca2+]i during which somatotropes were responsive to a subsequent PACAP pulse (type II response). Although Ca2+ profiles in response to both peptides were similar, PACAP38-induced [Ca2+]i rises were higher. Somatotrope response to PACAP38 or PACAP27 was markedly reduced by removing extracellular Ca2+, blocking Ca2+ entry through L-type voltage sensitive Ca2+ channels (VSCC), or inhibiting PKA. Conversely, Ca2+ depletion from intracellular stores or PLC inactivation did not affect the response to PACAP27 but considerably reduced maximal [Ca2+]i induced by PACAP38. We conclude that both peptides stimulate extracellular Ca2+ influx through L-type VSCC by a PKA-dependent mechanism. However, PACAP38 also triggers a PLC-mediated Ca2+ mobilization from intracellular stores, thereby indicating that the two molecular forms of PACAP activate common and distinct second messenger pathways within porcine somatotropes.
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The right cervical vagal nerve was stimulated in five dogs. In one dog, right thoracotomy was performed to isolate the vagal nerve. Bipolar hook electrodes were attached to the vagal nerve. The vagal nerve was stimulated (3-5 mA, 40 Hz) for a few seconds while suturing the coronary artery. Experiments were conducted in two groups. In Group I, two dogs received vagal stimulation via the right neck, and one dog received vagal stimulation via the right thoracic cavity approach. In Group H, all vagal stimulations were performed via the neck during intravenous infusion of diltiazem (10 mg/hrs) or verapamil (5 mg/hrs).
The objective of this work was to assess, in vitro, the passage of P-glycoprotein dependent drugs across brain capillary endothelial cells, when these drugs are associated with a reversing agent.
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The present study investigated the mechanisms of melatonin-induced inhibition of the ileal smooth muscle contraction. Rat isolated ileal smooth muscle strips were stimulated in an organ bath using carbachol (CAR) or potassium chloride (KCl) depolarization. Under these conditions, melatonin produced a concentration-dependent inhibition of muscle contraction (mean inhibitory concentration, IC50: 17.3 x 10(-6) M), which was not blocked by either tetrodotoxin (10(-6) M), hexamethonium (10(-4) M), or phentolamine (10(-6) M). The inhibitory effect of melatonin during CAR stimulation was blocked in a concentration-dependent manner by the presence of apamin (4.8 x 10(-9) M), a K(+)-channel blocker. By contrast, other K(+)-channel blockers such as 4-aminopyridine (10(-4) M to 5 x 10(-3) M), tetraethylammonium (10(-4) to 10(-1) M), and glibenclamide (10(-5) M) were ineffective. Additionally, the Ca(2+)-channel antagonists nitrendipine (IC50: 2.4 x 10(-9) M) and verapamil (IC50: 1.1 x 10(-7) M) also blocked the inhibitory action of melatonin. These results suggest that melatonin may interact with an apamin-sensitive, possibly Ca(2+)-activated, K+ channel and thus cause an inhibition of ileal smooth muscle contractions.
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In this study, our goal was to develop an efficient in situ test adapted to screen hepatotoxicity of various chemicals, a process which remains challenging during the early phase of drug development. The test was based on functional human hepatocytes using the HepaRG cell line, and automation of quantitative fluorescence microscopy coupled with automated imaging analysis. Differentiated HepaRG cells express most of the specific liver functions at levels close to those found in primary human hepatocytes, including detoxifying enzymes and drug transporters. A triparametric analysis was first used to evaluate hepatocyte purity and differentiation status, mainly detoxication capacity of cells before toxicity testing. We demonstrated that culturing HepaRG cells at high density maintained high hepatocyte purity and differentiation level. Moreover, evidence was found that isolating hepatocytes from 2-week-old confluent cultures limited variations associated with an ageing process occurring over time in confluent cells. Then, we designed a toxicity test based on detection of early mitochondrial depolarisation associated with permeability transition (MPT) pore opening, using JC-1 as a metachromatic fluorescent dye. Maximal dye dimerization that would have been strongly hampered by efficient efflux due to the active, multidrug-resistant (MDR) pump was overcome by coupling JC-1 with the MDR inhibitor verapamil. Specificity of this test was demonstrated and its usefulness appeared directly dependent on conditions supporting hepatic cell competence. This new hepatotoxicity test adapted to automated, image-based detection should be useful to evaluate the early MPT event common to cell apoptosis and necrosis and simultaneously to detect involvement of the multidrug resistant pump with target drugs in a human hepatocyte environment.
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All the implants were removed from animal body 4 weeks later for study. For the fibroblasts activity study, another 10 days of cell culture was done. The viability and proliferation of HSc fibroblasts in group C mice were significantly decreased at 10 days after explantation. The fibroblast numbers in the 3 groups were as follows: (A) 16.6×10⁵; (B) 1.5×10⁵; and (C) 0.4×10⁵ (P<0.05). At 4 weeks after implantation, group C showed the significantly least amount of type I collagen (A, 0.12 μg/mL; B, 0.07 μg/mL; C, 0.055 μg/mL; P<0.05). In the nonimplanted scars, the collagen in group C was 0.4 μg/mL, less than that in groups B (0.6 μg/mL) and A (1.7 μg/mL; P<0.05). Significant differences were observed in reduction of scar weight among the 3 groups (A, 85%; B, 82.3%; C, 78.6%; P<0.05). The combination therapy group, that is, group C, significant inhibition of FPCL contraction and delayed contraction of burn scar fibroblasts compared with the other groups. The FPCL contraction rate at 4 weeks in groups A, B, and C was 15.4%, 65%, and 73.4% of the original size, respectively (P<0.05).
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Treatment of Bacillus licheniformis cultures with biotic oligosaccharide elicitors is known to increase the production of the antibiotic bacitracin A. The mechanism of the elicitation is currently under investigation and in this paper we provide evidence on the modulatory role of Ca(2+) ions during this process. Addition of elicitors, mannan oligosaccharides, oligoguluronate and oligomannuronate to the liquid cultures resulted in 9.0, 5.2 and 5.0% increase in cytosolic Ca(2+) levels in B. licheniformis, while the presence of verapamil (Ca(2+) channel blocker) resulted in 74% decrease in bacitracin A levels, as compared to the control culture. We propose that Ca(2+) ions may acts as a secondary messenger in the regulation of the bacitracin A synthesis in the elicited B. licheniformis cultures.
EFV should not modify intestinal absorption of co-administered substrates of P-gp, but could decrease plasma concentrations of co-administered drugs metabolized by P450.
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Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy.
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Detectable levels of troponins are often found in serum of patients with atrial fibrillation (AF), and recent reports suggest that Tn concentrations are independently related to patient prognosis.
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Unlike in verapamil and metoprolol poisoning models, levosimendan did not improve CO or survival in propranolol poisoning. Epinephrine improved BP, but not CO, suggesting that its actions were due to peripheral vasoconstriction.
A single-pass "four-site" rat intestinal perfusion model and a cultured Caco-2 cell model were employed.
Among new taxoids, taxuspines A-H and J-T, and known taxoids containing taxol and taxol-type compounds with an N-acylphenylisoserine group at C-13 and an oxetane ring at C-4 and C-5 isolated from stems and leaves of the Japanese yew Taxus cuspidata Sieb. et Zucc., two non-taxol-type compounds remarkably reduced CaCl2-induced depolymerization of microtubules. Furthermore, seven non-taxol-type compounds increased cellular accumulation of vincristine in multidrug-resistant(MDR) tumor cells as potent as verapamil, while taxol and taxol-type compounds did not show such an activity. In addition, the non-taxol-type compounds enhancing vincristine accumulation inhibited competitively binding of azidopine to P-glycoprotein. These results suggest that some non-taxol-type taxoids may be useful for overcoming MDR in tumor cells.
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Single centre at a university hospital.
The study consisted of six groups (N=30; five rabbits/group): (1) Control with no pretreatment, monocrotaline injected groups: (solutions were perfused following termination of CPB for 60 min); (2) Control for pulmonary hypertension (PHT); (3) isoproteronol; (4) VIP 10(-6) M; (5) VIP 10(-5) M; (6) nitroglycerine. Normothermic CPB was instituted in thirty rabbits at a flowrate of 100 ml/kg/min for 120 min. Heart rate, mean arterial pressure (MAP), central venous, left atrium (LAP), pulmonary artery (PAP) pressures, pulmonary resistance (Rp), blood gases and ions were measured before and 15, 30, 45 and 60 min after CPB. The VIP 10(-5) M group was subjected to an additional 1.7 x 10(-6) M propranol and 2 mM verapamil infusions for a further 15 min.
Average time to death was 21.0±9.57 minutes for group C, 35.57±10.61 minutes for group S, 37.14±16.6 minutes for group L and 49.86±27.56 minutes for group SL. Time to death was significantly longer in other groups than in the control group (p<0.05).
An endovascular treatment of vasospasm following a subarachnoid aneurysmal haemorrhage is to be implemented if the patient presents clinical or biological symptoms arguing for brain ischemia in conjunction with increased Doppler velocities despite well controlled systemic haemodynamic. Treatment might be either pharmacological or haemodynamic. Calcium and phosphodiesterase inhibitors can be administered. The former could also provide a neuroprotective effect as compared to the latter. In Europe, nimodipine is widely used whereas nicardipine and verapamil are the major molecules administered in North America where iv nimodipine is not FDA approved. Papaverine is less used nowadays because of its short duration of action and of the risk of aggravation of raised intracranial pressure. Balloon angioplasty has a long lasting effect but can be applied only to proximal spasm. Complications of its use are rare but life threatening. In some cases, both the pharmacological approach and the mechanical approach are used in combination.
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In 6 healthy volunteers a multilumen perfusion catheter was used to generate a 20-cm isolated jejunal segment that was perfused with 80 mg verapamil. Simultaneously, 5 mg [(2)H(7)]verapamil was given intravenously. Blood, perfusate, and bile samples were analyzed for parent verapamil and its major metabolites.
The cerebrovascular selectivity and vasospasmolytic action of AJ-3941 ((+/-)-(E)-1-(3-fluoro-6, 11-dihydrodibenz[b,e]oxepin-11-yl)-4-(3-phenyl-2-propenyl)-p iperazine dimaleate. CAS 143110-70-7), a new calcium antagonist, were studied in isolated rabbit and dog arterial preparations. In rabbit arterial ring preparations, AJ-3941 dose-dependently inhibited the contractions of various arteries caused by high K(+)-depolarization (high K+) and prostaglandin F2 alpha (PG). The inhibitory potency of AJ-3941 varied in different arteries, in descending order as follows: high K+: basilar > coronary > femoral > renal > mesenteric artery, PG: basilar > coronary > > femoral and renal artery. The median inhibitory concentration (IC50) in the basilar artery was over 40 times lower than that in the mesenteric or femoral artery for which the weakest inhibition in the examined arteries was observed. This selective action of AJ-3941 for cerebral artery was also observed in the frontal and middle cerebral arteries of dogs. The selectivity for the rabbit basilar artery was higher than those of flunarizine and nicardipine. Additionally, the contractile response of the rabbit basilar artery induced by phorbol 12,13-dibutyrate (PDBu), an activator of protein kinase C (PKC), was greater than those of the arteries examined such as the coronary, femoral and mesenteric arteries. The response in the basilar artery was greatly reduced in Ca(2+)-free medium, while this was not the case in other arteries. AJ-3941 as well as H-7, an inhibitor of PKC, potently inhibited PDBu-induced contractile response in the basilar artery in the presence, but not in the absence of Ca2+ in the medium, whereas the existing calcium antagonists, diltiazem and nicardipine, did not inhibit the contractile response in both conditions. These results suggest that the PKC-dependent system which is mediated by influx of extracellular Ca2+ profoundly contributes to the contraction of the cerebral artery and that the cerebroselective-vasodilating effect of AJ-3941 may depend, at least partly, on the inhibition of the PKC-mediated contractile response. In rabbit basilar arteries, AJ-3941 caused a dose-dependent inhibition of the contraction induced by various vasospasmogens, such as endothelin-1 (ET), arachidonic acid, 15-hydroperoxy-eicosatetraenoic acid and the thromboxane A2-mimetic U-46619. Furthermore, when isolated basilar arteries of the dog were perfused intraluminally with AJ-3941 at the concentration that inhibits high K(+)- or PG-induced contraction in the rabbit basilar artery, AJ-3941 effectively antagonized the vasospasm induced by extraluminal application of PG or ET. However, when flunarizine, nicardipine, diltiazem or verapamil was used for intraluminal perfusion of the same preparations, none of these drugs exerted spasmolytic effect. These results indicate that AJ-3941 has cerebrovascular selective-vasospasmolytic action, and consequently is thought to be effective in cerebrovascular disorder such as vasospasm following subarachnoid hemorrhage.
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In the porcine model, intraluminal application of pharmacologic agents produced independent effects on ureteral dilation and peristalsis. Theophylline inhibited ureteral peristalsis, and verapamil produced acute proximal-ureteral dilation. The ability to alter ureteral diameter or peristaltic activity acutely may facilitate ureteroscopy.
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Cluster headache is a primary headache with a male predominance that presents in two forms: episodic and chronic, occurring at 45-to 60-day intervals with one to three headaches a day lasting 45 min to 2 h. An attack starts by a violent unilateral retro-ocular pain with sympathetic signs such as tearing and rhinorrhea. Diagnosis is made by questioning and therefore requires no complementary tests. Treatment for the attack consists of injectable sumatriptan or oxygen therapy, with long-term treatment with verapamil, lithium salts, or Topiramate; in certain cases in which the number of attacks is greater than two, injections of corticosteroids at the emergence of the Arnold nerve can be used, or in cases of attacks resistant to all treatments, hypothalamus stimulation surgery can be useful.
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Parkinson's disease (PD) is associated with a loss of neurons from the midbrain. The cause of PD is unknown, but it is established that certain neurotoxins can cause similar syndromes. The brain is normally protected from these noxious blood-borne chemicals by the blood-brain barrier which includes specialized proteins on the inside of blood vessels in the brain. These act as molecular efflux pumps and P-glycoprotein (P-gp) is an abundant representative. Vulnerability to PD appears codetermined by the genotype for the P-gp gene. We hypothesized that PD patients have reduced P-gp function in the blood-brain barrier. We used positron emission tomography to measure brain uptake of [(11)C]-verapamil, which is normally extruded from the brain by P-gp. Here, we show significantly elevated uptake of [(11)C]-verapamil (18%) in the midbrain of PD patients relative to controls. This is the first evidence supporting a dysfunctional blood-brain barrier as a causative mechanism in PD.