N-alkoxycarbonyl- and N-benzoyl-derivatization of the benzamidine-parent drug increased the apparent permeabilities across Caco-2 monolayers by a factor of 25-100 fold. Most prodrugs were transported mainly by passive diffusion, whereas the methoxycarbonyl-derivative EMD 122347 displayed directional transport from basolateral (BL) to apical (AP). This polarized efflux was concentration dependent (saturable kinetics with Km = 207 microM, Vmax = 0.275 nmol cm(-2) min(-1)) and could be reduced in the presence of verapamil (300 microM), an inhibitor of p-glycoprotein. Cell mediated cleavage of the prodrugs was low and showed only slight differences to hydrolysis in buffer solution, indicating a predominantly non enzymatic cleavage. Both peroral bioavailability (monkey) and the inhibition of ex-vivo platelet aggregation (guinea pig) gave the same rank order as the permeability coefficients obtained in Caco-2 monolayers.
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Chloroquine (CQ)-resistant Plasmodium falciparum malaria has been a global health catastrophe, yet much about the CQ resistance (CQR) mechanism remains unclear. Hallmarks of the CQR phenotype include reduced accumulation of protonated CQ as a weak base in the digestive vacuole of the erythrocyte-stage parasite, and chemosensitization of CQ-resistant (but not CQ-sensitive) P. falciparum by agents such as verapamil. Mutations in the P. falciparum CQR transporter (PfCRT) confer CQR; particularly important among these mutations is the charge-loss substitution K→T at position 76. Dictyostelium discoideum transformed with mutant PfCRT expresses key features of CQR including reduced drug accumulation and verapamil chemosensitization.
We recently found that overexpression of p185c-erbB2 in c-erbB2 transfected MDA-MB-435 breast cancer cells (435.eB transfectants) confers a 5-9-fold increase in Taxol resistance. To examine whether Taxol resistance is a common phenomenon in other c-erbB2 overexpressing breast cancer cell lines, we tested a panel of human breast cancer cell lines established from different patients and expressing pl85c-erbB2 at different levels for their sensitivity to Taxol and Taxotere, a synthetic taxoid. Higher expression of p185c-erbB2 in these breast cancer cell lines indeed correlated well with resistance to Taxol and Taxotere, and the degree of resistance was about 100-fold that in c-erbB2-overexpressing 435.eB transfectants, demonstrating that these breast cancer cells are highly resistant to Taxol. Since mdr-1-encoded p-glycoprotein (p170mdr-1) has been implicated in Taxol resistance, we next examined the p170mdr-1 levels in these breast cancer cell lines that are highly resistant to Taxol. Higher levels of p170mdr-1 expression were found in several breast cancer cell lines that are highly resistant to Taxol. Since these same breast cancer cell lines also expressed higher levels of p185c-erbB2, we sought to determine the relative contribution of p185c-erbB2 and p170mdr-1 overexpression to Taxol resistance. We first specifically down-regulated cell surface p185c-erbB2 using anti-p185c-erbB2 monoclonal antibodies and assayed sensitivity of these cells to Taxol. We next specifically inactivated p170mdr-1 function using p170mdr-1 blockers (thioridazine or verapamil) and again assayed Taxol sensitivity. Both p185c-erbB2 down-regulation and p170mdr-1 blockade significantly sensitized the breast cancer cell lines to Taxol. The results indicate that overexpression of either p185c-erbB2 or p170mdr-1 renders human breast cancer cells resistant to Taxol. Furthermore, p185c-erbB2 synergizes with p170mdr-1 conferring higher degrees of Taxol resistance. Finally, combination therapy (down-regulation of p185c-erbB2 plus blocking p170mdr-1 plus administration of Taxol) may be beneficial to breast cancer patients whose tumors express high levels of both p185c-erbB2 and p170mdr-1.
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In the present study, cross-drug resistance in multidrug-resistant (MDR) cells, which overexpress P-glycoprotein (Pgp), a mdr1 gene product, against Pgp-unrelated drugs, and its relevance to c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) activity were examined. The multidrug-resistant FM3A/M cells overexpressing Pgp were resistant to apoptotic cell death induced either by Pgp-related drugs including vincristine and vinblastine, which are pumped out by Pgp, or by the Pgp-unrelated drugs including 5'-fluorouracil (5-FU) and bleomycin, which are not targets for Pgp, compared with the parental FM3A cells. Verapamil reversed the resistance of FM3A/M cells to apoptosis induced by the Pgp-related drugs but not that induced by the Pgp-unrelated drugs. Interestingly, FM3A/M cells have shown significantly lower basal and drug-stimulated JNK/SAPK activities than FM3A cells. After transfection with pEBG-SEK or pEBG-SAPK constructs, FM3A/M cells recovered the basal and Pgp-unrelated drug-stimulated activities of JNK/SAPK and the susceptibility to Pgp-unrelated drug-induced apoptotic cell death comparable to those of FM3A cells. Furthermore, FM3A cells became resistant to apoptotic cell death induced by vincristine and 5-FU after transfection with pEBG-SEK(K --> R), a dominant negative inhibitory mutant of SEK. These results suggest that downregulation of JNK/SAPK activity appears to confer on Pgp-associated FM3A/M cells a cross-resistance to Pgp-unrelated drugs.
Permeation studies were performed with freshly excised mouse jejunum segments mounted in Ussing chambers. Absorptive (M-S) and secretive (S-M) transports were analyzed with and without verapamil, which is a P-gp inhibitor widely recognized. Apparent permeability coefficients (P(app) ) in both directions and in absence or presence of verapamil were determined for each test compound. The in vitro method was validated using five controls that included high and low permeable markers with known absorption fraction (Fa) and also well-known P-gp substrates. The integrity of intestinal membrane was guaranteed during the assay by measuring the transepithelial electrical resistance.
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UA pulsatility index (PI) significantly differed in women receiving tocolysis compared to controls after 48 h. DV PI increased in women receiving MgSO(4), whereas it decreased in the ritodrine and control groups. Ut.A values did not significantly change after 48 h in the groups. In women between the 26th and 32nd weeks, UA, MCA and DV PI did not significantly change after 48 h in the three groups. However, in women between the 32nd and 36th weeks UA and MCA PI significantly differed in the treatment groups compared to controls after 48 h. DV PI increased in women receiving MgSO(4), whereas it decreased in the ritodrine and control groups.
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Both surgery for recurrence and disease-free interval between the initial resection of an adrenocortical carcinoma and recurrence >12 months are associated with better overall survival.
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Concomitant intake with grapefruit juice increases the concentrations of many drugs in humans. The effect seems to be mediated mainly by suppression of the cytochrome P450 enzyme CYP3A4 in the small intestine wall. This results in a diminished first pass metabolism with higher bioavailability and increased maximal plasma concentrations of substrates of this enzyme. The effect was most pronounced in drugs with a high first pass degradation and in many cases has the clear potential to reach clinical relevance, as shown by an occasional change in drug effects or tolerability. For felodipine, nitrendipine, nisoldipine and saquinavir, the interaction was most marked with median increases of area under the curve (AUC) and/or the maximum (peak) plasma drug concentration after single-dose administration (Cmax) values exceeding 70% of respective control periods. Less pronounced, but possibly relevant, concentration increases were found for nifedipine, nimodipine, verapamil, cyclosporin, midazolam, triazolam and terfenadine. This list is not complete because many drugs have not been studied yet. The components of grapefruit juice which are the most probable causes of the interactions are psoralen derivatives, but the flavonoid naringenin may also contribute. Concomitant grapefruit juice intake does not generally decrease the variability of drug pharmacokinetic parameters. Therefore, it is recommended that patients refrain from drinking grapefruit juice when they are taking a drug that is extensively metabolised, unless a lack of interaction has already been demonstrated for the drug. It is also recommended that drugs possibly interacting with grapefruit juice should be appropriately labelled. A place for grapefruit juice as a drug-sparing agent in treatment involving expensive medicine cannot be derived from the information currently available on grapefruit juice interactions.
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WT HERG is blocked in a concentration-dependent manner by verapamil (half-maximal inhibition concentration [IC(50)]=5.1 micromol/L), and the steady state activation and inactivation parameters are shifted to more negative values. However, mutation to Ala of Y652 and F656 located on the S6 domain produced 16-fold and 20-fold increases in IC(50) for IHERG blockade, respectively. Simultaneously, the steady state activation and inactivation parameters for Y652A are also shifted to more negative values in the presence of the blockers.
Skin injuries and the consequent loss of tissue integrity triggers a sequence of cellular and biochemical events that lead to a healed wound. Any failure during this rather sophisticated process may result in pathological scarring.
Administration of beta-blockers reduces mortality among old persons during and after acute myocardial infarction. The American College of Cardiology/American Heart Association guidelines recommend that persons without contraindications to use of beta-blockers should be administered beta-blockers within a few days of myocardial infarction (if administration is not initiated acutely) and that their administration should be continued indefinitely. These guidelines also recommend the use of angiotensin converting enzyme inhibitors in treating persons within the first 24 h of suspected onset of acute myocardial infarction with ST-segment elevation in two or more anterior precordial leads or with congestive heart failure in the absence of significant hypotension or other contraindications to use of ACE inhibitors; and persons during and after convalescence from acute myocardial infarction with congestive heart failure associated with an abnormal left ventricular ejection fraction (LVEF) or with asymptomatic left ventricular systolic dysfunction with a LVEF < 40%. These guidelines state that there are no class I indications for using calcium antagonists after myocardial infarction. If patients have persistent angina pectoris after myocardial infarction despite treatment with beta-blockers and nitrates or hypertension inadequately controlled by other drugs, administration of a nondihydropyridine calcium antagonist such as verapamil or diltiazem should be added to the therapeutic regimen if the LVEF is normal. If the LVEF is abnormal, administration of amlodipine or felodipine should be added to the therapeutic regimen.
The results of our study demonstrated that SJW inhibits excitatory transmission of the rat urinary bladder and also directly inhibits smooth muscle contractility. The inhibitory effect on excitatory transmission could involve, at least in part, opioid receptors. SJW may be evaluated for its possible use in treating urinary incontinence in depressed patients.
Flow cytometry and imaging analysis were used to study the effects of combined and individual treatment of Tet and Ver on fibroblastic proliferation in vitro. Untreated control cells were used for comparison.
calan 180 mg
A rapid enantiomeric separation method using L-leucine as chiral selector was established. Capillary zone electrophoresis (CZE) has been used for the enantiomeric separation of twelve pharmaceutical racemates with bare fused silica capillary and employing L-leucine as chiral selector. The enantiomeric resolution was influenced by L-leucine concentration and pH of background electrolyte (BGE). The effects of the BGE types and concentrations on the enantiomeric separation were also investigated. The results showed that in the solution containing 50 mmol/L borax and 70 mmol/L L-leucine (pH 9.0), all the twelve drugs were on baseline separated in less than 11 minutes.
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Photoreceptor cells of the honeybee drone fire, in the presence of the polycationic aminoglycoside neomycin, repetitive slow spike-like potentials superimposed on the receptor potential plateau phase. We have used conventional intracellular recordings and microfluorometric intracellular Ca2+ measurements to characterize these spike potentials. We have shown that the spike frequency increases in a light-intensity-dependent manner. The spikes are fired only when light stimuli depolarize the cell from a resting potential of -50 to -60 mV to at least -40 to -45 mV; they are tetrodotoxin insensitive and blocked by the Ca2+ channel blockers Ni2+, Cd2+, omega-agatoxin TK, verapamil and methoxyverapamil. Depolarization of the photoreceptors with high extracellular K+ in the presence of neomycin in darkness does not generate spikes. Small intracellular Ca2+ oscillations superimposed on the plateau phase of the light-induced increase in intracellular free Ca2+ concentration have a similar temporal pattern as the spike-like potentials. We conclude that the spike-like potentials require stimulation by light and are generated by voltage-dependent Ca2+ channels localized on the soma of the photoreceptors, distal to the basal lamina.
There were no differences in measured baseline characteristics between the clarithromycin and azithromycin groups. Amlodipine was the most commonly prescribed calcium-channel blocker (more than 50% of patients). Coprescribing clarithromycin vs azithromycin with a calcium-channel blocker was associated with a higher risk of hospitalization with acute kidney injury (420 patients of 96,226 taking clarithromycin [0.44%] vs 208 patients of 94,083 taking azithromycin [0.22%]; absolute risk increase, 0.22% [95% CI, 0.16%-0.27%]; odds ratio [OR], 1.98 [95% CI, 1.68-2.34]). In a subgroup analysis, the risk was highest with dihydropyridines, particularly nifedipine (OR, 5.33 [95% CI, 3.39-8.38]; absolute risk increase, 0.63% [95% CI, 0.49%-0.78%]). Coprescription with clarithromycin was also associated with a higher risk of hospitalization with hypotension (111 patients of 96,226 taking clarithromycin [0.12%] vs 68 patients of 94,083 taking azithromycin [0.07%]; absolute risk increase, 0.04% [95% CI, 0.02%-0.07%]; OR, 1.60 [95% CI, 1.18-2.16]) and all-cause mortality (984 patients of 96,226 taking clarithromycin [1.02%] vs 555 patients of 94,083 taking azithromycin [0.59%]; absolute risk increase, 0.43% [95% CI, 0.35%-0.51%]; OR, 1.74 [95% CI, 1.57-1.93]).
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The sigma(1) receptor-mediated behavioral effect is dependent not only on rapid Ca(2+) influx, as observed for a classical antidepressant, but also on intracellular Ca(2+) mobilization.
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A total of 130 patients affected with Peyronie's disease were entered into a prospective trial. Patients with completely calcified plaques as determined by ultrasound evaluation were excluded. We divided the patients into three treatment groups: (A) shock waves alone in 21 patients; (B) a combination of shock waves and verapamil (perilesional injection) in 36 patients, and (C) verapamil alone in 73 patients. First, we treated all groups A and B patients 3 times, 20 min each time, with a Minilith SL1, and then only the patients of the second group received a complete cycle of twelve injections of verapamil (10 mg) every 2 weeks for 6 months. The group of 73 patients (group C) treated during the previous 2 years with a medical therapy (only injection of verapamil) was used as a control group.
calan 120 mg
When rapidity of onset (i.e. relaxation caused in the first minute) was considered, GTN or combinations containing GTN, caused a response that was significantly faster than the other vasodilators (P < 0.05). The maximum response caused by the GTN-V combination (61.4 +/- 9.6%) was significantly greater than all the other single dilators, SNP (35 +/- 4%) and N (10 +/- 3%) (P < 0.05). However, no synergistic effects were demonstrated.
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Propranolol reduced heart rate, cardiac output and arterial pulse wave velocity, and increased systemic vascular resistance clearly more effectively than placebo. In addition, captopril effectively decreased arterial resistance and pulse wave velocity. However, the influence of verapamil on cardiovascular parameters did not significantly differ from those observed in placebo-treated subjects. Exercise peak heart rate, peak blood pressure, and minute ventilation were reduced in subjects treated with propranolol, but not in those treated with captopril and verapamil, when compared to placebo.
Cardiovascular shock due to verapamil intoxication is often refractory to standard resuscitation methods. Recommended therapy includes prevention of further absorption of the drug, inotropic therapy, calcium gluconate, and hyperinsulinemia/euglycemia therapy. Often further measures are needed such as ventricular pacing or mechanical circulatory support. Still, mortality remains high. Levosimendan, an inotropic agent, that enhances myofilament response to calcium, increases myocardial contraction and could therefore be beneficial in verapamil intoxication. Here, we report the case of a 60-year-old patient with clinically severe verapamil poisoning who presented with shock, bradycardia, and sopor. Standard therapy including high-dose inotropes failed to ameliorate the signs of intoxication. But additional therapy with levosimendan led to rapid improvement. Based on this observation, the literature is reviewed focusing on utilization of levosimendan in the treatment of calcium channel blocker overdose. We suggest to consider levosimendan as additional treatment option in patients with cardiovascular shock due to verapamil intoxication that are refractory to standard management.
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To investigate the risk factors of symptomatic bradyarrhythmias in relation to β-blockers use.
Cancer stem cell (CSC) research has increased exponentially to gain further insight into the mechanisms underlying both carcinogenesis and chemotherapy resistance. The present study was performed to explore the potential value of a side population (SP) assay for identifying and characterizing putative CSCs among canine lymphoma cells. Canine lymphoma cells from cell lines and clinical samples were subjected to the SP assay consisting of Hoechst 33342 staining and subsequent flow cytometric analysis. The SP assay revealed various amounts of a SP fraction among the canine lymphoma cells. The percentages of SP were not affected by inhibitors of membrane transporters, verapamil hydrochloride, or fumitremorgin C. Most of the canine lymphoma cells expressed high levels of Bmi-1 and membrane transporter proteins such as ABCG2 and phosphorylated (p)-glycoprotein. This investigation lays the groundwork for further studies of the biological behaviors and molecular characteristics of CSCs in cases of canine lymphoma.
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Within muscular equivalents of cat lower esophageal sphincter (LES), the circular muscle develops greater spontaneous tone, whereas the sling muscle is more responsive to cholinergic stimulation. Smooth muscle contraction involves a combination of calcium release from stores and of calcium entry via several pathways. We hypothesized that there are differences in the sources of Ca(2+) used for contraction in sling and circular muscles and that these differences could contribute to functional asymmetry observed within LES. Contraction of muscle strips from circular and sling regions of LES was assessed in the presence of TTX. In Ca(2+)-free Krebs, tone was inhibited to a greater degree in circular than sling muscle. L-type Ca(2+) channel blockade with nifedipine or verapamil inhibited tone in LES circular but not sling muscle. Sarcoplasmic reticulum (SR) Ca(2+)-ATPase inhibitor cyclopiazonic acid (CPA) caused greater increase in tone in sling than in circular muscle. The phospholipase C inhibitor U-73122 and the SR inositol 1,4,5-trisphosphate [Ins(1,4,5)P(3)] receptor blocker 2-aminoethoxydiphenyl borate (2-APB) inhibited tone in circular and sling muscles, demonstrating that continuous release of Ca(2+) from Ins(1,4,5)P(3)-sensitive stores is important in tone generation in both muscles. In Ca(2+)-free Krebs, ACh-induced contractions (AChC) were inhibited to a greater degree in sling than circular muscles. However, nifedipine and verapamil greatly inhibited AChC in the circular but not sling muscle. Depletion of SR Ca(2+) stores with CPA or inhibition of Ins(1,4,5)P(3)-mediated store release with either U-73122 or 2-APB inhibited AChC in both muscles. We demonstrate that LES circular and sling muscles 1) use intracellular and extracellular Ca(2+) sources to different degrees in the generation of spontaneous tone and AChC and 2) use different Ca(2+) entry pathways. These differences hold the potential for selective modulation of LES tone in health and disease.