Calcium Channel-blocking Agents Research Articles

Incorporation of Silver-Doped Graphene Oxide Quantum Dots in Polyvinylidene Fluoride Membrane for Verapamil Removal

Verapamil hydrochloride, a calcium channel-blocking agent, is detectable in receiving water bodies and affects the well-being of aquatic organisms. Membrane filtration could be effective in removing such pharmaceutical contaminants. However, limited studies have employed commercial membranes, such as polyvinylidene fluoride (PVDF), in removing verapamil from water sources, owing to their low solution fluxes, poor antibacterial properties, and high surface hydrophobicity. Efforts are needed to create the PVDF membrane suitable for removing verapamil from water sources. In this study, PVDF composite membranes incorporated with from 0 to 0.10 wt% silver-doped graphene oxide quantum dots (Ag−GOQD) were evaluated in terms of their morphological structures, elemental composition, surface roughness, hydrophilicity, verapamil rejection capability, anti-fouling, and antibacterial capabilities. The pure PVDF membrane showed the lowest verapamil rejection (73.66 ± 2.45%), highest surface roughness (mean surface roughness, Sa = 123.80 nm), and least hydrophilic membrane surface (contact angle = 79.06 ± 4.53°) when compared to other membranes incorporated with nanocomposites. However, the membrane incorporated with 0.10 wt% Ag−GOQD showed the smoothest and the most hydrophilic membrane surface (Sa = 13.10 nm and contact angle = 53.60 ± 4.75°, respectively), associated with the highest verapamil rejection (96.04 ± 1.82%). A clear inhibition zone was spotted in the agar plate containing the membrane incorporated with Ag−GOQD, showing the antibacterial capability of the membrane. The overall improvement in morphological structures, surface smoothness, surface hydrophilicities, permeabilities, verapamil rejection abilities, and anti-fouling and antibacterial capabilities indicated a great potential to incorporate Ag−GOQD in PVDF membrane fabrication.

Swift electrochemical sensing of diltiazem employing highly-selective molecularly-imprinted 3-amino-4-hydroxybenzoic acid

• For the first time, an electrochemical molecularly-imprinted polymer was prepared for the selective detection of diltiazem, a calcium channel blocking agent. • GCE-MIP sensor was prepared by the electropolymerization of the 3-amino-4-hydroxybenzoic acid. • MIP fabrication procedure was thoroughly optimized giving reproducible, and repeatable analytical signal via square-wave voltammetry. • High linearity of the calibration curves with LOD of 0.12 and 0.26 μmol L −1 obtained for buffer and urine as the supporting electrolytes, respectively. • Possibility of using the optimized MIP for street-seized cocaine samples successfully demonstrated. Diltiazem is a calcium channel-blocking agent, efficient in treating various heart-related conditions and diseases. It has been used as a cutting agent in cocaine and prevents its common cardiotoxic effects. This paper presents a highly selective molecularly-imprinted sensor to detect diltiazem in buffer and urine. In addition, the possibility of using this sensor as a forensic tool for fingerprinting street-seized cocaine samples of heterogeneous composition was investigated. With thorough optimization of the fabrication process, it was possible to obtain a sensible and reproducible analytical signal via square-wave voltammetry (SWV) as the electroanalytical technique. The obtained analytical parameters for the samples in buffer, pH 7.4, were the limit of detection (LOD) of 0.12 µmol L −1 , the limit of quantification (LOQ) of 0.41 µmol L −1 , and inter-day reproducibility of 2%. For the samples in artificial urine, the analytical parameters were LOD of 0.26 µmol L −1 , LOQ of 0.88 µmol L −1 , and inter-day reproducibility of 9%. Decent linearity of the analytical signal with the increased concentration of diltiazem in the cocaine street samples suggested a high perspective of the proposed sensor for the forensic laboratory applications, more precisely, the determination of the seized samples' origins.

Green synthesis of 1,4-dihydropyridines using cobalt carbon nanotubes as recyclable catalysts

Heterocyclic compounds occur widely in nature and in drug molecules. The activity of many nitrogen-containing heterocyclic compounds is unique. For example, 1,4-dihydropyridines display good antitumor and antibacterial effects and can be commercially used as calcium channel blocker agents in the treatment of cardiovascular diseases. To reduce the use of toxic catalysts in the synthesis of 1,4-dihydropyridines, here we designed cobalt carbon nanotubes as a heterogeneous catalyst. We report the efficient synthesis of 1,4-dihydropyridines under mild conditions, which allows to access a wide array of 1,4-dihydropyridines from aromatic aldehyde in high yields, up to 96%. Advantages include the use of ethanol as solvent, low catalyst loading of 6% mol, short reaction time of 5–15 min, easy preparation and recyclable catalyst.

Selection of antihypertensive therapy in elderly patients, combination therapy: thiazide-like diuretics and calcium channel blockers

The article presents data about the prevalence and expected prognosis for arterial hypertension. Emphasis is placed on the selection of antihypertensive therapy in elderly patients. The features concerning the positive effect of the calcium channelblocking agent — amlodipine, thiazid­like diuretic — indapamide retard in the form of monotherapy and a combination of the above drugs on the course and prognosis of arterial hypertension in elderly patients are investigated. A clinical example of the use of the fixed dose combination amlodipine + indapamide retard is also introduced.

Chemometrics-assisted study of the interconversion between the crystalline forms of nimodipine

Nimodipine (NIM) is a calcium channel-blocking agent, which in the solid state exhibits two crystalline modifications, Mode I and Mode II. The first one is a racemic mixture, while the second is a conglomerate. Because the drug has poor aqueous solubility and Mode I is twice as soluble as Mode II, the former is widely preferred for the development of pharmaceutical forms. In order to study the effect of thermal stimuli on the behavior of NIM, an analytical method was developed coupling ATR-FTIR spectroscopy to Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS). The method allowed to monitor the transformations of each polymorph, their respective mixtures and commercial samples, during the thermal treatment.It was observed that Mode II experienced changes during the experiments and the chemometric technique provided the abundance profile and the pure spectra of the different species involved. In this way, it was established that Mode II has two transitions, at 116.8 °C and 131.9 °C, which reflect that Mode II is first transformed into Mode I, which then melts. The liquid phase solidifies to give an amorphous (AM) vitreous solid, which does not revert to the crystalline state. The analysis of a commercial sample of NIM exhibited the similar transformations than Mode II; however, a pronounced decrease was noted in the first transition temperature (95 °C), whereas the second remained essentially unchanged (131.6 °C). This could be a result of the presence of mixtures of Mode I and Mode II (0.32:0.68) in the bulk solid, as confirmed by the analysis of a physical mixture of crystals of Modes I and II.Therefore, it was concluded that the developed ATR-FTIR/MCR-ALS method is suitable for the detailed analysis of the crystalline forms of NIM in bulk drug and enables de study of their possible thermally promoted interconversions.

Molecular basis of the counteraction by calcium channel blockers of cyclosporine nephrotoxicity.

Nephrotoxicity is a serious side effect for the immunosuppressant drug cyclosporine A(CSA). In this study, we tested the hypothesis that administration of calcium channel blockers such as verapamil or nifedipine ameliorates renal CSA-induced renal dysfunction. Furthermore, our study investigates the roles of inflammatory, oxidative, and fibrotic pathways in CSA-induced renal dysfunction. Six groups of male rats ( n = 6/group) were used and received one of the following treatments for seven consecutive days: vehicle (Cremophor EL ip), CSA (25 mg·kg-1·day-1 ip), verapamil (2 mg·kg-1·day-1 ip), nifedipine (3 mg·kg-1·day-1 ip), CSA in the presence or absence of either verapamil, or nifedipine. Biochemical and histomorphometric analyses showed that rats treated with CSA exhibited clear signs of nephrotoxicity that included 1) proteinuria and elevations in serum creatinine and blood urea nitrogen, 2) mesangial expansion, 3) increases in glomerular and tubular type IV collagen expression, and 4) increases in the glomerulosclerosis and tubulointerstitial fibrosis indices. Although the single administration of nifedipine or verapamil had no significant effect on renal pathology, or its biochemical and physiological function, the concurrent use of either calcium channel blockers significantly and equipotently ameliorated the biochemical, morphological, and functional derangements caused by CSA. More importantly, we report that the oxidative (reactive oxygen species production, NADPH-oxidase activity, and dual oxidase 1/2 levels), fibrotic (transforming growth factor-β1 expression), and inflammatory (NF-κB expression) manifestations of renal toxicity induced by CSA were significantly reversed upon administration of nifedipine or verapamil. Together, these results highlight the efficacy of calcium channel-blocking agents in attenuating CSA-induced nephrotoxicity and predisposing biochemical and molecular machineries.

Do hypertension and calcium channel blocker agents increase the risk of Parkinson disease?

Do hypertension and calcium channel blocker agents increase the risk of Parkinson disease?

Analysis of parameters affecting autologous arteriovenous fistula functional maturation in a population of patients with end-stage renal disease

Objective To investigate demographic factors implicated in the functional maturation of autologous arteriovenous fistula in a population of patients with end-stage renal disease. Methods The data of 335 consecutive patients with end-stage renal disease who were performed autologous arteriovenous fistula from January 2010 to December 2015 were analyzed retrospectively. The parameters affecting autologous arteriovenous fistula functional maturation were screened. Results Overall arteriovenous fistula functional maturation rate was 78.14% (218/279). The arteriovenous fistula functional maturation rate was 68.33%(82/120) in diabetes and 85.54%(136/159) in non-diabetes, and there was significant difference (χ2=11.844, P<0.01). The arteriovenous fistula functional maturation rate was 62.26%(33/53) in hypoproteinemia and 81.86%(185/226) in non-hypoproteinemia, and there was significant difference (χ2=9.648, P<0.01). Diabetes and hypoproteinemia were the risk factors to promote functional maturation (OR=6.003, 8.476). The arteriovenous fistula functional maturation rate was 87.10%(81/93) in calcium channel blockers using and 73.66%(137/186) in non-calcium channel blockers using, and there was significant difference (χ2=6.556, P<0.05). Calcium channel blockers was the protective factor for promoting functional maturation (OR=0.086). Conclusions Diabetes and hypoproteinemia are found to be associated with functional non-maturation, while calcium channel-blocker agents are associated with better functional maturation. Key words: Renal dialysis; End-stage renal disease; Arteriovenous fistula; Maturation

EFFECT OF CALCIUM CHANNEL-BLOCKERS ON CLINICAL OUTCOMES OF IMPLANT RETAINED OVERDENTURE IN HYPERTENSIVE PATIENTS

Purpose: Calcium channel-blocking agents are used extensively for the management of hypertension. Gingival overgrowth around natural teeth has been previously reported in the literature with patients taking calcium channel-blocking agents. There are limited scientific documentations illustrating its effects around dental implants. This study compared the effects of Calcium channel-blocking agents (Amlodipine) and angiotensin receptor blockers (Valsartan) on dental implants retaining overdentures in hypertensive patients clinically and radiographically after two years of function. Materials and Methods: Twenty completely edentulous male hypertensive patients wearing mandibular overdentures retained by two implants (3.6*12mm Dentium Two– piece (Ball type) dental implant, Dentium Implant System, Korea) were included in this study, Patients were equally and randomly divided into two groups, Group (I) were managed by Amlodipine according to their physician to control the hypertension. Group (II) were managed by Valsartan according to their physician to control the hypertension. Each case was evaluated clinically concerning plaque index, gingival index, probing depth and implant stability by using OSSTELL ISQ and radiographically concerning marginal bone loss at baseline (overdenture insertion) and after 6, 12 and 24 months. Data were collected, tabulated and statistically analyzed using t-Student test. Results: No statistical significant difference was found between the two groups (P≥0.05). Conclusions: Based on the limitations of the present study and although no statistical difference was found between the effect of Amlodipine and Valsartan on dental implants under overdentures. Peridontium around implants in hypertensive patients managed by calcium channel blockers Amlodipine was affected more than that managed by Valsartan.

The Effect of Ginger Hydroalcholic Extract on Rat Ileal Contraction in Vitro

Background: Ginger is a medicinal plant with wide use around the world which has several therapeutic implications especially in gastrointestinal discomfort such as dyspepsia, flatulence, colic, diarrhea, nausea and vomiting. Objectives: Therefore, given the widespread use of ginger for the treatment of gastrointestinal diseases, in the present study we have investigated the eect of this herbal medicine and underlying mechanism on pre-contracted rat ileum segments. Materials and Methods: In this experimental study, 40 male rat divided to 5 groups (n = 8 in each group) randomly. Groups were consisting: ginger alone, KCl + ginger, carbachol + ginger, pretreated with L-NAME and KCl + ginger, pretreated with verapamil and KCl + ginger. To investigate the mechanism underlying relaxation induced by ginger extract on rat ileum, isolated rat ileum segments were pre-contracted by KCl 120 mol or carbachol 100 mol and then relaxation response induced by ginger hydroalcholic extracts (with 100 or 200 g/mL of organ bath) was studied in the presence of verapamil (a calcium channel blocker agents) and L-NAME (a nitric oxide synthase inhibitor). Results: Non-cumulative concentrations of ginger extract (100 and 200 g/mL) was able to decrease contractile responses to KCl (120 mol/mL of organ bath) and carbachol (100 mol/mL of organ bath) in a dose dependent manner (P < 0.05). Incubation of tissue with L-NAME (300 mol/mL) was not able to reduce the relaxation response; however incubation with verapamil inhibited the relaxation response induced by ginger extract. Conclusions: The relaxation response induced by ginger extract in the present study was not mediated by nitric oxide. However calcium channel may contribute to relaxation response.

Predictive parameters of arteriovenous fistula functional maturation in a population of patients with end-stage renal disease.

IntroductionWith increasing numbers of patients diagnosed with ESRD, arteriovenous fistula (AVF) maturation has become a major factor in improving both dialysis related outcomes and quality of life of those patients. Compared to other types of access it has been established that a functional AVF access is the least likely to be associated with thrombosis, infection, hospital admissions, secondary interventions to maintain patency and death.AimStudy of demographic factors implicated in the functional maturation of arteriovenous fistulas. Also, to explore any possible association between preoperative haematological investigations and functional maturation.MethodsWe performed a retrospective chart review of all patients with ESRD who were referred to the vascular service in the University Hospital of Limerick for creation of vascular access for HD. We included patients with primary AVFs; and excluded those who underwent secondary procedures.ResultsOverall AVF functional maturation rate in our study was 53.7% (52/97). Female gender showed significant association with nonmaturation (P = 0.004) and was the only predictor for non-maturation in a logistic regression model (P = 0.011). Patients who had history of renal transplant (P = 0.036), had relatively lower haemoglobin levels (P = 0.01) and were on calcium channel blockers (P = 0.001) showed better functional maturation rates.ConclusionFemale gender was found to be associated with functional non-maturation, while a history kidney transplant, calcium channel-blocker agents and low haemoglobin levels were all associated with successful functional maturation. In view of the conflicting evidence in the literature, large prospective multi-centre registry-based studies with well-defined outcomes are needed.

Pericardial fat is strongly associated with atrial fibrillation after coronary artery bypass graft surgery†

Recent evidence suggests that pericardial fat may represent an important risk factor for cardiovascular disease because of its unique properties and its proximity to cardiac structures. It has been reported that pericardial fat volume (PFV) is associated with atrial fibrillation (AF). The purpose of this study was to investigate the association between PFV and new-onset AF following coronary artery bypass graft surgery (CABG). PFV was measured using computed tomography in 83 patients with coronary artery disease scheduled to undergo elective isolated on-pump CABG. Patient characteristics, medical history and perioperative variables were prospectively collected. Any documented episode of new-onset postoperative AF until discharge was defined as the study end point. Twenty-eight patients (33.7%) developed postoperatively AF during hospital stay. There was no significant difference in demographics and comorbidities among patients that maintained sinus rhythm (SR) and their AF counterparts. In univariate analysis, patients with postoperative AF had significantly more pericardial fat compared with SR patients (195 ± 80 ml vs 126 ± 47 ml, P = 0.0001). Larger left atrial diameter was also associated with postoperative AF (42.4 ± 6.9 mm vs 39.3 ± 4.8 mm, P = 0.017). Additionally, the prebypass use of calcium channel-blocking agents was independently associated with a lower incidence of postoperative AF, confirmed also by multivariate analysis (P = 0.035). In multivariate logistic regression analysis, PFV was the strongest independent variable associated with the development of postoperative AF (odds ratio: 1.018, 95% confidence interval: 1.009-1.027, P = 0.0001). The best discriminant value assessed by receiver operating characteristic analysis was 129.5 ml (sensitivity 86% and specificity 56%). PFV is strongly associated with AF following CABG, independently of many traditional risk factors. Our findings suggest that PFV may represent a novel risk factor for postoperative AF. However, the role of pericardial fat in AF mechanism needs to be further delineated.

Microneedle-assisted delivery of verapamil hydrochloride and amlodipine besylate

The aim of this project was to study the effect of stainless steel solid microneedles and microneedle rollers on percutaneous penetration of verapamil hydrochloride and amlodipine besylate.Verapamil, 2-(3,4-dimethooxyphenyl)-5-[2-(3,4 dimethoxyphenyl)ethyl-methyl-amino]-2-propan-2-yl-pentanenitrile is a calcium channel blocker agent that regulates high blood pressure by decreasing myocardial contractilty, heart rate and impulse conduction. Amlodipine, (R, S)-2-[(2-aminoethoxy) methyl]-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1, 4-dihydropyridine, is a calcium channel blocker that is used for the management of hypertension and ischemic heart disease. Passive penetration of verapamil and amlodipine across the skin is low. In vitro studies were performed with microneedle-treated porcine ear skin using vertical static Franz diffusion cells (PermeGear, Hellertown, PA, USA). The receiver chamber contained 5ml of PBS (pH7.4) and was constantly maintained at 37°C temperature with a water circulation jacket. The diffusion area of the skin was 1.77cm2. The donor compartment was loaded with 1ml of the solution containing 2.5mg/ml of amlodipine besylate. The donor chamber was covered with parafilm to avoid evaporation. Passive diffusion across untreated porcine skin served as control. Aliquots were taken every 2h for 12h and analyzed by liquid chromatography–mass spectrometry. Transcutaneous flux of verapamil increased significantly from 8.75μg/cm2/h to 49.96μg/cm2/h across microneedle-roller treated porcine skin. Percutaneous flux of amlodipine besylate following the use of stainless steel microneedles was 22.39μg/cm2/h. Passive flux for the drug was 1.57μg/cm2/h. This enhancement of amlodipine flux was statistically significant. Transdermal flux of amlodipine with microneedle roller was 1.05μg/cm2/h in comparison with passive diffusion flux of 0.19μg/cm2/h. The difference in flux values was also statistically significant. Stainless steel solid microneedles and microneedle rollers increased percutaneous penetration of verapamil hydrochloride and amlodipine besylate. It may be feasible to develop transdermal microneedle patches for these drugs.

Utilizing In Vitro and PBPK Tools to Link ADME Characteristics to Plasma Profiles: Case Example Nifedipine Immediate Release Formulation

One of the most prominent food-drug interactions is the inhibition of intestinal cytochrome P450 (CYP) 3A enzymes by grapefruit juice ingredients, and, as many drugs are metabolized via CYP 3A, this interaction can be of clinical importance. Calcium channel-blocking agents of the dihydropyridine type, such as felodipine and nifedipine, are subject to extensive intestinal first pass metabolism via CYP 3A, thus resulting in significantly enhanced in vivo exposure of the drug when administered together with grapefruit juice. Physiologically based pharmacokinetic (PBPK) modeling was used to simulate pharmacokinetics of a nifedipine immediate release formulation following concomitant grapefruit juice ingestion, that is, after inhibition of small intestinal CYP 3A enzymes. For this purpose, detailed data about CYP 3A levels were collected from the literature and implemented into commercial PBPK software. As literature reports show that grapefruit juice (i) leads to a marked delay in gastric emptying, and (ii) rapidly lowers the levels of intestinal CYP 3A enzymes, inhibition of intestinal first pass metabolism following ingestion of grapefruit juice was simulated by altering the intestinal CYP 3A enzyme levels and simultaneously decelerating the gastric emptying rate. To estimate the in vivo dispersion and dissolution behavior of the formulation, dissolution tests in several media simulating both the fasted and fed state stomach and small intestine were conducted, and the results from the in vitro dissolution tests were used as input function to describe the in vivo dissolution of the drug. Plasma concentration-time profiles of the nifedipine immediate release formulation both with and without simultaneous CYP 3A inhibition were simulated, and the results were compared with data gathered from the literature. Using this approach, nifedipine plasma profiles could be simulated well both with and without enzyme inhibition. A reduction in small intestinal CYP 3A levels by 60% was found to yield the best results, with simulated nifedipine concentration-time profiles within 20% of the in vivo observed results. By additionally varying the dissolution input of the PBPK model, a link between the dissolution characteristics of the formulation and its in vivo performance could be established.

Safety and Efficiency of Calcium Channel Blockers Versus Beta‐blockers for Rate Control in Patients With Atrial Fibrillation and No Acute Underlying Medical Illness

Many patients with atrial fibrillation (AF) are not candidates for rhythm control and may require rate control, typically with beta-blocking (BB) or calcium channel blocking (CCB) agents. Although these patients appear to have a low 30-day rate of stroke or death, it is unclear if one class of agent is safer or more effective. The objective was to determine whether BBs or CCBs would have a lower hospital admission rate and to measure 30-day safety outcomes including stroke, death, and emergency department (ED) revisits. This retrospective cohort study used a database from two urban EDs to identify consecutive patients with ED discharge diagnoses of AF from April 1, 2006, to March 31, 2010. Comorbidities, rhythms, management, and immediate outcomes were obtained by manual chart review, and patients with acute underlying medical conditions were excluded by predefined criteria. Patients managed only with rate control agents were eligible for review, and patients receiving BB agents were compared to those receiving CCB agents. The primary outcome was the proportion of patients requiring hospital admission; secondary outcomes included the ED length of stay (LOS), the proportion of patients having adverse events, the proportion of patients returning within 7 or 30 days, and the number of patients having a stroke or dying within 30 days. A total of 259 consecutive patients were enrolled, with 100 receiving CCBs and 159 receiving BBs. Baseline demographics and comorbidities were similar. Twenty-seven percent of BB patients were admitted, and 31.0% of CCB patients were admitted (difference = 4.0%, 95% confidence interval [CI] = -7.7% to 16.1%), and there were no significant differences in ED LOS, adverse events, or 7- or 30-day ED revisits. One patient who received metoprolol had a stroke, and one patient who received diltiazem died within 30 days. In this cohort of ED patients with AF and no acute underlying medical illness who underwent rate control only, patients receiving CCBs had similar hospital admission rates to those receiving BBs, while both classes of medications appeared equally safe at 30 days. Both CCBs and BBs are acceptable options for rate control.

Interaction of eNOS polymorphism with MTHFR variants increases the risk of diabetic nephropathy and its progression in type 2 diabetes mellitus patients

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients.In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 ± 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients.After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (β-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine).In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the β-1/Cr (0.65 ± 4.29 vs. -1.93 ± 2.35 1/μmol × 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 ± 24.1 vs. 63.5 ± 21.3 vs. 41.9 ± 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0.001). On multivariate analysis, β-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (β = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (β = 2.426, P = 0.018), high-density lipoprotein cholesterol (β = -8.797, P = 0.03), baseline UAE (β = 0.002, P = 0.04), and mean CCr during treatment (β = -0.211, P = 0.006).In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.

Synergistic effects of the MTHFR C677T and A1298C polymorphisms on the increase risk of micro- and macro-albuminuria and progression of diabetic nephropathy among Iranians with type 2 diabetes mellitus

Long-term effects of angiotensin-converting enzyme inhibition and metabolic control in hypertensive type 2 diabetic patients.In hypertensive type 2 diabetic patients, treatment with angiotensin-converting enzyme (ACE) inhibitors is associated with a lower incidence of cardiovascular events than those treated with calcium channel-blocking agents. However, the long-term renal effects of ACE inhibitors in these patients remain inconclusive. In 1989, we commenced a placebo-controlled, double-blind, randomized study to examine the anti-albuminuric effects of enalapril versus nifedipine (slow release) in 102 hypertensive, type 2 diabetic patients. These patients have been followed up for a mean trial duration of 5.5 ± 2.2 years. We examined the determinants, including the effect of ACE inhibition on clinical outcomes in these patients.After a six-week placebo-controlled, run-in period, 52 patients were randomized double-blind to receive nifedipine (slow release) and 50 patients to receive enalapril. After the one-year analysis, which confirmed the superior anti-albuminuric effects of enalapril (-54%) over nifedipine (+11%), all patients were continued on their previously assigned treatment with informed consent. They were subdivided into normoalbuminuric (N = 43), microalbuminuric (N = 34), and macroalbuminuric (N = 25) groups based on two of three 24-hour urinary albumin excretion (UAE) measurements during the run-in period. Renal function was shown by the 24-hour UAE, creatinine clearance (CCr), and the regression coefficient of the yearly plasma creatinine reciprocal (β-1/Cr). Clinical endpoints were defined as death, cardiovascular events, and/or renal events (need for renal replacement therapy or doubling of baseline plasma creatinine).In the whole group, patients treated with enalapril were more likely to revert to being normoalbuminuric (23.8 vs. 15.4%), and fewer of them developed macroalbuminuria (19.1 vs. 30.8%) compared with the nifedipine-treated patients (P < 0.05). In the microalbuminuric group, treatment with enalapril (N = 21) was associated with a 13.0% (P < 0.01) reduction in 24-hour UAE compared with a 17.3% increase in the nifedipine group (N = 13). In the macroalbuminuric patients, enalapril treatment (N = 11) was associated with stabilization compared with a decline in renal function in the nifedipine group, as shown by the β-1/Cr (0.65 ± 4.29 vs. -1.93 ± 2.35 1/μmol × 10-3, P < 0.05) after adjustment for baseline values. Compared with the normoalbuminuric and microalbuminuric patients, those with macroalbuminuria had the lowest mean CCr (75.5 ± 24.1 vs. 63.5 ± 21.3 vs. 41.9 ± 18.5 mL/min, P < 0.001) and the highest frequency of clinical events (4.7 vs. 5.9 vs. 52%, P < 0.001). On multivariate analysis, β-1/Cr (R2 = 0.195, P < 0.001) was independently associated with baseline HbA1c (β = -0.285, P = 0.004), whereas clinical outcomes (R2 = 0.176, P < 0.001) were independently related to the mean low-density lipoprotein cholesterol (β = 2.426, P = 0.018), high-density lipoprotein cholesterol (β = -8.797, P = 0.03), baseline UAE (β = 0.002, P = 0.04), and mean CCr during treatment (β = -0.211, P = 0.006).In this prospective cohort analysis involving 102 hypertensive, type 2 diabetic patients with varying degrees of albuminuria followed up for a mean duration of five years, we observed the importance of good metabolic and blood pressure control on the progression of albuminuria and renal function. Treatment with enalapril was associated with a greater reduction in albuminuria than with nifedipine in the entire patient group, and especially in those with microalbuminuria. In the macroalbuminuric patients, the rate of deterioration in renal function was also attenuated by treatment with enalapril.

Hyperoxaluria-induced tubular ischemia: the effects of verapamil and vitamin E on apoptotic changes with an emphasis on renal papilla in rat model

An experimental study in rats was performed to evaluate the presence and the degree of both tubular apoptotic changes and crystallization at cortical, medullar and papillary regions of the kidney during hyperoxaluric phase and assess the possible protective effects of vitamin E and verapamil on these pathologic changes (particularly in papillary part of the affected kidneys). A total of 32 rats have been included into the study program. Hyperoxaluria was induced by continuous administration of ethylene glycol (0.75%). In addition to hyperoxaluria induction, animals in Groups 2 and 3 did receive a calcium channel-blocking agent (verapamil) and vitamin E, respectively. Histologic alterations of the kidneys including crystal formation together with apoptotic changes were evaluated on days 1, 14 and 28, respectively. Both apoptotic changes and the presence and degree of crystallization were assessed separately in renal cortical region, medulla and particularly papillary parts of the removed kidneys. Although verapamil did well limit the degree of crystal formation and apoptosis and brought it to the same levels observed in control group animals in all parts of the kidneys during intermediate phase, addition of vitamin E was failed to show the same protective effect during both intermediate and late phase evaluations. As demonstrated in our study, the limitation of both crystal deposition and apoptotic changes might be instituted by calcium channel-blocking agents. Clinical application of such agents in the prophylaxis of stone disease might limit the formation of urinary calculi, especially in recurrent stone formers.

Drug-Induced Gingival Hyperplasia

ImageA 37-year-old Spanish-speaking man presented with a complaint of tender, bleeding, and swollen gums. He had had an orthotopic heart transplant in 1997. His current mediations include Cyclosporine 125 mg bid and amlodipine 5 mg qd as well as CellCept, aspirin, and allopurinol for gout. Gingival overgrowth, also known as gingival hyperplasia, has been well described in the literature. The most recognized cause is drug-induced gingival enlargement from phenytoin (Dilantin), which is commonly used to treat patients with epileptic seizures. Less known drugs that contribute to this phenomenon are Cyclosporine, a potent immunosuppressant used in organ transplant recipients, and calcium channel blocker agents. The interaction of these medications with epithelial keratinocytes, fibroblasts, and collagen can lead to an overgrowth of gingival tissue, particularly in patients with poor oral hygiene, periodontal disease, and malpositioned teeth. Treatment for gingival hyperplasia includes discontinuing the drug or reducing its dose. In those for whom this is not possible, good oral hygiene and referral for surgical gingivectomy remain the only treatment. Gingival hyperplasia should be considered when treating organ transplant recipients on immunosuppressant therapy. Dr. McGregor is an assistant professor of emergency medicine at the Warren Alpert Medical School of Brown University and an attending at Rhode Island Hospital and the Miriam Hospital. Dr. Hsu-Hung is a resident in emergency medicine at the Warren Alpert Medical School of Brown University.

Docking and QSAR studies of new 1,4-dihydropyridines containing 4(5)-chloro-2-methyl-5(4)-imidazolyl substituent

1,4-Dihydropyridine (1,4-DHP) derivatives have been recognized as calcium channel blocker (CCB) agent. In this research, a newly synthesized dihydropyridine, containing 4-[4(5)-chloro-2-methyl-5(4)-imidazolyl] moiety, as subjected to docking study and QSAR analysis. DHPs were built by HYPERCHEM program, and conformational studies were performed through semi-empirical method followed by PM3 method. QSAR descriptors were obtained from the EDRAGON and HYPERCHEM. QSAR equations were derived from multilinear regression method. This simple equation can be used to estimate the CCB’s activity for new derivatives of this series of compounds. The sums of the HATS2v, Mor09p, Mor06p, and CIC5 were identified as the most significant descriptors. Docking study was performed using AutoDock4 program on all of the compounds. The results show that experimental pIC50 values agree with docking results for potent compounds. These computational studies can offer useful references for understanding the action mechanism and molecular design or modification of this series of the CCB agents.