Types Of Calcium Channel Blockers Research Articles

Hypoxia-Induced Impairment of Glucose Homeostasis: Sympathovagal Imbalance and the Potential Therapeutic Role of L/N type Calcium Channel Blocker Cilnidipine

Hypoxia-Induced Impairment of Glucose Homeostasis: Sympathovagal Imbalance and the Potential Therapeutic Role of L/N type Calcium Channel Blocker Cilnidipine

Long-Term Systemic Use of Calcium Channel Blockers and Incidence of Primary Open-Angle Glaucoma

PurposeTo evaluate the association between the systemic use of calcium channel blockers (CCBs) and primary open-angle glaucoma (POAG) using a diverse nationwide dataset. DesignRetrospective cohort study Subjects213,424 individuals aged 40 years and older in the National Institutes of Health (NIH) All of Us dataset, notable for its demographic, geographic and medical diversity and inclusion of historically underrepresented populations. Patients with a diagnosis of POAG prior to use of any kind of anti-hypertensive medication were excluded. MethodsBivariate and multivariable regression analyses were performed to evaluate associations between CCB use and POAG. CCB use was further divided into exposure to dihydropyridine CCBs and non-dihydropyridine CCBs, and subgroup analyses were performed using Chi-square and Fisher’s tests. Main Outcome MeasuresDiagnosis of POAG ResultsWithin our cohort, 2,772 participants (1.3%) acquired a diagnosis of POAG, while 210,652 (98.7%) did not. Among patients who developed POAG, the mean age was 73.3 years, 52.5% were female, and 48.2% identified as White. Among POAG patients, 32.6% used one or more CCB, 28.2% used a dihydropyridine CCB, and 2.2% used a non-dihydropyridine CCB. In bivariate analysis, use of any CCBs was associated with an increased risk of POAG (OR: 1.29, 95% CI: 1.27-1.31, p<0.001). In multivariable analysis adjusting for age, gender, race, ethnicity, and comorbidities such as diabetes, hyperlipidemia, and hypertension, use of any CCBs remained associated with an increased risk of developing POAG (OR: 1.52, 95% CI: 1.33-1.74, p<0.001). When stratified by type of CCB, the use of dihydropyridine CCBs (OR: 1.31, 95% CI: 1.14-1.50, p<0.001) was associated with increased POAG risk. ConclusionsUse of dihydropyridine calcium channel blockers was associated with a significantly higher risk of developing POAG, both before and while adjusting for demographic factors and comorbid medical conditions.

Direct investigations of the effects of nicardipine on calcium channels of astrocytes by Atomic Force Microscopy

Calcium channel blockers (CCB) of astrocytes can blockade the calcium ions entry through the voltage gated calcium channels (VGCC), and is widely used in the diseases related with VGCC of astrocytes. But many aspects of the interaction mechanisms between the CCB and VGCC of astrocytes still remain unclear due to the limited resolution of the approaches. Herein the effects of the nicardipine (a type of CCB) on VGCC of astrocytes were investigated at very high spatial, force and electrical resolution by multiple modes of Atomic Force Microscopy (AFM) directly. The results reveal that after the addition of nicardipine, the recognition signals of VGCC disappeared; the specific unbinding forces vanished; the conductivity of the astrocytes decreased (the current decreased about 2.9 pA and the capacitance was doubled); the surface potential of the astrocytes reduced about 14.2 mV. The results of electrical properties investigations are consistent with the simulation experiments. The relations between these biophysical and biochemical properties of VGCC have been discussed. All these demonstrate that the interactions between nicardipine and VGCC have been studied at nanometer spatial resolution, at picoNewton force resolution and very high electrical signal resolution (pA in current, pF in capacitance and 0.1 mV in surface potential) level. The approaches are considered to be high resolution and high sensitivity, and will be helpful and useful in the further investigations of the effects of other types of CCB on ion channels, and will also be helpful in the investigations of mechanisms and therapy of ion channelopathies.

Interaction between tacrolimus and calcium channel blockers based on CYP3A5 genotype in Chinese renal transplant recipients.

To investigate the effect of calcium channel blockers (CCBs) on tacrolimus blood concentrations in renal transplant recipients with different CYP3A5 genotypes. This retrospective cohort study included renal transplant recipients receiving tacrolimus-based immunosuppressive therapy with or without CCBs in combination. Patients were divided into combination and control groups based on whether or not they were combined with CCBs, and then further analyzed according to the type of CCBs (nifedipine/amlodipine/felodipine). Propensity score matching was conducted for the combination and the control groups using SPSS 22.0 software to reduce the impact of confounding factors. The effect of different CCBs on tacrolimus blood concentrations was evaluated, and subgroup analysis was performed according to the patients' CYP3A5 genotypes to explore the role of CYP3A5 genotypes in drug-drug interactions between tacrolimus and CCBs. A total of 164 patients combined with CCBs were included in the combination groups. After propensity score matching, 83 patients with nifedipine were matched 1:1 with the control group, 63 patients with felodipine were matched 1:2 with 126 controls, and 18 patients with amlodipine were matched 1:3 with 54 controls. Compared with the controls, the three CCBs increased the dose-adjusted trough concentration (C0/D) levels of tacrolimus by 41.61%-45.57% (P < 0.001). For both CYP3A5 expressers (CYP3A5*1*1 or CYP3A5*1*3) and non-expressers (CYP3A5*3*3), there were significant differences in tacrolimus C0/D between patients using felodipine/nifedipine and those without CCBs (P < 0.001). However, among CYP3A5 non-expressers, C0/D values of tacrolimus were significantly higher in patients combined with amlodipine compared to the controls (P = 0.001), while for CYP3A5 expressers, the difference in tacrolimus C0/D values between patients with amlodipine and without was not statistically significant (P = 0.065). CCBs (felodipine/nifedipine/amlodipine) can affect tacrolimus blood concentration levels by inhibiting its metabolism. The CYP3A5 genotype may play a role in the drug interaction between tacrolimus and amlodipine. Therefore, genetic testing for tacrolimus and therapeutic drug monitoring are needed when renal transplant recipients are concurrently using CCBs.

P/Q type (Cav2.1) Calcium Channel Blocker ω-Agatoxin IVA Alters Cleaved Caspase-3 and BDNF Expressions in the Rat Brain and Suppresses Seizure Activity.

High-voltage-gated calcium channels have pivot role in the cellular and molecular mechanisms of various neurological disorders, including epilepsy. Similar to other calcium channels, P/Q-type calcium channels (Cav2.1) are also responsible for vesicle release at synaptic terminals. Up to date, there are very limited reports showing the mechanisms of Cav2.1 in epileptogenesis. In the present study, we investigated the anticonvulsive and neuroprotective effects of ω-agatoxin IVA, a specific Cav2.1 blocker, in a chemical kindling model of epileptogenesis. Righting reflex and inclined plane tests were used to assess motor coordination. Electroencephalography was recorded for electrophysiological monitoring of seizure activity in freely moving rats. Immunohistochemical analyses were performed for brain-derived neurotrophic factor (BDNF) and cleaved caspase-3 expressions in the prefrontal cortex, striatum, hippocampus, and thalamic nucleus. ω-Agatoxin IVA injected into the right lateral ventricle significantly prolonged the onset of seizures in a dose-dependent manner. In addition, repeated intraperitoneal administrations of ω-agatoxin IVA significantly suppressed the development of kindling and epileptic discharges without altering motor coordination. In addition, ω-agatoxin IVA significantly increased BDNF expressions, and decreased cleaved caspase-3 expressions in the brain when compared to PTZ + saline group. Our current study emphasizes the significance of the inhibition of P/Q type calcium channels by ω-agatoxin IVA, which suppresses the development of epileptogenesis and provides a new potential pathway for epilepsy treatment.

P3: ECMO and Calcium Channel Blocker Overdose: A Systematic Review

Introduction: The increasing indications and prevalence of extracorporeal membrane oxygenation (ECMO) are evident by the exponential increase in ECMO in the last decade. In recent literature, ECMO use has sustained patients who have intentionally or unintentionally overdosed on cardiac medications. Specifically, calcium channel blocker overdose (CCBOD) can lead to significant cardiopulmonary dysfunction and has increased in recent years. Calcium channel blockers (CCB) block L-type voltage gated calcium channels throughout the body, and overdose results in cardiac depression, vasoplegia, and hyperglycemia. Expert consensus and poison control centers both recommend treatment with calcium, high dose insulin, inotropes, and vasopressors. Our systematic review evaluated when to initiate ECMO in the CCBOD population and the mortality rate with ECMO use. Methods: An electronic literature review was conducted to identify all relevant studies for CCB use and ECMO. PRISMA guidelines for systematic review were followed. Rayyan was used as a screening tool for blinding the authors from each other, and abstracts and full texts were reviewed by three independent authors. Inclusion criteria were strictly limited to CCB ingestion without polypharmacy. A data collection tool was devised and data was independently collected by two authors prior to statistical analysis. Data points included demographics, a list of currently recommended medical treatments for CCBOD, ECMO cannulation type, and survival to hospital discharge. Results: After exclusion of duplicates, 314 abstracts were reviewed; of these 25 papers were included from 6 different countries, with the median year of the study publication 2019. From the 25 papers, 26 patients were studied with an average patient age of 32.7 years with 42% male and 58% female. Between male and female there was no significant difference in age, type of CCB taken, or days on ECMO. Average time on ECMO was 4.3 days. Venoarterial and venovenous ECMO use were 92.3% and 7.7%, respectively. Survival to hospital discharge was 84.6%. Prior to ECMO cannulation, patients received up to six medical treatments for CCBOD, with the majority receiving four to five treatments (53.8%). There was no correlation between number of therapies and days on ECMO (r=0.092, P=0.684). Conclusion: Our systematic review demonstrates that ECMO is a newly used and possibly valuable therapy for CCBOD when medical treatment fails. Most patients received aggressive medical therapies and still were unstable enough to require ECMO. Survival to discharge after ECMO for CCBOD is substantially higher than standard VV or VA ECMO uses. While medical management is still the main therapy for CCBOD, our results show that a persistently unstable patient may benefit from prompt evaluation at an ECMO center for treatment.

Overview of Blood Pressure amongst Hypertension Patients at Kawiley District Kauditan, North Minahasa Regency

Hypertension is a condition where the blood pressure is elevated. It occurs worldwide with an increasing incidence rate year by year, therefore still is an interesting topic of research as an effort to manage this disease. Long term uncontrolled high blood pressure may lead to several complications such as cardiovascular diseases, kidney disease and stroke. Monitoring blood pressure regularly and patients’ adherence to medication will lower the risk of complications. This study aims to explore the blood pressure of patients with hypertension at Kawiley and their adherence to taking anti hypertension drugs. This is an analytical descriptive survey with cross sectional approach. Respondents have been recruited from primary health care facilities. Blood pressures were taken according to standardized operation procedure using a digital measurement. Medication usage have been recorded, tabulated and analyzed. Results show from 54 respondents, consisting of 16 (29.6%) male and 38 (70.4%) female with the average age of 64 years old. Average systolic blood pressure (SBP) for all respondents is 133.5 mmHg and diastolic blood pressure (DBP) is 83.4 mmHg, with no big differences amongst the gender. About 18 respondents have systolic BP higher than 140mmHg (average 148.4mmHg) and 13 respondents with diastolic BP more than 90mmHg (average 94.1mmHg). (41 of the 54 respondents) consistently take their medications as prescribed. Systolic blood pressure of those who are not consistent with their antihypertension medications is greater than 130 mmHg. Most of the respondents only use one type of calcium channel blocker as an antihypertension medication. In conclusion, most respondents stick to taking their medications as directed, and the average blood pressure among respondents with hypertension is within the normal range. It is advised that hypertensive patients periodically check their blood pressure to prevent serious problems.

PERIODONTAL TREATMENT OF GINGIVAL OVERGROWTH DUE TO AMLODIPINE USE: CASE SERIES

Aim: A common side effect of calcium channel blockers, which are frequently used in the treatment of patients with hypertension and cardiovascular problems, is that they can cause overgrowth in gingiva. Gingival overgrowths should be treated because they create inaccessible areas, making oral hygiene practices difficult due to increased plaque retention. In this case series, clinical properties of gingival overgrowths deriving from the usage of amlodipine, which is a type of calcium channel blockers and its treatment protocols are explained.&#x0D; Methods: Three male patients aged 15, 60 and 45 applied to our clinic with the complaints of gingival overgrowth and bleeding. In the anamnesis, it was learned that they were using antihypertensive medication containing amlodipine. In the first session, scaling and root planning applications were performed. Then, the patients who were given detailed oral hygiene instructions, consulted with the relevant physicians. It was deemed appropriate to replace the drug the patients were using with another antihypertensive drug, which is an alternative that does not lead to gingival overgrowth. After the controls performed at certain time intervals and oral hygiene evaluations, it was observed that a perfect recovery was achieved. In addition to these, gingivoplasty was performed using classic surgical method under local anesthesia on one case.&#x0D; Results: All three patients showed uneventful healing without any complications. During periodic controls, it was observed that patients’ complaints disappeared, the gingiva regained their natural physiological form, aesthetically pleasing results were achieved, no recurrences were observed in the 6th month and periodontal health could be maintained.&#x0D; Conclusion: The treatment protocol for gingival overgrowth due to drug use includes the replacement or discontinuation of the current drug with an alternative drug with the physician's consultation, after the initial periodontal treatment and oral hygiene practices, periodontal surgical procedures and regular controls in severe cases.

A Randomized, Open-Label, Two-way Crossover Bioequivalence Study of Cilacar Tablet Compared with Atelec Tablet in Healthy Volunteers Under Fasting Condition

Cilnidipine is a novel L/N type calcium channel blocker, approved in several countries world-wide for the treatment of hypertension and is also well-established for its varied pleiotropic benefits. Cilnidipine was first approved in India in 2007, for the treatment of mild to moderate hypertension and since then has been a widely trusted and prescribed molecule. We conducted an open label, analyst blind, randomized, two-treatment, two-period, two sequence, single dose, crossover study to assess and compare the bioequivalence of test product Cilacar 10 mg and 20 mg tablet with reference product Atelec® 10 mg and 20 mg tablet, respectively in healthy volunteers. Blood samples were collected pre-dose and at regular intervals post-dose up to 24 hours. Plasma drug levels were determined with a validated chromatographic method. Pharmacokinetic parameter (Cmax), (AUC0–t), (AUC0–∞), (Tmax), (T½) and (Kel) was calculated. The 90% confidence intervals on the mean of difference between Cilacar 10 mg and Atelec® 10 mg were 82.61% to 121.80%, 88.35% to 109.72%, and 87.54% to 110.52% and The 90% confidence intervals on the mean of difference between Cilacar 20 mg and Atelec® 20 mg were 89.65% to 116.08%, 88.09% to 111.30%, and 88.35% to 110.79% for Cmax, AUC (0-t) and AUC (0–∞) respectively. All the volunteers completed the study. It can be concluded from the results, the test product Cilacar 10 mg and 20 mg and the reference product Atelec® 10 mg and 20 mg tablet met the required bioequivalence criteria. Both products were safe and well tolerated.&#x0D; Keywords Bioequivalence, Cilnidipine, Calcium channel blocker, Hypertension, and Blood pressure

Calcium Channels in the Heart: Disease States and Drugs.

Calcium ions are the major signaling ions in the cells. They regulate muscle contraction, neurotransmitter secretion, cell growth and migration, and the activity of several proteins including enzymes and ion channels and transporters. They participate in various signal transduction pathways, thereby regulating major physiological functions. Calcium ion entry into the cells is regulated by specific calcium channels and transporters. There are mainly six types of calcium channels, of which only two are prominent in the heart. In cardiac tissues, the two types of calcium channels are the L type and the T type. L-type channels are found in all cardiac cells and T-type are expressed in Purkinje cells, pacemaker and atrial cells. Both these types of channels contribute to atrioventricular conduction as well as pacemaker activity. Given the crucial role of calcium channels in the cardiac conduction system, mutations and dysfunctions of these channels are known to cause several diseases and disorders. Drugs targeting calcium channels hence are used in a wide variety of cardiac disorders including but not limited to hypertension, angina, and arrhythmias. This review summarizes the type of cardiac calcium channels, their function, and disorders caused by their mutations and dysfunctions. Finally, this review also focuses on the types of calcium channel blockers and their use in a variety of cardiac disorders.

Solubility of Nifedipine by Shake Flask UV-Spectrometry; Review of Safety Concerns in Pregnancy

Nifedipine is chemically dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate, a dihydropyridine derivative used frequently as anti-hypertensive. It is a L- type calcium channel blocker (CCB). Few analogical discrepancies were found between Nifedipine’s clinical output report and chemical analysis of solubility. The ambition of this research is to conduct a re-check and proper quantification of partition co-efficient (logP) of Nifedipine and clarify the discrepancy and rectify if any mistake has been done in recent past. The method used is the “gold standard” shake-flask method followed by analysis through UV-scpectrophotmetry.

Drug Repurposing Patent Applications April–June 2021

Drug Repurposing Patent Applications April–June 2021

AMLODIPINE-INDUCED TESTICULAR DNA DAMAGE AND ITS MODIFICATION BY A HERBAL PREPARATION IN WISTAR ALBINO RATS

The present study originated from the reports of adverse effects on male reproductive potential caused by the dihydropyridine derivative type calcium channel blockers, which are widely used agents for different cardiovascular disorders. The study was conducted to verify whether the repeated administration of this type of calcium channel blockers can cause any testicular DNA damage and if so, whether the damage can be modified by the co-administration of a herbal protective agent. The study was conducted in male Wistar albino rats. The testicular DNA damage of different groups of rats was evaluated by comet assay taking percentage DNA in comet tail as the main parameter. It was found that oral administration of the widely used dihydropyridine type calcium channel blocker amlodipine produced a duration- dependent and significant (P&lt;0.001) DNA damage in the testes of Wistar albino rats. The co- administration of the alcoholic extract of seeds of Asteracantha longifolia produced a dose dependent and significant ((P&lt;0.001) protective effect against this amlodipine-induced testicular DNA damage.

An antihypertensive agent benidipine is an effective neuroprotective and antiepileptic agent: an experimental rat study

ABSTRACT Background Benidipine is an L, N and T type calcium channel blocker drug that is widely used as an antihypertensive drug. Objective For the first time in the literature, it was aimed to investigate the effectiveness of benidipine in controlling epileptic seizure and preventing the development of neurodegeneration in epilepsy. Methods An experimentally epilepsy model was produced with pentylenetetrazole, and rats were divided into seven groups, in different benidipine treatment doses or with valproic acid combinations. The epileptic activities of all rats were recorded according to the Fisher&Kittner classification. Biochemical parameters, histopathological Caspase-3 activity, Wyler hippocampal sclerosis, gliosis and neuronal degenerations were investigated. Results It was found that in the post-hoc analysis of epileptic activities, there was a similar antiepileptic scores among the treatment groups. IL-1 level was found to be significantly lower in the benidipine 4 mg/kg group, and TNF-alpha was lower in the group given valproic acid+benidipine 2 mg/kg (p<0.05). The other biochemical parameters were not found to be significant. Neural degeneration levels in the brain tissues were statistically significant (p<0.001). Compared with the healthy group, the most neural degeneration was in the control group, the least neural degeneration was in the valproic acid+benidipine 4 mg/kg group. Conclusions For the first time in the literature, benidipine, alone or combined with valproic acid, were found to have a statistically significant antiepileptic efficacy, and provided neuroprotection when combined with valproic acid. Benidipine will be a promising agent in the treatment of epilepsy with its antiepileptic and neuroprotective effects.

Verapamil-containing silicone gel reduces scar hypertrophy.

A hypertrophic scar is a common dermal fibroproliferative lesion usually treated with topical silicone. Verapamil, a type of calcium channel blocker, is considered a candidate drug for the treatment of hypertrophic scars. Here, we report that the addition of verapamil to topical silicone gel enhances treatment outcomes of hypertrophic scars. Upon creation of hypertrophic scars with the rabbit ear model, varying concentrations of verapamil‐added silicone gel (0.1, 1, and 10 mg/g) were applied daily for 28 days. After the animals were euthanised, microscopic measurement was performed for (a) scar elevation index (SEI), (b) fibroblast count, and (c) capillary count. On gross analysis, features of hypertrophic scars were significantly alleviated in the verapamil‐added groups. On histologic examination, verapamil‐added groups showed (a) reduced SEI (1.93 (1.79‐2.67) for control vs 1.34 (1.21‐1.51) for silicone only and 1.13 (1.01‐1.65) for verapamil‐added silicone), (b) fibroblast count 700.5 (599.5‐838.5) for control, 613.25 (461‐762.5) for silicone only, and 347.33 (182.5‐527) for verapamil‐added silicone), and (c) capillary formation (52 (35.5‐96.5) for control, 46 (28‐64.5) for silicone only, and 39.83(24‐70) for verapamil‐added silicone) (Kruskal‐Wallis test, P < .05). On western blot, expression levels of collagen I protein was lower in the 1 mg/g and 10 mg/g verapamil‐added silicone compared with control. Therefore, we suggest a therapeutic concentration of verapamil‐added silicone gel of at least over 1 mg/g. Further study regarding maximally effective concentration and deeper insight into the mechanism of action should follow.

Use of Calcium Channel Blockers and Risk of Active Tuberculosis Disease: A Population-Based Analysis.

Calcium channel blockers (CCBs) are known to reduce the availability of iron-an important mineral for intracellular pathogens. Nonetheless, whether the use of CCBs modifies the risk of active tuberculosis in the clinical setting remains unclear. To determine whether CCBs may modify the risk of active tuberculosis disease, we conducted a nested case-control study using the National Health Insurance Research Database of Taiwan between January 1999 and December 2011. Conditional logistic regression and disease risk score adjustment were used to calculate the risk of active tuberculosis disease associated with CCB use. Subgroup analyses investigated the effect of different types of CCBs and potential effect modification in different subpopulations. A total of 8164 new active tuberculosis cases and 816 400 controls were examined. Use of CCBs was associated with a 32% decrease in the risk of active tuberculosis (relative risk [RR], 0.68 [95% CI, 0.58-0.78]) after adjustment with disease risk score. Compared with nonuse of CCBs, the use of dihydropyridine CCBs was associated with a lower risk of tuberculosis (RR, 0.63 [95% CI, 0.53-0.79]) than nondihydropyridine CCBs (RR, 0.73 [95% CI, 0.57-0.94]). In contrast, use of β-blockers (RR, 0.99 [95% CI, 0.83-1.12]) or loop diuretics (RR, 0.88 [95% CI, 0.62-1.26]) was not associated with lower risk of tuberculosis. In subgroup analyses, the risk of tuberculosis associated with the use of CCBs was similar among patients with heart failure or cerebrovascular diseases. Our study confirms that use of dihydropyridine CCBs decreases the risk of active tuberculosis.

Comparison of Usage Patterns and Outcomes by Dual Type Calcium Channel Blockers in Patients with Chronic Kidney Disease

Comparison of Usage Patterns and Outcomes by Dual Type Calcium Channel Blockers in Patients with Chronic Kidney Disease

Calcium channel blockers for people with chronic kidney disease requiring dialysis.

Calcium channel blockers (CCBs) are used to manage hypertension which is highly prevalent among people with chronic kidney disease (CKD). The treatment for hypertension is particularly challenging in people undergoing dialysis.To assess the benefits and harms of calcium channel blockers in patients with chronic kidney disease requiring dialysis.We searched the Cochrane Kidney and Transplant Register of Studies to 27 April 2020 through contact with the Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.All randomised controlled trials (RCTs) and quasi-RCTs that compared any type of CCB with other CCB, different doses of the same CCB, other antihypertensives, control or placebo were included. The minimum study duration was 12 weeks.Two authors independently assessed study quality and extracted data. Statistical analyses were performed using a random-effects model and results expressed as risk ratio (RR), risk difference (RD) or mean difference (MD) with 95% confidence intervals (CI).This review included 13 studies (24 reports) randomising 1459 participants treated with long-term haemodialysis. Nine studies were included in the meta-analysis (622 participants). No studies were performed in children or in those undergoing peritoneal dialysis. Overall, risk of bias was assessed as unclear to high across most domains. Random sequence generation and allocation concealment were at low risk of bias in eight and one studies, respectively. Two studies reported low risk methods for blinding of participants and investigators, and outcome assessment was blinded in 10 studies. Three studies were at low risk of attrition bias, eight studies were at low risk of selective reporting bias, and five studies were at low risk of other potential sources of bias. Overall, the certainty of the evidence was low to very low for all outcomes. No events were reported for cardiovascular death in any of the comparisons. Other side effects were rarely reported and studies were not designed to measure costs. Five studies (451 randomised adults) compared dihydropyridine CCBs to placebo or no treatment. Dihydropyridine CCBs may decrease predialysis systolic (1 study, 39 participants: MD -27.00 mmHg, 95% CI -43.33 to -10.67; low certainty evidence) and diastolic blood pressure level (2 studies, 76 participants; MD -13.56 mmHg, 95% CI -19.65 to -7.48; I2 = 0%, low certainty evidence) compared to placebo or no treatment. Dihydropyridine CCBs may make little or no difference to occurrence of intradialytic hypotension (2 studies, 287 participants; RR 0.54, 95% CI 0.25 to 1.15; I2 = 0%, low certainty evidence) compared to placebo or no treatment. Other side effects were not reported. Eight studies (1037 randomised adults) compared dihydropyridine CCBs to other antihypertensives. Dihydropyridine CCBs may make little or no difference to predialysis systolic (4 studies, 180 participants: MD 2.44 mmHg, 95% CI -3.74 to 8.62; I2 = 0%, low certainty evidence) and diastolic blood pressure (4 studies, 180 participants: MD 1.49 mmHg, 95% CI -2.23 to 5.21; I2 = 0%, low certainty evidence) compared to other antihypertensives. There was no evidence of a difference in the occurrence of intradialytic hypotension (1 study, 92 participants: RR 2.88, 95% CI 0.12 to 68.79; very low certainty evidence) between dihydropyridine CCBs to other antihypertensives. Other side effects were not reported. Dihydropyridine CCB may make little or no difference to predialysis systolic (1 study, 40 participants: MD -4 mmHg, 95% CI -11.99 to 3.99; low certainty evidence) and diastolic blood pressure (1 study, 40 participants: MD -3.00 mmHg, 95% CI -7.06 to 1.06; low certainty evidence) compared to non-dihydropyridine CCB. There was no evidence of a difference in other side effects (1 study, 40 participants: RR 0.13, 95% CI 0.01 to 2.36; very low certainty evidence) between dihydropyridine CCB and non-dihydropyridine CCB. Intradialytic hypotension was not reported.The benefits of CCBs over other antihypertensives on predialysis blood pressure levels and intradialytic hypotension among people with CKD who required haemodialysis were uncertain. Effects of CCBs on other side effects and cardiovascular death also remain uncertain. Dihydropyridine CCBs may decrease predialysis systolic and diastolic blood pressure level compared to placebo or no treatment. No studies were identified in children or peritoneal dialysis. Available studies have not been designed to measure the effects on costs. The shortcomings of the studies were that they recruited very few participants, had few events, had very short follow-up periods, some outcomes were not reported, and the reporting of outcomes such as changes in blood pressure was not done uniformly across studies. Well-designed RCTs, conducted in both adults and children with CKD requiring both haemodialysis and peritoneal dialysis, evaluating both dihydropyridine and non-dihydropyridine CCBs against other antihypertensives are required. Future research should be focused on outcomes relevant to patients (including death and cardiovascular disease), blood pressure changes, risk of side effects and healthcare costs to assist decision-making in clinical practice.

Intracerebroventricular administration of N-type calcium channel blocker ziconotide displays anticonvulsant, anxiolytic, and sedative effects in rats: A preclinical and pilot study

ObjectiveZiconotide (ω-conotoxin MVIIA peptide) is a novel analgesic agent acting on voltage-gated calcium channels and is administered intrathecally for neuropathic pain. While antiepileptic activities of other types of calcium channel blockers (T- or L-type) are well established, there is no information regarding the effect of ziconotide as an N-type calcium channel antagonist in pentylenetetrazol-induced seizures or its anxiolytic and sedative activities. The present study is the first to report on these effects. MethodsTo evaluate the anticonvulsant activity of ziconotide in the pentylenetetrazol (60 mg/kg) seizure model, ziconotide was administered intracerebroventricular (i.c.v.) as a single dose (1 μg/rat) or repeatedly (chronic administration: 0.1, 0.3, or 1 μg/rat once a day for seven days). The anxiolytic and sedative actions of ziconotide were evaluated with the elevated plus maze, light/dark (LD) box, and pentobarbital-induced sleep tests. Immediately after behavioral testing, the amygdala was completely removed bilaterally to determine corticosterone levels by immunoassay. ResultsIn all dosing regimens, ziconotide significantly decreased the seizure frequency and also delayed the latency period compared with control. Chronic administration affected the percentage of mortality protection, while a single dose of ziconotide did not. In behavioral tests, ziconotide significantly increased both the number of entries and the percentage of time spent in the open arms of the elevated plus maze. Furthermore, ziconotide significantly increased the latency period and the number of entries into the light compartment during the LD box examination. Chronic administration of ziconotide significantly reduced the latency to sleep and increased sleeping time, whereas these parameters were not affected by a single dose. Additionally, amygdala corticosterone levels were significantly decreased in rats treated with ziconotide compared with control. ConclusionZiconotide displays beneficial neurobehavioral effects in a model of epilepsy with anxiety as its comorbid event. It seems that at least one of the mechanisms involved in these effects is associated with a decrease in brain corticosterone levels. The main advantage of ziconotide over benzodiazepines (routine anxiolytic and sedative drugs) is that it does not cause tolerance, dependency, and addiction. Therefore, more than ever, it is necessary to improve the convenience of drug delivery protocols and attenuate the adverse effects associated with ziconotide-based therapies.

The Effects of Different Calcium Channel Blockers on Aldosterone-Producing Adenoma Cells.

Purpose: The aim of this study is to examine the effects of different kinds of calcium channel blockers (CCBs) on primary aldosterone-producing adenoma (APA) mainly with KCNJ5 mutations. Primary cultured APA cells were treated with different calcium channel blockers (L/T type CCB benidipine, T-type CCB mibefradil and L-type CCB nifedipine), and aldosterone secretagogues with or without nifedipine. Aldosterone level, aldosterone synthase (CYP11B2) mRNA expression and cell proliferation were detected. The results showed that all three CCBs significantly inhibit aldosterone secretion and CYP11B2 mRNA expression. Benidipine was relatively more effective than mibefradil or nifedipine. In addition, only mibefradil marginally inhibited cell proliferation. Adrenocorticotropin (ACTH) had a much stronger effect in stimulating aldosterone secretion and promoting cell proliferation from APA's than angiotensin II (ATII). Different from ACTH and ATII, potassium had no effect. Nifedipine inhibited the basal and ACTH-, ATII-elicited aldosterone secretion. Twenty three of 24 APAs had somatic KCNJ5 mutation. In conclusion, benidipine, mibefradil and nifedipine significantly inhibit aldosterone secretion in primary cultured APA cells.