Effect of felodipine on indomethacin-induced gastric ulcers in rats.

Felodipine is a calcium channel blocker with antioxidant and anti-inflammatory properties. Researchers have stated that oxidative stress and inflammation also play a role in the pathophysiology of gastric ulcers caused by nonsteroidal anti-inflammatory drugs. The aim of this study was to investigate the antiulcer effect of felodipine on indomethacin-induced gastric ulcers in Wistar rats and compare it with that of famotidine. The antiulcer activities of felodipine (5 mg/kg) and famotidine were investigated biochemically and macroscopically in animals treated with felodipine (5 mg/kg) and famotidine in combination with indomethacin. The results were compared with those of the healthy control group and the group administered indomethacin alone. It was observed that felodipine suppressed the indomethacin-induced malondialdehyde increase (P<0.001); reduced the decrease in total glutathione amount (P<0.001), reduced the decrease superoxide dismutase (P<0.001), and catalase activities (P<0.001); and significantly inhibited ulcers (P<0.001) at the tested dose compared with indomethacin alone. Felodipine at a dose of 5 mg/kg reduced the indomethacin-induced decrease in cyclooxygenase-1 activity (P<0.001) but did not cause a significant reduction in the decrease in cyclooxygenase-2 activity. The antiulcer efficacy of felodipine was demonstrated in this experimental model. These data suggest that felodipine may be useful in the treatment of nonsteroidal anti-inflammatory drug-induced gastric injury.

L-Type Ca2+ Channel Inhibition Rescues the LPS-Induced Neuroinflammatory Response and Impairments in Spatial Memory and Dendritic Spine Formation.

Ca2+ signaling is implicated in the transition between microglial surveillance and activation. Several L-type Ca2+ channel blockers (CCBs) have been shown to ameliorate neuroinflammation by modulating microglial activity. In this study, we examined the effects of the L-type CCB felodipine on LPS-mediated proinflammatory responses. We found that felodipine treatment significantly diminished LPS-evoked proinflammatory cytokine levels in BV2 microglial cells in an L-type Ca2+ channel-dependent manner. In addition, felodipine leads to the inhibition of TLR4/AKT/STAT3 signaling in BV2 microglial cells. We further examined the effects of felodipine on LPS-stimulated neuroinflammation in vivo and found that daily administration (3 or 7 days, i.p.) significantly reduced LPS-mediated gliosis and COX-2 and IL-1ß levels in C57BL/6 (wild-type) mice. Moreover, felodipine administration significantly reduced chronic neuroinflammation-induced spatial memory impairment, dendritic spine number, and microgliosis in C57BL/6 mice. Taken together, our results suggest that the L-type CCB felodipine could be repurposed for the treatment of neuroinflammation/cognitive function-associated diseases.

Severity of coeliac disease and clinical management study when using a CYP3A4 metabolised medication: a phase I pharmacokinetic study.

OBJECTIVE: Severity of coeliac disease depends in part on the extent of small intestinal mucosa injury. Patients with the most abnormal pathology have loss of duodenal villi CYP3A4, a drug-metabolising enzyme that inactivates many drugs. These patients are hypothesised to have greater systemic concentrations of felodipine, a drug which normally has low oral bioavailability secondary to intestinal CYP3A4-mediated metabolism. It serves as a representative for a class containing many medications. DESIGN: A phase I, open-label, single-dose, pharmacokinetic study. SETTING: London, Ontario, Canada. PARTICIPANTS: Patients with coeliac disease (n=47) with positive serology and healthy individuals (n=68). MAIN OUTCOME MEASURES: Patients with coeliac disease-upper gastrointestinal endoscopy and oral felodipine pharmacokinetics study within a 3-week period. Healthy individuals-oral felodipine pharmacokinetics study with water and grapefruit juice. RESULTS: Coeliac stratification categories: Group A (n=15, normal), B+C (n=16, intraepithelial lymphocytosis with/without mild villous blunting) and D (n=16, moderate/severe villous blunting). Groups A, B+C and D had linear trends of increasing felodipine AUC0-8; mean±SEM, 14.4±2.1, 17.6±2.8, 25.7±5.0; p<0.05) and Cmax (3.5±0.5, 4.0±0.6, 6.4±1.1; p<0.02), respectively. Healthy subjects receiving water had lower felodipine AUC0-8 (11.9±0.9 vs 26.9±0.9, p=0.0001) and Cmax (2.9±0.2 vs 7.7±0.2, p=0.0001) relative to those receiving grapefruit juice. CONCLUSIONS: Increased felodipine concentrations in patients with coeliac disease were most probably secondary to decreased small intestinal CYP3A4 expression. Patients with severe coeliac disease and healthy individuals with grapefruit juice had equivalently enhanced effect. Thus, patients with severe coeliac disease would probably experience similarly altered drug response, including overdose toxicity, from many important medications known to be metabolised by CYP3A4. Patients with coeliac disease with severe disease should be considered for other clinical drug management, particularly when there is the potential for serious drug toxicity.

Influence of 3 calcium channel blockers on gingival overgrowth in a population of severe refractory hypertensive patients.

OBJECTIVE: The aim of the current study was to assess the association between 3 different calcium channel blockers (CCBs) (nifedipine, amlodipine and felodipine) and gingival overgrowth in patients with a diagnosis of severe refractory hypertension. METHODS: One hundred and sixty-two patients with severe refractory hypertension, taking CCBs, were selected. Gingival overgrowth was graded and periodontal measurements were recorded (probing pocket depth, clinical attachment level, plaque index and bleeding on probing). Unconditional multivariable binary logistic regression analyses were performed to assess the association between CCB intake and gingival overgrowth after adjusting for potential confounders. RESULTS: Of the 162 patients, 26 (16.0%) were current smokers and 101 (62.3%) were females. The mean age (SD) was 54.1 (8.5) years and the median age (range) 52.5 (39-78) years. Gingival overgrowth was observed in 55 patients (34.0%). Nifedipine was the most common medication (35.2%; 57 of 162). The results of multiple binary logistic regression showed statistically significant associations between CCB intake (exposure) and gingival overgrowth (outcome) after adjusting for the variables treatment time with antihypertensive and plaque index. Patients with gingival overgrowth were 2.5 (odds ratio = 2.46; 95% confidence interval: 1.04-5.82) and 4.0 (odds ratio = 3.90; 95% confidence interval: 1.47-10.35) times more likely to be taking nifedipine and amlodipine, respectively, than patients without gingival overgrowth. On the other hand, this significant association was not observed for felodipine. CONCLUSION: Nifedipine and amlodipine, but not felodipine, were associated with gingival overgrowth in patients with severe refractory hypertension.

Pharmacology, Efficacy and Safety of Felodipine with a Focus on Hypertension and Angina Pectoris.

Calcium channel blockers (CCBs) are a heterogeneous group of drugs often used in the therapy for hypertension and angina. Though CCBs are generally similar in terms of their efficacy yet, they differ in their ability of causing selective inhibition in the contractility of vascular smooth muscle in comparison to cardiac muscle. Felodipine is one of the most vascular selective of the available CCBs and it has no negative inotropic effects at clinically administered doses. Focus of this review is to comprehensively summarize the pharmacokinetics, efficacy, safety and tolerability of felodipine. This review is based on evaluation of relevant literature on felodipine using meta-database PubMed and ScienceDirect and internet search engine (Google Scholar). Clinical studies summarized in this review testify, on technical lines, the clinical efficacy, safety and placebo- like tolerability profile of felodipine, administered alone as well as in combination.

Calcium Antagonists Use and Its Association with Lower Urinary Tract Symptoms: A Cross-Sectional Study.

BACKGROUND: Lower urinary tract symptoms (LUTS) have been reported amongst the side effects of calcium antagonists (CA). CAs act on the bladder by affecting the ability of the detrusor muscle to create enough contractile force to overcome obstruction to normal voiding. We aimed to determine the relationship between CA use and LUTS in general medical inpatients. METHODS AND FINDINGS: In this cross-sectional study we recruited 278 medical inpatients (including 85 CA users) aged ≥40 (72.1±13.7) years. LUTS was assessed using the International Prostate Symptoms Score (IPSS) questionnaire. A Logistic regression model using a 'backwards-elimination' strategy was used to identify variables associated with LUTS and for calculating the adjusted odds ratios and the 95% confidence intervals (CI). After adjusting for other risk factors and drugs, patients on amlodipine/nifedipine and diltiazem/verapamil (compared to non-users) were more likely to suffer from severe LUTS [Males: 12.45(CI: 1.57-98.63) and Females: 7.75(CI: 0.94-63.94)] and moderate-to-severe LUTS [Males: 17.43(CI: 2·26-134.39) and Females: 47.8(CI: 6.22-367.37)]. Patients on felodipine/lercanidipine were less likely to suffer from either severe or moderate-to-severe LUTS. Further, 19 (22.4%) CA-users were on treatment for LUTS compared to 18 (9.3%) of the non-users group, p = 0.003. Both male and female CA-users were three times more likely to be on alpha-blockers than non-users, p<0.001. CA-users were more likely to have undergone urinary tract-related surgery (Males: two times, p = 0.07 and females: nine times, p = 0.029). The study was limited by the fact that a causal relationship could not be established between CA use and LUTS. CONCLUSIONS: Our results demonstrate an association between CA use and an increasing severity of LUTS. They also demonstrate that CA-users are more likely to have medical or surgical treatment for LUTS. However, these CA's effects on LUTS vary, and the use of highly vascular selective agents does not appear to pose significant risk.

Effect of felodipine with irbesartan or metoprolol on sexual function and oxidative stress in women with essential hypertension.

OBJECTIVE: To evaluate the impact of felodipine with irbesartan on sexual function compared with felodipine with metoprolol in hypertensive women. METHODS: This was a prospective, randomized, parallel, active-controlled, open-label study (ClinicalTrials.org: NCT01238705) in 160 women (18-60 years) with mild or moderate hypertension, randomized to a once-daily treatment with felodipine combined with irbesartan or metoprolol for 48 weeks. Patients' sexual function was evaluated using a female sexual function index (FSFI) questionnaire at baseline and after 24 and 48 weeks of therapy. Levels of serum estradiol, testosterone, 8-hydroxy-2'-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) were measured. RESULTS: The two combination regimens were similarly effective in lowering blood pressure. After 48 weeks, in felodipine-irbesartan group, total scores of FSFI improved (P < 0.001). Items showing improvement in scores corresponded to desire, arousal and orgasm (P < 0.001; P = 0.002; P = 0.049, respectively). Levels of estradiol increased under treatment with felodipine-irbesartan (P = 0.003) and decreased under felodipine-metoprolol treatment (P < 0.001). The concentration of testosterone declined after felodipine-irbesartan therapy (P < 0.001) and increased under felodipine-metoprolol treatment (P < 0.001). In the felodipine-irbesartan group, decreases of 8-OHdG, 4-HNE (P < 0.001) and MDA (P < 0.001) were observed. The felodipine-irbesartan combination resulted in less oxidative stress. The differences in changes in 8-OHdG, 4-HNE and MDA between the two groups were significant (P < 0.05). CONCLUSION: These results suggested that the felodipine-irbesartan combination regimen improved sexual function in hypertensive women, whereas felodipine-metoprolol regiment did not. The reason for the different influence of these two combination therapy on female sexual function might be their different impacts on oxidative stress and hormone levels.

Use of clopidogrel and calcium channel blockers and risk of major adverse cardiovascular events.

BACKGROUND: The CYP3A4 inhibition by calcium channel blockers (CCBs) may attenuate the effectiveness of clopidogrel. Using time-varying drug exposure ascertainment, we examined whether CCB use modified the association between clopidogrel use and major adverse cardiovascular events (MACE) after coronary stent implantation. DESIGN: We conducted this population-based cohort study in western Denmark (population 3 million) using medical databases. We identified all 13,001 patients with coronary stent implantation between 2002 and 2005 and their comorbidities. During 12-month follow-up, we tracked the use of clopidogrel and CCBs and the rate of MACE (composite of myocardial infarction, ischaemic stroke, stent thrombosis, target lesion revascularization, or cardiac death). We used Cox regression to compute hazard ratios, controlling for potential confounders. RESULTS: Overall, the 12-month risk for MACE was 14·5%. The rate was 130 per 1000 person years for concomitant clopidogrel and CCB use, 106 for clopidogrel without CCB use, 213 for CCB without clopidogrel use, and 248 for no use of either drug. The adjusted hazard ratio for MACE comparing clopidogrel use with nonuse was 0·52 [95% confidence interval (CI): 0·42-0·64] for CCB users and 0·48 (95% CI: 0·42-0·54) for nonusers, yielding an interaction effect, i.e. relative rate increase, of 1·09 (95% CI: 0·86-1·38). The adjusted hazard ratio for MACE comparing CCB use with nonuse was 1·06 (95% CI: 0·89-1·25) among clopidogrel users. CONCLUSIONS: Concomitant use of CCBs as a class did not modify the protective effect of clopidogrel and was not associated with increased cardiovascular risk among patients using clopidogrel after coronary stent implantation.

Pharmacokinetics of felodipine extended-release tablets in healthy Taiwanese subjects: a retrospective review.

The objective of this study was to investigate the pharmacokinetics of felodipine (CAS 72509-76-3) in healthy male Taiwanese subjects. This is a retrospective review of five felodipine pharmacokinetic studies completed in Taiwan. A total of 100 evaluable healthy Taiwanese males were enrolled in these studies. The subjects received 5 mg (n = 80) or 10 mg (n = 20) of Plendil (felodipine extended-release tablets; felodipine ER) once daily for 6 days. The mean +/- SD t(max,ss,) CG(max,ss) and AUG(tau) of dose normalized to 10 mg felodipine was 3.32 +/- 1.33 h, 13.12 +/- 5.34 nmol/L and 136.33 +/- 63.18 nmol x h/L, respectively. By using Kolmogorov-Smirnov's test and probit plots, the results indicated that the frequency distribution of AUC/dose, C(min)/dose and CL/F was bimodal. Compared to data from the literature, the mean C(max,ss) and AUG(tau) of 5 mg felodipine in healthy young Taiwanese subjects were similar to or slightly lower than data from Swedish, Danish, Turkish and Canadian studies in healthy young subjects who received 10 mg felodipine. Comparable C(max) values and approximately 30% lower AUC values were observed when comparing the 5 mg Taiwanese data to data in healthy elderly German subjects who also received 5 mg felodipine. Taiwanese subjects might have lower CYP3A4 activity to metabolize felodipine, which is similar to the phenomenon observed with nifedipine.

[Comparative eficacy of antihypertensive therapy in patients with arterial hypertension and various sensitivity to salt].

In 102 patients with high risk (52 patients with history of myocardial infarction, 50 patients with history of cerebral stroke within previous 6-48 months) arterial hypertension (AH) we studied clinical efficacy on angiotensin converting enzyme inhibitor (ACEI) lisinopril, calcium antagonist felodipine, and nonselective - -blocker carvedilol in dependence on salt sensitivity of AH. Efficacy of treatment was assessed with the help of office pressure measurement and 24 hour arterial pressure monitoring before and after 12 weeks of therapy. Patients who showed 10 or more mm Hg lowering of AP at transition from high salt (15 g/day) to low salt ( 3 g/day) diet were considered salt sensitive. On the basis of obtained results optimal for the treatment of AH in salt resistant patients are ACEI while in the treatment of salt sensitive patients it is expedient to administer calcium antagonists. The use of -adrenoblockers is equally effective in AH with various salt sensitivity.

[Efficacy, safety and tolerance of Felodipine controlled release tablets and Felodipine controlled release tablets associated combination therapy in the treatment of mild to moderate essential hypertension in China].

OBJECTIVE: To evaluate the efficacy, safety and tolerance of Felodipine controlled release tablets and Felodipine controlled release tablets associated combination each with Metoprolol, Lisinopril or Hydrochlorothiazide in the 12 weeks treatment of mild to moderate essential hypertension in China. METHODS: Multicenter, random samples, and open study have been processed. RESULTS: (1)After 12 weeks associated combination treatment of anti-hypertension, the percentages of the persons who had attained the target were 80.2% of ITT group in Felodipine controlled release tablets associated combination with Hydrochlorothiazide, 74.1% of ITT group in with Metoprolol,and 80.5% of ITT group in with Lisinopril, respectively. (2)Mean reductions of systolic/diastolic blood pressure from baseline were 16.8/10.6 mm Hg in combination with Hydrochlorothiazide, 16.6/10.7 mm Hg in combination with Metoprolol,and 18.0/12.8 mm Hg in combination with Lisinopril each. There was no significant difference among these three groups (P>0.05). With the Felodipine controlled release tablets treatment alone, the mean reductions from baseline was 24.8/17.5 mm Hg. But in combination with Lisinopril, the blood pressure could lower more quickly, and then could reach the target more rapidly. (3)In the ITT group, the drug compliance with Felodipine controlled release tablets was 97.7%, with those in combination with Hydrochlorothiazide 89.8%, with those in combination with Metoprolol 100.0%, and with those in combination with Lisinopril 96.4%. The main adverse event related to Felodipine was headache, and to Lisinopril was cough. CONCLUSION: Antihypertensive drug Felodipine controlled release tablets are good and effective. And Felodipine controlled release tablet associated combination each with Metoprolol, Lisinopril or Hydrochlorothiazide can make most patients reach the treatment target, with safety, good tolerance, and high compliance.

Different roles of pummelo furanocoumarin and cytochrome P450 3A5*3 polymorphism in the fate and action of felodipine.

OBJECTIVE: Herein we aim to test if pummelo furanocoumarins can inhibit cytochrome P450 (CYP) 3A both in vitro and in vivo, and to explore the influence of CYP3A5*3 (GenBank AC005020: A22893-->G) polymorphism in the pharmacokinetics and pharmacological response to felodipine. METHOD: Fruit juices of pummelo grapefruit (Citrus paradisi Macf., G), 'Guanximiyou' (C. grandis Osbeck vs. Guanxi, P) and 'Changshanhuyou' (C. changshanhuyou Y.B. Chang, H) were selected by screening Citrus fruit juices for their furanocoumarin contents and their inhibition of testosterone 6beta-hydroxylation in human liver microsomes. Twelve healthy male Chinese were administered 250 mL G, P, H or water (W) alternatively with 26-mumol (10-mg) plain tablet felodipine, and were observed for 12 h. RESULTS: G had more furanocoumarins and at higher levels than P while H had none, and their potencies for in vitro CYP3A inhibition were in the order as G > P > H. The geometric mean and 90% confidence intervals of pharmacokinetic parameters for human oral felodipine with G, P, H and W were respectively as follows: peak plasma concentration (nmol.L(-1)), 37 (32-44), 25 (21-29), 19 (16-22) and 18 (15-21); area under the plasma concentration-time curve (nmol.h.L(-1)), 118 (103-136), 84 (73-97), 64 (56-74) and 59 (51-68). Subjects showed higher heart rates with G than with H or W. CYP3A5*3 polymorphism showed no significant effect on felodipine pharmacokinetics and related hemodynamic changes. CONCLUSIONS: This work supports the hypothesis that CYP3A inhibition by furanocoumarins caused pummelo fruit juice-drug interaction; while the role of CYP3A5 in the population pharmacokinetics of felodipine and blood pressure response appear to be limited.

Drug-associated gingival enlargement: case report and review of aetiology, management and evidence-based outcomes of treatment.

"Gingival enlargement" is the term now used to describe medication-related gingival overgrowth or gingival hyperplasia (AAP, 2004), a condition commonly induced by three main classes of drugs: anticonvulsants, antihypertensive calcium antagonists and the immunosuppressant cyclosporin. It is important that the health practitioner is aware of the potential aetiologic agents and characteristic features in order to be able to accurately diagnose and successfully manage patients who present with a condition such as outlined in the following case presentation.

Felodipine-influenced gingival enlargement in an uncontrolled type 2 diabetic patient.

BACKGROUND: The potential of calcium channel blockers (CCBs) to induce gingival enlargement (GE) as well as the influence of diabetes mellitus on periodontal tissues has been well documented. This case report documents a conservative clinical approach to the management of felodipine-influenced gingival enlargement and displays a clinical and histologic case of felodipine-influenced GE in an undiagnosed type 2 diabetic patient. METHODS: At the initial examination, a medical consultation was requested and two incisional biopsies were taken for pathological evaluation. The patient was diagnosed with uncontrolled type 2 diabetes. Felodipine was withdrawn and the diabetes was controlled before dental treatment was initiated. The patient then underwent selective extractions and full-mouth scaling and root planing as well as oral hygiene instructions. No surgical therapy was indicated. RESULTS: The histological results demonstrated the presence of elongated rete pegs; fibrous hyperplasia; a low-grade chronic inflammatory infiltrate, predominantly consisting of lymphocytes; and collagen bundle groups randomly distributed. These features were similar to those present in other drug-influenced GE. Clinical results have demonstrated almost complete resolution of GE after the withdrawal of felodipine and the control of diabetes. Further improvements were seen after scaling and root planing and oral hygiene instructions. No recurrences were noted 12 months after initial therapy. CONCLUSIONS: This report demonstrated that the control of systemic factors seemed to have the most influence on success for this particular case. Since the control of diabetes was managed at the same time as the felodipine withdrawal, it remains difficult to speculate how these two factors impacted both the severity of the GE and the therapeutic results. More importantly, the conservative treatment rendered demonstrated the stability of periodontal status during maintenance phase and the avoidance of surgical interventions.

Safety and efficacy of therapeutically equivalent doses of sustained-release formulations of isradipine and felodipine.

This open-label, drug substitution study was conducted to determine if subjects receiving sustained-release isradipine (SR-I) can be safely switched to sustained-release felodipine (SR-F) and to assess whether SR-I provides better 24-hour blood pressure (BP) control than SR-F. Forty-one men receiving either SR-F 5 mg or SR-F 10 mg once daily for at least 6 months were switched to an equivalent dose of SR-I; BP was measured 2, 4, and 6 weeks after substitution. Significant reductions in systolic BP were seen in the SR-I 10 mg group after 4 weeks and they remained significantly lower through 6 weeks (p< or =0.05). Diastolic BP was reduced, but not significantly. After 6 weeks, SR-F therapy was reinstated, and BP returned toward baseline values. No serious adverse events were reported. SR-I can be safely substituted for SR-F and may provide better 24-hour control of BP than SR-F.

Evaluation of a therapeutic conversion from amlodipine to felodipine.

STUDY OBJECTIVES: To determine patient satisfaction with and tolerability of a conversion from a long-acting calcium channel blocker, amlodipine, to felodipine. Secondary objectives were to compare the effect of the change on blood pressure and heart rate and the economic impact of the change. DESIGN: Retrospective study. SETTING: Veterans Affairs health care system. PATIENTS: Two hundred eighty-three men who were taking amlodipine to manage hypertension. INTERVENTION: Patients who were converted to felodipine were mailed a survey quantifying subjective symptoms; the survey also included questions specific to the change program. Transitory blood pressure and heart rate measurements retrieved by electronic chart review were evaluated during therapy with both amlodipine and felodipine. MEASUREMENTS AND MAIN RESULTS: Ninety-five percent of patients were satisfied with the conversion process and tolerated the switch from amlodipine to felodipine. Mean systolic and diastolic blood pressures were reduced by 4.4 and 2.6 mm Hg, respectively (p=0.166 and 0.187, respectively). Heart rate was reduced significantly by 4.2 beats/minute (p=0.008). The conversion realized a net annual drug cost savings of approximately dollars 16,000. CONCLUSION: Our patient population was satisfied with the conversion from amlodipine to felodipine, and the new drug was found to be effective, well tolerated, and associated with a modest cost reduction.

Comparative effect of lercanidipine, felodipine, and nifedipine GITS on blood pressure and heart rate in patients with mild to moderate arterial hypertension: the Lercanidipine in Adults (LEAD) Study.

This multicenter, double-blind, parallel-group study compared the effects of three dihydropyridine calcium channel blockers (lercanidipine, felodipine, and nifedipine gastrointestinal therapeutic system) on blood pressure and heart rate in 250 patients with mild to moderate hypertension (diastolic blood pressure > or =95 and 109 mm Hg). Patients were randomized to 4 weeks of treatment with once-daily doses of lercanidipine 10 mg, felodipine 10 mg, or nifedipine gastrointestinal therapeutic system 30 mg. After 4 weeks of treatment, the dose was doubled in nonresponding patients. At 8 weeks, no significant differences in blood pressure were observed among the three groups. Increases in heart rate in all three groups induced by stressful conditions before and after treatment were not exacerbated during active treatment. The incidence of adverse drug reactions was lower in the lercanidipine and nifedipine groups than in the felodipine group (p<0.05); in particular, the incidence of edema for lercanidipine was 5.5% vs. 13% for felodipine and 6.6% for nifedipine.