Neuro-modulatory impact of felodipine against experimentally-induced Parkinson's disease: Possible contribution of PINK1-Parkin mitophagy pathway.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder, characterized by motor and psychological dysfunction. Palliative treatment and dopamine replenishment therapy are the only available therapeutic options. Calcium channel blockers (CCBs) have been reported to protect against several neurodegenerative disorders. The current study was designed to evaluate the neuroprotective impact of Felodipine (10 mg/kg, orally) as a CCB on motor and biochemical dysfunction associated with experimentally induced PD using rotenone (2.5 mg/kg, IP) and to investigate the underlying mechanisms. Rotenone induced deleterious neuromotor outcomes, typical of those associated with PD. The striatum revealed increased oxidative burden and NO levels with decreased antioxidant capacity. Nrf2 content significantly decreased with the accumulation of α-synuclein and tau proteins in both the substantia nigra and striatum. These observations significantly improved with felodipine treatment. Of note, felodipine increased dopamine levels in the substantia nigra and striatum as confirmed by the suppression of inflammation and the significant reduction in striatal NF-κB and TNF-α contents. Moreover, felodipine enhanced mitophagy, as confirmed by a significant increase in mitochondrial Parkin and suppression of LC3a/b and SQSTM1/p62. In conclusion, felodipine restored dopamine synthesis, attenuated oxidative stress, inflammation, and mitochondrial dysfunction, and improved the mitophagy process resulting in improved PD-associated motor impairment.

Efficacy of felodipine and enalapril in the treatment of essential hypertension with coronary artery disease and the effect on levels of Salusin-ß, Apelin, and PON1 gene expression in patients.

This study aimed to analyze the effect of felodipine combined with enalapril in the treatment of patients with essential hypertension and coronary artery disease. Also, the effect of these medicines was evaluated on the peripheral blood Salusin-ß, Apelin levels, and PON1 gene expression. For this purpose, 110 patients with essential hypertension combined with coronary heart disease, admitted to the hospital from January 2019 to January 2021, were selected and randomly divided into two groups. The control group was given felodipine treatment alone, and the study group was treated with combined application of felodipine and enalapril. The treatment effect, peripheral blood Salusin-ß, Apelin, PON1 gene expression, and the safety of medication were compared between the two groups. The results showed that the post-treatment systolic blood pressure in the study group was 119.77 ± 5.23 mm Hg and diastolic blood pressure was 86.84 ± 5.42 mm Hg, both of which were significantly lower than those in the control group (127.81 ± 6.92 mm Hg and 95.13 ± 6.08 mm Hg), with statistically significant differences (p<0.05). The effective rates of the study group and the control group were 92.73% and 74.54% respectively, with statistically significant differences (P<0.05). The post-treatment peripheral blood Salusin-ßlevel in the study group was 3.77±0.53mmol/L, and Apelin was 1.94±0.58µg/L, with statistically significant differences compared to the control group (P<0.05). The PON1 gene expression in the study group was higher than those in the control group after treatment (P<0.05). Also, the results showed that there was no statistical difference in adverse reactions between the two groups (P>0.05). According to these results, the combination of felodipine and enalapril in patients with essential hypertension combined with coronary artery disease can effectively lower the patients' blood pressure and improve their peripheral blood Salusin-ß, Apelin levels, and PON1 gene expression, thus enhancing the patients' therapeutic effect with few adverse effects and high safety.

Insights into Dissolution and Solution Chemistry of Multidrug Formulations of Antihypertensive Drugs.

Using fixed dose combinations of drugs instead of administering drugs separately can be beneficial for both patients and the health care system, but the current understanding of how multidrug formulations work at the molecular level is still in its infancy. Here, we explore dissolution, solubility, and supersaturation of various drug combinations in amorphous formulations. The effect of chemical structural similarity on combination behavior was investigated by using structurally related compounds of both drugs. The effect of polymer type on solution behavior was also evaluated using chemically diverse polymers. Indapamide (IPM) concentration decreased when combined with felodipine (FDN) or its analogues, which occurred even when the IPM solution was undersaturated. The extent of solubility decrease of FDN was less than that of IPM from the dissolution of an equimolar formulation of the drugs. No significant solubility decrease was observed for FDN at low contents of IPM which was also observed for other dihydropyridines, whereas FDN decreases at high contents of IPM. This was explained by the complex nature of the colloidal precipitates of the combinations which impacts the chemical potential of the drugs in solution at different levels. The maximum achievable concentration of FDN and IPM during dissolution of the polyvinylpyrrolidone-based amorphous solid dispersion was higher than the value measured with the hydroxypropyl methylcellulose acetate succinate-based formulation. This emphasizes the significance of molecular properties and chemical diversity of drugs and polymers on solution chemistry and solubility profiles. These findings may apply to drugs administered as a single dosage form or in separate dosage forms and hence need to be well controlled to assure effective treatments and patient safety.

Felodipine induces autophagy in mouse brains with pharmacokinetics amenable to repurposing.

Neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Huntington's disease manifest with the neuronal accumulation of toxic proteins. Since autophagy upregulation enhances the clearance of such proteins and ameliorates their toxicities in animal models, we and others have sought to re-position/re-profile existing compounds used in humans to identify those that may induce autophagy in the brain. A key challenge with this approach is to assess if any hits identified can induce neuronal autophagy at concentrations that would be seen in humans taking the drug for its conventional indication. Here we report that felodipine, an L-type calcium channel blocker and anti-hypertensive drug, induces autophagy and clears diverse aggregate-prone, neurodegenerative disease-associated proteins. Felodipine can clear mutant α-synuclein in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug. This is associated with neuroprotection in mice, suggesting the promise of this compound for use in neurodegeneration.

Protective and therapeutic effect of felodipine against bleomycin-induced pulmonary fibrosis in mice.

Idiopathic pulmonary fibrosis (IPF) involves alveolar epithelial injury and abnormal collagen production caused by activated fibroblasts; transforming growth factor (TGF)-ß1 is implicated in this activation. In this study, we screened for chemicals capable of inhibiting TGF-ß1-induced collagen production in cultured fibroblasts from medicines already in clinical use. We selected felodipine based on its extent of collagen production inhibition, clinical safety profile, and other pharmacological activity. Felodipine is a dihydropyridine Ca2+ channel blocker that has been used clinically to treat patients with high blood pressure. Felodipine suppressed collagen production within LL29 cells in the presence of TGF-ß1, but not in its absence. Intratracheal administration of felodipine prevented bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction. Felodipine also improved pulmonary fibrosis, as well as lung and respiratory function when administered after fibrosis development. Furthermore, administration of felodipine suppressed a bleomycin-induced increase in activated fibroblasts in the lung. We also found other dihydropyridine Ca2+ channel blockers (nifedipine and benidipine) inhibited collagen production in vitro and partially prevented bleomycin-induced pulmonary fibrosis, alteration of lung mechanics and respiratory dysfunction in vivo. We propose that these Ca2+ channel blockers may be therapeutically beneficial for IPF patients.

Long-term outcomes of lercanidipine versus other calcium channel blockers in newly diagnosed hypertension: a nationwide cohort study.

OBJECTIVE: Calcium channel blockers (CCBs) have been proved to have beneficial effects on cardiovascular (CV) outcomes, especially in stroke. Lercanidipine, a highly lipophilic CCB, lacks data regarding long-term outcomes including: CV, stroke, renal and all-cause mortality. This retrospective cohort study aims to clarify this. PATIENTS AND METHODS: A total of 144,630 newly diagnosed hypertension (HTN) patients (age: 18-65 years) in 2005 from the Taiwan's National Health Insurance Research Database were enrolled in this observational study. A pure hypertension population was fetched by excluding all chronic diseases in the Charlson Comorbidities Index. Patients were stratified into the lercanidipine group (n = 1303) and the propensity-score-matched comparative group (nifedipine, amlodipine or felodipine, n = 15,301). RESULTS: Compared to other CCBs, lercanidipine didn't have a significant difference on the study endpoints. In individual head-to-head comparisons, lercanidipine was shown to be superior to nifedipine in incident stroke with an adjusted HR with 95% CI of 0.526 (0.347-0.797) (p = .0025). The key limitations were that personal variables, such as smoking habits, alcohol intake, body mass index and physical activity and blood pressure profiles were not available in the nationwide registry database. CONCLUSION: In newly diagnosed patients with hypertension, lercanidipine was superior to nifedipine in the six-year period when the analyzed endpoint was stroke.

Effects of lercanidipine hydrochloride versus felodipine sustained-release on day-to-day home blood pressure variability.

OBJECTIVE: The objective of this study was to compare the effectiveness of lercanidipine with felodipine in patients with mild-to-moderate hypertension on day-to-day home blood pressure variability. METHODS: This is a sub-study of a multicenter, randomized, open-label, parallel group and active controlled clinical trial. Hypertensive patients aged 18-75 (i.e. diastolic blood pressure ≥90 mmHg and <110 mmHg; systolic blood pressure ≥140 mmHg and <180 mmHg) and 24 h mean BP >130/80 mmHg) were eligible for this study. During the study, blood pressure (BP) and heart rate (HR) were recorded. The day-to-day BP variability (BPV) and HR variability (HRV) were obtained by the standard deviation (SD) of daily BP/HR average (of six readings) in 7 days. RESULTS: There were 186 patients (89 and 97 patients in the lercanidipine and felodipine groups, respectively) included in this study. Lercanidipine hydrochloride 10 mg/d and felodipine sustained-release tablets 5 mg/d were given to their respective groups. After 6 weeks of treatment, SD of home BP significantly reduced compared with baseline in both groups (P < .05) while SD of home HR also changed significantly after treatment (P < .05). There was no significant difference in SD of home BPV between the lercanidipine and felodipine groups after treatment. CONCLUSION: Treatment with lercanidipine and felodipine both resulted in reduction of BPV and HRV. There was no significant inter-group difference in reduction of BPV between the groups. Lercanidipine is an effective antihypertensive drug in improving BPV. National clinical trial: NCT01520285.

Differential effects of enalapril-felodipine versus enalapril-lercanidipine combination drug treatment on sympathetic nerve traffic and metabolic profile in obesity-related hypertension.

Scanty information is available on the effects of combination drug treatment based on an ACE inhibitor and a calcium channel blocker on the neurometabolic alterations characterizing obesity-related hypertension (OHT). After 2-week run-in with enalapril (20 mg), 36 OHTs were randomized according to a double-blind crossover design to a combination therapy with either lercanidipine 10 mg (L) or felodipine extended release 5 mg (F), each lasting 8 weeks. Measurements included clinic and ambulatory blood pressure (BP) and heart rate, homeostasis model assessment index, plasma norepinephrine, and muscle sympathetic nerve activity. Patients with uncontrolled BP were then uptitrated to 20 mg/d (L) and 10 mg/d (F) combined with enalapril 20 mg, respectively, for further 8 weeks. For similar BP reductions, enalapril-lercanidipine (EL) caused norepinephrine and MSNA increases significantly less pronounced than those seen with enalapril-felodipine, the lesser sympathoexcitation observed with EL being coupled with a significant improvement in homeostasis model assessment index. This was the case also when L and F were uptitrated in the combination. In OHT, at variance from enalapril-felodipine, EL combination is almost entirely devoid of any major sympathoexcitatory effect and is associated with an improvement in insulin sensitivity.

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.

Lercanidipine hydrochloride versus felodipine sustained-release for mild-to-moderate hypertension: a multi-center, randomized clinical trial.

OBJECTIVE: Lercanidipine hydrochloride and felodipine sustained-release tablets comparison for the treatment of patients with mild-to-moderate primary hypertension. RESEARCH DESIGN AND METHODS: The study was designed as a multicenter, randomized, open-label, parallel-group clinical trial. A total of 281 adult patients (18-75 years) with a mild-to-moderate primary hypertension diagnosis were randomly assigned, in a 1:1 ratio, to lercanidipine hydrochloride (n = 139; 81 males) or felodipine sustained-release tablets (n = 142; 87 males). Study duration was 8 weeks, including two run-in weeks and 6 weeks of treatment. MAIN OUTCOME MEASURES: The mean seated diastolic blood pressure (BP) change from baseline to 6 weeks of treatment was the primary endpoint. Main secondary efficacy parameters were: (i) mean seated systolic BP change from baseline to 6 weeks of treatment; (ii) normalization BP rate. The incidence of adverse events was also considered. RESULTS: BP monitoring showed a significant decrease compared with baseline in diastolic BP (lercanidipine: from 96 ± 4 to 83 ± 6 mmHg, p < 0.0001; felodipine: from 96 ± 4 to 82 ± 5 mmHg, p < 0.0001). The mean systolic BP decreased, when compared with baseline values, by 18 mmHg and 19 mmHg in the lercanidipine and felodipine arm, respectively (p < 0.0001 versus baseline for both comparisons). The normalization rates of BP were 79.5% and 87.2%, in the lercanidipine and felodipine groups, respectively (in-office monitoring; p = n.s.). In total, 73 patients experienced 103 AEs: 26.6% (37/139) in the lercanidipine group and 25.3% (36/142) in the felodipine arm (p = n.s.). The analysis of safety showed no unexpected adverse events. CONCLUSIONS: Although the overall short follow-up of the present study should be taken into account, lercanidipine is an effective and safe treatment option for BP control in adult patients with mild-to-moderate primary hypertension.

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.

Effects of felodipine combined with puerarin on ACE2-Ang (1-7)-Mas axis in renovascular hypertensive rat.

This study aimed to investigate the effect of combination of felodipine+puerarin on ACE2-Ang (1-7)-Mas axis, and to explore the protective effect of the combination against kidney in renovascular hypertensive rats. Goldblatt rats were randomly divided into 5 groups as follows: 4 groups which were treated with felodipine (Felo), puerarin (Pue), Felo+Pue, and Felo+captopril (Cap), respectively, and a control group of animals that were administrated with distilled water. Contents of Ang II and Ang (1-7) in renal tissues were determined by ELISA kit. The mRNA expression of ACE2/Mas and ACE/AT1 in kidneys was analyzed by RT-PCR. After 8weeks of treatment, compared with Goldblatt group, Felo+Pue reduced SBP, DBP and HR (p<0.01 or p<0.05), ameliorated renal interstitial fibrosis, decreased the level of Ang II and increased that of Ang (1-7), upregulated mRNA expression of ACE2 and Mas, decreased that of ACE and AT1, and downregulated protein expression of TGF-ß1 in kidneys (p<0.01). Compared with Felo group, Felo+Pue decreased DBP and HR more markedly, attenuated fibrosis, decreased Ang II levels and increased those of Ang (1-7), upregulated mRNA expression of ACE2 in bilateral kidneys and that of Mas in ischemic kidney, downregulated that of ACE in bilateral kidneys and that of AT1 in ischemic kidney, and decreased expression of TGF-ß1 protein significantly. In a word, a combination of Felo+Pue has a more efficient therapeutic effect on DBP and HR, and contributes to a better protection against renal interstitial fibrosis.

[Efficacy and safety of aranidipine in Chinese patients with mild-to-moderate essential hypertension].

OBJECTIVE: To assess the efficacy and safety of aranidipine versus retard-released felodipine in Chinese patients with mild-to-moderate essential hypertension. METHODS: This was a multicenter, randomized, double-blind, placebo and active antihypertensive drug parallel-controlled study. After 2 weeks of placebo run-in period, 315 patients at 6 centers with diastolic blood pressure (DBP) between 95 to 109 mm Hg (1 mm Hg = 0.133 kPa) while systolic blood pressure (SBP) below 180 mm Hg were randomized to receive aranidipine 5-20 mg/d (n = 126) or retard-released felodipine 5-10 mg/d (n = 126) for 12 weeks. Others (n = 63) received placebo for 4 weeks. Their blood pressures were evaluated at baseline and the end of Weeks 4, 8 and 12. RESULTS: After a 12-week treatment, SBP decreased from 148.8 ± 10.7 mm Hg to (132.8 ± 11.2) mm Hg while DBP dropped from ( 98.4 ± 2.8) mm Hg to (83.9 ± 7.5) mm Hg. There were significant differences with the baseline values (P < 0.0001). After a 4-week treatment, the reductions of SBP in aranidipine and retard-released felodipine groups were (12.1 ± 11.0) mm Hg and (12.2 ± 11.2) mm Hg while the reductions of DBP in two groups (11.8 ± 6.9) mm Hg and (12.1 ± 7.9) mm Hg respectively. The reductions of SBP and DBP in two groups were (2.3 ± 8.4) mm Hg and (4.0 ± 5.1) mm Hg and they were significantly superior to that in placebo group (P < 0.0001). But no significant difference existed between aranidipine and retard-released felodipine groups. Also no significant differences were found between these two antihypertensive therapy groups at the end of Weeks 4, 8 and 12 in the reduction of blood pressure, total response rate and blood pressure control rate. But 20 mg daily aranidipine was significantly superior to 10 mg daily retard-released felodipine in the control rates of SBP and DBP. Adverse events occurred at 24.22% and 29.92% in aranidipine and retard-released felodipine groups respectively (P = 0.305). CONCLUSION: Administration of aranidipine 5-20 mg/d can effectively control blood pressure and is not inferior to retard-released felodipine 5-10 mg/d. The efficacy of 20 mg/d aranidipine is superior to that of retard-released felodipine 5-10 mg/d. And the effectiveness and safety of aranidipine are similar to those of retard-released felodipine.

Antihypertensive effect of low-frequency transcutaneous electrical nerve stimulation (TENS) in comparison with drug treatment.

Hypertension is a major risk factor for vascular disease, yet blood pressure (BP) control is unsatisfactory low, partly due to side-effects. Transcutaneous electrical nerve stimulation (TENS) is well tolerated and studies have demonstrated BP reduction. In this study, we compared the BP lowering effect of 2.5 mg felodipin once daily with 30 min of bidaily low-frequency TENS in 32 adult hypertensive subjects (mean office BP 152.7/90.0 mmHg) in a randomized, crossover design. Office BP and 24-h ambulatory BP monitoring (ABPM) were performed at baseline and at the end of each 4-week treatment and washout period. Felodipin reduced office BP by 10/6 mmHg (p <0.001 respectively) and after washout BP rose to a level still significantly lower than at baseline. TENS reduced office BP by 5/1.5 mmHg (p <0.01, ns). After TENS washout, BP was further reduced and significantly lower than at baseline, but at levels similar to BP after felodipin washout and therefore reasonably caused by factors other than the treatment per se. ABPM revealed a significant systolic reduction of 3 mmHg by felodipin, but no significant changes were noted after TENS. We conclude that our study does not present any solid evidence of BP reduction of TENS.

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.

The effect of metoprolol alone and combined metoprolol-felodipin on the digital microcirculation of patients with primary Raynaud's syndrome.

OBJECTIVES: Calcium channel inhibitors have beneficial impact on microcirculation, but beta-blocker effect is controversial. Clinicians still do not agree on beta-blocker combination with other treatments in the management of impaired microcirculation. The aim of the present study was to describe the effects of beta-blocker metoprolol monotherapy and combined with calcium channel inhibitor felodipin on digital microcirculation in primary Raynaud's syndrome. METHODS: We enrolled in this study 46 patients suffering from both hypertension and primary Raynaud's syndrome. Fifteen patients were treated with beta-blocker monotherapy (metoprolol), 13 received combined beta-blocker and calcium channel blocker therapy (felodipin and metoprolol), while 18 patients without any medications served as controls. Measurement of digital microcirculation was carried out with laser Doppler scanner. RESULTS AND CONCLUSIONS: Our investigation concludes that the concurrent administration of beta-blockers with calcium channel inhibitors positively reduces symptoms in patients suffering from Raynaud's syndrome.