Calcium Channel Blockers Research Papers (original) (raw)

2025, Revista da Sociedade Brasileira de Medicina Tropical

Verapamil, was assayed to record its modulating effect upon Brazilian Plasmodium falciparum isolates resistant to chloroquine. Other cardiovascular drugs known to be modulating agents in resistant malaria and/or multidrug-resistant neoplasias, including nifedipine, nitrendipine, diltiazem and propranolol, were also evaluated. Concentrations similar to those for cardiovascular therapy were used in the in vitro microtechnique for antimalarial drug susceptibility. Intrinsic antiplasmodial activity was observed from the lowest concentrations without a significant modulating action. Other reported modulating agents, such as the antipsychotic drug trifluoperazine and the antidepressants desipramine and imipramine, demonstrated similar responses under the same experimental conditions. Results suggest a much higher susceptibility of Brazilian strains, as well as an indifferent behaviour in relation to modulating agents.

2025

HOBt) were obtained from Novabiochem and used as supplied. Butyltrithiocarbonate propanoic acid (BTCPA), was obtained from Dulux, and used as supplied and azo-iso-butyronitrile (AIBN) was obtained from Aldrich, and precipitated from methanol prior to use. Hünig's base [di(isopropyl)ethylamine, DIPEA], trifluoroacetic acid (TFA), trifluoroethanol (TFE), 2,2' pentamethyldiethylenetriamine (PMDETA), sulphuryl chloride, and all solvents were ordered through Sigma-Aldrich and used as received. CuBr, used in the click reactions, was obtained from Aldrich and purified by suspending it in acetic acid (6 g in 50 ml) for 20 min. Pure CuBr was filtered off, washed with cold EtOH (100%, 2 x 20 ml), dried under vacuum and stored under nitrogen. The monomer, hydroxyl ethyl acrylate (HEA) was purified as described in literature. Azido Fmoc-L-Lysine (1): Azido Fmoc-L-Lysine was using Stick's diazo transfer agent, using a method adapted from his procedure for similar compounds. Sulfuryl chloride (8.05 ml, 100 mmol) was added dropwise to an ice cold suspension of sodium azide (6.50 g, 100 mml) in acetonitrile (100 ml) and stirred overnight at room temperature. The mixture was then recooled to 0°C and imidazole (12.95g, 190 mmol) was added over 20 min. After stirring for a further 3h at room temperature, the solution was diluted with EtOAc (200 ml), washed with water (2 x 200 ml) and

2025, BMJ

Editor-Lindberg et al suggested that the use of calcium channel blockers increases the risk of suicide. 1 Methodological problems, however, render that conclusion uncertain. In a cross sectional ecological study they found a weak but significant correlation between rates of suicide and use of calcium channel blockers, expressed as numbers of defined daily doses dispensed by pharmacies in 152 municipalities in Sweden. The defined daily dose is, however, a technical unit for studies of use of drugs 2 ; defined daily doses might differ twofold or more from the daily doses actually prescribed. Therefore, when used for other purposes, such as an estimate of individuals at risk (as in Lindberg et al's paper), methods based on the defined daily dose require validation. 3 The authors also carried out a historical cohort study of patients with an index prescription of an antihypertensive drug. They found that "five users of calcium channel blockers (three men and two women, one with uncertain intent) and four nonusers (three men and one women, none with uncertain intent) committed suicide" within seven years after they bought the index drug in 1988 or 1989. A minimum requirement for applying statistics on the outcome in nine individuals is to validate exposure as well as outcome. One misclassification in this study would mean that the difference was no longer significant. One of the "suicides" in the calcium channel blocker cohort was not even a certain suicide but an undetermined unnatural death. The remaining eight cases of alleged suicide were not validated against death certificates or medical records. It is not known whether these nine patients were taking an antihypertensive drug at the time of death, whether they were depressed, etc. Potential confounders, such as the severity of hypertension, comorbidity, concomitant drug treatment, and history of depression or use of antidepressants, were not controlled for, although such prescription data are available in the database and medical records can be made available for validation purposes in this population. 4 It is vital that the non-experimental nature of pharmacoepidemiology is recognised. If the association between calcium channel blockers and suicide can be confirmed by validation of exposure and outcome, this association has to be confirmed in independent studies before any causality is established.

2025, JACC: Heart Failure

2025, Journal of Hypertension

Objective(s) To study the changes in macrophage inducible nitric oxide synthase (iNOS) activity, plasma levels of nitrite, lipid peroxidation (LPO) and melatonin in human essential hypertension before and 6 months after 4 mg/day lacidipine treatment. The study was carried out in a total of 25 subjects -11 healthy subjects and 14 hypertensive patients. Blood pressure and peripheral blood samples were taken before and after 6 months of lacidipine treatment (4 mg/day). Methods Systolic (SBP) and diastolic blood pressure (DBP), renal function, lipid and carbohydrate metabolism, renin, aldosterone and catecholamine levels were measured by routine methods. The activity of macrophage iNOS and plasma nitrite, LPO and melatonin levels were also measured. Conclusions Besides reducing blood pressure, lacidipine treatment significantly decreased plasma LPO and macrophage iNOS activity, without changes in NO. Melatonin significantly increases in hypertensive patients, returning to control after lacidipine. Thus, lacidipine reduced blood pressure and free radicals, avoiding the oxidative damage to endothelium. It is suggested that administration of lacidipine plus melatonin may enhance the beneficial effects of each drug in essential hypertension.

2025, Журнал аналитической химии

Verapamil is a calcium channel blocking agent which has found widespread use in the management of supraventricular tachyarrhythmias, angina pectoris, hypertrophic cardiomyopathy and hypertension. It is converted to its biologically active metabolite nor verapamil in liver by cytochrome P450. In present communi cation, synthesis and characterization of nor verapamil and development of reverse phase high performance liq uid chromatographic method for the quantification of nor verapamil along with verapamil in plasma has been carried out. The characterization of nor verapamil was carried out using GC MS, FT IR and NMR spectros copy. The separation was carried out with an isocratic JASCO RP HPLC system using 5 μm KYA TECH HiQ Sil C 18 HS column (250 mm × 4.6 mm internal diameter) as a stationary phase and methanol : water : 0.01 M orthophosphoric acid : triethylamine [70 : 30 : 2 : 0.5, v/v/v/v] as mobile phase. The flow rate was maintained at 1.0 mL/min and UV detection at 222 nm. The calibration for verapamil and nor verapamil were found to be linear over concentration range of 50-300 ng/mL with correlation coefficient (n = 6) of 0.9995 and 0.9997, respectively. This method was validated according to USFDA guidelines. The method was found to be simple, accuare, precise sensitive and selective for the determination of verapamil and nor verapamil in plasma and thus useful in bioequivalence studies of verapamil.

2025, Expert Opinion on Therapeutic Patents

Tetrahydro-N,N-dimethyl-4-(3-fluorophenyl)-2′-(2-phenylvinyl)carbonyl-spiro[cyclohexane-1,1′(1′H)-pyrido[3,4-b]indole]-4-amine citrate (cis-diastereoisomer) AMD-7 cis :... more

Tetrahydro-N,N-dimethyl-4-(3-fluorophenyl)-2′-(2-phenylvinyl)carbonyl-spiro[cyclohexane-1,1′(1′H)-pyrido[3,4-b]indole]-4-amine citrate (cis-diastereoisomer) AMD-7 cis : 2′,3′,4′,9′-Tetrahydro-N,N-dimethyl-4-(3-fluorophenyl)-2′-(3,4-dimethoxybenzyl)carbonyl-spiro[cyclohexane-1,1′(1′H)-pyrido[3,4-b]indole]-4-amine(cis-diastereoisomer) C07C: Acyclic or carbocyclic compounds C07F: Acyclic, carbocyclic, or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium CB1 and CB2 receptors: Cannabinoid receptor type 1 and 2 CFA: Complete Freund's adjuvant CHO cells: Chinese hamster ovary cells DHβCD: 6-DTBP complexed with 2-hydroxypropyl-β-cyclodextin EC 5O : Half maximal effective concentration EPAC: Exchange protein directly activated by cAMP ESI-09: 3-(5-tert-Butyl-isoxazol-3-yl)-2-[(3-chlorophenyl)-hydrazono]-3-oxo-propionitrile FDA: Food and Drug Administration KRB-5b: Compound was synthesized from 2,6-xylidine NaV 1.7 channel: Na(V)1.7 sodium channel ORL1: Receptor and µ-opioid receptor

2025, Chemical Biology & Drug Design

N-type voltage-dependent Ca 2+ channels (Ca V 2.2) are located at nerve endings in the central and peripheral nervous systems and are strongly associated with the pathological processes of cerebral ischemia and neuropathic pain. Ca V 2.2 blockers such as the ωconotoxin MVIIA (Prialt) are analgesic and have opioid-sparing effects. With the aim to develop new multi-target analgesic compounds, we designed the first ω-conotoxin/opioid peptidomimetics based on the enkephalin-like sequence Tyr-D-Ala-Gly-Phe (for the opioid portion) and two fragments derived from the loop-2 pharmacophore of ω-conotoxin MVIIA. Antinociceptive activity evaluated in vitro and in vivo revealed differential affinity for Ca V 2.2 and opioid receptors and no significant synergistic activity.

2025, Kocaeli Üniversitesi Sağlık Bilimleri Dergisi

Amaç: Gebelik sırasında sigara ve alkol tüketimi doğum eylemi üzerinde istenmeyen etkilere neden olmaktadır. Altta yatan mekanizmalar hala tam olarak anlaşılmamış olmakla birlikte, bozulmuş miyometriyum fonksiyonel yanıtları bu komplikasyonların nedenlerinden biri olabilir. Bu çalışmada, kronik sigara ve alkol tüketiminin izole term-gebe sıçan miyometriyum şeritlerinin fonksiyonel yanıtlarına etkisini araştırdık. Yöntem: 21 Wistar albino sıçanı üç gruba ayrıldı: Kontrol; Sigara grubu, sıçanlar 12 hafta boyunca sigara dumanına maruz kaldı; Alkol grubu, sıçanlara 12 hafta boyunca etanol uygulandı (n = 7, her bir grupta). Doğum dönemlerinde bulunan sıçanlardan izole edilen miyometriyal düz kas şeritleri, izometrik kayıt almak üzere organ banyosuna yerleştirildi. Karbakol (10-8-10-4 M), oksitosin (10-9-10-3 M) ve diltiazem (10-8-10-4 M) kümülatif konsantrasyonlarının miyometriyal spontan kasılmalar üzerindeki etkileri ölçüldü. Bulgular: Karbakol kasılma yanıtlarının amplitüd ve frekansl...

2025, Journal of Biological Chemistry

2025, Evidence-based complementary and alternative medicine : eCAM

Eurycoma longifolia (Simaroubaceae) is a popular folk medicine that has traditionally been used in Southeast Asia as an antimalarial, aphrodisiac, antidiabetic, and antimicrobial and in antipyretic remedies. This study evaluates the effects of Eurycoma longifolia extract on cytochrome P450 (CYP) enzyme-mediated drug metabolism to predict the potential for herb-drug interactions. Methanolic extract of E. longifolia root was tested at concentrations of 1, 3, 10, 30, 100, 300, and 1000 µg/mL in human liver microsomes or individual recombinant CYP isozymes. The CYP inhibitory activity was measured using the cocktail probe assay based on liquid chromatography-tandem mass spectrometry. E. longifolia showed weak, concentration-dependent inhibition of CYP1A2, CYP2A6, and CYP2C19. The inhibitory effects on these CYP isozymes were further tested using individual recombinant CYP isozymes, showing IC50 values of 324.9, 797.1, and 562.9 μg/mL, respectively. In conclusion, E. longifolia slightly ...

2025

Push-Pull Osmotic Pump (PPOP) tablets of a slightly water soluble model drug were developed and compared to a commercial product. Results showed that irrespective of the multiple steps involved in manufacture of such dosage forms, developed tablets demonstrated equivalent performance to commercial tablets with respect to physical properties, drug release and push-pull pattern. The developed system could provide a platform to yield satisfactory results for similar drug candidates.

2025, Journal of the American College of Cardiology

The demands on a pulmonary arterial hypertension (PAH) treatment algorithm are multiple and in some ways conflicting. The treatment algorithm usually includes different types of recommendations with varying degrees of scientific evidence. In addition, the algorithm is required to be comprehensive but not too complex, informative yet simple and straightforward. The type of information in the treatment algorithm are heterogeneous including clinical, hemodynamic, medical, interventional, pharmacological and regulatory recommendations. Stakeholders (or users) including physicians from various specialties and with variable expertise in PAH, nurses, patients and patients' associations, healthcare providers, regulatory agencies and industry are often interested in the PAH treatment algorithm for different reasons. These are the considerable challenges faced when proposing appropriate updates to the current evidence-based treatment algorithm.The current treatment algorithm may be divided into 3 main areas: 1) general measures, supportive therapy, referral strategy, acute vasoreactivity testing and chronic treatment with calcium channel blockers; 2) initial therapy with approved PAH drugs; and 3) clinical response to the initial therapy, combination therapy, balloon atrial septostomy, and lung transplantation. All three sections will be revisited highlighting information newly available in the past 5 years and proposing updates where appropriate. The European Society of Cardiology grades of recommendation and levels of evidence will be adopted to rank the proposed treatments. (J Am Coll Cardiol 2013;62:D60-72) ª 2013 by the American College of Cardiology Foundation The complexity of the treatment algorithm for pulmonary arterial hypertension (PAH) has progressively increased since the 2nd World Symposium on Pulmonary Hypertension (WSPH) in Evian, France in 1998 when, apart from calcium channel blockers (CCBs) for vasoreactive patients, the only approved therapy was epoprostenol administered by continuous intravenous infusion (1). Five years later at the 3rd WSPH held in Venice, Italy, in 2003, the treatment algorithm had expanded From the

2025, Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Università di Napoli, Secondo ateneo

The prevention of symptomatic heart failure represents the treatment of patients in the A and B stages of AHA/ACC heart failure classification. Stage A refers to patients without structural heart disease but at risk to develop chronic heart failure. The major risk factors in stage A are hypertension, diabetes, atherosclerosis, family history of coronary artery disease and history of cardiotoxic drug use. In this stage, blockers hypertension is the primary area in which beta blockers may be useful. Beta blockers seem not to be superior to other medication in reducing the development of heart failure due to hypertension. Stage B heart failure refers to structural heart disease but without symptoms of heart failure. This includes patients with asymptomatic valvular disease, asymptomatic left ventricular (LV) dysfunction, previous myocardial infarction with or without LV dysfunction. In asymptomatic valvular disease no data are available on the efficacy of beta blockers to prevent heart...

2025, Journal of Scleroderma and Related Disorders

antibodies also allowed us to participate in a EUSTAR study (accepted for publication in Journal of Rheumatology). We encourage EUSTAR registration as we demonstrate its favourable impact on participation in clinical research, patient screening and treatment. Cohort descriptions of SSc are recent and very scarce in Portugal ( ). We anticipate it will facilitate further characterization of SSc across healthcare settings.

2025, British Journal of Clinical Pharmacology

Aims Some reports have suggested that calcium channel blockers may be associated with an increased incidence of depression or suicide. There is a paucity of evidence from large scale studies. The aim of this study was to assess rates of depression with calcium channel antagonists using data from prescription event monitoring studies. Methods Observational studies on large cohorts of patients using lisinopril, enalapril (ACE inhibitors), nicardipine (type 2 calcium channel blocker) and diltiazem (type 3 calcium channel blocker) were conducted, using prescription‐event monitoring. Rates of depression in the different drugs and rate ratios (95% CI) were computed. Results The crude overall rates of depression during treatment were 1.89, 1.92 and 1.62 per 1000 patient months for the ACE inhibitors, diltiazem and nicardipine, respectively. Using the ACE inhibitors as the reference group, the rate ratios for depression were 1.07 (0.82–1.40) and 0.86 (0.69–1.08) for diltiazem and nicardi...

2025, American Journal of Otolaryngology

We investigated the frequency of tinnitus in fibromyalgia patients and the effect of drugs used for routine fibromyalgia on tinnitus. Methods: We included 101 diagnosed fibromyalgia patients. After detailed ear nose throat examination, audiometric tests and tinnitus handicap index (THI) were performed. After the tests, routine treatment for fibromyalgia was started by the physical therapy and rehabilitation department. Two months after the beginning of the treatment, THI were repeated again and the results were statistically evaluated. Results: All patients included in the study were women. 74.3% of the patients had tinnitus. Pregabalin and selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant-treated patients were evaluated; In both groups, there was a statistically significant difference between pre-and post-treatment tinnitus levels (p < .001). However, there was no statistically significant difference between pregabalin group and diloxetine group according to treatment results. Conclusions: The incidence of tinnitus is high in fibromyalgia patients. That pregabalin and duloxetine agents routinely used in fibromyalgia require further experimental and human studies in order to be able to use in tinnitus.

2025, Cardiovascular Drugs and Therapy

To determine the effect of dihydropyridines on the metabolism of propranolol, we studied the effects of a single oral dose of nicardipine, nifedipine, and BAY-K-8644 on the pharmacokinetics of propranolol in male Wistar rats fitted with a catheter in the jugularis vein. Oral propranolol (15 mg/kg and 1.5 mg/kg) and intravenous propranolol (1.5 rag/ kg) were administered either alone or together with oral nicardipine (2.5 mg/kg). Oral propranolol (15 mg/kg) was administered with oral nifedipine (1.5 mg/kg) and with oral BAY-K-8644 (1.5 mg/kg). Nicardipine increased significantly the AUC and Cm~ of oral propranolol (1.5 mg/kg and 15 rag/ kg). However, the plasma concentration time curve of intravenous propranolol (1.5 mg/kg) was unaffected. Nifedipine also significantly increased the AUC and Cma x of oral propranolol (15 mg/kg), whereas with BAY-K-8644 there was only a slight increase in the bioavailability of oral propranolol (15 mg/kg). The results indicate that the dihydropyridine calcium antagonists decrease the metabolism of propranolol as a result of a decrease in first-pass clearance. Although an interaction at the level of cytochrome P450 may also be involved, the results of the present study suggest that the inhibitory effect can be largely attributed to changes in liver blood flow.

2025, European Journal of Clinical Pharmacology

A single-blind, single-center study was conducted to investigate the short-term safety and efficacy of carvedilol, a new cardiovascular agent, when added to 25 mg hydrochlorothiazide (HCTZ) as combination therapy for patients inadequately treated with HCTZ alone. A total of 18 patients entered the baseline study phase, during which they received 25 mg HCTZ once daily for 4 weeks; 16 of these patients (8 men and 8 women) entered the combination treatment phase. All patients had a supine diastolic blood pressure (DBP) of _ 95 mmHg prior to receiving the first dose of combination treatment. Combination treatment consisted of 25 mg HCTZ plus 12.5 mg carvedilol once daily for 2 days, followed by a forced titration of the carvedilol dose to 25 mg for 7 days. After 2 days of 12.5 mg carvedilol plus 25 mg HCTZ once daily, mean trough blood pressure was reduced as compared with baseline values. Of 16patients, 6 (38%) achieved a trough supine DBP of < 90 mmHg. After i additional week of combination therapy with 25 mg carvedilol, 8 of 15 patients (53%) achieved a trough supine DBP of < 90 mmHg and 14 of 15 patients (93%) achieved that of < 95 mmHg. At each visit during the combination treatment phase, the acute reduction in blood pressure was greatest during the first 2 h after dosing. The heart rate was minimally affected by combination treatment with carvedilol at either trough levels or acutely after dosing. Nine patients experienced adverse events during combination treatment. One patient withdrew because of dizziness and fatigue. In conclusion, at an initial dose of 12.5 mg once daily, carvedilol can be safely added to HCTZ in patients whose hypertension is inadequately controlled by HCTZ alone. Results suggest that some patients may be effectively treated with 12.5 mg carvedilol added to diuretics; upward titration of carvedilol should occur after adequate evaluation of the response to this initial dose.

2025, European Journal of Clinical Pharmacology

2025, Cardiovascular Drugs and Therapy

2025, British Journal of Clinical Pharmacology

The influence of a single oral dose of nicardipine 30 mg on the pharmacokinetics and pharmacodynamics of propranolol 80 mg was investigated in twelve healthy volunteers. 2 Co-administration of nicardipine significantly increased the AUC and the mean Cmax of propranolol. 3 Blood pressure and heart rate tended to decrease more when propranolol and nicardipine were administered together than when propranolol was given alone, but differences are of doubtful significance. 4 The results indicate that nicardipine alters the pharmacokinetics of propranolol by impaired hepatic 'first-pass' clearance, but pharmacodynamics were little affected.

2025, The heart surgery forum

Free radicals and neutrophils are potent sources of ischemia-reperfusion injury (I/R) and they can be limited by the use of exogenous application of some therapeutic agents. The objective of this study was to compare the effects of cilostazol and diltiazem hydrochloride in a rat hind limb model of I/R injury. Methods: Skeletal muscles submitted to 2 hours of ischemia by placing an aneurysm clip to femoral artery and reperfused after 1, 2 and 4 hours. Seventy-two Wistar-Albino rats were randomly divided into mainly four groups according to treatment agents: Group I (control group) was treated with saline; Group II was treated with diltiazem hydrochloride; Group III was treated with cilostazol in 30% dimethyl sulphoxide; and Group IV was treated with 30% dimethyl sulphoxide intraperitoneally. These four main groups also subdivided into three subgroups according to duration of the reperfusion times. Blood samples were taken and all rats were sacrificed. Results: Cilostazol-treated gr...

2025, American Journal of Obstetrics and Gynecology

The prevalence of pre-existing obesity in the pregnant population continues to increase. Obesity itself is associated with adverse cardiovascular outcomes later in life, and pregnancy may compound this risk. The objective of our study was to evaluate whether pregnancy increases the risk of cardiovascular abnormalities later in life beyond the risks associated with pre-pregnancy obesity, using a well characterized animal model. STUDY DESIGN: Virgin CD-1 female mice were placed on standard (SF) or high fat (HF) diet. After 3 months, mice were randomly allocated to a breeding versus non breeding group resulting in 4 groups: primigravid on SF (SF-PG) or HF (HF-PG) and nulligravid on SF (SF-NG) or HF (HF-NG). The primigravid group proceeded through a normal pregnancy and delivery. After weaning of the primigravid group, all animals were contemporaneously placed on SF diet. At 6 months post partum, PG mice were age-matched to NG mice and fitted with telemetric transducers for systolic (SBP) and diastolic blood (DBP) pressure recordings in the conscious, unrestrained animals. Student t-test and Mann-Whitney test were used for statistical analysis (significance: pϽ0.05). RESULTS: There were no differences in BP between nulligravid HF and SF mice. The primigravid HF mice exposed to pregnancy had significantly higher SBP (pϭ0.04) than SF-PG mice. Comparisons within diet groups revealed that SF-NG had significantly higher SBP (pϭ0.03) and DBP (pϭ0.04) than SF-PG mice (Figure ). HF-NG group exhibited significantly higher DBP (pϭ0.03) and a trend towards higher SBP compared with HF-PG (Figure ) CONCLUSION: A normal pregnancy is a protective factor against hypertension later in life in both obese and non-obese animals.

2025, Hepatology

Estudios Cientı ´ficos (CECS) was from Fuerza Ae ´rea de Chile, I. Municipalidad de Las Condes, and a group of Chilean private companies (AFP Provida, CODELCO, Empresas CMPC, Telefo ´nica del Sur y Masisa S.A.) is also acknowledged. Support was also obtained through the International Program of the Howard Hughes Medical Institute and Ca ´tedra Presidencial en Ciencias (to Francisco V. Sepu ´lveda). CECS is a Millennium Science Institute.

2025, Monatshefte für Chemie - Chemical Monthly

Polyhydroquinolines (PHQs) are the unsymmetrical Hantzsch derivatives of 1,4-dihydropyridines with several biological applications. In this work, new fatty 2-and 3-substituted PHQ derivatives from different fatty acids and fatty alcohol feedstocks were synthesized at good yields via a four-component reaction (4CR). The antioxidant activities of fatty PHQs were investigated using three different antioxidant methods. The experiments showed that the compounds derived from 2-nitrobenzaldehyde and fatty palmitic (C16:0) and oleic (C18:1) chains showed better antioxidant activity. This revealed that combining the ortho NO 2 group in the aromatic ring with the insertion of fatty chains in the PHQ core contributed to the antioxidant activity. However, among all the fatty PHQs tested, the fatty 2-substituted compound derived from oleyl alcohol and 2-nitrobenzaldehyde showed the highest antioxidant activity (EC 50 , 2.11-4.69 mM), which was similar to those of the antioxidant standards butylated hydroxytoluene (EC 50 , 1.98-6.47 mM) and vitamin E (EC 50 , 1.19-5.88 mM). In addition, this lipophilic compound showed higher antioxidant activity than the antihypertensive drug nifedipine (EC 50 , 49.25-126.86 mM). These results indicate that the new fatty PHQs may find novel applications as antioxidant additives.

2025, European Journal of Obstetrics & Gynecology and Reproductive Biology

It is the development of proteinuria in pregnancy-induced hypertension which is associated with an increased perinatal mortality. There is some evidence to suggest that labetalol may diminish the amount of proteinuria in.patients who have already developed proteinuric pre-eclampsia. A randomised controlled study design was used to investigate whether labetalol treatment, started when a persistent diastolic blood pressure greater than 90 mmHg was observed, influenced the subsequent development of proteinuria. One hundred and fourteen women with singleton pregnancies and hypertension in the absence of proteinuria were randomised to receive either labetalol or no antihypertensive therapy. At recruitment maternal age, blood pressure and gestation were similar in both the labetalol and control groups. There was no difference in the frequency, quantity or timing of subsequent proteinuria between treatment and control groups. Overall 34% of primigravidae and 10% of parous women developed proteinuria. Labetalol did, however, control the blood pressure in 45 of the 51 treated women (88%) within 24 h. This effect was often shortlived requiring dose escalation after 3 to 5 days in the majority of cases. Labetalol was well tolerated and no significant maternal toxicity was noted.

2025, arXiv (Cornell University)

The cerebrospinal fluid (CSF) constitutes an interface through which chemical cues can reach and modulate the activity of neurons located at the epithelial boundary within the entire nervous system. Here, we investigate the role and functional connectivity of a class of GABAergic sensory neurons contacting the CSF in the vertebrate spinal cord, and referred to as CSF-cNs. The remote activation of CSF-cNs was shown to trigger delayed slow locomotion in the zebrafish larva, suggesting that these cells modulate components of locomotor central pattern generators (CPGs). Combining anatomy, electrophysiology, and optogenetics in vivo, we show that CSF-cNs form active GABAergic synapses onto V0-v glutamatergic interneurons, an essential component of locomotor CPGs. We confirmed that activating CSF-cNs at rest induced delayed slow locomotion in the fictive preparation. In contrast, the activation of CSF-cNs promptly inhibited ongoing slow locomotion. Moreover, selective activation of rostral CSF-cNs during ongoing activity disrupted rostrocaudal propagation of descending excitation along the spinal cord, indicating that CSF-cNs primarily act at the premotor level. Altogether, our results demonstrate how a spinal GABAergic sensory neuron can tune the excitability of locomotor CPGs in a statedependent manner by projecting onto essential components of the excitatory premotor pool.

2025

Objective: To determine the effect of cilostazol on carotico-vertebral system compliance, distensibilty, stiffness, flows and other vascular events through non-invasive methods in patients with stable IC/PAD. Method: Our study was performed in Elazig training and research hospital between January 2012 and December 2012. Twenty-nine patients (22 male, 7 female) who had been treated with cilostazol 100 mg twice daily during six month were included in the study. Ultrasound measurements of carotid and vertebral arteries were performed at baseline, at 3 and 6 months after starting of treatment and the evaluation of the arterial stiffness measurements were performed by the pre-defined method. Results: The mean age of the participants was 64.64 years. Pulsatility index, resistive index, sistolic/diastolic velocity ratio and intima-media thickness values were decreased in carotid and vertebral arteries, elastic modulus were decreased in carotid arteries while cross-sectional compliance, cro...

2025, Journal of Pharmacology and Experimental Therapeutics

To be able to address the question how neurotransmitters or pharmacological agents influence activity of neuronal populations in freely moving animals, the combidrive was developed. The combidrive combines an array of 12 tetrodes to perform ensemble recordings with a moveable and replaceable microdialysis probe to locally administer pharmacological agents. In this study, the effects of cumulative concentrations of tetrodotoxin, lidocaine, and muscimol on neuronal firing activity in the prefrontal cortex were examined and compared. These drugs are widely used in behavioral studies to transiently inactivate brain areas, but little is known about their effects on ensemble activity and the possible differences between them. The results show that the combidrive allows ensemble recordings simultaneously with reverse microdialysis in freely moving rats for This work was supported by Nederlandse Organisatie voor Wetenschappelijk Onderzoek Grant 903-47-084 and ZonMW-TOP 912-02-050. E.v.D. and G.v.d.P. contributed equally to this article. Article, publication date, and citation information can be found at .

2025, Pharmacognosy Journal

Introduction: The present study aimed to compare the effects of the angiotensin II receptor blocker candesartan and the calcium channel blocker amlodipine on blood pressure and metabolic profile in nondiabetic hypertensive patients. Methods: The study involved non-diabetic patients with mild to moderate hypertension. They were randomly assigned to receive candesartan or amlodipine for 24 weeks, parameters were evaluated at baseline and after 12 weeks and 24 weeks for each patient group. Results: Candesartan and amlodipine both reduced blood pressure and the HOMA-IR index significantly (P < 0.05, 24 weeks vs. baseline). Candesartan was more effective than amlodipine in lowering blood pressure and HOMA-IR, although the difference was not significant statistically. Conclusion: Both candesartan and amlodipine are extremely effective at reducing blood pressure in moderate hypertension patients. Candesartan cilexetil has a major benefit in terms of tolerability, as it reduces the risk of developing metabolic dysregulation.

2025, Biophysical Journal

Associative learning is essential for cognitions. To better understand the mechanisms underlying associative learning, we examined whether the association of two signals induces a process that one signal evokes a recall of another signal, or turned around, and how glutamatergic receptor-channels are regulated to be involved in this reciprocal information retrieval (crossmodal reflex). In our mouse model, the two sensory systems, whisker-tobarrel cortex and olfaction-to-piriform cortex, were associatively activated by simultaneously stimulating whiskers and olfaction. This training procedure for 2 weeks led to odorant-induced whisker motion and whiskerinduced olfaction responses. After this cross-modal reflex onset, the barrel and piriform cortices connected each other. Local filed potentials in vivo showed that the neurons in both barrel cortex and piriform cortex turned into processing whisker signal and odor one, respectively. The activity patterns of these cortical neurons in response to whisker signal and odorant one were distinct. These results indicate that the associative activation of barrel cortex and piriform cortex makes network neurons being able to store both whisker and odor signals as well as to recognize their differences through distinct encodings. With this reciprocal information retrieval, either of two associated signals can induce two responsive behaviors for wellorganized cognitions and responses to environmental alerts. In terms of synaptic plasticity, we found that excitatory postsynaptic currents mediated by ionotropic glutamatergic receptor-channels in pyramidal neurons were upregulated in their amplitudes and frequency. By genome-wide sequencing, we observed that the upregulations of neuropilin (NMDAR accessory unit), AMPAR1 precursor, neuroligin 1~3 and tyrosine kinase in these cortical areas were associated with the cross-modal reflex and glutamate receptorchannel upregulation.

2025, Urology

Objectives. To evaluate the short-term effects of different intracavernosal agents and to investigate the antifibrotic effect of verapamil combined with these intracavernosal agents. Methods. Forty-five Sprague-Dawley rats weighing 400 to 500 g each (mean weight 435.27 Ϯ 13.65 g) were equally divided into nine groups (n ϭ 5). Papaverine (group 1), alprostadil (group 2), sodium nitroprusside (group 3), and verapamil (group 4) were injected alone intracavernously in 0.2-mL doses. Verapamil combined with papaverine, alprostadil, and sodium nitroprusside in 0.2-mL doses (0.1 mL verapamil and 0.1 mL vasoactive agent) were injected in groups 5 through 7. Group 8 was kept as a control group without injection, and isotonic saline alone was injected in group 9 during the same period. The intracavernous injection was done twice weekly with a 4-day interval. At the end of the study, total penectomy and multiple liver biopsies were performed to evaluate the histopathologic effects of the vasoactive agents and to test the liver function. Results. In all groups, the structure of the corpora cavernosa was well preserved generally and appeared similar to the control tissue. However, localized edema, fibrosis, macrophage infiltration, and polymorphonuclear leukocytes were found only at the injection site. Although these findings were not different from the findings in the saline and alprostadil groups, they were slightly more extensive in the papaverine and sodium nitroprusside alone groups and also in the vasoactive agent plus verapamil groups. Although mononuclear lymphocyte infiltration was found in the portal areas, advancing into the liver parenchyma, the liver function tests were within normal limits. Conclusions. We observed that intracavernous injection, except with nitroprusside, caused focal intracavernosal fibrosis and edema. We believe these effects might not be caused by just the drug, but also by needle trauma, since general fibrosis was not observed in the short term. However, nitroprusside has a severe fibrotic effect on cavernosal tissue in the short term. Moreover, intracavernous verapamil injection could not prevent the fibrosis in the short term.

2025, Journal of the American College of Cardiology

We investigated the effect of oral verapamil on clinical outcome and angiographic restenosis after percutaneous coronary intervention (PCI). BACKGROUND Thus far, there is no established systemic pharmacologic approach for the prevention of restenosis after PCIs. Five small studies reported encouraging results for calcium channel blockers. Our randomized double-blind trial included 700 consecutive patients with successful PCI of a native coronary artery. Patients received the calcium channel blocker verapamil, 240 mg twice daily for six months, or placebo. Primary clinical end point was the composite rate of death, myocardial infarction, and target vessel revascularization (TVR) during one-year follow-up; the angiographic end point was late lumen loss at the six-month follow-up angiography. We obtained complete clinical follow-up in 95% of the patients, and scheduled angiography was performed in 94%. The proportion of patients treated with stents was 83%. The primary clinical end point was reached in 67 (19.3%) patients on verapamil and in 103 (29.3%) patients on placebo (relative risk [RR] 0.66 [95% confidence interval (CI) 0.48 to 0.89]; p ϭ 0.002). This difference between the groups was driven by TVR (17.5% with verapamil vs. 26.2% with placebo; RR 0.67 [95% CI 0.49 to 0.93]; p ϭ 0.006). Late lumen loss was 0.74 Ϯ 0.70 mm with verapamil and 0.81 Ϯ 0.75 mm with placebo (p ϭ 0.11). Compared with placebo, verapamil reduced the rate of restenosis Ն75% (7.8% vs. 13.7%; RR 0.57 [95% CI 0.35 to 0.92]; p ϭ 0.014). CONCLUSIONS Verapamil compared with placebo improves long-term clinical outcome after PCI of native coronary arteries by reducing the need for TVR. This was caused by a reduction in the rate of high-grade restenosis. (

2025, Cell Calcium

In our previous paper [1], we reported that La 3+ was a useful tool to discriminate between RACE (receptor-activated Ca 2+ entry) and SOCE (store-operated Ca 2+ entry) in the human umbilical vein endothelial cell line, EA.hy926. In particular at 10 μM, La 3+ almost fully blocked SOCE (activated by thapsigargin, TG) while it appeared to have no effect on RACE (activated by histamine). In course of the continuation of this work, our experiments revealed that the lack of inhibitory effect of La 3+ on RACE was a regrettable artifact, due to the presence of phosphate in the histamine batch we were using. Indeed the batch of histamine was a phosphate salt and not a chloride salt. Testing the block of La 3+ on the histamine-Cl response revealed that La 3+ is equally efficient to inhibit the RACE than reported on SOCE. This suggests that the phosphate formed a complex with La 3+ , thus precluding its inhibitory effect on histamine-PO 4 induced Ca 2+ entry. However, the other evidence presented in the paper in favor of two separate Ca 2+ entry pathways in endothelial cells were confirmed and are still valid.

2025, Cell Calcium

2025, The Journal of Neuroscience

2025, The Netherlands journal of medicine

Phaeochromocytoma is a rare catecholamine-secreting neuroendocrine tumour with a high cardiovascular morbidity and mortality if left untreated. Surgical resection is the only curative therapy. During surgery there is a high risk of massive release of catecholamines, which can result in potentially fatal hypertensive crises and cardiac arrhythmias. Administration of vasoactive drugs such as (non)selective alpha- and beta-antagonists and calcium channel blocking agents have reduced the operation risk. Guidelines for the preoperative medical management of the patient with a phaeochromocytoma are mainly based on retrospective studies and case reports. We reviewed the relevant literature on this subject. In addition, we compared the several preoperative treatment protocols of the eight university medical centres in the Netherlands.

2025, The American Journal of Medicine

2025, European Journal of Clinical Pharmacology

Objective The pharmacokinetics of nimodipine following enteral administration in the early phase after subarachnoid haemorrhage (SAH) has not been described. If a sufficient absorption could be achieved with enterally administered nimodipine, this would be more feasible dosage form and result in a significant reduction in pharmaceutical costs given that the parenteral formulation of nimodipine currently used is tenfold more expensive than the enteral formulation. Methods This was a pilot study in which 17 patients with aneurysmal SAH were randomly assigned to receive nimodipine within 24 h after initial bleeding either as an 60 mg tablet/suspension at 4-h intervals, or as a continuous intravenous infusion of 2 mg/h. Serum nimodipine concentrations were measured during the 4 h following the first dose, and at 24 and 72 h on a validated gas chromatography mass spectrometer (GC-MS). Results Nimodipine AUC values (expressed in μg min/ml) were lower in the eight SAH patients receiving enteral nimodipine [AUC 0-4 range: 0.13-5.4 (median: 0.32); AUC 24-28 range: 0.16-6.1 (0.71); AUC 72-76 range: 0.47-20.6 (1.9)] than in the nine patients receiving a continuous intravenous infusion of nimodipine [AUC 0-4 range: 2.4-4.9 (3.4), p=0.059; AUC 24-28 range: 4.7-10.3 (7.3), p=0.001; AUC 72-76 range: 3.4-8.6 (6.9), p=0.001]. In three of five good-grade SAH patients receiving nimodipine tablets the AUC values were comparable to those of the intravenous administration, but in two good-grade patients with tablets and in all three poor-grade (Hunt&Hess, grade IV) SAH patients receiving the suspension, the rate and extent of nimodipine absorption was negligible. Conclusion This pilot study indicates that the rate and extent of nimopidine absorption following enteral administration in some acute SAH patients could be negligible, and this may particularly be the case in patients with a decreased level of consciousness.

2025

Background Levosulpiride, a dopamine D2 receptor antagonist commonly used in India for gastrointestinal disorders, has been increasingly associated with extrapyramidal symptoms (EPS), especially with prolonged use and in fixed-dose combinations (FDCs) with proton pump inhibitors (PPIs). Despite its widespread use, awareness of its neurological adverse effects remains limited. Objective To present a case series highlighting the clinical profile, management, and outcomes of patients who developed extrapyramidal symptoms (EPS) following levosulpiride use, with an emphasis on the importance of early detection and rational prescribing practices. Methods A prospective observational case series was conducted at the ADR Monitoring Centre of Maharaja Krushna Chandra Gajapati Medical College and Hospital, Berhampur, Odisha. Fifteen patients presenting with neurological symptoms following levosulpiride administration were systematically evaluated. Detailed clinical histories, imaging, and laboratory investigations were performed to rule out alternative causes. Causality was assessed using the WHO-UMC scale, and all cases were reported to PvPI. Levosulpiride was withdrawn in all cases, and treatment was tailored to symptom type. Results Among 15 patients (8 females, 7 males; aged 18-66 years), drug-induced Parkinsonism was most common (10 cases), followed by acute dystonia (2), tardive dyskinesia (2), and akathisia (1). The onset ranged from 9 to 164 days postlevosulpiride initiation. Most patients improved post-withdrawal. Fixed-dose combinations were implicated in prolonged exposure. Conclusion Levosulpiride, even at therapeutic doses, can cause significant and sometimes persistent extrapyramidal symptoms. This case series underscores the importance of restricting its use to short durations, monitoring for neurological symptoms, and educating both prescribers and patients. Regulatory action against inappropriate FDCs and improved pharmacovigilance reporting are warranted to ensure safer therapeutic outcomes. Recommendations Use levosulpiride short-term with regular neurological checks. Educate patients and caregivers to recognize early symptoms. Avoid high-risk groups. Prefer safer alternatives. Stop immediately if EPS occurs. Report to pharmacovigilance. Avoid unnecessary fixed-dose combinations.

2025, Journal of Pharmacy and Pharmacology

Overexpression of P-glycoprotein (P-gp) by tumours results in multidrug resistance (MDR) to structurally and functionally unrelated chemotherapeutic drugs. Combined therapy with MDR-related cytotoxins and MDR modulators is a promising strategy to overcome clinical MDR. This study was performed to explore the MDR reversal activity of a novel compound 2-[4-(2-pyridin-2-yl-vinyl) phenyl]-4,5-bis-(4-N,N-diethylaminophenyl)-1(H)-imidazole (FG020318) in-vitro and in-vivo. Tetrazolium (MTT) assay was used to evaluate the ability of FG020318 to reverse drug resistance in two P-gp-expressing tumour cell lines, KBv200 and MCF-7/adr. Intracellular doxorubicin accumulation was determined by fluorescence spectrophotometry in MCF-7/adr cell line. The effect of FG020318 on P-gp function was demonstrated by rhodamine 123 (Rh123) accumulation in KBv200 cells. KBv200 cell xenograft models were established to study the in-vivo effect of FG020318 on reversing MDR. FG020318 was not cytotoxic by itself a...

2025, PLOS ONE

Experimental studies have identified a complex link between neurodegeneration, b-amyloid (Ab) and calcium homeostasis. Here we asked whether early phase b-amyloid pathology in transgenic hAPP SL mice exaggerates the ischemic lesion and remote secondary pathology in the thalamus, and whether a non-selective calcium channel blocker reduces these pathologies. Transgenic hAPP SL (n = 33) and non-transgenic (n = 30) male mice (4-5 months) were subjected to unilateral cortical photothrombosis and treated with the non-selective calcium channel blocker bepridil (50 mg/kg, p.o., once a day) or vehicle for 28 days, starting administration 2 days after the operation. Animals were then perfused for histological analysis of infarct size, Ab and calcium accumulation in the thalamus. Cortical photothrombosis resulted in a small infarct, which was associated with atypical Ab and calcium accumulation in the ipsilateral thalamus. Transgenic mice had significantly smaller infarct volumes than non-transgenic littermates (P,0.05) and ischemia-induced rodent Ab accumulation in the thalamus was lower in transgenic mice compared to non-transgenic mice (P,0.01). Bepridil decreased calcium load in the thalamus (P,0.01). The present data suggest less pronounced primary and secondary pathology in hAPP SL transgenic mice after ischemic cortical injury. Bepridil particularly decreased calcium pathology in the thalamus following ischemia.

2025, Pan African Medical Journal

Introduction: Uncontrolled hypertension is a leading modifiable risk factor for cardiovascular disease morbidity and mortality. Data on adequacy of blood pressure control in Kenya is scarce. This study aimed at assessing the level of blood pressure control among hypertensive patients on follow-up in a regional referral hospital. Methods: Data regarding blood pressure, antihypertensive medication use, and comorbidities was abstracted from medical records of 452 hypertensive patients seen in Nyeri Provincial General Hospital between January and March 2013. Adequate blood pressure control was defined as a systolic pressure < 140 mmHg (< 130 mmHg for diabetic hypertensive patients) and a diastolic pressure < 90 mmHg (< 80 mmHg for diabetic hypertensive patients). Data was entered and analyzed using STATA 9 (StataCorp, Inc, Texas, USA). Results: Only 33.4% of patients had a blood pressure within the recommended limits. In multivariate analysis, using a calcium channel blocker was significantly associated with good blood pressure control (OR, 2.1; 95% CI, 1.4, 3.3). On the other hand, old age (≥ 60 years), being diabetic, and the use of three or more antihypertensive drugs were associated with reduced odds of good blood pressure control (OR, 0.64; 95% CI, 0.43; OR, 0.54; 95% CI, 0.36, 0.81; and OR, 0.41; 95% CI, 0.26, 0.64, respectively). Conclusion: Poorly controlled blood pressure is an important public health concern among hypertensive patients in this region. Elderly patients, those with diabetes, and those on multidrug regimens are at higher risk for poor blood pressure control and warrant closer attention.

2025, Academic Emergency Medicine

Objectives: Recent animal research and clinical case reports suggest benefit from high-dose insulin therapy (HDIT) for the treatment of calcium channel blocker (CCB) toxicity. One molecular signaling pathway, the phosphatidylinositol 3-kinase (PI3K) pathway, that contributes to CCB toxicity and the efficacy of HDIT, was examined for a role in this phenomenon. Methods: A differentiated 3T3-L1 adipocyte model system was utilized to characterize metabolic and molecular signaling events dysregulated in response to acute CCB toxicity. Glucose uptake assays were performed in the presence of representatives of three classes of CCB drugs, and the ability of HDIT to reverse observed inhibition was assessed. Western blot analyses were utilized to probe which insulindependent signaling pathway was inhibited by CCB toxicity. Results: Representative compounds from the dihydropyridine and phenylalkylamine classes of CCBs were more effective at inhibiting glucose uptake in differentiated 3T3-L1 adipocytes than a representative from the benzothiazepine class. Phosphorylation at serine 473 of the Akt protein (P-Akt), a protein representing a common pathway for insulin receptors (IR), insulinlike growth factor receptors (IGFR), and hybrid receptors formed by IR and IGFR subunits, was abolished in the presence of toxic doses of the phenylalkylamine CCB verapamil. Phosphorylation at serine 473 of Akt was rescued in the presence high concentrations of insulin. Conclusions: These data suggest that dysregulation of the insulin-dependent PI3K pathway is partially responsible for insulin resistance and the hyperglycemic state observed in response to acute CCB toxicity.

2025, The Journal of Neuroscience

The identification of the molecular mechanisms involved in nicotine addiction and its cognitive consequences is a worldwide priority for public health. Novelin vivoparadigms were developed to match this aim. Although the β2 subunit of the neuronal nicotinic acetylcholine receptor (nAChR) has been shown to play a crucial role in mediating the reinforcement properties of nicotine, little is known about the contribution of the different α subunit partners of β2 (i.e., α4 and α6), the homo-pentameric α7, and the brain areas other than the ventral tegmental area (VTA) involved in nicotine reinforcement. In this study, nicotine (8.7–52.6 μg free base/kg/inf) self-administration was investigated with drug-naive mice deleted (KO) for the β2, α4, α6 and α7 subunit genes, their wild-type (WT) controls, and KO mice in which the corresponding nAChR subunit was selectively re-expressed using a lentiviral vector (VECmice). We show that WT mice, β2-VECmice with the β2 subunit re-expressed exclusiv...

2025, The Journal of Immunology

Ca2+ mobilization is central to many cellular processes, including stimulated exocytosis and cytokine production in mast cells. Using single cell stimulation by IgE-specific Ag and high-speed imaging of conventional or genetically encoded Ca2+ sensors in rat basophilic leukemia and bone marrow-derived rat mast cells, we observe Ca2+ waves that originate most frequently from the tips of extended cell protrusions, as well as Ca2+ oscillations throughout the cell that usually follow the initiating Ca2+ wave. In contrast, Ag conjugated to the tip of a micropipette stimulates local, repetitive Ca2+ puffs at the region of cell contact. Initiating Ca2+ waves are observed in most rat basophilic leukemia cells stimulated with soluble Ag and are sensitive to inhibitors of Ca2+ release from endoplasmic reticulum stores and to extracellular Ca2+, but they do not depend on store-operated Ca2+ entry. Knockdown of transient receptor potential channel (TRPC)1 and TRPC3 channel proteins by short hai...

2025, Annals of the New York Academy of Sciences

2025, Circulation Research

Aortic smooth muscle isolated from spontaneously hypertensive rats (SHR) and normotensive, age-matched Wistar Kyoto rats (WKY) was precontracted by potassium chloride. The relaxant effect of nifedipine (NIF) was much more pronounced in SHR than in WKY, while the relaxation produced by nitroglycerin (NTG) was similar in both tissues. EC50s were (in - log [M]) NIF:SHR 13.1 +/- 0.4 and WKY 9.4 +/- 0.2 (p less than 0.05); NTG:SHR 7.35 +/- 0.3 and WKY 7.26 +/- 0.18 (NS). Aortas from SHR were less sensitive to the contractile effect of Ca2+ than their WKY controls (EC50 was 3.18 +/- 0.03 in WKY and 2.76 +/- 0.13 in SHR, p less than 0.05). The relaxant effect of NIF was dissociated from its effect on Ca2+ influx in SHR aortas. NIF 10(-10) M relaxed the muscle by 100% without producing Ca2+ influx blockage, and NIF 10(-9) and 10(-8) M induced Ca2+ influx blockage while the muscle continued in the relaxed state. Chemically skinned aortic fibers from SHR were less sensitive to the contractile...