Channel Blocker Research Articles

Характеристика факторів серцево-судинного ризику в пацієнтів з артеріальною гіпертензією, які приймають подвійну комбінацію антигіпертензивних препаратів: результати дослідження ФАКТОР-дуо

The aim – to study the characteristics of cardiovascular risk factors, the structure and effectiveness of treatment in hypertensive patients (pts) on the background of a dual combination of antihypertensive drugs, to evaluate the efficacy and tolerability of calcium channel blockers (CCB) (amlodipine and lercanidipine) when added to the combination of renin-angiotensin-aldosterone system (RAAS) inhibitor with a diuretic.Materials and methods. A multicenter study with 1616 hypertensive pts who received dual combination antihypertensive therapy. Cardiovascular risk factors were studied (smoking status, alcohol consumption, physical activity, family history of cardiovascular disease), concomitant cardiovascular diseases, carbohydrate metabolism disorders, and body mass index were determined, and current antihypertensive therapy and its effectiveness were evaluated based on office blood pressure (BP) measurements. Amlodipine 5-10 mg/day or lercanidipine 10–20 mg/day was added to the combination of RAAS blocker with a diuretic in the case of office BP ≥ 140/90 mm Hg. 1198 hypertensive pts received triple combined therapy. The effectiveness and tolerability of the treatment were evaluated after 4 weeks according to data from office BP measurements and home BP monitoring (HBPM). Lercanidipine was taken by 76 % of pts and amlodipine was taken by 24 % of pts.Results and discussion. Hypertensive pts were characterized by a significant prevalence of obesity (38.6 %), smoking (27.9 %), and insufficient physical activity (31.2 %). A significantly higher percentage of smoking and alcohol consumption was registered among men, while a lower level of physical activity was registered among women. Concomitant type 2 diabetes was present in almost a quarter of pts, stroke/TIA in 8.7 %, and myocardial infarction/revascularization in 8.3 %. At the same time, 53.2 % of the pts received statin therapy, and 64.7 % received antiplatelet drugs.Conclusions. The addition of CCB contributed to office BP target achievement in 69.1 % of pts, and optimal BP according to HBPM data in 54.3 % of pts. Lercanidipine and amlodipine have demonstrated comparable antihypertensive efficacy. Lercanidipine demonstrated a better tolerability profile compared to amlodipine: the incidence of side effects was significantly lower, respectively, 3.6 vs. 12.3 %; edema of the lower legs occurred in 6.5 times more often under amlodipine treatment than lercanidipine.

Pharmacological management of prolonged seizures in Dravet syndrome including intravenous phenytoin.

Dravet syndrome (DS) is an infantile onset developmental and epileptic encephalopathy. Sodium channel blockers are known to exacerbate seizures in this syndrome. Due to its high incidence, the management of prolonged seizures is crucial for DS patients. There is still ambiguity regarding the use of intravenous phenytoin for prolonged seizure in DS patients mainly due to the lack of data, raising concern about the safety of it use. We conducted a retrospective study (from January 2009 to January 2020) aiming to assess the management of prolonged seizures in DS with a focus on the use of intravenous phenytoin. Data were collected for patients admitted to our hospital for seizures lasting >5 min. Among 52 identified patients in our database, 23 experienced 59 prolonged seizures managed in our hospital. Only four seizures ceased without rescue medication. Notably, the use of intravenous phenytoin was not associated with discernible adverse effects and was effective in stopping status epilepticus in 71% of cases. This study suggests the safety and efficacy of intravenous phenytoin for prolonged seizure in DS. There is a need for broader investigations of emergency treatments for evidence-based recommendations for the emergency plan of each patient.

Use of antihypertensive agents and its present perspective: an observational retrospective study

Objectives: To evaluate the utilization of antihypertensive agents for the patients of Hypertension and subsequently their health outcome at a Tertiary Care Level Hospital and to observe the relationship among demographic profile of the patients. Materials and Methods: An observational retrospective study was undertaken collecting total 680 patients’ data from patient admission ticket of a Tertiary Care Level Hospital. Mainly drugs used and outcome of the patients were recorded. Of all patients 306 were found to be treated with calcium channel blockers (CCBs), 77 with angiotensin receptor blockers (ARBs), 229 with CCBs plus ARBs, 46 with CCBs plus ARBs and beta blockers and only 22 patients got CCBs, ARBs and diuretics. Data were statistically analysed in respect of demographic profile, drugs used and clinical features of the patients. Results: Best outcome was observed in patients treated with solely CCBs where in 289 out of 306 patients, hypertension was controlled. 194 out of 229 patients with CCBs and ARBs showed desired outcomes. 41 out of 77 with only ARBs, 29 out of 46 with CCBs, ARBs and beta blockers and 16 out of 22 with CCBs, ARBs and diuretics ended with positive results. Conclusion: Calcium channel blockers alone and in few cases in combination with angiotensin receptor blocking agents are very effective in controlling hypertension. Keywords: Hypertension, calcium channel blockers and angiotensin receptor blockers

Evaluation of SK-N-SH Cells as a Model for NMDA Receptor Induced Toxicity.

Over the years, the number of patients with neurodegenerative diseases is constantly rising illustrating the need for new neuroprotective drugs. A promising treatment approach is the reduction of excitotoxicity induced by rising (S)-glutamate levels and subsequent NMDA receptor overactivation. To facilitate the search for new NMDA receptor inhibitors neuronal cell models are needed. In this study, we evaluated the suitability of human SK-N-SH cells to serve as a cell model for neurodegeneration induced by NMDA receptor overstimulation. The cytoprotective effect of the unselective NMDA receptor blocker ketamine as well as the GluN2B-selective inhibitor WMS14-10 was evaluated utilizing different cell viability assays, such as endpoint (LDH, CCK-8, DAPI/FACS) and time dependent methods (bioimpedance). Non-differentiated as well as differentiated SK-N-SH cells express GluN1 and GluN2B subunits. Furthermore, 50 mM (S)-glutamate led to an instantaneous decrease in cell survival. Only application of unselective channel blocker ketamine could protect differentiated cells against this effect, while the selective inhibitor WMS14-10 did not significantly increase cell survival. SK-N-SH cells show an increased sensitivity to (S)-glutamate mediated cytotoxicity with higher differentiation level, that is only partially induced by NMDA receptor overstimulation. Furthermore, we showed that only unselective NMDA receptor inhibition can partially reverse (S)-glutamate-induced toxicity.

Simultaneous use of venlafaxine and calcium channel blockers on tolerance to morphine: The role of mitochondrial damage and oxidative stress in the brain

BackgroundOne of the reasons for tolerance to morphine is increased oxidative stress and dysfunction of cell mitochondria in the hippocampus. Venlafaxine and calcium channel blockers can protect mitochondrial function. The investigation of the role of mitochondrial damage and oxidative stress in the simultaneous use of venlafaxine and calcium channel blockers on the acute analgesic effects of morphine and the induction of tolerance to its effects in mice was assessed. MethodIn this experimental study, to induce tolerance to morphine, NMRI mice were treated with 50 mg/kg morphine for three consecutive days and 5 mg/kg morphine on the fourth day. Venlafaxine (20 mg/kg) alone or in combination with calcium channel blockers, nimodipine (10 mg/kg), and diltiazem (40 mg/kg) was administered 30 min before morphine, and the hot plate test was used. Then, hippocampal mitochondria were isolated by differential centrifugation method, and the levels of mitochondrial dehydrogenase activity, mitochondrial membrane potential, mitochondrial ROS production rate, as well as the content of glutathione and malondialdehyde in hippocampal mitochondria, were measured. ResultsThe administration of venlafaxine-nimodipine and venlafaxine-diltiazem increased morphine's acute analgesic effects (P < 0.05) and reduced the induction and expression of tolerance to the analgesic effects of morphine (P < 0.05). Morphine significantly decreased MTT and GSH and increased MDA, mitochondrial membrane damage, and ROS compared to the control group (P < 0.01). Injection of venlafaxine-nimodipine and also venlafaxine-diltiazem 30 min before morphine can improve these alterations (P < 0.05). Discussion and conclusionOur data showed that the simultaneous use of venlafaxine with calcium channel blockers could increase the acute analgesic effects of morphine and reduce the induction and expression of tolerance to it. Also, the preventive and protective roles of simultaneous administration of venlafaxine and calcium channel blockers on morphine-induced mitochondrial oxidative stress and damage during the tolerance test were achieved.

Obstructive sleep apnea -related hypertension: a review of the literature and clinical management strategy.

Obstructive Sleep Apnea (OSA) and hypertension have a high rate of co-occurrence, with OSA being a causative factor for hypertension. Sympathetic activity due to intermittent hypoxia and/or fragmented sleep is the most important mechanisms triggering the elevation in blood pressure in OSA. OSA-related hypertension is characterized by resistant hypertension, nocturnal hypertension, abnormal blood pressure variability, and vascular remodeling. In particular, the prevalence of OSA is high in patients with resistant hypertension, and the mechanism proposed includes vascular remodeling due to the exacerbation of arterial stiffness by OSA. Continuous positive airway pressure therapy is effective at lowering blood pressure, however, the magnitude of the decrease in blood pressure is relatively modest, therefore, patients often need to also take antihypertensive medications to achieve optimal blood pressure control. Antihypertensive medications targeting sympathetic pathways or the renin-angiotensin-aldosterone system have theoretical potential in OSA-related hypertension, Therefore, beta-blockers and renin-angiotensin system inhibitors may be effective in the management of OSA-related hypertension, but current evidence is limited. The characteristics of OSA-related hypertension, such as nocturnal hypertension and obesity-related hypertension, suggests potential for angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucose-dependent insulinotropic polypeptide receptor/ glucagon-like peptide-1 receptor agonist (GIP/GLP-1 RA). Recently, OSA has been considered to be caused not only by upper airway anatomy but also by several non-anatomic mechanisms, such as responsiveness of the upper airway response, ventilatory control instability, and reduced sleep arousal threshold. Elucidating the phenotypic mechanisms of OSA may potentially advance more personalized hypertension treatment strategies in the future. Clinical characteristics and management strategy of OSA-related hypertension. OSA obstructive sleep apnea, BP blood pressure, ABPM ambulatory blood pressure monitoring, CPAP continuous positive airway pressure, LVH left ventricular hypertrophy, ARB: angiotensin II receptor blocker, SGLT2i Sodium-glucose cotransporter 2 inhibitors, ARNI angiotensin receptor-neprilysin inhibitor, CCB calcium channel blocker, GIP/GLP-1 RA glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist.

Definition, classification and diagnosis of pulmonary hypertension.

Pulmonary hypertension (PH) is a haemodynamic condition characterised by elevation of mean pulmonary arterial pressure (mPAP) >20 mmHg, assessed by right heart catheterisation. Pulmonary arterial wedge pressure (PAWP) and pulmonary vascular resistance (PVR) distinguish pre-capillary PH (PAWP ≤15 mmHg, PVR >2 Wood Units (WU)), isolated post-capillary PH (PAWP >15 mmHg, PVR ≤2 WU) and combined post- and pre-capillary PH (PAWP >15 mmHg, PVR >2 WU). Exercise PH is a haemodynamic condition describing a normal mPAP at rest with an abnormal increase of mPAP during exercise, defined as a mPAP/cardiac output slope >3 mmHg/L/min between rest and exercise. The core structure of the clinical classification of PH has been retained, including the five major groups. However, some changes are presented herewith, such as the re-introduction of "long-term responders to calcium channel blockers" as a subgroup of idiopathic pulmonary arterial hypertension, the addition of subgroups in group 2 PH and the differentiation of group 3 PH subgroups based on pulmonary diseases instead of functional abnormalities. Mitomycin-C and carfilzomib have been added to the list of drugs with "definite association" with PAH. For diagnosis of PH, we propose a stepwise approach with the main aim of discerning those patients who need to be referred to a PH centre and who should undergo invasive haemodynamic assessment. In case of high probability of severe pulmonary vascular disease, especially if there are signs of right heart failure, a fast-track referral to a PH centre is recommended at any point during the clinical workup.

Discovery of New Highly Potent Histamine H3 Receptor Antagonists, Calcium Channel Blockers, and Acetylcholinesterase Inhibitors.

At present, one of the most promising strategies to tackle the complex challenges posed by Alzheimer's disease (AD) involves the development of novel multitarget-directed ligands (MTDLs). To this end, we designed and synthesized nine new MTDLs using a straightforward and cost-efficient one-pot Biginelli three-component reaction. Among these newly developed compounds, one particular small molecule, named 3e has emerged as a promising MTDL. This compound effectively targets critical biological factors associated with AD, including the simultaneous inhibition of cholinesterases (ChEs), selective antagonism of H3 receptors, and blocking voltage-gated calcium channels. Additionally, compound 3e exhibited remarkable neuroprotective activity against H2O2 and Aβ1-40, and effectively restored cognitive function in AD mice treated with scopolamine in the novel object recognition task, confirming that this compound could provide a novel and innovative therapeutic approach for the effective treatment of AD.

Discovery of selective Orai channel blockers bearing an indazole or a pyrazole scaffold

The calcium release activated calcium (CRAC) channel is highly expressed in T lymphocytes and plays a critical role in regulating T cell proliferation and functions including activation of the transcription factor nuclear factor of activated T cells (NFAT), cytokine production and cytotoxicity. The CRAC channel consists of the Orai pore subunit and STIM (stromal interacting molecule) endoplasmic reticulum calcium sensor. Loss of CRAC channel mediated calcium signaling has been identified as an underlying cause of severe combined immunodeficiency (SCID), leading to drastically weakened immunity against infections. Gain-of-function mutations in Orai and STIM have been associated with tubular aggregated myopathy (TAM), a skeletal muscle disease. While a number of small molecules have shown activity in inhibiting the CRAC signaling pathway, the usefulness of those tool compounds is limited by their off-target activity against TRPM4 and TRPM7 ion channels, high lipophilicity, and a lack of understanding of their mechanism of action. We report structure-activity relationship (SAR) studies that resulted in the characterization of compound 4k [1-(cyclopropylmethyl)-N-(3-fluoropyridin-4-yl)-1H-indazole-3-carboxamie] as a fast onset, reversible, and selective CRAC channel blocker. 4k fully blocked the CRAC current (IC50: 4.9 μM) and the nuclear translocation of NFAT at 30 and 10 μM, respectively, without affecting the electrophysiological function of TRPM4 and TRPM7 channels. Computational modeling appears to support its direction binding to Orai proteins that form the transmembrane CRACchannel.

The Safety of Calcium Channel Blockers in Controlling Blood Pressure During Cardiac Surgery: A Meta-analysis of Random Controlled Trials

Background: Intraoperative hypertension is a very common critical condition in cardiac surgery, which may lead to myocardial ischemia, affect the smooth progress of the operation, and even lead to the death of the patient. Therefore, it is necessary to manage perioperative hypertension in cardiac surgery. At present, there are various types of drugs for hypertension control in clinical practice, and it is necessary to select vasoactive drugs suitable for cardiac surgery. Methods: A systematic search was conducted in PubMed (Medline), Embase, and the Cochrane Library databases to compare the safety of calcium channel blockers and other antihypertensive drugs in controlling hypertension during cardiac surgery, with the search ending in July 2024. For continuous variables, we utilized combined weighted mean difference (WMD) with a 95% confidence interval (CI) and risk ratio (RR) with a 95% confidence interval to assess both efficacy and safety. Results: A total of six randomized controlled trials were included, with a total of 1886 patients. There was no significant difference in mortality between calcium channel blockers and other vasodilators (RR=0.75, 95% CI: 0.45,1.26, P =0.28; I2=0%, P=0.75). Also, there was no significant difference in the incidence of atrial fibrillation (RR=1.09, 95% CI: 0.94,1.26, P=0.26; I2=13%, P=0.33). In addition, there were no significant differences in the incidence of myocardial infarction (RR=0.76, 95% CI: 0.41,1.39, P=0.37; I2=0%, P=0.55) and renal insufficiency (RR=0.92, 95% CI: 0.65,1.31, P=0.66; I2=40%, P=0.19) between the two groups. Finally, there was no significant difference in the incidence of total adverse events between the two groups (RR=1.05, 95% CI: 0.87,1.27, P=0.60; I2=0%, P=0.68). Conclusion: Compared with other vasodilators, there is no significant difference in the safety of calcium channel blockers in controlling blood pressure in cardiac surgery.

Genetic Insights Into Perinatal Outcomes of Maternal Antihypertensive Therapy During Pregnancy

Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended fetal harm. Yet, maternal prescriptive drug use for chronic conditions such as hypertension is common. To investigate potential causal relationships between perturbing maternal genetic variants influencing antihypertensive drug targets and perinatal outcomes among offspring using mendelian randomization (MR). This 2-sample MR study used individual-level single-nucleotide variation (SNV) outcome data from mother-father-offspring trios with complete genetic and phenotypic information from the Norwegian Mother, Father and Child Cohort Study (MoBa) and summary-level SNV exposure data from UK Biobank participants sourced from the Integrative Epidemiology Unit OpenGWAS project. Pregnant individuals were recruited across Norway during their routine ultrasonography examination at 18 weeks' gestation between June 1999 and December 2008, and mothers, fathers, and offspring were followed up after birth. Novel genetic instruments for maternal antihypertensive drug targets that act via systolic blood pressure (SBP) were derived from individual-level data analyzed in January 2018. Two-sample multivariable MR analysis of these maternal drug targets and offspring outcomes were performed between January 2023 and April 2024. Maternal genetic variants associated with drug targets for treatments of hypertension, as specified in the National Health Service dictionary of medicines and devices. Offspring outcomes were Apgar score at 1 minute and 5 minutes, offspring developmental score at 6 months, birth length, birth weight z score, gestational age, head circumference, and congenital malformation. Maternal hypertensive disorders of pregnancy were a positive control. The MoBa sample contained 29 849 family trios, with a mean (SD) maternal age of 30.2 (18.6) years and a mean (SD) paternal age of 32.8 (13.1) years; 51.1% of offspring were male. Seven independent SNVs were identified as influencing maternal SBP via the antihypertensive drug target instruments. For higher levels of maternal SBP acting through the CACNB2 calcium channel blocker target, the estimated change in gestational age was 3.99 days (95% CI, 0.02-7.96 days) per 10-mm Hg decrease in SBP. There was no evidence of differential risk for measured perinatal outcomes from maternal SBP acting through drug targets for multiple hypertensive subclasses, such as between the ADRB1 β-adrenoceptor-blocking target and risk of congenital malformation (estimated odds ratio, 0.28 [95% CI, 0.02-4.71] per 10-mm Hg decrease in SBP). Maternal and paternal SBP acting through the EDNRA vasodilator antihypertensive target did not have a potential causal effect on birth weight z score, with respective β estimates of 0.71 (95% CI, -0.09 to 1.51) and 0.72 (95% CI, -0.08 to 1.53) per 10-mm Hg decrease in SBP. The findings provided little evidence to indicate that perturbation of maternal genetic variants for SBP that influence antihypertensive drug targets had potential causal relationships with measures of perinatal development and health within this study. These findings may be triangulated with existing literature to guide physicians and mothers in decisions about antihypertensive use during pregnancy.

The KCa3.1 channel blocker TRAM-34 and minocycline prevent fructose-induced hypertension in rats.

High fructose consumption increases blood pressure through microglia-related neuroinflammation in rats. Since intermediate-conductance calcium-activated potassium channels (KCa3.1) potentiates microglial reactivity, we examined whether the pretreatment with the KCa3.1 channel blocker TRAM-34 or minocycline prevents hypertension development in fructose-fed rats. The study involved male Wistar rats that were given either a high fructose (10% in drinking water) or a tap water for 21 days. Fructose groups also received minocycline or TRAM-34 systemically for 21 days. We measured systolic and diastolic blood pressure (SBP and DBP), heart rate (HR) periodically with tail-cuff; proinflammatory cytokines and insulin levels in plasma via ELISA, and neuroinflammatory markers in the nucleus tractus solitarii (NTS) by qPCR at the end of 21 days. We also examined endothelium-dependent hyperpolarization (EDH)-type vasorelaxations in isolated mesenteric arteries of the rats ex vivo. SBP, DBP, and HR increased in the fructose group. Both minocycline and TRAM-34 significantly prevented these increases. Fructose intake also increased plasma IL-6, IL-1β, TNF-α, and insulin levels, whereas pretreatment with TRAM-34 prevented these increases as well. Iba-1, but not CD86 levels were significantly higher in the NTS samples of fructose-fed hypertensive rats which implied microglial proliferation. EDH-type vasorelaxations mediated by endothelial KCa3.1 attenuated in the fructose group; however, TRAM-34 did not cause further deterioration in the relaxations. TRAM-34 is as effective as minocycline in preventing fructose-induced hypertension without interfering with the EDH-type vasodilation. Furthermore, TRAM-34 relieves high fructose-associated systemic inflammation.

Nicardipine-chitosan nanoparticles alleviate thioacetamide-induced acute liver injury by targeting NFκB/NLRP3/IL-1β signaling in rats: Unraveling new roles beyond calcium channel blocking

Liver inflammatory diseases are marked by serious complications. Notably, nicardipine (NCD) has demonstrated anti-inflammatory properties, but its benefits in liver inflammation have not been studied yet. However, the therapeutic efficacy of NCD is limited by its short half-life and low bioavailability. Therefore, we aimed to evaluate the potential of NCD-loaded chitosan nanoparticles (ChNPs) to improve its pharmacokinetic profile and hepatic accumulation. Four formulations of NCD-ChNPs were synthesized and characterized. The optimal formulation (NP2) exhibited a mean particle diameter of 172.6 ± 1.94 nm, a surface charge of +25.66 ± 0.93 mV, and an encapsulation efficiency of 88.86 ± 1.17 %. NP2 showed good physical stability as a lyophilized powder over three months. It displayed pH-sensitive release characteristics, releasing 77.15 ± 5.09 % of NCD at pH 6 (mimicking the inflammatory microenvironment) and 52.15 ± 3.65 % at pH 7.4, indicating targeted release in inflamed liver tissues. Pharmacokinetic and biodistribution studies revealed that NCD-ChNPs significantly prolonged NCD circulation time and enhanced its concentration in liver tissues compared to plain NCD. Additionally, the study investigated the protective effects of NCD-ChNPs in thioacetamide-induced liver injury in rats by modulating the NFκB/NLRP3/IL-1β signaling axis. NCD-ChNPs effectively inhibited NFκB activation, reduced NLRP3 inflammasome activation, and subsequent release of IL-1β, which correlated with improved hepatic function and reduced inflammation and oxidative stress. These findings highlight the potential of NCD-ChNPs as a promising nanomedicine strategy for the treatment of liver inflammatory diseases, warranting further investigation into their clinical applications, particularly in hypertensive patients with liver inflammatory conditions.

Intravenous Lidocaine Response as a Predictor for Oral Oxcarbazepine Efficacy in Neuropathic Pain Syndrome: A Prospective Cohort Study.

BACKGROUND Providing pain relief for patients with neuropathic pain syndrome (NPS) is difficult, as sodium-channel blockers pose serious adverse events (AEs). Intravenous (i.v.) lidocaine infusion responses may identify patients likely to benefit from oral sodium channel blockers. We evaluated i.v. lidocaine responses to predict oral oxcarbazepine (OXC) efficacy in patients with NPS. MATERIAL AND METHODS This prospective cohort study administered one-time 3 mg/kg i.v. lidocaine infusion to patients with NPS. Numeric rating scale (NRS) pain scores and AEs were observed. Next, OXC 150 mg was prescribed; dosages were increased by 150 mg every 3 days until ≥50% pain reduction or the maximum tolerable dose or 1800 mg/day was reached. NRS, rescue drug requirements, and AEs were evaluated by phone at 1, 3, and 5 weeks and clinic visits at 2, 4, and 6 weeks. Depression, Anxiety &amp; Stress Scales 21 (DASS-21), and EuroQol-Five Dimensions-Five Levels (EQ-5D-5L) questionnaires were assessed at baseline and in week 6. RESULTS Of 46 patients, 14 discontinued due to intolerable AEs, and 32 were in the final analysis. Average post-intervention NRS significantly decreased from 6.8±1.7 (baseline) to 3.8±2.0 (lidocaine) and 4.1±2.3 (OXC); P<0.001. Negative and positive predictive values for OXC efficacy were 76.2% (95% CI: 61.6-86.5%) and 54.5% (95% CI: 32-75.4%), respectively. Six weeks after OXC treatment, 20 and 11 patients achieved ≥30% pain reduction and ≥50% pain relief, respectively. EQ-5D-5L (P=0.018) and DASS-21 stress dimension (P<0.001) significantly improved. CONCLUSIONS Negative responses to i.v. lidocaine predicted a lack of oral OXC response. AEs of OXC may have obscured an analgesic effect.

FEATURES OF DRUG-DRUG INTERACTIONS BETWEEN RIVAROXABAN AND P-GLYCOPROTEIN INHIBITOR DEPENDING ON CYP3A4/A5 GENE POLYMORPHISM IN PATIENTS 80 YEARS AND OLDER WITH NONVALVULAR ATRIAL FIBRILLATION

Abstract Introduction. Increased risk of bleeding associated with rivaroxaban administration is associated with polymorphism of genes involved in its biotransformation, as well as with the use of drugs that inhibit common metabolic pathways. However, the data are contradictory. Objective of the work.To study the features of drug-drug interactions between rivaroxaban and a P-glycoprotein inhibitor (using verapamil as an example) depending on the polymorphism of the CYP3A4 (rs35599367)and CYP3A5 (rs776746)genes in patients aged 80 years and older with non-valvular atrial fibrillation. Material and methods. A total of 128 patients (median age 87.5 years [83-90 years], 75% women) were examined. All patients underwent genotyping for the studied polymorphisms, determination of the minimum steady-state concentration of rivaroxaban (Cmin,ss), standardization of the minimum steady-state concentration of rivaroxaban per daily dose (Cmin,ss /D), determination of prothrombin time (PT) in plasma, and analysis of medical records for the presence of clinically relevant non-major bleeding (CRNMB). Results.Co-administration of rivaroxaban with verapamil compared with patients receiving rivaroxaban without calcium channel blockers in CYP3A4gene CC carriers resulted in higher values of Cmin,ss(73.8 [49-113.5] vs 40.5 [25.6-73.3] ng/ml), Cmin,ss /D (2.5 [1.7-4.0] vs 4.7 [2.9-7.7] ng/ml/mg), PT (14.8 [13.3-17.3] vs 14.0 [12.6-14.5] sec) and CRNMB (10/30 (33.3%) vs 6/45 (13.3%) cases), (p0.05). In carriers of the GG gene, CYP3A5resulted in higher values of Cmin,ss (74.7 [50.6-108.8] vs 40.2 [25.7-72.3] ng/ml), Cmin,ss /D 4.6 [3.0-7.3] vs 2.5 [1.7-4.0] ng/ml/mg), PT (14.6 [12.8-15.2] vs 14.0 [12.6-14.5] sec) and CRNMB (10/27 (37%) vs 5/40 (12.5%) cases), (p0.05). And in GA+AA carriers of the CYP3A5gene, it resulted in higher values of Cmin,ss (88.1 [5.5-88.1] vs 52.8 [25.0-77.2] ng/ml), Cmin,ss /D 5.7 [0.4-5.7] vs 3.5 [1.7-5.2] ng/ml/mg), (p0.05). In CT carriers of the CYP3A4 gene, the combined use of rivaroxaban with verapamil was not observed in our sample. Conclusions:Carriers of the homozygous wild-type CYP3A4/A5 genotype showed high pharmacokinetic variability to verapamil (a strong P-glycoprotein inhibitor and a moderate CYP3A4 inhibitor).

Identifying potential repurposable medications for Parkinson’s disease through Mendelian randomization analysis

Observational studies have suggested the potential benefits of several medications for Parkinson’s disease (PD) and their potential for repurposing. However, the conclusions drawn from these studies are not entirely consistent. To address this inconsistency, we used the two-sample Mendelian randomization (MR) method to explore the putative causal relationships between 23 medications and the risk and progression of PD. We applied inverse-variance weighted meta-analysis (IVW) to combine MR estimates. Additionally, sensitivity analyses were conducted to evaluate the robustness of the results. Our genetic evidence suggests that thyroid preparations and calcium channel blockers reduce the risk of PD, and salicylic acid and derivatives slow the progression of PD motor symptoms. Additionally, genetic evidence also suggests that four medications were associated with PD risk or progression, but the sensitivity analysis revealed that three of the medications may have interference caused by reverse causality. Our findings suggest that there are weak causal relationships between several medications and the risk or progression of PD. Though further replication studies are needed to verify these findings, these new insights may help in understanding the etiology of the disease, generate new clues related to drug discovery, and quantify the risk of future drug intake.

Purinergic control of apical ion conductance by luminal ATP in rat colonic epithelium

ATP, released e.g. after cell damage or during inflammation, can alter ion transport across the intestinal mucosa via stimulation of purinergic receptors in the basolateral as well as in the apical membrane of epithelial cells. When ATP acts from the serosal side, it induces an increase in short-circuit current (Isc) via Cl− secretion across the colonic epithelium. In contrast, mucosal ATP or its derivative, BzATP, predominantly stimulating ionotropic P2X4 and P2X7 receptors, evoke an increase in Isc, which could not be explained by Cl− secretion. The underlying ion currents after stimulation of apical purinergic receptors in rat distal colon are still unclear and were investigated in the present study.Ussing chamber experiments revealed that the Isc induced by mucosal ATP was dependent on the presence of mucosal Ca2+ and inhibited by the K+ channel blocker, Ba2+, indicating the involvement of Ca2+-dependent K+ channels. Blockade of the transepithelial Isc by lanthanides (La3+, Gd3+) suggests that Ca2+ enters the epithelium via nonselective cation channels. Experiments with basolaterally depolarized epithelia confirmed the activation of apical lanthanide-sensitive Na+- and Ca2+-permeable cation channels by ATP. Putative candidates might be TRP channels, from which several subtypes were detected in colonic tissue in RT-PCR experiments. In addition, the activation of an apical Cl− conductance was observed when suitable Cl− concentration gradients were applied. Consequently, mucosal ATP, acting as ‘danger signal’, stimulates cation and anion channels in the apical membrane to induce a secretory response as part of the local defence mechanism in the intestinal epithelium.

Evidence to support cultivated fruiting body of Ophiocordyceps sinensis (Ascomycota)'s role in relaxing airway smooth muscle

Ethnopharmacological relevanceOphiocordyceps sinensis (O. sinensis) is a genus of Ascomycete fungus that is endemic to the alpine meadows of the Tibetan Plateau and adjoining Himalayas. It has been used traditionally as a tonic to improve respiratory health in ancient China as well as to promote vitality and longevity. Bioactive components found in O. sinensis such as adenosine, cordycepin, 3-deoxyadenosine, L-arginine and polysaccharides have gained increasing interest in recent years due to their antioxidative and other properties, which include anti-asthmatic, antiviral, immunomodulation and improvement of general health. Aim of the studyThis study's primary aim was to investigate the effect of a cultivated fruiting body of O. sinensis strain (OCS02®) on airways patency and the secondary focus was to investigate its effect on the lifespan of Caenorhabditis elegans. Materials and methodsA cultivated strain, OCS02®, was employed and the metabolic profile of its cold-water extract (CWE) was analysed through liquid chromatography-mass spectrometry (LC-MS). Organ bath approach was used to investigate the pharmacological properties of OCS02® CWE when applied on airway tissues obtained from adult male Sprague-Dawley rats. The airway relaxation mechanisms of OCS02® CWE were explored using pharmacological tools, where the key regulators in airway relaxation and constriction were investigated. For the longevity study, age-synchronised, pos-1 RNAi-treated wild-type type Caenorhabditis elegans at the L4 stage were utilised for a lifespan assay. ResultsVarious glycopeptides and amino acids, particularly a high concentration of L-arginine, were identified from the LC-MS analysis. In airway tissues, OCS02® CWE induced a significantly greater concentration-dependent relaxation when compared to salbutamol. The relaxation response was significantly attenuated in the presence of NG-Nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ) and several K+ channel blockers. The longevity effect induced by OCS02® CWE (5 mg/mL and above) was observed in C. elegans by at least 17%. ConclusionsThese findings suggest that the airway relaxation mechanisms of OCS02® CWE involved cGMP-dependent and cGMP-independent nitric oxide signalling pathways. This study provides evidence that the cultivated strain of OCS02® exhibits airway relaxation effects which supports the traditional use of its wild O. sinensis in strengthening respiratory health.

WISNet: A deep neural network based human activity recognition system

Nowadays, Human Activity Recognition (HAR) is a key research area with many ubiquitous innovative solutions, where both accelerometer and gyroscope data provide information about an observed person’s physical activity. HAR offers a diverse variety of important applications, including healthcare, burglary detection, workplace monitoring, and emergency identification. Traditional recognition approaches rely on extracting handmade features from the obtained data to identify the typeof human action. Additionally, the efficacy of these works is dependent upon the specific customized features that are chosen. One potential approach to tackle this issue is to utilize Convolutional Neural Networks (CNN) to automatically learn the relevant features. In this paper, we propose a deep learning model, WISNet, a custom 1D-CNN approach to recognize six complex human activities: Jogging, Walking Downstairs, Sitting, Standing, Walking and Climbing Upstairs. The model includes a Convolved Normalized Pooled (CNPM) Block to generate significant features from the initial layers. An Identity and Basic (IDBN) Block is incorporated to extract residual progressive features for capturing complex sequential data dependencies. Channel and Spatial attention (CASb) Block is integrated with the network to prioritize or minimize essential features based on relative weights. The proposed WISNet model achieved an enhanced accuracy and F1-score of 96.41 % and 0.95 for the HAR dataset by surpassing the existing transfer learning architectures such as Gated Recurrent Units (GRU), Long Short-Term Memory (LSTM), and Recurrent Neural Network (SimpleRNN). By strategically integrating the CNPM, IDBN, and CASb blocks, this study aims to tackle distinct challenges encountered in the classification process by enhancing the discernment of features essential for the precise identification of multi-class human activity recognition. The seamless integration of these blocks within the model plays a pivotal role in elevating the overall performance of the WISNet architecture. The work also validates WISNet with similar open-source datasets (UCI-HAR and KU-HAR) and dissimilar open-source datasets (Sleep state detection, Fall detection, and ECG Heartbeat).

Differences in Healthcare Resource Use and Cost by Pharmacotherapy Among Patients with Symptomatic Obstructive Hypertrophic Cardiomyopathy: Real-World Analysis of Claims Data.

For symptomatic obstructive hypertrophic cardiomyopathy (oHCM), limited evidence exists on healthcare resource utilization (HRU) and cost for patients with symptomatic oHCM by treatment categories. We evaluated whether HRU and costs vary by initial treatment in symptomatic oHCM. This is a retrospective study of medical and pharmacy claims from 2016 to 2021 to identify (per International Classification of Disease Tenth Revision diagnosis codes) adult patients in the USA with symptomatic oHCM. Patients included in the study cohort were required to be treatment naïve (≥ 12 months' activity before first treatment) and symptomatic (fatigue, chest pain, syncope, dyspnea, heart failure, or palpitations within 3 months of index date). Patients were grouped by first index treatment [beta blocker (BB), calcium channel blockers (CCB), disopyramide, combination therapy], and HRU and costs [per person per year (PPPY), in USD] by initial treatment were reported. Among 7334 patients with symptomatic oHCM, initial treatment included BB (65.8%), CCB (21.1%), disopyramide (1.2%), or BB + CCB (11.9%). Overall, 87.2% were prescribed monotherapy. Outpatient visits were the main driver of all-cause HRU (mean 11.5 PPPY), and varied by initial treatment (BB: 11.0, CCB: 10.5, disopyramide: 7.2, combination therapy: 12.1). All-cause urgent care visits were more frequent than inpatient visits (means: 5.4 and 0.83 PPPY, respectively). All-cause incurred costs were $46,628 PPPY overall and varied by treatment (BB: $47,029, CCB: $42,124, disopyramide: $27,007, combination therapy: $54,024). In this large, US-based cohort of patients with symptomatic oHCM, initial therapy was most commonly BB and CCB monotherapy. Costs and HRU were high for most patients, but greater for those treated initially with combination therapy.