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1.
NPJ Syst Biol Appl ; 10(1): 22, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38429306

RESUMO

In the initial hours following the application of the calcium channel blocker (CCB) nifedipine to microtissues consisting of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we observe notable variations in the drug's efficacy. Here, we investigate the possibility that these temporal changes in CCB effects are associated with adaptations in the expression of calcium ion channels in cardiomyocyte membranes. To explore this, we employ a recently developed mathematical model that delineates the regulation of calcium ion channel expression by intracellular calcium concentrations. According to the model, a decline in intracellular calcium levels below a certain target level triggers an upregulation of calcium ion channels. Such an upregulation, if instigated by a CCB, would then counteract the drug's inhibitory effect on calcium currents. We assess this hypothesis using time-dependent measurements of hiPSC-CMs dynamics and by refining an existing mathematical model of myocyte action potentials incorporating the dynamic nature of the number of calcium ion channels. The revised model forecasts that the CCB-induced reduction in intracellular calcium concentrations leads to a subsequent increase in calcium ion channel expression, thereby attenuating the drug's overall efficacy. The data and fit models suggest that dynamic changes in cardiac cells in the presence of CCBs may be explainable by induced changes in protein expression, and that this may lead to challenges in understanding calcium based drug effects on the heart unless timings of applications are carefully considered.


Assuntos
Células-Tronco Pluripotentes Induzidas , Miócitos Cardíacos , Humanos , Bloqueadores dos Canais de Cálcio/farmacologia , Cálcio , Canais de Cálcio
2.
Sci Rep ; 14(1): 6355, 2024 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-38491009

RESUMO

We aim to determine the safety and efficacy of clevidipine for neurocritical patients. To comprehensively identify relevant studies, a systematic search strategy was employed using the following keywords: "clevidipine", "high blood pressure", "hypertension", "Neuroscience Intensive Care", "neuro critical", and "neurosurgical patients". Searches were conducted in the Clinicaltrials.gov, PubMed, and EuroPMC databases, with the search extending until September 1, 2023. The primary outcomes of interest were the time needed to achieve the target systolic blood pressure (SBP) and the percentage of time a patient remained within the targeted SBP range. Secondary outcomes included SBP values, duration of intensive care unit (ICU) stay in days, rates of hypotension, and rates of tachycardia. We included five retrospective cohort studies (n = 443), utilizing nicardipine as the primary comparator. Comparison of the time to reach target systolic blood pressure (SBP) revealed no significant difference between medications (SMD = - 1.09, p = 0.33). Likewise, the achieved SBP target showed no notable distinction (RR = 1.15, p = 0.81). However, clevidipine exhibited a slightly higher percentage of time within the target SBP range (SMD = 0.33, p = 0.04), albeit with moderate heterogeneity. Importantly, all included studies were retrospective cohort studies, underscoring the methodological context of the investigation. Clevidipine and the control group were found to be comparable in terms of achieving target SBP. Clevidipine may have a slight advantage in maintaining blood pressure within the desired range, but further research is needed to confirm this finding.


Assuntos
Anti-Hipertensivos , Hipertensão , Piridinas , Humanos , Pressão Sanguínea , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento , Hipertensão/tratamento farmacológico
3.
PLoS One ; 19(3): e0299985, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38507360

RESUMO

PURPOSE: To examine the association of several antihypertensive medication classes with incidence of Parkinson's disease (PD), taking into account possible underlying conditions. METHODS: In a case-control study based on a large primary care database and including 21,981 PD cases and 21,981 non-PD controls matched for age, sex, and possible treatment indications associations with different antihypertensive medication groups, including diuretics, betablockers, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin-II receptor-blockers and PD were examined. RESULTS: Antihypertensive medications overall were associated with a lower risk of subsequent diagnosis of PD (OR: 0.94, 95% CI 0.90-0.97), with the negative association most significant for medications acting on the renin-angiotensin-aldosterone system. A positive association with diagnosis of PD was only seen for betablockers and restricted to those with relatively young age and not in those with longer treatment duration. CONCLUSION: When taking into account underlying diagnoses, antihypertensive medications overall were associated with a reduced incidence of PD.


Assuntos
Hipertensão , Doença de Parkinson , Humanos , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Estudos de Casos e Controles , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/epidemiologia , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Atenção Primária à Saúde , Antagonistas de Receptores de Angiotensina/uso terapêutico
4.
Hypertension ; 81(4): 811-822, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38507511

RESUMO

BACKGROUND: The zona glomerulosa of the adrenal gland is responsible for the synthesis and release of the mineralocorticoid aldosterone. This steroid hormone regulates salt reabsorption in the kidney and blood pressure. The most important stimuli of aldosterone synthesis are the serum concentrations of angiotensin II and potassium. In response to these stimuli, voltage and intracellular calcium levels in the zona glomerulosa oscillate, providing the signal for aldosterone synthesis. It was proposed that the voltage-gated T-type calcium channel CaV3.2 is necessary for the generation of these oscillations. However, Cacna1h knock-out mice have normal plasma aldosterone levels, suggesting additional calcium entry pathways. METHODS: We used a combination of calcium imaging, patch clamp, and RNA sequencing to investigate calcium influx pathways in the murine zona glomerulosa. RESULTS: Cacna1h-/- glomerulosa cells still showed calcium oscillations with similar concentrations as wild-type mice. No calcium channels or transporters were upregulated to compensate for the loss of CaV3.2. The calcium oscillations observed were instead dependent on L-type voltage-gated calcium channels. Furthermore, we found that L-type channels can also partially compensate for an acute inhibition of CaV3.2 in wild-type mice. Only inhibition of both T- and L-type calcium channels abolished the increase of intracellular calcium caused by angiotensin II in wild-type. CONCLUSIONS: Our study demonstrates that T-type calcium channels are not strictly required to maintain glomerulosa calcium oscillations and aldosterone production. Pharmacological inhibition of T-type channels alone will likely not significantly impact aldosterone production in the long term.


Assuntos
Canais de Cálcio Tipo L , Zona Glomerulosa , Camundongos , Animais , Zona Glomerulosa/metabolismo , Canais de Cálcio Tipo L/metabolismo , Bloqueadores dos Canais de Cálcio/farmacologia , Aldosterona/metabolismo , Sinalização do Cálcio , Cálcio/metabolismo , Angiotensina II/farmacologia , Angiotensina II/metabolismo
6.
BMJ Case Rep ; 17(3)2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38442964

RESUMO

We report a case of Raynaud's phenomenon in a patient with psoriatic arthritis (PsA). A middle-aged right-handed housewife presented with complaints of severely painful hand discolouration for 1 week, which usually worsened with cold exposure. She was diagnosed with PsA 6 months earlier. Her PsA was well controlled with weekly methotrexate. Physical examination showed no features of scleroderma or skin necrosis of her right hand. Both radial pulses were strong and symmetrical. Her nailfolds were visibly normal. The extractable nuclear antigen panel and other blood investigations were negative for scleroderma and other possible causes of secondary Raynaud's phenomenon. Occupational or environmental factors were also excluded. Dermatoscope examination of the nailfolds revealed some areas of dilated capillary loops, areas of vascular sparing and proximal nail fold telangiectasia. The diagnosis of secondary Raynaud's phenomenon was made, and an oral calcium channel blocker was started. The patient had significant improvement in symptoms shortly afterwards.


Assuntos
Artrite Psoriásica , Doença de Raynaud , Esclerodermia Localizada , Feminino , Pessoa de Meia-Idade , Humanos , Artrite Psoriásica/complicações , Artrite Psoriásica/diagnóstico , Artrite Psoriásica/tratamento farmacológico , Doença de Raynaud/complicações , Doença de Raynaud/diagnóstico , Bloqueadores dos Canais de Cálcio , Mãos , Metotrexato
7.
BMJ Open ; 14(3): e080982, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38458796

RESUMO

INTRODUCTION: Calcium channel blockers (CCB), a commonly prescribed antihypertensive (AHT) medicine, may be associated with increased risk of breast cancer. The proposed study aims to examine whether long-term CCB use is associated with the development of breast cancer and to characterise the dose-response nature of any identified association, to inform future hypertension management. METHODS AND ANALYSIS: The study will use data from 2 of Australia's largest cohort studies; the Australian Longitudinal Study on Women's Health, and the 45 and Up Study, combined with the Rotterdam Study. Eligible women will be those with diagnosed hypertension, no history of breast cancer and no prior CCB use at start of follow-up (2004-2009). Cumulative dose-duration exposure to CCB and other AHT medicines will be captured at the earliest date of: the outcome (a diagnosis of invasive breast cancer); a competing risk event (eg, bilateral mastectomy without a diagnosis of breast cancer, death prior to any diagnosis of breast cancer) or end of follow-up (censoring event). Fine and Gray competing risks regression will be used to assess the association between CCB use and development of breast cancer using a generalised propensity score to adjust for baseline covariates. Time-varying covariates related to interaction with health services will also be included in the model. Data will be harmonised across cohorts to achieve identical protocols and a two-step random effects individual patient-level meta-analysis will be used. ETHICS AND DISSEMINATION: Ethical approval was obtained from the following Human research Ethics Committees: Curtin University (ref No. HRE2022-0335), NSW Population and Health Services Research Ethics Committee (2022/ETH01392/2022.31), ACT Research Ethics and Governance Office approval under National Mutual Acceptance for multijurisdictional data linkage research (2022.STE.00208). Results of the proposed study will be published in high-impact journals and presented at key scientific meetings. TRIAL REGISTRATION NUMBER: NCT05972785.


Assuntos
Neoplasias da Mama , Hipertensão , Feminino , Humanos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Neoplasias da Mama/induzido quimicamente , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Estudos Longitudinais , Mastectomia , Austrália/epidemiologia , Hipertensão/tratamento farmacológico , Estudos Observacionais como Assunto , Metanálise como Assunto
8.
Rev Med Liege ; 79(2): 104-109, 2024 Feb.
Artigo em Francês | MEDLINE | ID: mdl-38356427

RESUMO

Vasoreactive pulmonary arterial hypertension (PAH) in children is a form of idiopathic PAH that responds to vasoreactive testing with nitric oxide (NO) by a significant decrease of pulmonary vascular resistances and pressure. Oral calcium channel antagonists (CCA) that allow pulmonary arterial vasodilation are the treatment of choice. The therapeutic effect is strongly depending on adequate drug intake. In growing children, drug dose must be adapted to weight. In case of unavailability of low-dose pharmaceutical preparations, officinal formulations become mandatory. Officinal formulations may be related to a multitude of errors at different steps including prescription, transcription, preparation and administration. This may have life-threatening consequences for the child.To illustrate this, we report a case of a compounding error with underdosage of CCA, leading to acute cardiovascular failure in an adolescent with vasoreactive PAH.


L'hypertension artérielle pulmonaire (HTAP) vasoréactive chez l'enfant est une forme d'HTAP idiopathique qui répond au test de vasoréactivité au monoxyde d'azote (NO) par une diminution significative des pressions et résistances vasculaires pulmonaires. Le traitement de choix de cette forme d'HTAP est l'administration d'antagonistes des canaux calciques (ACC) par voie orale. Ce traitement entraîne une vasodilatation artérielle pulmonaire, elle-même étroitement dépendante de la prise adéquate du médicament. Chez les enfants en croissance, la dose du médicament doit être adaptée au poids. De façon générale, en l'absence de préparation à faible dose disponible dans les laboratoires pharmaceutiques, l'utilisation de formulations officinales devient obligatoire. De la prescription à l'administration, en passant par la transcription et la préparation, de nombreuses erreurs humaines et techniques peuvent survenir qui peuvent impacter la morbi-mortalité de l'enfant. Nous rapportons le cas d'une adolescente avec HTAP vasoréactive chez qui une erreur de préparation magistrale avec sous-dosage de l'ACC a conduit à une décompensation cardio-vasculaire aiguë et discutons de mesures préventives potentielles.


Assuntos
Hipertensão Pulmonar , Adolescente , Humanos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Óxido Nítrico/uso terapêutico
9.
J Med Case Rep ; 18(1): 68, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38308385

RESUMO

BACKGROUND: Calcium channel blocker poisoning is one of the most lethal cardiac drugs overdoses. Calcium and high-dose insulin infusion are the first-line therapy for symptomatic patients, and Intralipid emulsion infusion is useful for refractory cases. CASE PRESENTATION: In this report, we describe a 17-year-old Iranian girl who took 250 mg of the drug for a suicidal attempt and presented with refractory hypotension and non-cardiogenic pulmonary edema treated successfully with the guidance of invasive hemodynamic parameters. CONCLUSION: For complicated cases, in addition to supportive care and adjuvant therapy such as high-dose insulin and Intralipid, it is mandatory to utilize advanced hemodynamic monitoring to treat hypotension in severe calcium channel blocker poisoning to guide the treatment.


Assuntos
Overdose de Drogas , Monitorização Hemodinâmica , Hiperinsulinismo , Hipotensão , Feminino , Humanos , Adolescente , Bloqueadores dos Canais de Cálcio , Irã (Geográfico) , Insulina/uso terapêutico , Overdose de Drogas/tratamento farmacológico , Overdose de Drogas/complicações , Hipotensão/induzido quimicamente , Hipotensão/tratamento farmacológico , Hipotensão/complicações , Hiperinsulinismo/tratamento farmacológico
10.
Aust J Gen Pract ; 53(1-2): 33-35, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38316476

RESUMO

BACKGROUND: Anal fissure (AF) is the second most common anorectal complaint in healthcare settings. The presentation might be acute or chronic, characterised by severe pain with defaecation that persists for one to two hours. Non-surgical and surgical interventions are available based on the severity and persistence of the fissure. OBJECTIVE: The aim of this article is to review the pathophysiology, clinical presentation and management of AF under current guidelines. DISCUSSION: The aetiology of AF is unclear, although it is commonly associated with local trauma or associated chronic conditions. Acute AF is first treated with conservative therapy, including dietary fibre and sitz baths. Addition of topical nitrates, topical calcium channel blockers or botulinum toxin injection is indicated with failure of conservative treatment or at medical discretion. Surgical options are considered if AF persists despite treatment. Most present as hypertonic, but special consideration is needed for hypotonic or secondary presentations.


Assuntos
Fissura Anal , Humanos , Fissura Anal/diagnóstico , Fissura Anal/etiologia , Fissura Anal/terapia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Nitratos/uso terapêutico , Dor/tratamento farmacológico , Tratamento Conservador
11.
Adv Ther ; 41(3): 1284-1303, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38310194

RESUMO

INTRODUCTION: In contrast to the antihypertensive effect of esaxerenone, there is little evidence of its cardioprotective effect. We investigated the efficacy and safety of esaxerenone in patients with uncontrolled hypertension and left ventricular hypertrophy taking a renin-angiotensin system inhibitor (RASi) or calcium-channel blocker (CCB). METHODS: This was a multicenter, open-label, exploratory study with a 24-week treatment period. Esaxerenone was orally administered at an initial dose of 2.5 mg/day (maximum dose: 5 mg/day). The primary endpoints were the change in morning home systolic blood pressure (BP)/diastolic BP and change and percentage change in left ventricular mass index (LVMI) from baseline to end of treatment (EOT). Key secondary endpoints included change from baseline in bedtime home and office BP, achievement rate of target BP, and safety. RESULTS: In total, 60 patients were enrolled. Morning home systolic/diastolic BP was significantly decreased from baseline to EOT in the total population (- 11.5/ - 4.7 mmHg, p < 0.001) and in both the RASi and CCB subcohorts (all p < 0.01). Significant reductions in bedtime home and office BP were shown in the total population and both subcohorts. LVMI was also significantly decreased from baseline to EOT in the total population (- 9.9 g/m2, - 8.5%, both p < 0.001) and both subcohorts (all p < 0.05). The incidences of treatment-emergent adverse events (TEAEs) and drug-related TEAEs were 35.0% and 3.3%, respectively; most were mild or moderate. No new safety concerns were identified. CONCLUSION: Esaxerenone showed favorable antihypertensive and cardioprotective effects and safety in hypertensive patients with cardiac hypertrophy. TRIAL REGISTRATION: Japan Registry of Clinical Trials (jRCTs071190043).


Assuntos
Hipertensão , Hipertrofia Ventricular Esquerda , Pirróis , Sulfonas , Humanos , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Estudos Prospectivos , Pirróis/efeitos adversos , Sulfonas/efeitos adversos
12.
Eur J Pharmacol ; 967: 176416, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38342359

RESUMO

Cav3.2 T-type calcium channels are important targets for pain relief in rodent models of inflammatory and neuropathic pain. Even though many T-type channel blockers have been tested in mice, only one molecule, ABT-639, has been tested in phase II clinical studies and did not produce analgesic effects over placebo. Here we examined the effects of ABT-639 on Cav3.2 channel activity in tsA-201 cells and dorsal root ganglion (DRG) neurons, in comparison with another established Cav3.2 inhibitor Z944. These experiments revealed that Z944 mediated ∼100-fold more potent inhibition of Cav3.2 currents than ABT-639, with the latter blocking channel activity by less than 15 percent when applied at a concentration of 30 µM. A slight increase in ABT-639 potency was observed at more depolarized holding potentials, suggesting that this compound may act preferentially on inactivated channels. We tested the effects of both compounds in the Complete Freund's Adjuvant (CFA) model of chronic inflammatory pain, and in partial sciatic nerve injury model of neuropathic pain in mice. In the neuropathic pain model, both Z944 and ABT-639 reversed mechanical hypersensitivity to similar degrees when delivered systemically, but remarkably, when delivered intrathecally, only Z944 was effective. In the CFA model, both compounds reversed thermal hyperalgesia upon systemic delivery, but only Z944 mediated pain relief upon intrathecal delivery, indicating that ABT-639 acts primarily at peripheral sites. ABT-639 lost its analgesic effects in CFA treated Cav3.2 null mice, indicating that these channels are essential for ABT-639-mediated pain relief despite its poor inhibition of Cav3.2 currents.


Assuntos
Canais de Cálcio Tipo T , Dor Crônica , Compostos Heterocíclicos com 2 Anéis , Neuralgia , Camundongos , Animais , Neuralgia/tratamento farmacológico , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Hiperalgesia/tratamento farmacológico , Modelos Animais de Doenças , Dor Crônica/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia
13.
PLoS Negl Trop Dis ; 18(2): e0011993, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38408129

RESUMO

Spotted fever group rickettsiae are tick-borne obligate intracellular bacteria that infect microvascular endothelial cells. Humans and mammalian infection results in endothelial cell barrier dysfunction and increased vascular permeability. We previously demonstrated that treatment of Rickettsia parkeri-infected cells with the calcium channel blocker benidipine significantly delayed vascular barrier permeability. Thus, we hypothesized that benidipine, known to be safe and effective for other clinical processes, could reduce rickettsia-induced vascular permeability in vivo in an animal model of spotted fever rickettsiosis. Based on liver, lung and brain vascular FITC-dextran extravasation studies, benidipine did not reliably impact vascular permeability. However, it precipitated a deleterious effect on responses to control sublethal R. parkeri infection. Animals treated with benidipine alone had no clinical signs or changes in histopathology and splenic immune cell distributions. Benidipine-treated infected animals had marked increases in tissue and blood bacterial loads, more extensive inflammatory histopathologic injury, and changes in splenic architecture and immune cell distributions potentially reflecting diminished Ca2+ signaling, reduced innate immune cell activation, and loss of rickettsial propagation control. Impaired T cell activation by R. parkeri antigen in the presence of benidipine was confirmed in vitro with the use of NKT cell hybridomas. The unexpected findings stand in stark contrast to recent discussions of the benefits of calcium channel blockers for viral infections and chronic infectious or inflammatory diseases. A role for calcium channel blockers in exacerbation of human rickettsiosis and acute inflammatory infections should be evaluated by a retrospective review of patient's outcomes and medications.


Assuntos
Di-Hidropiridinas , Infecções por Rickettsia , Rickettsia , Rickettsiose do Grupo da Febre Maculosa , Humanos , Camundongos , Animais , Modelos Animais de Doenças , Bloqueadores dos Canais de Cálcio , Células Endoteliais/patologia , Infecções por Rickettsia/microbiologia , Rickettsia/fisiologia , Rickettsiose do Grupo da Febre Maculosa/patologia , Imunidade Inata , Mamíferos
14.
Cochrane Database Syst Rev ; 2: CD004184, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38353289

RESUMO

BACKGROUND: Variation in blood pressure levels display circadian rhythms. Complete 24-hour blood pressure control is the primary goal of antihypertensive treatment and reducing adverse cardiovascular outcomes is the ultimate aim. This is an update of the review first published in 2011. OBJECTIVES: To evaluate the effectiveness of administration-time-related effects of once-daily evening versus conventional morning dosing antihypertensive drug therapy regimens on all-cause mortality, cardiovascular mortality and morbidity, total adverse events, withdrawals from treatment due to adverse effects, and reduction of systolic and diastolic blood pressure in people with primary hypertension. SEARCH METHODS: We searched the Cochrane Hypertension Specialised Register via Cochrane Register of Studies (17 June 2022), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 6, 2022); MEDLINE, MEDLINE In-Process and MEDLINE Epub Ahead of Print (1 June 2022); Embase (1 June 2022); ClinicalTrials.gov (2 June 2022); Chinese Biomedical Literature Database (CBLD) (1978 to 2009); Chinese VIP (2009 to 7 August 2022); Chinese WANFANG DATA (2009 to 4 August 2022); China Academic Journal Network Publishing Database (CAJD) (2009 to 6 August 2022); Epistemonikos (3 September 2022) and the reference lists of relevant articles. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing the administration-time-related effects of evening with morning dosing monotherapy regimens in people with primary hypertension. We excluded people with known secondary hypertension, shift workers or people with white coat hypertension. DATA COLLECTION AND ANALYSIS: Two to four review authors independently extracted data and assessed trial quality. We resolved disagreements by discussion or with another review author. We performed data synthesis and analyses using Review Manager Web for all-cause mortality, cardiovascular mortality and morbidity, serious adverse events, overall adverse events, withdrawals due to adverse events, change in 24-hour blood pressure and change in morning blood pressure. We assessed the certainty of the evidence using GRADE. We conducted random-effects meta-analysis, fixed-effect meta-analysis, subgroup analysis and sensitivity analysis. MAIN RESULTS: We included 27 RCTs in this updated review, of which two RCTs were excluded from the meta-analyses for lack of data and number of groups not reported. The quantitative analysis included 25 RCTs with 3016 participants with primary hypertension. RCTs used angiotensin-converting enzyme inhibitors (six trials), calcium channel blockers (nine trials), angiotensin II receptor blockers (seven trials), diuretics (two trials), α-blockers (one trial), and ß-blockers (one trial). Fifteen trials were parallel designed, and 10 trials were cross-over designed. Most participants were white, and only two RCTs were conducted in Asia (China) and one in Africa (South Africa). All trials excluded people with risk factors of myocardial infarction and strokes. Most trials had high risk or unclear risk of bias in at least two of several key criteria, which was most prominent in allocation concealment (selection bias) and selective reporting (reporting bias). Meta-analysis showed significant heterogeneity across trials. No RCTs reported on cardiovascular mortality and cardiovascular morbidity. There may be little to no differences in all-cause mortality (after 26 weeks of active treatment: RR 0.49, 95% CI 0.04 to 5.42; RD 0, 95% CI -0.01 to 0.01; very low-certainty evidence), serious adverse events (after 8 to 26 weeks of active treatment: RR 1.17, 95% CI 0.53 to 2.57; RD 0, 95% CI -0.02 to 0.03; very low-certainty evidence), overall adverse events (after 6 to 26 weeks of active treatment: RR 0.89, 95% CI 0.67 to 1.20; I² = 37%; RD -0.02, 95% CI -0.07 to 0.02; I² = 38%; very low-certainty evidence) and withdrawals due to adverse events (after 6 to 26 weeks active treatment: RR 0.76, 95% CI 0.47 to 1.23; I² = 0%; RD -0.01, 95% CI -0.03 to 0; I² = 0%; very low-certainty evidence), but the evidence was very uncertain. AUTHORS' CONCLUSIONS: Due to the very limited data and the defects of the trials' designs, this systematic review did not find adequate evidence to determine which time dosing drug therapy regimen has more beneficial effects on cardiovascular outcomes or adverse events. We have very little confidence in the evidence showing that evening dosing of antihypertensive drugs is no more or less effective than morning administration to lower 24-hour blood pressure. The conclusions should not be assumed to apply to people receiving multiple antihypertensive drug regimens.


Assuntos
Anti-Hipertensivos , Hipertensão , Humanos , Anti-Hipertensivos/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão Essencial/induzido quimicamente , Hipertensão Essencial/complicações , Hipertensão Essencial/tratamento farmacológico
15.
Ulus Travma Acil Cerrahi Derg ; 30(2): 73-79, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38305651

RESUMO

BACKGROUND: Spinal cord injury is a devastating trauma that leaves survivors at risk for several medical complications throughout their lives. Lercanidipine, a third-generation calcium channel blocker, possesses anti-apoptotic, anti-inflammatory, and antioxidative properties. This study aimed to evaluate the neuroprotective effects of lercanidipine in an experimental spinal cord trauma model. METHODS: Twenty-one Wistar rats were randomly assigned to three groups. Group 1 (G1) underwent laminectomy. Group 2 (G2) were subjected to trauma following laminectomy. Group 3 (G3) were exposed to trauma following laminectomy and treated with lercanidipine. Lercanidipine was administered intraperitoneally for seven days. Histopathological and immunohistochemical evaluations were conducted. RESULTS: Regarding Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, there was no significant difference among the groups. However, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) levels were significantly different across the groups. G2 had significantly higher NF-κB levels compared to G1 and G3. CONCLUSION: Lercanidipine, a third-generation calcium channel blocker, is effective against inflammatory responses induced in spinal cord injury. Further studies are required to determine its capability in preventing apoptosis or improving functional recovery. To the best of our knowledge, this study is the first in the literature to examine the neuroprotective effects of lercanidipine on spinal cord injury.


Assuntos
Di-Hidropiridinas , Fármacos Neuroprotetores , Traumatismos da Medula Espinal , Ratos , Animais , Ratos Wistar , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , NF-kappa B , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico , Traumatismos da Medula Espinal/complicações , Apoptose , Anti-Inflamatórios/uso terapêutico
16.
J Clin Hypertens (Greenwich) ; 26(3): 241-250, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38319613

RESUMO

Microalbuminuria and hyperuricemia management are crucial for the integrated management of hypertensive patients. This retrospective post hoc analysis aims to evaluate the optimal allisartan-isoproxil-based combination regimen for hypertensive patients with microalbuminuria or hyperuricemia. A total of 460 hypertensive patients with microalbuminuria and 486 hypertensive patients with hyperuricemia were included in this study. All patients were initially treated with allisartan-isoproxil for 4 weeks. Thereafter, patients with blood pressure (BP) < 140/90 mmHg continued the monotherapy for 8 weeks; patients with BP ≥140/90 mmHg were randomly assigned in a 1:1 ratio to receive allisartan-isoproxil + amlodipine (Group A + C) or allisartan-isoproxil + indapamide (Group A + D) for 8 weeks. The changes of BP, urinary albumin and serum uric acid (UA) were measured. In patients with microalbuminuria, the urinary albumin/creatinine ratio (UACR) significantly decreased by 10.4 mg/g in Group A + C (vs. baseline p = .0035) and 24.2 mg/g in Group A + D (vs baseline p < .0001), intergroup p = NS. In patients with hyperuricemia, serum UA level decreased by 44.5 µmol/L in Group A + C (vs. baseline p = .0003), but increased by 27.2 µmol/L in Group A + D (vs. baseline p = .0167), intergroup p < .0001. The results suggest that for hypertensive patients with microalbuminuria, angiotensin receptor blocker (ARB) + calcium channel blocker (CCB) or ARB+ diuretic both are good choices based on their improvement of microalbuminuria and BP. But for patients with hyperuricemia, ARB + diuretic may further increase the level of UA.


Assuntos
Compostos de Bifenilo , Hipertensão , Hiperuricemia , Imidazóis , Humanos , Anti-Hipertensivos/farmacologia , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/induzido quimicamente , Antagonistas de Receptores de Angiotensina/uso terapêutico , Antagonistas de Receptores de Angiotensina/farmacologia , Estudos Retrospectivos , Ácido Úrico , Hiperuricemia/complicações , Hiperuricemia/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anlodipino , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/farmacologia , Pressão Sanguínea , Diuréticos/uso terapêutico , Albuminúria/tratamento farmacológico , Albuminas/farmacologia , Albuminas/uso terapêutico , Quimioterapia Combinada
17.
Elife ; 122024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38335126

RESUMO

The function of the smooth muscle cells lining the walls of mammalian systemic arteries and arterioles is to regulate the diameter of the vessels to control blood flow and blood pressure. Here, we describe an in silico model, which we call the 'Hernandez-Hernandez model', of electrical and Ca2+ signaling in arterial myocytes based on new experimental data indicating sex-specific differences in male and female arterial myocytes from murine resistance arteries. The model suggests the fundamental ionic mechanisms underlying membrane potential and intracellular Ca2+ signaling during the development of myogenic tone in arterial blood vessels. Although experimental data suggest that KV1.5 channel currents have similar amplitudes, kinetics, and voltage dependencies in male and female myocytes, simulations suggest that the KV1.5 current is the dominant current regulating membrane potential in male myocytes. In female cells, which have larger KV2.1 channel expression and longer time constants for activation than male myocytes, predictions from simulated female myocytes suggest that KV2.1 plays a primary role in the control of membrane potential. Over the physiological range of membrane potentials, the gating of a small number of voltage-gated K+ channels and L-type Ca2+ channels are predicted to drive sex-specific differences in intracellular Ca2+ and excitability. We also show that in an idealized computational model of a vessel, female arterial smooth muscle exhibits heightened sensitivity to commonly used Ca2+ channel blockers compared to male. In summary, we present a new model framework to investigate the potential sex-specific impact of antihypertensive drugs.


High blood pressure is a major risk factor for heart disease, which is one of the leading causes of death worldwide. While drugs are available to control blood pressure, male and female patients can respond differently to treatment. However, the biological mechanisms behind this sex difference are not fully understood. Blood pressure is controlled by cells lining the artery walls called smooth muscle cells which alter the width of blood vessels. On the surface of smooth muscle cells are potassium and calcium channels which control the cell's electrical activity. When calcium ions enter the cell via calcium channels, this generates an electrical signal that causes the smooth muscle to contract and narrow the blood vessel. Potassium ions then flood out of the cell via potassium channels to dampen the rise in electrical activity, causing the muscle to relax and widen the artery. There are various sub-types of potassium and calcium channels in smooth muscle cells. Here, Hernandez-Hernandez et al. set out to find how these channels differ between male and female mice, and whether these sex differences could alter the response to blood pressure medication. The team developed a computational model of a smooth muscle cell, incorporating data from laboratory experiments measuring differences in cells isolated from the arteries of male and female mice. The model predicted that the sub-types of potassium and calcium channels in smooth muscle cells varied between males and females, and how the channels impacted electrical activity also differed. For instance, the potassium channel Kv2.1 was found to have a greater role in controlling electrical activity in female mice, and this sex difference impacted blood vessel contraction. The model also predicted that female mice were more sensitive than males to calcium channel blockers, a drug commonly prescribed to treat high blood pressure. The findings by Hernandez-Hernandez et al. provide new insights into the biological mechanisms underlying sex differences in response to blood pressure medication. They also demonstrate how computational models can be used to predict the effects of drugs on different individuals. In the future, these predictions may help researchers to identify better, more personalized treatments for blood pressure.


Assuntos
Bloqueadores dos Canais de Cálcio , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Camundongos , Masculino , Feminino , Animais , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/metabolismo , Músculo Liso Vascular/metabolismo , Artérias/metabolismo , Pressão Sanguínea , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Cálcio/metabolismo , Mamíferos/metabolismo
18.
Emergencias (Sant Vicenç dels Horts) ; 36(1): 65-66, feb. 2024.
Artigo em Espanhol | IBECS | ID: ibc-229851

RESUMO

¿Cuál es el objetivo de esta revisión? En esta primera actualización de una revisión publicada en 2010. Se pretendía averiguar si los bloqueadores de los canales del calcio (BCC) pueden prevenir eventos cardiovasculares perjudiciales, como el ictus, el infarto de miocardio y la insuficiencia cardiaca, en comparación con otros antihipertensivos (hipotensores) utilizados en personas con presión arterial elevada (hipertensión). Fundamento. La disminución adecuada de la presión arterial elevada en personas con hipertensión puede reducir la cantidad de complicaciones importantes de la hipertensión, como el ictus, el infarto de miocardio, la insuficiencia cardiaca congestiva e incluso la muerte. Los BCC se utilizan como medicación de primera línea para reducir la presión arterial, pero se ha debatido si esta es la mejor forma de reducir los eventos cardiovasculares nocivos. Fecha de búsqueda. La evidencia está actualizada hasta el 1 de septiembre de 2020. Características del estudio. Se encontraron 23 estudios relevantes realizados en Europa, Norteamérica, Oceanía, Israel y Japón. Los estudios compararon el tratamiento con tratamiento con BCC frente al tratamiento con otras clases de fármacos hipotensores en personas con hipertensión e incluyeron 153.849 participantes. El seguimiento de los participantes en los ensayos osciló entre 2 y 5,3 años. Resultados clave. No hubo diferencias en las muertes por todas las causas entre los BCC y otros fármacos hipotensores. Los diuréticos probablemente reducen los eventos cardiovasculares totales y la insuficiencia cardiaca congestiva más que los BCC. Los BCC probablemente reducen los eventos cardiovasculares totales más que los bloqueadores beta... (AU)


Assuntos
Humanos , Hipertensão/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico
19.
Emergencias (Sant Vicenç dels Horts) ; 36(1): 65-66, feb. 2024.
Artigo em Espanhol | IBECS | ID: ibc-EMG-469

RESUMO

¿Cuál es el objetivo de esta revisión? En esta primera actualización de una revisión publicada en 2010. Se pretendía averiguar si los bloqueadores de los canales del calcio (BCC) pueden prevenir eventos cardiovasculares perjudiciales, como el ictus, el infarto de miocardio y la insuficiencia cardiaca, en comparación con otros antihipertensivos (hipotensores) utilizados en personas con presión arterial elevada (hipertensión). Fundamento. La disminución adecuada de la presión arterial elevada en personas con hipertensión puede reducir la cantidad de complicaciones importantes de la hipertensión, como el ictus, el infarto de miocardio, la insuficiencia cardiaca congestiva e incluso la muerte. Los BCC se utilizan como medicación de primera línea para reducir la presión arterial, pero se ha debatido si esta es la mejor forma de reducir los eventos cardiovasculares nocivos. Fecha de búsqueda. La evidencia está actualizada hasta el 1 de septiembre de 2020. Características del estudio. Se encontraron 23 estudios relevantes realizados en Europa, Norteamérica, Oceanía, Israel y Japón. Los estudios compararon el tratamiento con tratamiento con BCC frente al tratamiento con otras clases de fármacos hipotensores en personas con hipertensión e incluyeron 153.849 participantes. El seguimiento de los participantes en los ensayos osciló entre 2 y 5,3 años. Resultados clave. No hubo diferencias en las muertes por todas las causas entre los BCC y otros fármacos hipotensores. Los diuréticos probablemente reducen los eventos cardiovasculares totales y la insuficiencia cardiaca congestiva más que los BCC. Los BCC probablemente reducen los eventos cardiovasculares totales más que los bloqueadores beta... (AU)


Assuntos
Humanos , Hipertensão/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/uso terapêutico
20.
BMC Med ; 22(1): 6, 2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38166843

RESUMO

BACKGROUND: Mental disorders are among the top causes of disease burden worldwide. Existing evidence regarding the repurposing of antihypertensives for mental disorders treatment is conflicting and cannot establish causation. METHODS: We used Mendelian randomization to assess the effects of angiotensin-converting-enzyme inhibitors (ACEIs), beta blockers (BBs), and calcium channel blockers (CCBs) on risk of bipolar disorder (BD), major depression disorder (MDD), and schizophrenia (SCZ). We used published genetic variants which are in antihypertensive drugs target genes and correspond to systolic blood pressure (SBP) in Europeans and East Asians, and applied them to summary statistics of BD (cases = 41,917; controls = 371,549 in Europeans), MDD (cases = 170,756; controls = 329,443 in Europeans and cases = 15,771; controls = 178,777 in East Asians), and SCZ (cases = 53,386; controls = 77,258 in Europeans and cases = 22,778; controls = 35,362 in East Asians) from the Psychiatric Genomics Consortium. We used inverse variance weighting with MR-Egger, weighted median, weighted mode, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. We performed gene-specific analysis and utilized various methods to address potential pleiotropy. RESULTS: After multiple testing correction, genetically proxied ACEIs were associated with an increased risk of SCZ in Europeans (odds ratio (OR) per 5 mmHg lower in SBP 2.10, 95% CI 1.54 to 2.87) and East Asians (OR per 5 mmHg lower in SBP 2.51, 95% CI 1.38 to 4.58). Genetically proxied BBs were not associated with any mental disorders in both populations. Genetically proxied CCBs showed no benefits on mental disorders. CONCLUSIONS: Antihypertensive drugs have no protection for mental disorders but potential harm. Their long-term use among hypertensive patients with, or with high susceptibility to, psychiatric illness needs careful evaluation.


Assuntos
Anti-Hipertensivos , Transtorno Depressivo Maior , Transtornos Mentais , Humanos , Inibidores da Enzima Conversora de Angiotensina , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , População do Leste Asiático , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , População Europeia
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