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1.
J Assoc Physicians India ; 72(4): 54-58, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38881084

RESUMO

Calcium channel blockers (CCBs) are widely used antihypertensive agents due to their effectiveness in reducing blood pressure (BP), along with their good tolerability and evidence of reducing hypertension (HTN)-related cardiovascular and renal diseases. Cilnidipine, a unique dihydropyridine calcium antagonist, exhibits potent inhibitory action on both N-type and L-type voltage-dependent calcium channels. With excellent oral absorption and a prolonged duration of action, it demonstrates a significant antihypertensive effect. It effectively reduces BP both systolic and diastolic while providing renal, neurological, and cardiovascular protection. Unlike L-type CCBs, cilnidipine does not increase pulse rates (PRs) and is associated with reduced occurrence of pedal edema. Cilnidipine is an effective treatment choice for individuals with mild to moderate essential HTN, whether it is administered alone or in conjunction with other treatment modalities.


Assuntos
Anti-Hipertensivos , Bloqueadores dos Canais de Cálcio , Di-Hidropiridinas , Hipertensão , Di-Hidropiridinas/uso terapêutico , Di-Hidropiridinas/farmacologia , Humanos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Canais de Cálcio Tipo N/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Canais de Cálcio Tipo L
2.
BMJ ; 385: e079108, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38897628

RESUMO

Resistant hypertension is defined as blood pressure that remains above the therapeutic goal despite concurrent use of at least three antihypertensive agents of different classes, including a diuretic, with all agents administered at maximum or maximally tolerated doses. Resistant hypertension is also diagnosed if blood pressure control requires four or more antihypertensive drugs. Assessment requires the exclusion of apparent treatment resistant hypertension, which is most often the result of non-adherence to treatment. Resistant hypertension is associated with major cardiovascular events in the short and long term, including heart failure, ischemic heart disease, stroke, and renal failure. Guidelines from several professional organizations recommend lifestyle modification and antihypertensive drugs. Medications typically include an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, a calcium channel blocker, and a long acting thiazide-type/like diuretic; if a fourth drug is needed, evidence supports addition of a mineralocorticoid receptor antagonist. After a long pause since 2007 when the last antihypertensive class was approved, several novel agents are now under active development. Some of these may provide potent blood pressure lowering in broad groups of patients, such as aldosterone synthase inhibitors and dual endothelin receptor antagonists, whereas others may provide benefit by allowing treatment of resistant hypertension in special populations, such as non-steroidal mineralocorticoid receptor antagonists in patients with chronic kidney disease. Several device based approaches have been tested, with renal denervation being the best supported and only approved interventional device treatment for resistant hypertension.


Assuntos
Anti-Hipertensivos , Hipertensão , Humanos , Hipertensão/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/terapia , Anti-Hipertensivos/uso terapêutico , Resistência a Medicamentos , Quimioterapia Combinada , Bloqueadores dos Canais de Cálcio/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia
3.
Medicine (Baltimore) ; 103(24): e37856, 2024 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-38875375

RESUMO

BACKGROUND: Currently, most studies primarily focus on directly comparing the efficacy and safety of angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs), the two major classes of antihypertensive drugs. Moreover, the majority of studies are based on randomized controlled trials and traditional meta-analyses, with few exploring the efficacy and safety comparisons among various members of ACEIs and CCBs. METHODS: ACEIs and CCB were searched for in randomized controlled trials in CNKI, Wanfang, VIP, China Biology Medicine Disc (Si-noMed), PubMed, EMbase, and Cochrane Library databases. The search can be conducted till November 2022. Stata software (version 16.0) and R 4.1.3 was used for statistical analysis and graphics plotting, applying mvmeta, gemtc, and its packages. Meta-regression analysis was used to explore the inconsistencies of the studies. RESULTS: In 73 trials involving 33 different drugs, a total of 9176 hypertensive patients were included in the analysis, with 4623 in the intervention group and 4553 in the control group. The results of the analysis showed that, according to the SUCRA ranking, felodipine (MD = -12.34, 95% CI: -17.8 to -6.82) was the drug most likely to be the best intervention for systolic blood pressure, while nitrendipine (MD = -8.01, 95% CI: -11.71 to -4.18) was the drug most likely to be the best intervention for diastolic blood pressure. Regarding adverse drug reactions, nifedipine (OR = 0.32, 95% CI: 0.14-0.74) was the drug most likely to be the safest. CONCLUSION: The research findings indicate that nifedipine is the optimal intervention for reducing systolic blood pressure in hypertensive patients, nitrendipine is the optimal intervention for reducing diastolic blood pressure in hypertensive patients, and felodipine is the optimal intervention for safety.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Bloqueadores dos Canais de Cálcio , Hipertensão , Humanos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Metanálise em Rede , Anti-Hipertensivos/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Nifedipino/uso terapêutico
4.
Pharmacogenomics J ; 24(4): 19, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38890281

RESUMO

Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.


Assuntos
Bloqueadores dos Canais de Cálcio , Nimodipina , Farmacogenética , Hemorragia Subaracnóidea , Humanos , Nimodipina/administração & dosagem , Nimodipina/efeitos adversos , Hemorragia Subaracnóidea/tratamento farmacológico , Hemorragia Subaracnóidea/genética , Hemorragia Subaracnóidea/complicações , Pessoa de Meia-Idade , Feminino , Masculino , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Idoso , Farmacogenética/métodos , Resultado do Tratamento , Relação Dose-Resposta a Droga , Adulto , Medicina de Precisão/métodos , Vasoespasmo Intracraniano/tratamento farmacológico
5.
Blood Press ; 33(1): 2350981, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38824645

RESUMO

OBJECTIVE: Few studies have evaluated the performance of non-drug-adjusted primary aldosteronism (PA) screening. Therefore, we aimed to examine the consistency between PA screening results with and without drug adjustment and to explore the effectiveness of screening without drug adjustment. METHODS: This prospective study included 650 consecutive patients with a high risk of incidence PA. Patients who initially screened positive underwent rescreening with drug adjustments and confirmatory tests. Regarding the remaining patients, one of every three consecutive patients underwent rescreening with drug adjustments and confirmatory tests. The changes in aldosterone and renin concentrations were compared between patients with essential hypertension (EH) and those with PA before and after drug adjustment. Sensitivity and specificity were used to assess the diagnostic performance of screening without drug adjustment, using the confirmatory test results as the reference. RESULTS: We screened 650 patients with hypertension for PA. Forty-nine patients were diagnosed with PA and 195 with EH. Regarding drugs, 519 patients were taking angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), calcium channel blockers (CCBs), or diuretics alone or in combination. Forty-one patients were taking beta-blockers. Ninety patients were taking beta-blockers in combination with other drugs. In patients treated with ACEIs, ARBs, CCBs, or diuretics alone, or in combination, or beta-blockers alone, PA positivity was determined using the criteria, aldosterone-to-renin ratio (ARR) >38 pg/mL/pg/mL and plasma aldosterone concentration (PAC) >100 pg/mL, and negativity, using the criteria, ARR <9 pg/mL/pg/mL; the sensitivity and specificity were 94.7% and 94.5%, respectively. After drug adjustment, the sensitivity and specificity of screening were 92.1% and 89%, respectively. CONCLUSIONS: In patients not treated with beta-blockers combined with others, when ARR >38 pg/mL/pg/mL and plasma aldosterone concentration (PAC) >100 pg/mL, or, ARR <9 pg/mL/pg/mL, non-drug-adjusted screening results were identical to with drug adjustment. Non-drug-adjusted screening could reduce the chance of medication adjustment, enable patients to continue their treatments and avoiding adverse effects, is of clinical importance.


Primary aldosteronism (PA) is the most common form of endocrine hypertension. The risk of stroke, myocardial infarction, heart failure, atrial fibrillation, and deterioration of kidney function is higher in PA than in essential hypertension (EH), even with the same blood pressure (BP) levels. However, many patients remain undiagnosed because most antihypertensive drugs substantially interfere with PA screening results, which makes drug adjustment necessary. This can be a time-consuming and unsafe process, requiring 4­6 weeks, and could lead to a hypertensive crisis and other complications. Some studies have suggested that certain antihypertensive drugs can be continued during PR screening. However, few studies have evaluated the performance of non-drug-adjusted PA screening. Therefore, in this prospective study, we aimed to compare patients with hypertension and a high risk of PA before and after drug adjustment and to use confirmatory test results as a reference to explore the diagnostic or exclusion effect. We found that non-drug-adjusted screening performs similarly to drug-adjusted screening in a particular group of patients. Our findings could aid in preventing unnecessary drug adjustment for PA screening, thereby reducing the risk in these patients.


Assuntos
Aldosterona , Hiperaldosteronismo , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/sangue , Hiperaldosteronismo/tratamento farmacológico , Feminino , Pessoa de Meia-Idade , Masculino , Estudos Prospectivos , Aldosterona/sangue , Renina/sangue , Adulto , Bloqueadores dos Canais de Cálcio/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertensão/sangue , Hipertensão/diagnóstico , Anti-Hipertensivos/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Programas de Rastreamento/métodos , Idoso , Antagonistas de Receptores de Angiotensina/uso terapêutico
6.
Kardiologiia ; 64(5): 26-32, 2024 May 31.
Artigo em Russo | MEDLINE | ID: mdl-38841786

RESUMO

Based on a clinical case report, the article shows the individual selection of effective therapy for a patient with arterial hypertension and dyslipidemia. Taking into account the risk factors for cardiovascular diseases, Equamer® was selected as a fixed combination of amlodipine + lisinopril + rosuvastatin capsules 10 mg+20 mg+10 mg (Gedeon Richter Plc, Budapest, Hungary). In the patient with hypertension, ischemic heart disease was verified, and stenting of the anterior descending artery was performed. According to the clinical guidelines, when arterial hypertension is associated with ischemic heart disease, the drug therapy of choice should be a combination of dihydropyridine slow calcium channel blockers with an angiotensin-converting enzyme inhibitor. The fixed triple combination of amlodipine, lisinopril, and rosuvastatin is one of the most appropriate in this clinical situation; this combination targets the two major risk factors for cardiovascular diseases, arterial hypertension and dyslipidemia.


Assuntos
Anlodipino , Combinação de Medicamentos , Dislipidemias , Hipertensão , Humanos , Anlodipino/administração & dosagem , Anti-Hipertensivos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Dislipidemias/tratamento farmacológico , Dislipidemias/complicações , Hipertensão/tratamento farmacológico , Lisinopril/administração & dosagem , Lisinopril/uso terapêutico , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/uso terapêutico , Resultado do Tratamento
7.
AAPS PharmSciTech ; 25(5): 133, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38862767

RESUMO

Nifedipine (NIF) is a dihydropyridine calcium channel blocker primarily used to treat conditions such as hypertension and angina. However, its low solubility and low bioavailability limit its effectiveness in clinical practice. Here, we developed a cocrystal prediction model based on Graph Neural Networks (CocrystalGNN) for the screening of cocrystals with NIF. And scoring 50 coformers using CocrystalGNN. To validate the reliability of the model, we used another prediction method, Molecular Electrostatic Potential Surface (MEPS), to verify the prediction results. Subsequently, we performed a second validation using experiments. The results indicate that our model achieved high performance. Ultimately, cocrystals of NIF were successfully obtained and all cocrystals exhibited better solubility and dissolution characteristics compared to the parent drug. This study lays a solid foundation for combining virtual prediction with experimental screening to discover novel water-insoluble drug cocrystals.


Assuntos
Bloqueadores dos Canais de Cálcio , Cristalização , Redes Neurais de Computação , Nifedipino , Solubilidade , Eletricidade Estática , Nifedipino/química , Cristalização/métodos , Bloqueadores dos Canais de Cálcio/química
8.
J Drugs Dermatol ; 23(6): 446-449, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38834225

RESUMO

Acne vulgaris is a common chronic dermatological condition characterized by obstruction and inflammation of pilosebaceous units. Recent research on a different dermatologic condition has demonstrated that the use of vasodilatory medications is associated with a decreased relative risk of rosacea. This finding is significant due to the overlapping inflammatory pathways involved in rosacea and acne. Herein, a retrospective cohort study was designed to determine the correlation between vasodilator usage and the risk of developing acne within 5 years, contrasting it with thiazide diuretics, chosen as a control due to its non-vasodilatory antihypertensive mechanism and availability of data. Angiotensin-converting enzyme (ACE) inhibitors (RR, 0.775; 95% CI, 0.727-0.826; P<0.05), angiotensin receptor blockers (ARBs) (RR, 0.739; 95% CI, 0.685-0.797; P<0.05), beta-blockers (BB) (RR, 0.829; 95% CI, 0.777-0.885; P<0.05), and calcium channel blockers (CCB) usage (RR, 0.821, 95% CI, 0.773-0.873; P<0.05) were associated with a significantly lower risk of developing acne within 5 years of initiating therapy compared to thiazide diuretics. It is unclear if thiazide diuretics are more likely to cause acne within the adult population or if vasodilators are protective against the development of acne. Finding mechanisms and therapeutics that lower the risk of developing acne is of significant public health interest, and this study provides a step toward this endeavor. Further research is required to uncover the underlying mechanisms for this reduction in the development of acne.  J Drugs Dermatol. 2024;23(6):446-449.     doi:10.36849/JDD.8362.


Assuntos
Acne Vulgar , Vasodilatadores , Humanos , Acne Vulgar/tratamento farmacológico , Acne Vulgar/epidemiologia , Estudos Retrospectivos , Masculino , Adulto , Feminino , Vasodilatadores/administração & dosagem , Pessoa de Meia-Idade , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/administração & dosagem , Bloqueadores dos Canais de Cálcio/efeitos adversos , Adulto Jovem , Antagonistas de Receptores de Angiotensina/efeitos adversos , Antagonistas de Receptores de Angiotensina/administração & dosagem , Antagonistas de Receptores de Angiotensina/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas Adrenérgicos beta/efeitos adversos
9.
Molecules ; 29(10)2024 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-38792145

RESUMO

The Cupressaceae family includes species considered to be medicinal. Their essential oil is used for headaches, colds, cough, and bronchitis. Cedar trees like Chamaecyparis lawsoniana (C. lawsoniana) are commonly found in urban areas. We investigated whether C. lawsoniana exerts some of its effects by modifying airway smooth muscle (ASM) contractility. The leaves of C. lawsoniana (363 g) were pulverized mechanically, and extracts were obtained by successive maceration 1:10 (w:w) with methanol/CHCl3. Guinea pig tracheal rings were contracted with KCl, tetraethylammonium (TEA), histamine (HIS), or carbachol (Cch) in organ baths. In the Cch experiments, tissues were pre-incubated with D-600, an antagonist of L-type voltage-dependent Ca2+ channels (L-VDCC) before the addition of C. lawsoniana. Interestingly, at different concentrations, C. lawsoniana diminished the tracheal contractions induced by KCl, TEA, HIS, and Cch. In ASM cells, C. lawsoniana significantly diminished L-type Ca2+ currents. ASM cells stimulated with Cch produced a transient Ca2+ peak followed by a sustained plateau maintained by L-VDCC and store-operated Ca2+ channels (SOCC). C. lawsoniana almost abolished this last response. These results show that C. lawsoniana, and its active metabolite quercetin, relax the ASM by inhibiting the L-VDCC and SOCC; further studies must be performed to obtain the complete set of metabolites of the extract and study at length their pharmacological properties.


Assuntos
Cálcio , Chamaecyparis , Contração Muscular , Músculo Liso , Extratos Vegetais , Quercetina , Traqueia , Animais , Cobaias , Músculo Liso/efeitos dos fármacos , Músculo Liso/metabolismo , Contração Muscular/efeitos dos fármacos , Quercetina/farmacologia , Quercetina/química , Traqueia/efeitos dos fármacos , Traqueia/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Chamaecyparis/química , Cálcio/metabolismo , Masculino , Bloqueadores dos Canais de Cálcio/farmacologia , Histamina/metabolismo , Canais de Cálcio Tipo L/metabolismo , Folhas de Planta/química
10.
J Prev Alzheimers Dis ; 11(3): 672-683, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38706283

RESUMO

BACKGROUND: We aimed to explore whether the relationships of blood pressures (BPs) with Alzheimer's disease (AD) endophenotypes varied by usage of antihypertensive drugs (AHDs). METHODS: A total of 765 non-demented older adults (mean age: 74.4 years; female: 43.1%) with a self-reported history of hypertension were followed for 6 years. Multiple linear regression and linear-mixed effect models were used to investigate the interaction effects of five categories of AHDs (angiotensin-converting enzyme inhibitors [ACEI], angiotensin II receptor blockers [ARBs], ß-blocker, calcium channel blockers [CCB], diuretic) with BPs (systolic blood pressure [SBP], diastolic blood pressure [DBP], and pulse pressure [PP]) on AD core pathology and neurodegenerative markers. RESULTS: After Bonferroni correction, significant interaction effects of BPs with AHDs were observed. Elevated SBP or PP in late-life was associated with higher levels of cerebral Aß burden (diuretic alone/ß-blocker × SBP), higher levels of CSF tau proteins (diuretic × SBP/PP, ARBs/CCB × SBP), and lower volume of entorhinal region (ß-blocker × SBP, diuretic × PP) only among hypertensive patients who received no anti-hypertensive treatments, while these associations became compromised or null for users of specific AHDs except for ACEI. Compared to taking other classes of AHDs, elevated SBP in late-life was associated with lower cerebral Aß burden in diuretic users (padjusted = 0.08) and was associated with higher CSF tau proteins in ACEI alone users (padjusted = 0.03). Longitudinal data validated the above-mentioned interaction effects on changes of cerebral Aß burden (padjusted < 0.05), CSF tau proteins (padjusted < 0.10), and brain atrophy (padjusted < 0.05). CONCLUSIONS: The relationships of late-life BP with AD pathology and neurodegeneration could be modified by anti-hypertensive treatments and varied by AHD classification. These findings provide preliminary evidence for tailored BP management strategy for preventing AD among late-life hypertensive adults.


Assuntos
Doença de Alzheimer , Anti-Hipertensivos , Pressão Sanguínea , Hipertensão , Humanos , Idoso , Feminino , Masculino , Hipertensão/tratamento farmacológico , Doença de Alzheimer/tratamento farmacológico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo , Biomarcadores/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Idoso de 80 Anos ou mais , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico
11.
Sci Rep ; 14(1): 11720, 2024 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-38778154

RESUMO

We studied the inhibitory actions of docosahexaenoic acid (DHA) on the contractions induced by carbachol (CCh), angiotensin II (Ang II), and bradykinin (BK) in guinea pig (GP) gastric fundus smooth muscle (GFSM), particularly focusing on the possible inhibition of store-operated Ca2+ channels (SOCCs). DHA significantly suppressed the contractions induced by CCh, Ang II, and BK; the inhibition of BK-induced contractions was the strongest. Although all contractions were greatly dependent on external Ca2+, more than 80% of BK-induced contractions remained even in the presence of verapamil, a voltage-dependent Ca2+ channel inhibitor. BK-induced contractions in the presence of verapamil were not suppressed by LOE-908 (a receptor-operated Ca2+ channel (ROCC) inhibitor) but were suppressed by SKF-96365 (an SOCC and ROCC inhibitor). BK-induced contractions in the presence of verapamil plus LOE-908 were strongly inhibited by DHA. Furthermore, DHA inhibited GFSM contractions induced by cyclopiazonic acid (CPA) in the presence of verapamil plus LOE-908 and inhibited the intracellular Ca2+ increase due to Ca2+ addition in CPA-treated 293T cells. These findings indicate that Ca2+ influx through SOCCs plays a crucial role in BK-induced contraction in GP GFSM and that this inhibition by DHA is a new mechanism by which this fatty acid inhibits GFSM contractions.


Assuntos
Angiotensina II , Bradicinina , Carbacol , Ácidos Docosa-Hexaenoicos , Fundo Gástrico , Contração Muscular , Músculo Liso , Animais , Cobaias , Ácidos Docosa-Hexaenoicos/farmacologia , Bradicinina/farmacologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Músculo Liso/metabolismo , Carbacol/farmacologia , Contração Muscular/efeitos dos fármacos , Angiotensina II/farmacologia , Fundo Gástrico/efeitos dos fármacos , Fundo Gástrico/fisiologia , Fundo Gástrico/metabolismo , Verapamil/farmacologia , Cálcio/metabolismo , Masculino , Humanos , Canais de Cálcio/metabolismo , Células HEK293 , Bloqueadores dos Canais de Cálcio/farmacologia , Imidazóis/farmacologia
12.
Int J Mol Sci ; 25(9)2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38731963

RESUMO

Venom peptides have evolved to target a wide range of membrane proteins through diverse mechanisms of action and structures, providing promising therapeutic leads for diseases, including pain, epilepsy, and cancer, as well as unique probes of ion channel structure-function. In this work, a high-throughput FLIPR window current screening assay on T-type CaV3.2 guided the isolation of a novel peptide named ω-Buthitoxin-Hf1a from scorpion Hottentotta franzwerneri crude venom. At only 10 amino acid residues with one disulfide bond, it is not only the smallest venom peptide known to target T-type CaVs but also the smallest structured scorpion venom peptide yet discovered. Synthetic Hf1a peptides were prepared with C-terminal amidation (Hf1a-NH2) or a free C-terminus (Hf1a-OH). Electrophysiological characterization revealed Hf1a-NH2 to be a concentration-dependent partial inhibitor of CaV3.2 (IC50 = 1.18 µM) and CaV3.3 (IC50 = 0.49 µM) depolarized currents but was ineffective at CaV3.1. Hf1a-OH did not show activity against any of the three T-type subtypes. Additionally, neither form showed activity against N-type CaV2.2 or L-type calcium channels. The three-dimensional structure of Hf1a-NH2 was determined using NMR spectroscopy and used in docking studies to predict its binding site at CaV3.2 and CaV3.3. As both CaV3.2 and CaV3.3 have been implicated in peripheral pain signaling, the analgesic potential of Hf1a-NH2 was explored in vivo in a mouse model of incision-induced acute post-surgical pain. Consistent with this role, Hf1a-NH2 produced antiallodynia in both mechanical and thermal pain.


Assuntos
Canais de Cálcio Tipo T , Modelos Animais de Doenças , Hiperalgesia , Dor Pós-Operatória , Venenos de Escorpião , Animais , Canais de Cálcio Tipo T/metabolismo , Canais de Cálcio Tipo T/química , Camundongos , Venenos de Escorpião/química , Venenos de Escorpião/farmacologia , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/metabolismo , Cálcio/metabolismo , Masculino , Humanos , Bloqueadores dos Canais de Cálcio/farmacologia , Bloqueadores dos Canais de Cálcio/química
13.
Discov Med ; 36(184): 882-897, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38798249

RESUMO

Cardiovascular disease stands as the leading cause of death globally, with hypertension emerging as an independent risk factor for its development. The worldwide prevalence of hypertension hovers around 30%, encompassing a staggering 1.2 billion patients, and continues to escalate annually. Medication plays a pivotal role in managing hypertension, not only effectively regulating blood pressure (BP) but also substantially mitigating the occurrence of cardiovascular and cerebrovascular diseases. This review comprehensively outlines the categories, mechanisms, clinical applications, and drawbacks of conventional antihypertensive drugs. It delves into the five primary pharmacological classifications, namely ß-receptor blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and diuretics. The emphasis is placed on elucidating the mechanisms, advantages, and research progress of novel antihypertensive drugs targeting emerging areas. These include mineralocorticoid receptor antagonists (MRAs), atrial natriuretic peptides (ANPs), neutral endopeptidase inhibitors (NEPIs), sodium-dependent glucose transporter 2 inhibitors (SGLT-2Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs), endothelin receptor antagonists (ERAs), soluble guanylate cyclase (sGC) agonists, brain aminopeptidase A inhibitors (APAIs), and small interfering ribonucleic acids (siRNAs) targeting hepatic angiotensinogen. Compared to conventional antihypertensive drugs, these novel alternatives exhibit favorable antihypertensive effects with minimal adverse reactions. This review serves as a valuable reference for future research and the clinical application of antihypertensive drugs.


Assuntos
Inibidores da Enzima Conversora de Angiotensina , Anti-Hipertensivos , Hipertensão , Humanos , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Hipertensão/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Bloqueadores dos Canais de Cálcio/farmacologia , Animais , Antagonistas Adrenérgicos beta/uso terapêutico , Antagonistas Adrenérgicos beta/farmacologia , Diuréticos/uso terapêutico , Diuréticos/farmacologia , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico
14.
Int J Cardiol ; 408: 132137, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38705205

RESUMO

BACKGROUND: Limited knowledge of antihypertensive treatment of the elderly potentially impedes effective strategies for hypertension management in this growing patient group. We aimed to investigate temporal trends for first-line drug choice for antihypertensive treatment and treatment continuity among patients ≥75 years from 2000 to 2021. METHODS: Using nationwide Danish registers, patients ≥75 years initiated for the first time on antihypertensive drugs: Angiotensin converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARB), beta blockers (BB), calcium channel blockers (CCB), thiazides, or combinations, were identified. Patients with other indications than hypertension were excluded. Treatment continuity was described using claimed prescriptions the first 180 days following study entry. RESULTS: From 2000 to 2021, 170,769 patients (median age 80 years [interquartile range:77-84], 60.3% female) were included. From 2000 to 2003 to 2015-2021 the proportion of first-line drug choice increased for ACEi (8.7% to 14.9%), ARB (4.1% to 23.9%), and CCB (10.7% to 27.6%), decreased for thiazides (60.6% to 15.9%) and remained stable for BB (12.9% to 14.1%) and combinations (2.9% to 3.6%). For 157,457 patients alive after 180 days, discontinuation was highest among patients initiated on thiazides (28.3%) whereas most patients continued the same single drug regimen if they started on ACEi (55.2%), ARB (65.0%), BB (57.2%) or CCB (59.3%). CONCLUSIONS: From 2000 to 2021 thiazides have been replaced by ACEi, ARB and CCB. Thiazides had the lowest treatment continuity while ARB appeared preferred slightly over ACEi. Differences in adherence in relation to first-line drug choice may warrant scrutiny regarding recommendations for the elderly.


Assuntos
Anti-Hipertensivos , Hipertensão , Sistema de Registros , Humanos , Feminino , Masculino , Idoso , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Anti-Hipertensivos/uso terapêutico , Idoso de 80 Anos ou mais , Estudos de Coortes , Dinamarca/epidemiologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Continuidade da Assistência ao Paciente/tendências , Antagonistas de Receptores de Angiotensina/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico
15.
AAPS PharmSciTech ; 25(5): 95, 2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38710921

RESUMO

Verapamil hydrochloride (VRP), an antihypertensive calcium channel blocker drug has limited bioavailability and short half-life when taken orally. The present study was aimed at developing cubosomes containing VRP for enhancing its bioavailability and targeting to brain for cluster headache (CH) treatment as an off-label use. Factorial design was conducted to analyze the impact of different components on entrapment efficiency (EE%), particle size (PS), zeta potential (ZP), and percent drug release. Various in-vitro characterizations were performed followed by pharmacokinetic and brain targeting studies. The results revealed the significant impact of glyceryl monooleate (GMO) on increasing EE%, PS, and ZP of cubosomes with a negative influence on VRP release. The remarkable effect of Poloxamer 407 (P407) on decreasing EE%, PS, and ZP of cubosomes was observed besides its influence on accelerating VRP release%. The DSC thermograms indicated the successful entrapment of the amorphous state of VRP inside the cubosomes. The design suggested an optimized formulation containing GMO (50% w/w) and P407 (5.5% w/w). Such formulation showed a significant increase in drug permeation through nasal mucosa with high Er value (2.26) when compared to VRP solution. Also, the histopathological study revealed the safety of the utilized components used in the cubosomes preparation. There was a significant enhancement in the VRP bioavailability when loaded in cubosomes owing to its sustained release favored by its direct transport to brain. The I.N optimized formulation had greater BTE% and DTP% at 183.53% and 90.19%, respectively in comparison of 41.80% and 59% for the I.N VRP solution.


Assuntos
Administração Intranasal , Encéfalo , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Glicerídeos , Mucosa Nasal , Tamanho da Partícula , Verapamil , Administração Intranasal/métodos , Animais , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Verapamil/administração & dosagem , Verapamil/farmacocinética , Distribuição Tecidual , Glicerídeos/química , Mucosa Nasal/metabolismo , Disponibilidade Biológica , Ratos , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/administração & dosagem , Poloxâmero/química , Masculino , Química Farmacêutica/métodos , Ratos Wistar , Nanopartículas/química
17.
J Assoc Physicians India ; 72(1): 22-26, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38736070

RESUMO

INTRODUCTION: Azelnidipine, a selective calcium channel blocker, effectively lowers blood pressure (BP) and heart rate (HR) in hypertensive patients, as demonstrated in a retrospective real-world evidence (RWE) study in Indian patients. MATERIALS AND METHODS: This was a retrospective cohort study that included 882 patients aged 18 years or older who had been on azelnidipine treatment for the last 3 months for mild to moderate hypertension (HTN). A structured proforma was utilized to gather data from prescribing physicians to assess the efficacy of azelnidipine (8 and 16 mg) as monotherapy or in combination with other antihypertensive drugs. The primary endpoints of the study were to capture changes in systolic blood pressure (SBP) and diastolic BP (DBP) from baseline to the subsequent visits (4 and 12 weeks), while the secondary endpoints were to measure similar changes in the diabetic group and to estimate the proportion of patients achieving target BP of <130/80 mm Hg and <140/90 mm Hg, respectively. RESULTS: The overall mean reduction of systolic/diastolic BP from baseline to 12 weeks was 13.92/7.91 mm Hg (p-value < 0.0001). The mean reduction of systolic/diastolic BP from baseline to 12 weeks was 11.77/7.43 mm Hg (p-value < 0.0001) in newly diagnosed HTN patients, while in known cases of HTN, it was 16.50/8.48 mm Hg (p-value < 0.0001). In the diabetic group, the mean reduction was 15.35/8.69 mm Hg (p-value < 0.0001). Overall the study showed that in 44 (4.99%) and 408 (46.26%) patients, target BP of <130/80 mm Hg and <140/90 mm Hg, respectively was achieved. The mean change in HR from baseline was a reduction of 5.22 beats/minute. CONCLUSION: Azelnidipine can be an effective antihypertensive drug to treat mild to moderate HTN in Indian patients.


Assuntos
Anti-Hipertensivos , Ácido Azetidinocarboxílico , Pressão Sanguínea , Bloqueadores dos Canais de Cálcio , Di-Hidropiridinas , Hipertensão , Humanos , Di-Hidropiridinas/uso terapêutico , Ácido Azetidinocarboxílico/análogos & derivados , Ácido Azetidinocarboxílico/uso terapêutico , Estudos Retrospectivos , Hipertensão/tratamento farmacológico , Masculino , Bloqueadores dos Canais de Cálcio/uso terapêutico , Feminino , Pessoa de Meia-Idade , Índia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Adulto , Idoso , Resultado do Tratamento
18.
J Assoc Physicians India ; 72(1): 88-95, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38736080

RESUMO

The rapidly increasing burden of hypertension is responsible for premature deaths from cardiovascular disease (CVD), renal disease, and stroke, with a tremendous public health and financial burden. Hypertension detection, treatment, and control vary worldwide; it is still low, particularly in low- and middle-income countries (LMICs). High blood pressure (BP) and CVD risk have a strong, linear, and independent association. They contribute to alarming numbers of all-cause and CVD deaths. A major culprit for increased hypertension is sympathetic activity, and further complications of hypertension are heart failure, ischemic heart disease (IHD), stroke, and renal failure. Now, antihypertensive interventions have emerged as a global public health priority to reduce BP-related morbidity and mortality. Calcium channel blockers (CCB) are highly effective vasodilators. and the most common drugs used for managing hypertension and CVD. Cilnidipine, with both L- and N-type calcium channel blocking activity, is a promising 4th generation CCB. It causes vasodilation via L-type calcium channel blockade and inhibits the sympathetic nervous system (SNS) via N-type calcium channel blockade. Cilnidipine, which acts as a dual L/N-type CCB, is linked to a reduced occurrence of pedal edema compared to amlodipine, which solely blocks L-type calcium channels. The antihypertensive properties of cilnidipine are very substantial, with low BP variability and long-acting properties. It is beneficial for hypertensive patients to deal with morning hypertension and for patients with abnormal nocturnal BP due to exaggerated sympathetic nerve activation. Besides its BP-lowering effect, it also exhibits organ protection via sympathetic nerve inhibition and renin-angiotensin-aldosterone system inhibition; it controls heart rate and proteinuria. Reno-protective, neuroprotective, and cardioprotective effects of cilnidipine have been well-documented and demonstrated.


Assuntos
Bloqueadores dos Canais de Cálcio , Di-Hidropiridinas , Hipertensão , Humanos , Hipertensão/tratamento farmacológico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Di-Hidropiridinas/uso terapêutico , Índia/epidemiologia , Anti-Hipertensivos/uso terapêutico , Consenso , Comorbidade
19.
Circulation ; 149(20): 1549-1564, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38606558

RESUMO

BACKGROUND: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. METHODS: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. RESULTS: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. CONCLUSIONS: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.


Assuntos
Bloqueadores dos Canais de Cálcio , Cateterismo Cardíaco , Hipertensão Arterial Pulmonar , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Hipertensão Arterial Pulmonar/diagnóstico , Hipertensão Arterial Pulmonar/mortalidade , Resultado do Tratamento , Bloqueadores dos Canais de Cálcio/uso terapêutico , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Adulto , Idoso , Anti-Hipertensivos/uso terapêutico
20.
Obstet Gynecol ; 143(6): 819-823, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38626448

RESUMO

There are limited data on the causative agents and characteristics of drug-induced liver injury in pregnant individuals. Data from patients with drug-induced liver injury enrolled in the ongoing multicenter Drug-Induced Liver Injury Network between 2004 and 2022 and occurring during pregnancy or 6 months postpartum were reviewed and compared with cases of drug-induced liver injury in nonpregnant women of childbearing age. Among 325 individuals of childbearing age in the Drug-Induced Liver Injury Network, 16 cases of drug-induced liver injury (5%) occurred during pregnancy or postpartum. Compared with drug-induced liver injury in nonpregnant women, pregnancy-related drug-induced liver injury was more severe ( P <.05). One elective termination and three miscarriages were documented; there were no maternal deaths. We recommend that isoniazid for latent tuberculosis be deferred to the postpartum period whenever feasible and that ß-blockers or calcium channel blockers rather than methyldopa be used for hypertension management during pregnancy.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Complicações na Gravidez , Humanos , Feminino , Gravidez , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Adulto , Complicações na Gravidez/tratamento farmacológico , Estados Unidos/epidemiologia , Adulto Jovem , Isoniazida/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Período Pós-Parto , Metildopa/efeitos adversos , Antagonistas Adrenérgicos beta/efeitos adversos , Antituberculosos/efeitos adversos
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