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1.
Contemp Clin Trials ; 116: 106754, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35390512

RESUMO

BACKGROUND: Recent US guidelines recommend chlorthalidone over other thiazide-type diuretics for the treatment of hypertension based on its long half-life and proven ability to reduce CVD events. Despite recommendations most clinicians prescribe hydrochlorothiazide (HCTZ) over chlorthalidone (CTD). No randomized controlled data exist comparing these two diuretics on cardiovascular outcomes. METHODS: The Diuretic Comparison Project (DCP) is a multicenter, two-arm, parallel, Prospective Randomized Open, Blinded End-point (PROBE) trial testing the primary hypothesis that CTD is superior to HCTZ in the prevention of non-fatal CVD events and non-cancer death. Patients with hypertension taking HCTZ 25 or 50 mg were randomly assigned to either continue their current HCTZ or switch to an equipotent dose of CTD. The primary outcome is time to the first occurrence of a composite outcome consisting of a non-fatal CVD event (stroke, myocardial infarction, urgent coronary revascularization because of unstable angina, or hospitalization for acute heart failure) or non-cancer death. The trial randomized 13,523 patients at 72 VA medical centers. The study is conducted by a centralized research team with site procedures embedded in the electronic health record and all data collected through administrative claims data, with no study related visits for participants. The trial will have 90% power to detect an absolute reduction in the composite event rate of 2.4%. RESULTS: Enrollment ended in November 2021. There are 4128 participting primary care providers and 16,595 patients individually consented to participate, 13,523 of whom were randomized. CONCLUSIONS: DCP should provide much needed evidence as to whether CTD is superior to HCTZ in preventing cardiovascular events in hypertensive patients. CLINICAL TRIAL REGISTRATION: NCT02185417 [https://clinicaltrials.gov/ct2/show/NCT02185417].


Assuntos
Clortalidona , Hipertensão , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Clortalidona/farmacologia , Clortalidona/uso terapêutico , Diuréticos/uso terapêutico , Registros Eletrônicos de Saúde , Humanos , Hidroclorotiazida/farmacologia , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Estudos Prospectivos
2.
Evid Based Dent ; 23(1): 38-39, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35338330

RESUMO

Data sources Data was from The Health Improvement Network (THIN) database from January 1999 to May 2016.Study selection This was a series of population-based, case-control studies looking to evaluate the association between hydrochlorothiazide (HCTZ) exposure and skin, lip and oral cancer in the UK population.Case/control selection Using the THIN database, patients with the following outcomes were grouped: squamous cell carcinoma (SCC) skin cancer; basal cell carcinoma (BCC) skin cancer; melanoma; lip cancer and oral cancer. Patients within the lip cancer and oral cancer groups were accepted with a history of non-melanoma skin cancer (NMSC). Patients in the SCC and BCC groups were not accepted with a history of cancer. Patients with a history of organ transplantation, human immunodeficiency virus (HIV) or immunosuppressant drug use before the index date were not accepted, due to the risk of predisposition to cancer. Controls were randomly selected using incidence density sampling. Up to 100 controls were randomly selected, matched on sex, exact year of birth and calendar year of cohort entry for lip cancer. However, for the remaining outcomes, only 20 controls were matched as above. Adults with incident NMSC, melanoma, lip cancer and oral cancer were matched to controls. Incidence rate ratios (IRRs) for the aforementioned outcomes were calculated for every cumulative HCTZ exposure.Data analysis Odds ratios were calculated using conditional logistic regression. Associations were presented using a two-year HCTZ exposure lag-time and a five-year HCTZ exposure lag-time. Associations were evaluated using sensitivity analysis, restricted to patients with at least ten years' follow-up. There was adjustment for smoking status and BMI. Published incidence rates were used to calculate the absolute risk estimate for SCC as the incidence of SCC in the cohort was less than expected. For high-dose cumulative HCTZ exposure, the number of patients needed to treat to cause one additional cancer (number needed to harm) per year overall was estimated using rate differences. Analysis was carried out using SAS Enterprise Guidev7.1 and STATAv15.Results Relative incidence of SCC, BCC and lip cancer was significantly elevated with every use of HCTZ. Relative incidence of melanoma and oral cancer was not significantly elevated with HCTZ exposure. Smoking was inversely associated with BCC and melanoma risk, but significantly increased the risk of lip and oral cavity cancers. SCC risk was not strongly associated with smoking. Significantly reduced risk of SCC, BCC melanoma and oral cavity cancer was associated with a BMI ≥30 kg/m2.Conclusions The risk of NMSC and lip cancer in a UK population is increased with cumulative high-dose HCTZ exposure. It is therefore important for dentists to note as it may increase suspicion of lesions in patients taking these medications.


Assuntos
Carcinoma Basocelular , Neoplasias Labiais , Neoplasias Cutâneas , Adulto , Carcinoma Basocelular/induzido quimicamente , Carcinoma Basocelular/epidemiologia , Humanos , Hidroclorotiazida/efeitos adversos , Incidência , Neoplasias Labiais/induzido quimicamente , Neoplasias Labiais/epidemiologia , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/patologia , Reino Unido/epidemiologia
3.
Clin J Am Soc Nephrol ; 17(4): 507-517, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35314480

RESUMO

BACKGROUND AND OBJECTIVES: The vasopressin V2 receptor antagonist tolvaptan is the only drug that has been proven to be nephroprotective in autosomal dominant polycystic kidney disease (ADPKD). Tolvaptan also causes polyuria, limiting tolerability. We hypothesized that cotreatment with hydrochlorothiazide or metformin may ameliorate this side effect. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a clinical study and an animal study. In a randomized, controlled, double-blind, crossover trial, we included 13 tolvaptan-treated patients with ADPKD. Patients were treated for three 2-week periods with hydrochlorothiazide, metformin, or placebo in random order. Primary outcome was change in 24-hour urine volume. We also measured GFR and a range of metabolic and kidney injury markers. RESULTS: Patients (age 45±8 years, 54% women, measured GFR of 55±11 ml/min per 1.73 m2) had a baseline urine volume on tolvaptan of 6.9±1.4 L/24 h. Urine volume decreased to 5.1 L/24 h (P<0.001) with hydrochlorothiazide and to 5.4 L/24 h (P<0.001) on metformin. During hydrochlorothiazide treatment, plasma copeptin (surrogate for vasopressin) decreased, quality of life improved, and several markers of kidney damage and glucose metabolism improved. Metformin did not induce changes in these markers or in quality of life. Given these results, the effect of adding hydrochlorothiazide to tolvaptan was investigated on long-term kidney outcome in an animal experiment. Water intake in tolvaptan-hydrochlorothiazide cotreated mice was 35% lower than in mice treated with tolvaptan only. Combination treatment was superior to "no treatment" on markers of disease progression (kidney weight, P=0.003 and cystic index, P=0.04) and superior or equal to tolvaptan alone. CONCLUSIONS: Both metformin and hydrochlorothiazide reduced tolvaptan-caused polyuria in a short-term study. Hydrochlorothiazide also reduced polyuria in a long-term animal model without negatively affecting nephroprotection. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_03_21_CJN11260821.mp3.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Hidroclorotiazida , Rim , Metformina , Rim Policístico Autossômico Dominante , Poliúria , Adulto , Animais , Antagonistas dos Receptores de Hormônios Antidiuréticos/efeitos adversos , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Estudos Cross-Over , Feminino , Humanos , Hidroclorotiazida/farmacologia , Hidroclorotiazida/uso terapêutico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Masculino , Metformina/farmacologia , Metformina/uso terapêutico , Camundongos , Pessoa de Meia-Idade , Rim Policístico Autossômico Dominante/tratamento farmacológico , Poliúria/induzido quimicamente , Poliúria/prevenção & controle , Qualidade de Vida , Receptores de Vasopressinas/uso terapêutico , Tolvaptan/efeitos adversos , Tolvaptan/uso terapêutico , Resultado do Tratamento
4.
Sci Rep ; 12(1): 4957, 2022 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-35322136

RESUMO

Meniere's disease (MD) is a chronic disease that causes episodic vertigo, fluctuating hearing loss, and aural fullness, initially managed by dietary salt reduction, and use of diuretics. Our prior research in autoimmune inner ear disease (AIED) demonstrated that in peripheral blood mononuclear cell (PBMC) from corticosteroid-resistant AIED patients, increased production, processing and release of interleukin-1ß (IL-1ß) is observed and hearing could be improved with use of anakinra, an interleukin-1 receptor antagonist. We have further identified that in these AIED patients, IL-1ß is uniquely processed to a 28 kDa pro-inflammatory product by caspase-7. In the present study, we characterize the production, processing and release of the pro-inflammatory cytokines IL-1ß and IL-6 from PBMC of MD (n = 14) patients in response to sodium chloride (NaCl), and determined the effect of the diuretic triamterene-hydrocholothiazide (T-HCTZ), or anakinra in these patients. We observed that PBMC cultured with NaCl from MD patients show processing of IL-1ß to the 28 kDa product, and that this product is abrogated with T-HCTZ. Our observations are consistent with other autoimmune diseases where high concentrations of NaCl caused release of pro-inflammatory cytokines and may provide further insight as to the mechanism of disease progression in MD patients.


Assuntos
Doenças Autoimunes , Doença de Meniere , Citocinas/metabolismo , Humanos , Hidroclorotiazida/farmacologia , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-1beta/farmacologia , Leucócitos Mononucleares/metabolismo , Doença de Meniere/tratamento farmacológico , Cloreto de Sódio/farmacologia
5.
Int J Clin Pharmacol Ther ; 60(4): 192-206, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35103587

RESUMO

BACKGROUND: A fixed-dose combination (FDC) of candesartan cilexetil, hydrochlorothiazide and rosuvastatin (CC/HCTZ/RSV) has been developed to enhance patient compliance in the primary prevention of cardiovascular diseases. OBJECTIVE: To evaluate if the combination of the product components in the new FDC capsule formulation affects their respective pharmacokinetic and in vitro dissolution patterns. MATERIALS AND METHODS: In vitro dissolution profiles were compared in USP-43 and in biorelevant dissolution media. In vivo comparisons were obtained in a randomized, open-label, single-dose, two-treatment, two-way crossover study in 24 healthy subjects. During each treatment period, subjects received the test formulation (FDC hard capsule containing CC/HCTZ/RSV) or the reference formulation (co-administration of a FDC CC/HCTZ tablet and a RSV tablet). Plasma samples were collected periodically over 48 hours post-dose. Safety and tolerability were assessed. RESULTS: Dissolution profiles of all active drugs in the Test (capsule) and Reference Products (as tablets) were within the tolerance dissolution criteria of USP-43 conditions. HCTZ dissolution profiles were closely similar whereas those for RSV and CC did not match at specific pHs. In the pharmacokinetic study, the 90% confidence intervals (CIs) for the geometric least-square mean ratios of Cmax, AUC0-last, and AUC0-inf were 0.95 - 1.18, 0.95 - 1.15 and 0.95 - 1.13 (CC); 0.91 - 1.10, 0.96 - 1.08, and 0.96 - 1.09 (HCTZ) and 0.82 - 1.23, 0.81 - 1.13, and 0.82 - 1.12 (RSV), respectively. All adverse events were mild. CONCLUSION: The new FDC product (Sinlip Prevent), a stable FDC hard capsule, was bioequivalent (similar pharmacokinetics) when compared to the co-administration of the components and may be considered as a suitable and simplified medication for cardiovascular disease management.


Assuntos
Hidroclorotiazida , Adulto , Benzimidazóis , Compostos de Bifenilo , Estudos Cross-Over , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Hidroclorotiazida/efeitos adversos , Rosuvastatina Cálcica/efeitos adversos , Rosuvastatina Cálcica/farmacocinética , Comprimidos , Tetrazóis , Equivalência Terapêutica
6.
Am J Cardiol ; 167: 62-67, 2022 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-35034692

RESUMO

Uncontrolled hypertension is an important cardiovascular risk factor and therefore requires effective approaches to patient management. This study assessed approaches to the management of patients with Stage 2 hypertension by cardiologists in India. This was a retrospective, multicenter, observational, case-based questionnaire study. Data on demographic characteristics, risk factors associated with Stage 2 hypertension, use of antihypertensive medications, side effects, and approaches to education for 2,540 patients were extracted from questionnaire responses provided by 508 cardiologists. The study population of patients with Stage 2 hypertension had a mean age of 55.0 years. Most of the patients (62.6%) were aged 30 to 60 years and diabetes mellitus was the most prevalent comorbidity (48.9%). Triple antihypertensive therapy was being used by 760 patients, and 634 and 1,146 patients were receiving 4 and 5 different antihypertensive medications, respectively. Telmisartan, amlodipine, chlorthalidone, hydrochlorothiazide, spironolactone, metoprolol, and prazosin were the commonly prescribed drugs. Ankle edema (27.7%) was the most frequent side effect of therapy. Pharmacotherapy was supported by patient education and lifestyle modifications for better blood pressure control. The standardized approach to the collection and assessment of these contemporary data provides useful insights into the characteristics and treatment of patients with Stage 2 hypertension in India.


Assuntos
Cardiologistas , Cardiologia , Hipertensão , American Heart Association , Anlodipino/efeitos adversos , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Humanos , Hidroclorotiazida , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Índia/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
7.
Hypertension ; 79(4): 813-826, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35045721

RESUMO

BACKGROUND: Potassium-induced natriuresis may contribute to the beneficial effects of potassium on blood pressure but has not been well-characterized in human postmenopausal hypertension. We determined the time course and magnitude of potassium-induced natriuresis and kaliuresis compared with hydrochlorothiazide in 19 hypertensive Hispanic postmenopausal women. We also determined the modulating effects of sodium intake, sodium-sensitivity, and activity of the thiazide-sensitive NCC (sodium-chloride cotransporter). METHODS: Sixteen-day inpatient confinement: 8 days low sodium followed by 8 days high sodium intake. During both periods, we determined sodium and potassium excretion following 35 mmol oral KCl versus 50 mg hydrochlorothiazide. We determined sodium-sensitivity as change in 24-hour systolic pressure from low to high sodium. We determined NCC activity by standard thiazide-sensitivity test. RESULTS: Steady-state sodium intake was the key determinant of potassium-induced natriuresis. During low sodium intake, sodium excretion was low and did not increase following 35 mmol KCl indicating continued sodium conservation. Conversely, during high sodium intake, sodium excretion increased sharply following 35 mmol KCl to ≈37% of that produced by hydrochlorothiazide. Under both low and high sodium intake, 35 mmol potassium was mostly excreted within 5 hours, accompanied by a sodium load reflecting the steady-state sodium intake, consistent with independent regulation of sodium/potassium excretion in the human distal nephron. CONCLUSIONS: Potassium-induced natriuresis was not greater in sodium-sensitive versus sodium-resistant hypertensives or hypertensives with higher versus lower basal NCC activity. We studied an acute KCl challenge. It remains to further characterize potassium-induced natriuresis during chronic potassium increase and when potassium is administered a complex potassium-containing meal.


Assuntos
Hipertensão , Sódio na Dieta , Feminino , Humanos , Hidroclorotiazida/farmacologia , Hipertensão/tratamento farmacológico , Natriurese , Pós-Menopausa , Potássio , Sódio , Sódio na Dieta/farmacologia
8.
AAPS PharmSciTech ; 23(1): 56, 2022 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-35043282

RESUMO

Crystal engineering is an emerging tool for altering the physicochemical properties of drug candidates. The objective of the current investigation was to develop cocrystals of hydrochlorothiazide (HCT) with coformers such as nicotinamide (NIC), resorcinol (RSL), and catechol (CAT) using hot-melt extrusion (HME) technology. The liquid-assisted grinding (LAG) method was used to prepare cocrystals by grinding the drug and coformer in a definite molar ratio as a reference and to check the feasibility of cocrystal formation. Cocrystals were prepared using HME and evaluated with differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffractometry, and scanning electron microscopy and compared with LAG cocrystals. Barrel temperature was the critical process parameter for producing high-quality cocrystals in HME. All cocrystals exhibited improved solubility compared to the native drug, and HCT-NIC cocrystals showed a two-fold increase in solubility. Similarly, HCT-RSL and HCT-CAT showed higher solubility profiles and improved diffusion/permeability characteristics compared to that of the pure HCT due to the drug-coformer interactions in the cocrystals. In this study, the solubility of the coformer was the key factor determining cocrystal solubilization. However, hot-melt extrusion is an alternative technology for creating pharmaceutical cocrystals and has potential for industrial scale-up.


Assuntos
Hidroclorotiazida , Preparações Farmacêuticas , Varredura Diferencial de Calorimetria , Cristalização , Permeabilidade , Solubilidade
9.
Comb Chem High Throughput Screen ; 25(2): 307-323, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33353534

RESUMO

BACKGROUND: Solubility/dissolution is said to be the key factor that influences the oral bioavailability of drug and is also the rate limiting step in formulation development. OBJECTIVE: Hydrochlorothiazide (HCZ) is a BCS Class IV drug with low solubility and low permeability. The present work aimed to increase the solubility of hydrochlorothiazide using blends of natural and synthetic hydrotropes. METHODS: Two hydrotropes one from natural (piperazine) and other from the synthetic origin (sodium benzoate) were selected for the formulation of solid dispersion (SD) of HCZ. Preliminary trial batches were prepared by considering the safe dose of both the selected hydrotropes i.e. sodium benzoate (SB) and piperazine (PP). A 32 full factorial design was opted for preparing the optimized solid dispersion of hydrochlorothiazide. RESULTS: The quadratic models were found to be best fitted for the studied responses, which were percent solubility and in-vitro drug release. The results showed increased solubility and in-vitro drug release of HCZ solid dispersions as a function of increasing levels of both hydrotropes. CONCLUSION: In this work, it was concluded that the use of natural hydrotropes along with synthetic hydrotropes gave an effective and safe approach for the solubility enhancement of the HCZ.


Assuntos
Hidroclorotiazida , Disponibilidade Biológica , Liberação Controlada de Fármacos , Solubilidade
10.
Hypertension ; 79(2): 413-423, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34879704

RESUMO

Certain classes of antihypertensive drug may exert specific, blood pressure (BP)-independent protective effects on end-organ damages such as left ventricular hypertrophy, although the overall evidence has not been definitive in clinical trials. To unravel antihypertensive drug-induced gene expression changes that are potentially related to the amelioration of end-organ damages, we performed in vivo phenotypic evaluation and transcriptomic analysis on the heart and the kidney, with administration of antihypertensive drugs to two inbred strains (ie, hypertensive and normotensive) of rats. We chose 6 antihypertensive classes: enalapril (angiotensin-converting enzyme inhibitor), candesartan (angiotensin receptor blocker), hydrochlorothiazide (diuretics), amlodipine (calcium-channel blocker), carvedilol (vasodilating ß-blocker), and hydralazine. In the tested rat strains, 4 of 6 drugs, including 2 renin-angiotensin system inhibitors, were effective for BP lowering, whereas the remaining 2 drugs were not. Besides BP lowering, there appeared to be some interdrug heterogeneity in phenotypic changes, such as suppressed body weight gain and body weight-adjusted heart weight reduction. For the transcriptomic response, a considerable number of genes showed prominent mRNA expression changes either in a BP-dependent or BP-independent manner with substantial diversity between the target organs. Noticeable changes of mRNA expression were induced particularly by renin-angiotensin system blockade, for example, for genes in the natriuretic peptide system (Nppb and Corin) in the heart and for those in the renin-angiotensin system/kallikrein-kinin system (Ren and rat Klk1 paralogs) and those related to calcium ion binding (Calb1 and Slc8a1) in the kidney. The research resources constructed here will help corroborate occasionally inconclusive evidence in clinical settings.


Assuntos
Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Coração/efeitos dos fármacos , Rim/efeitos dos fármacos , Miocárdio/metabolismo , Transcriptoma/efeitos dos fármacos , Anlodipino/farmacologia , Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Carvedilol/farmacologia , Diuréticos/farmacologia , Enalapril/farmacologia , Hidralazina/farmacologia , Hidroclorotiazida/farmacologia , Rim/metabolismo , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Sistema Renina-Angiotensina/efeitos dos fármacos , Tetrazóis/farmacologia
11.
Hypertension ; 79(2): 379-390, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34852633

RESUMO

Nalfurafine is a G-protein-biased KOR (kappa opioid receptor) agonist that produces analgesia and lacks central nervous system adverse effects. Here, we examined the cardiovascular and renal responses to intravenous and oral nalfurafine alone and in combination with furosemide, hydrochlorothiazide, or amiloride. We hypothesized that nalfurafine, given its distinct mechanism of vasopressin inhibition, would increase urine output to these diuretics and limit electrolyte loss. Following catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion and were then administered an intravenous bolus of nalfurafine, a diuretic, or a combination. Mean arterial pressure, heart rate, and urine output were recorded for 90 minutes. In another study, rats were placed in metabolic cages and administered drug in an oral volume load. Hourly urine samples were then collected for 5 hours. Intravenous and oral nalfurafine produced a marked diuresis, antinatriuresis, antikaliuresis, and a decrease in mean arterial pressure. Compared with diuretic treatment alone, intravenous coadministration with nalfurafine significantly increased urine output to furosemide and hydrochlorothiazide and decreased sodium and potassium excretion. Notably, mean arterial pressure was reduced with nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral coadministration of nalfurafine significantly increased urine output to hydrochlorothiazide and decreased sodium and potassium excretion, whereas combination with furosemide only limited the amount of sodium excreted. Further, both intravenous and oral coadministration of nalfurafine enhanced the diuresis to amiloride and decreased sodium excretion. Together, these findings demonstrate that nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, offering a new approach to treat several cardiovascular conditions.


Assuntos
Analgésicos Opioides/farmacologia , Diurese/efeitos dos fármacos , Diuréticos/farmacologia , Morfinanos/farmacologia , Receptores Opioides kappa/agonistas , Compostos de Espiro/farmacologia , Animais , Furosemida/farmacologia , Hidroclorotiazida/farmacologia , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley
12.
J AOAC Int ; 105(2): 623-629, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-34519824

RESUMO

BACKGROUND: Determination of a multi-component mixture by HPLC requires many preliminary runs for method development which is both time-consuming and expensive due to the usage of large solvent volumes. OBJECTIVE: In the present study, the main objective was to reduce the preliminary runs that are required for optimizing the method conditions and also shorten the run time of analysis to be suitable for quality control laboratories where there are a large number of samples to be analyzed. METHODS: That was achieved using a two-factor, three-level response surface experiment which is a multivariate design that predicts the significant factors for optimizing the studied responses. RESULTS: The response surface design suggests that both acetonitrile ratio and flow rate are significant factors for full resolution of the studied mixture: atenolol, amiloride, and hydrochlorothiazide. The studied mixture was fully separated and determined in less than 5 min with perfect resolution. CONCLUSION: Experimental design is a very beneficial tool for optimization of the method conditions in HPLC, especially if the studied mixture ingredients have overlapping peaks. For atenolol, amiloride, and hydrochlorothiazide, acetonitrile and flow rate were found to be the significant factors that affected the resolution of the studied mixture. HIGHLIGHTS: Response surface design is a powerful tool that could be used for predicting the significant factors for separation in HPLC. Optimization of the method conditions was done using a limited number of preliminary runs. The studied ternary mixture was fully separated in less than 5 min with the aid of experimental design.


Assuntos
Anti-Hipertensivos , Hidroclorotiazida , Amilorida/análise , Amilorida/farmacologia , Cromatografia Líquida de Alta Pressão/métodos , Hidroclorotiazida/análise , Modelos Teóricos
14.
J Sep Sci ; 45(4): 824-831, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34910855

RESUMO

Determination of a widely used antihypertensive combination of atenolol and hydrochlorothiazide was achieved by rapid and eco-friendly high-performance liquid chromatography method combined with fluorescence detection. The response surface methodology is conducive to the complete separation of the two drugs in a shorter analysis time. The separation of the mixture was achieved using an Inertsil C18 analytical column (150 × 4.6 mm, 5 µ). The mobile phase used was ethanol: potassium dihydrogen phosphate at pH 3 (65:35 v/v) and the flow rate was 0.7 mL/min. The fluorescence detector operated at excitation and emission wavelengths of 230 and 310 nm (atenolol) and 270 and 375 nm (hydrochlorothiazide). The linearity of the developed method covered a concentration of atenolol of 0.05-5 µg/mL and a concentration of hydrochlorothiazide of 0.02-1 µg/mL. The greenness of the developed method was evaluated by analytical eco-scale and the recently reported evaluation method, that is, green analytical procedure index, and it was found to be an excellent, sensitive, and green alternative to the reported methods. The developed method was validated according to the ICH guidelines and compared with the reference method. No significant difference was found in terms of accuracy.


Assuntos
Atenolol , Hidroclorotiazida , Anti-Hipertensivos , Atenolol/análise , Cromatografia Líquida de Alta Pressão/métodos , Hidroclorotiazida/análise
15.
Adv Ther ; 39(2): 923-942, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34918194

RESUMO

INTRODUCTION: The aim of the study was to evaluate the efficacy and safety of fixed-dose combination (FDC) of metoprolol, telmisartan, and chlorthalidone in patients with essential hypertension and stable coronary artery disease (CAD) who showed inadequate response to dual therapy. METHODS: In this phase III, open-label, multicenter study, 254 adults with stable CAD having uncontrolled hypertension despite being treated with FDC of metoprolol (25/50 mg) and telmisartan (40 mg) were included. Patients received either of the following FDC for 24 weeks: metoprolol (25 mg), telmisartan (40 mg), and chlorthalidone (12.5 mg) (FDC1; n = 139) or metoprolol (50 mg), telmisartan (40 mg), and chlorthalidone (12.5 mg) (FDC2; n = 115) tablets once daily. The FDCs were developed using the novel Wrap Matrix™ platform technology. Primary endpoint assessed the mean change in seated diastolic blood pressure (SeDBP) and seated systolic blood pressure (SeSBP) from baseline to 24 weeks. Secondary efficacy endpoints included proportion of patients achieving < 90 mmHg SeDBP (SeDBP responder) and < 140 mmHg SeSBP (SeSBP responder) at weeks 12, 16, 20, and 24. Safety was assessed throughout the study. RESULTS: A total of 243 (95.70%) patients completed study. The mean change in BP from baseline (FDC1, 155/96 mmHg; FDC2, 165/98 mmHg) to week 24 (FDC1, 128/82 mmHg; FDC2, 131/83 mmHg) was statistically significant (both groups p < 0.0001). Within FDC1 and FDC2, the mean change from baseline to week 24 in SeDBP (82.60 mmHg and 83.09 mmHg) and SeSBP (128.07 mmHg and 131.29 mmHg) was statistically significant (both groups p < 0.0001). At week 24, in FDC1, 80.15% and 84.73% were SeDBP and SeSBP responders, respectively; in FDC2, 79.46% and 74.11% were SeDBP and SeSBP responders, respectively. No serious adverse events or deaths were reported. CONCLUSION: Triple FDCs of metoprolol, telmisartan, and chlorthalidone were considered effective and well tolerated in patients with hypertension who respond inadequately to dual therapy. CLINICAL TRIAL REGISTRATION: CTRI/2016/11/007491.


The increasing prevalence of hypertension in India requires immediate attention. To adequately manage blood pressure and ensure compliance to medications, innovative treatment options involving combination therapy with three or more drugs to treat hypertension need to be explored. Fixed-dose combination (FDC) of three antihypertension drugs, viz., metoprolol, telmisartan, and chlorthalidone, were tested in Indian patients who could not respond adequately to dual treatment. The rationale behind using a combination of three drug types was to take advantage of the complementary actions of each drug class for an enhanced treatment effect. The two variants of FDCs were tested in 254 adults with the most common form of heart disease, i.e., stable coronary artery disease. Changes in seated diastolic and systolic blood pressure (SeDBP and SeSBP) were measured to assess the effectiveness of the FDC. The mean changes in SeDBP and SeSBP were statistically significant by the end of the study, i.e., it determined that results are not explainable by chance alone. A greater proportion of patients (range 74­84%) achieved their target BPs with the FDC used in the study. The FDC variants were well tolerated without any reports of serious adverse events or deaths. Overall, this triple combination therapy option was effective and considered safe to be administered to hypertensive Indian adults with stable coronary artery disease who did not respond adequately to dual antihypertension therapy.


Assuntos
Doença da Artéria Coronariana , Hipertensão , Adulto , Anlodipino , Anti-Hipertensivos , Pressão Sanguínea , Clortalidona/farmacologia , Clortalidona/uso terapêutico , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Quimioterapia Combinada , Hipertensão Essencial/complicações , Hipertensão Essencial/tratamento farmacológico , Humanos , Hidroclorotiazida/uso terapêutico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Imidazóis/uso terapêutico , Metoprolol/farmacologia , Metoprolol/uso terapêutico , Telmisartan/farmacologia , Telmisartan/uso terapêutico , Tetrazóis/uso terapêutico
16.
Hypertens Res ; 45(3): 464-473, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34952949

RESUMO

This study aimed to identify the metabolomic alterations associated with hypertension (HTN) and the response of blood pressure (BP) to thiazide diuretics. A total of 50 participants previously untreated for HTN were prospectively recruited. After a 2-week lifestyle adjustment, 30 participants with systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg were classified into the HTN group and prescribed hydrochlorothiazide (HCTZ) at 50 mg per day for 2 weeks. The remaining 20 participants, who had relatively normal BP, were assigned to the normotension group. Metabolomic profiles related to the response of BP to thiazide diuretics were analyzed. A total of 73 differential metabolites were found to be associated with HTN, and 27 metabolites were significantly changed upon HCTZ treatment (HCTZ-sensitive metabolites). Among the identified metabolites, 7 (aspartate, histidine, C5-DC, C5-M-DC, C14:1, phosphatidylcholine ae C34:1, and phosphatidylcholine ae C34:3) were positively associated with HTN and decreased in abundance upon HCTZ treatment (HCTZ-reduced/HTN-associated metabolites). Moreover, multivariate analysis of 20 metabolites whose baseline levels were associated with the response of BP revealed that aspartate, glutamate, lysophosphatidylcholine C16:0, lysophosphatidylcholine C20:3, and sphingomyelin C24:1 were independently related to systolic BP reduction, and lysophosphatidylcholine C20:3 was independently associated with diastolic BP reduction. In conclusion, we identified 5 metabolites independently related to BP changes with HCTZ treatment. An advanced biomarker profile of thiazide-induced metabolomic changes may provide a clue with which to further explore the complex and mixed effects of thiazide treatment in a clinical setting.


Assuntos
Hipertensão , Inibidores de Simportadores de Cloreto de Sódio , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Diuréticos/uso terapêutico , Quimioterapia Combinada , Humanos , Hidroclorotiazida/uso terapêutico , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Resultado do Tratamento
17.
Xenobiotica ; 51(12): 1372-1388, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34842039

RESUMO

1. Model evaluation is an important issue in population analyses. Our aim was to perform and illustrate metrics and techniques for internal and external evaluation with an application to population pharmacokinetics of hydrochlorothiazide (HCTZ).2. A nonlinear mixed effects model was used to study the pharmacokinetics of HCTZ. In addition, different types of internal assessment tools and external metrics were used for model evaluation. External evaluation was performed using an alternative dataset that included data from an independent group of subjects. For comparison, a previously published population pharmacokinetic model for HCTZ was applied to the same data.3. A two-compartment model with first-order oral absorption using a constant time delay between administration and absorption and first-order elimination best described HCTZ pharmacokinetics. Age had a statistically significant effect on HCTZ clearance. The final model performed adequately in the internal and external assessment tests. The final model showed better predictive performance than the other previously published HCTZ model.4. Finally, a robust population pharmacokinetic model for HCTZ in adults was constructed and validated internally and externally. Incorporating analytical assessment of nonlinear pharmacokinetics into the modelling may be a promising approach to improve the predictive power of the model.


Assuntos
Hidroclorotiazida , Adulto , Humanos , Cinética
18.
Open Vet J ; 11(3): 342-345, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722194

RESUMO

Background: The use of thiazide diuretics is recommended in the American College of Veterinary Internal Medicine guidelines for advanced heart failure due to mitral insufficiency (MI) in dogs. However, there are no large-scale reports of the use of thiazide diuretics in dogs with advanced heart failure. Aim: This retrospective study evaluated the therapeutic effect of concomitant hydrochlorothiazide (HTCZ) with loop diuretics in dogs with heart failure. Methods: The study included 14 dogs diagnosed with advanced pulmonary edema with MI at two facilities. In all cases, high-dose loop diuretics (torsemide; 0.78-4 mg/kg/day) did not improve pulmonary edema. The results of the echocardiography and renal function tests before and after the administration of HTCZ (0.2-0.84 mg/kg/day) in addition to torsemide were statistically compared. Results: The echocardiographic data demonstrated significant improvement in relation to cardiac stress; left atrium to the aorta ratio, normalized left ventricular internal dimension in diastole, and E wave velocity (m/s) after HTCZ administration. However, blood urea nitrogen and creatinine levels increased, and potassium levels decreased, indicating a decline in renal function following HTCZ administration. Conclusion: This study suggests that the administration of HTCZ in combination with loop diuretics may be beneficial during advanced heart failure due to MI in dogs. The results can also be extended to patients who are resistant to loop diuretics, resulting in the improvement of cardiac function. However, as the combination of HTCZ and loop diuretics can deteriorate renal function, caution should be exercised prior to making recommendations regarding its use, and renal function should be monitored.


Assuntos
Doenças do Cão , Insuficiência Cardíaca , Animais , Doenças do Cão/tratamento farmacológico , Cães , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/veterinária , Hidroclorotiazida/uso terapêutico , Estudos Retrospectivos , Inibidores de Simportadores de Cloreto de Sódio e Potássio
19.
J Cardiovasc Pharmacol Ther ; 26(6): 724-735, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34623176

RESUMO

BACKGROUND: Thiazides are one of the most common antihypertensive drugs used for hypertension treatment and hydrochlorothiazide (HCTZ) is the most frequently used diuretic for hypertension treatment. The Rho/Rho-kinase (ROCK) path plays a key function in cardiovascular remodeling. We hypothesized that in preclinical hypertension HCTZ reduces myocardial ROCK activation and consequent myocardial remodeling. METHODS: The preclinical model of deoxycorticosterone (DOCA)-salt hypertension was used (Sprague-Dawley male rats). After 3 weeks, in 3 different groups: HCTZ, the ROCK inhibitor fasudil or spironolactone was added (3 weeks). After 6 weeks myocardial hypertrophy and fibrosis, cardiac levels of profibrotic proteins, mRNA levels (RT PCR) of pro remodeling and pro oxidative molecules and ROCK activity were determined. RESULTS: Blood pressure, myocardial hypertrophy and fibrosis were reduced significantly by HCTZ, fasudil and spironolactone. In the heart, increased levels of the pro-fibrotic proteins Col-I, Col-III and TGF-ß1 and gene expression of pro-remodeling molecules TGF-ß1, CTGF, MCP-1 and PAI-1 and the pro-oxidative molecules gp91phox and p22phox were significantly reduced by HCTZ, fasudil and spironolactone. ROCK activity in the myocardium was increased by 54% (P < 0.05) as related to the sham group and HCTZ, spironolactone and fasudil, reduced ROCK activation to control levels. CONCLUSIONS: HCTZ reduced pathologic LVH by controlling blood pressure, hypertrophy and myocardial fibrosis and by decreasing myocardial ROCK activation, expression of pro remodeling, pro fibrotic and pro oxidative genes. In hypertension, the observed effects of HCTZ on the myocardium might explain preventive outcomes of thiazides in hypertension, specifically on LVH regression and incident heart failure.


Assuntos
Anti-Hipertensivos/farmacologia , Cardiomegalia/tratamento farmacológico , Fibrose/tratamento farmacológico , Coração/efeitos dos fármacos , Hidroclorotiazida/farmacologia , Hipertensão/tratamento farmacológico , Animais , Pressão Sanguínea/efeitos dos fármacos , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Hipertensão/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Fator de Crescimento Transformador beta1/metabolismo , Quinases Associadas a rho/metabolismo
20.
Cancer Epidemiol Biomarkers Prev ; 30(11): 2114-2121, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34493493

RESUMO

BACKGROUND: Because of continuous hyperglycemia and hyperinsulinemia and the use of photosensitizing drug, hydrochlorothiazide (HCTZ), the risk of cutaneous squamous cell carcinoma (cSCC) might be increased among patients with diabetes. This study aimed to estimate the risk of cSCC among HCTZ users with type 2 diabetes, and to determine whether thiazide-like diuretics, another drug in the same class with HCTZ, would be safer. METHODS: We linked the benchmarking database in Dutch primary care, the Netherlands Cancer Registry, and the Dutch Personal Records Database (1998-2019). All 71,648 patients were included, except for those who had a history of skin cancer prior to cohort entry. We used Cox modeling to estimate the HRs and 95% confidence intervals for cSCC. The model was adjusted by cumulative exposure to each antihypertensive, age, sex, smoking, body mass index, blood pressure, serum creatinine, other confounding drug use at cohort entry, and cohort entry year. RESULTS: There were 1,409 cSCC events (23 among thiazide-like diuretics users), during a follow-up of 679,789 person-years. Compared with no HCTZ use, the adjusted HRs for HCTZ use were 1.18 (1.00-1.40) for ≤2 years, 1.57 (1.32-1.88) for 2 to 4 years, and 2.09 (1.73-2.52) for >4 years. The HR was 0.90 (0.79-1.03) for an additional year of thiazide-like diuretic use. CONCLUSIONS: In patients with diabetes, exposure to HCTZ for >2 years is associated with an increased risk of cSCC, whereas no increased risk associated with thiazide-like diuretics was observed. IMPACT: The potential increased risk of cSCC should be a consideration when prescribing HCTZ, with thiazide-like diuretics offering a safer alternative.


Assuntos
Carcinoma de Células Escamosas/etiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diuréticos/efeitos adversos , Hidroclorotiazida/efeitos adversos , Neoplasias Cutâneas/etiologia , Idoso , Diuréticos/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Humanos , Hidroclorotiazida/administração & dosagem , Masculino , Pessoa de Meia-Idade , Transtornos de Fotossensibilidade/induzido quimicamente , Transtornos de Fotossensibilidade/complicações , Modelos de Riscos Proporcionais , Estudos Prospectivos , Sistema de Registros
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