RESUMEN
PURPOSE: Long-term use of hydrochlorothiazide increases the risk of non-melanoma skin cancer. We aimed to evaluate potential changes in the use of hydrochlorothiazide in Switzerland after a direct healthcare professional communication (DHPC) in November 2018 by Swissmedic. METHODS: We performed interrupted time-series analyses using a large Swiss healthcare claims database (2015-2021). Within monthly intervals, we quantified the total number of claims and the total dispensed 'defined daily doses' (DDD) for preparations containing (1) hydrochlorothiazide, (2) angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II-receptor blockers (ARB), (3) calcium-channel blockers (CCB) and (4) thiazide-like diuretics per 10 000 persons. Using segmented linear regression, we quantified the pre-DHPC trend, the immediate change and the post-DHPC change in trend for total claims and DDD for the four drug classes weighted for the demographic distribution of the Swiss population. RESULTS: ACE inhibitors and ARB were the most frequently claimed antihypertensive drugs with 300-400 claims per 10 000 persons, which increased by 5.4% during the study period. The average number of hydrochlorothiazide claims (157/10 000 persons in 2015) declined by 35% between 2015 and 2021. The decrease started prior to the DHPC, but the DHPC was associated with an immediate 6.1% decline and an accelerated decline in claims over time after the DHPC (similar results for DDD). This coincided with a 23% increase in claims of CCB (dihydropyridine type) over 7 years, whereas use of other antihypertensives increased less. CONCLUSION: Our results suggest that the DHPC by Swissmedic in 2018 accelerated a pre-existing decline in the use of hydrochlorothiazide in Switzerland.
Asunto(s)
Antihipertensivos , Hidroclorotiazida , Análisis de Series de Tiempo Interrumpido , Neoplasias Cutáneas , Humanos , Suiza/epidemiología , Hidroclorotiazida/efectos adversos , Antihipertensivos/efectos adversos , Neoplasias Cutáneas/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Bases de Datos Factuales/estadística & datos numéricos , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antagonistas de Receptores de Angiotensina/efectos adversos , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiologíaRESUMEN
BACKGROUND: Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease (AIBD). Some reports suggest that it has a drug-related pathogenesis especially anti-hypertensive drug. CASE PRESENTATION: A 67-year-old man with a 7-year history of essential hypertension was prescribed enalapril maleate for 5 months. He presented at our department with pain, ulcers, and blisters on the oral mucosa. We performed clinical, histopathology, and direct immunofluorescence examinations, and findings were consistent with the diagnostic criteria for MMP. Consequently, we consulted with the cardiovascular physician and agreed to discontinue the enalapril maleate replacing it with irbesartan/hydrochlorothiazide tablets and topical corticosteroid therapies instead. The lesions healed without recurrence. CONCLUSIONS: ABID induced by antihypertensive drugs have been reported, and enalapril maleate has been implicated as an antihypertensive agent that may trigger AIBDs, such as MMP. This case highlights the potential relationship between antihypertensive drugs and MMP, of which clinicians should be aware to accurately diagnose and promptly relieve patients' pain.
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Antihipertensivos , Enalapril , Penfigoide Benigno de la Membrana Mucosa , Humanos , Enalapril/efectos adversos , Enalapril/uso terapéutico , Masculino , Anciano , Antihipertensivos/efectos adversos , Antihipertensivos/uso terapéutico , Penfigoide Benigno de la Membrana Mucosa/tratamiento farmacológico , Penfigoide Benigno de la Membrana Mucosa/diagnóstico , Hipertensión/tratamiento farmacológico , Hipertensión/complicaciones , Irbesartán/uso terapéutico , Hidroclorotiazida/efectos adversos , Hidroclorotiazida/uso terapéuticoRESUMEN
The pathogenesis of cutaneous tumors has been known for decades yet remains largely unexplained or incompletely understood. The reason for this mystery lies in the concepts of photosensitivity and phototoxicity: how do they arise or what actually causes them? Recently published data in the medical literature link certain nitrosamines such as nitrosomorpholine, for example, to gene and phototoxicity in humans. A number of other nitrosamines analogous in action and structure are found as contaminants in about 300 of the most widely distributed pharmaceuticals worldwide: NDEA, NDMA, NMBA and many others. These contaminated drugs include beta blockers/ bisoprolol/, thiazide diuretics/ hydrochlorothiazide/, antiarrhythmics/ propafenone/, ACE inhibitors/ lisinopril/, but also a number of other drugs which are, according to the FDA, found to have contaminants with a certain carcinogenic potency ranging between 1 and 5. The phototoxicity and genotoxicity of these contaminants, attributed to the pathogenesis of skin tumors, still remain a mystery. The problems of the intake of the above-mentioned groups of drugs arise mainly on the basis of the official bulletins of the regulatory bodies, namely that: in practice, the intake of polymedication could in many cases also be considered as regular, permanent, long-term intake of contaminants/carcinogens/mutagens of heterogeneous type, also known as nitrosamines or NDSRIs. Nitrosamines are genome modifiers in humans and cause acquired mutations. Their concomitant administration in the context of standard, but currently not yet officially declared as contaminated polymedication, would be able to block certain tumor suppressor genes (p53) as well as activate RAS oncogenes. Or in practice- daily administration of a particular combination of drugs could activate the cascades of carcinogenesis regulating the genesis of skin cancer. Precisely because of this fact, it should not be surprising to anyone that the concurrent intake of the aforementioned drugs could also be associated with the clinical manifestation of multiple keratinocytic tumors. We describe a consecutive case of a patient who developed 4 keratinocytic tumors: 2 basal cell carcinomas, 1 keratoacanthoma, and 1 squamous cell carcinoma on a background of potentially contaminated polymedication with propafenone, lisinopril, hydrochlorothiazide, and bisoprolol. Recently published innovative international data on the topic are discussed in the context of concepts such as drug-mediated nitrosogenesis, photonitrosо-carcinogenesis and metabolic programming/ reprogramming of the tumor cell.
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Antihipertensivos , Neoplasias Cutáneas , Humanos , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Antihipertensivos/farmacología , Lisinopril/farmacología , Lisinopril/uso terapéutico , Bisoprolol/farmacología , Bisoprolol/uso terapéutico , Nitrosaminas , Masculino , Hidroclorotiazida/farmacología , Carcinoma Basocelular/metabolismo , Carcinoma Basocelular/tratamiento farmacológico , Carcinoma Basocelular/patología , Carcinoma Basocelular/genética , Antiarrítmicos/farmacología , Femenino , Reprogramación MetabólicaRESUMEN
Special attention is given to the pharmacological treatment of combined medication of Carvedilol and hydrochlorothiazide which is the most effective and the most beneficial therapy for hypertensive patients with diabetes and various metabolic comorbidities. This work represents spectrophotometric platform scenarios based on factorized spectrum (FS) using interpoint data difference resolution scenarios (IDDRS) coupled with spectrum subtraction method (SS) for the concurrent quantification of carvedilol (CAR) and hydrochlorothiazide (HCT) when present together in a combination without the need for any initial physical separation steps. This IDD resolution scenario based on manipulating the zero-order spectra (D0) of both drugs in the mixture with various spectral features at different wavelength regions (200-400 nm), region I (220-250 nm), region II (240-300 nm) and region III (270-320 nm) via absorbance resolution (AR) and induced absorbance resolution (IAR) methods coupled with corresponding spectrum subtraction (SS). The calibration curves were established across the linearity ranges of 2.0-12.0 µg/mL at 242.50 nm and 4.0-40.0 µg/mL at 285.5 nm for CAR and 1.0-11.0 µg/mL at 226.10 nm and 2.0-20.0 µg/mL at 270.5 nm for HCT. Moreover, methods' validation was confirmed via ICH guidelines. A Multicenter comparison between sensitivity, specificity in respect resolution sequence were applied using different wavelength regions with various concentration ranges was applied and finally spectral resolution recommendation is issued and cumulative validation score (CVS) is calculated as an indicator in the risk analysis. In quality control laboratories, the studied approaches are applicable for conducting analysis on the mentioned drugs. In addition, the selection of spectrophotometry aligns with the principles of green analytical chemistry, an approach that resonates with the overarching theme of minimizing environmental impact. Via four metric tools named: analytical greenness (AGREE), green analytical procedure index (GAPI), analytical eco-scale, and national environmental method index (NEMI), methods' greenness profile was guaranteed.
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Carvedilol , Hidroclorotiazida , Espectrofotometría , Carvedilol/análisis , Hidroclorotiazida/análisis , Espectrofotometría/métodos , Medición de Riesgo , Humanos , Antihipertensivos/análisisRESUMEN
The Na+-Cl- cotransporter (NCC) drives salt reabsorption in the kidney and plays a decisive role in balancing electrolytes and blood pressure. Thiazide and thiazide-like diuretics inhibit NCC-mediated renal salt retention and have been cornerstones for treating hypertension and edema since the 1950s. Here we determine NCC co-structures individually complexed with the thiazide drug hydrochlorothiazide, and two thiazide-like drugs chlorthalidone and indapamide, revealing that they fit into an orthosteric site and occlude the NCC ion translocation pathway. Aberrant NCC activation by the WNKs-SPAK kinase cascade underlies Familial Hyperkalemic Hypertension, but it remains unknown whether/how phosphorylation transforms the NCC structure to accelerate ion translocation. We show that an intracellular amino-terminal motif of NCC, once phosphorylated, associates with the carboxyl-terminal domain, and together, they interact with the transmembrane domain. These interactions suggest a phosphorylation-dependent allosteric network that directly influences NCC ion translocation.
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Hidroclorotiazida , Inhibidores de los Simportadores del Cloruro de Sodio , Miembro 3 de la Familia de Transportadores de Soluto 12 , Fosforilación , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/química , Humanos , Hidroclorotiazida/farmacología , Hidroclorotiazida/química , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Animales , Clortalidona/metabolismo , Clortalidona/química , Clortalidona/farmacología , Proteínas Quinasas/metabolismo , Proteínas Quinasas/química , Diuréticos/farmacología , Diuréticos/química , Diuréticos/metabolismo , Tiazidas/farmacología , Tiazidas/química , Tiazidas/metabolismo , Células HEK293 , Modelos Moleculares , Proteínas Serina-Treonina QuinasasRESUMEN
BACKGROUND: Acute declines in estimated glomerular filtration rate (eGFR) occur commonly after starting angiotensin-converting enzyme inhibitors. Whether declines in eGFR that occur after simultaneously starting angiotensin-converting enzyme inhibitors with other antihypertensive agents modifies the benefits of these agents on cardiovascular outcomes is unclear. METHODS AND RESULTS: We identified predictors of acute declines in eGFR (>15% over 3 months) during randomization to benazepril plus amlodipine versus benazepril plus hydrochlorothiazide in the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial. We then determined the relation between declines in eGFR (treated as a binary variable, ≤15% versus >15% and separately, as a restricted spline variable) and the composite risk of fatal and nonfatal cardiovascular events using Cox proportional hazards models. We included 10 714 participants (median age 68 years [Q1 63, Q3 73]), of whom 1024 reached the trial end point over median follow-up of 2.8 years. Predictors of acute declines in eGFR>15% over 3 months included assignment to hydrochlorothiazide (versus amlodipine) and higher baseline albuminuria. Overall, declines in eGFR ≥15% (versus <15%) were associated with a 26% higher hazard of cardiovascular outcomes (95% CI, 1.07-1.48). In spline-based analysis, risk for cardiovascular outcomes was higher in the hydrochlorothiazide arm at every level of decline in eGFR compared with the same magnitude of eGFR decline in the amlodipine arm. CONCLUSION: Combined use of benazepril and amlodipine remains superior to benazepril and hydrochlorothiazide for cardiovascular outcomes, regardless of the magnitude of the decline in eGFR that occurred with initiation of therapy.
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Amlodipino , Inhibidores de la Enzima Convertidora de Angiotensina , Antihipertensivos , Benzazepinas , Quimioterapia Combinada , Tasa de Filtración Glomerular , Hidroclorotiazida , Hipertensión , Humanos , Amlodipino/uso terapéutico , Amlodipino/efectos adversos , Hidroclorotiazida/uso terapéutico , Hidroclorotiazida/efectos adversos , Masculino , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Anciano , Persona de Mediana Edad , Benzazepinas/uso terapéutico , Benzazepinas/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Hipertensión/diagnóstico , Antihipertensivos/uso terapéutico , Antihipertensivos/efectos adversos , Resultado del Tratamiento , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/epidemiología , Riñón/fisiopatología , Riñón/efectos de los fármacos , Factores de Tiempo , Factores de Riesgo , Medición de Riesgo , Bloqueadores de los Canales de Calcio/uso terapéutico , Bloqueadores de los Canales de Calcio/efectos adversosRESUMEN
ABSTRACT: Because of its greater reduction of major adverse cardiovascular events (MACE), chlorthalidone is recommended over hydrochlorothiazide as the preferred diuretic for patients with primary hypertension. However, hydrochlorothiazide is more commonly prescribed than chlorthalidone for this condition. This article reviews recent studies investigating the effectiveness of chlorthalidone and hydrochlorothiazide in reducing MACE, to help clinicians make an evidence-based informed decision on which diuretic to prescribe.
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Antihipertensivos , Clortalidona , Diuréticos , Hidroclorotiazida , Hipertensión , Humanos , Clortalidona/administración & dosificación , Clortalidona/uso terapéutico , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/uso terapéutico , Hipertensión/tratamiento farmacológico , Diuréticos/administración & dosificación , Diuréticos/uso terapéutico , Antihipertensivos/administración & dosificación , Antihipertensivos/uso terapéutico , Enfermedades Cardiovasculares/prevención & control , Enfermedades Cardiovasculares/tratamiento farmacológicoRESUMEN
BACKGROUND: Poststroke cognitive impairment is prevalent worldwide, with no satisfactory preventative therapeutic strategies. We report on the effect of a cardiovascular polypill on cognitive performance among recent stroke survivors. METHODS AND RESULTS: The SMAART (Stroke Minimization through Additive Anti-atherosclerotic Agents in Routine Treatment) trial was a phase II randomized trial primarily assessing the polypill versus usual care for secondary prevention after a recent ischemic stroke. Participants allocated to the experimental arm were provided 2 Polycaps taken orally once a day for 12 months. A capsule of Polycap contained aspirin 100 mg, simvastatin 20 mg, hydrochlorothiazide 12.5 mg, ramipril 5 mg, and atenolol 50 mg. Participants in the usual care arm received standard secondary prevention therapy. We compared slopes of the trajectory of raw scores in the executive, language, memory, and visuospatial cognitive domains and aggregated cognitive scores over 12 months via a linear mixed-effects model. We enrolled 148 eligible participants (n=74 in each arm) and 59 versus 64 participants in the polypill and usual care arms, respectively, at month 12. Compared with the usual care arm, the slopes of cognitive performance over 12 months in the polypill arm were steeper by 2.02 units (95% CI, 0.52-3.53), P=0.009 in executive domain, 1.88 units (95% CI, 0.42-3.34), P=0.012 in language domain, 2.60 (0.03-5.17), P=0.049 in memory domain, 0.55 (-0.80 to 1.91), P=0.42 in the visuospatial domain, and global cognitive performance 6.87 units (95% CI, 1.44-12.30), P=0.013. CONCLUSIONS: The cardiovascular polypill is associated with a signal of better cognitive performance over 12 months among stroke survivors. Further definitive trials are warranted. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT03329599.
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Atenolol , Cognición , Combinación de Medicamentos , Hidroclorotiazida , Humanos , Femenino , Masculino , Persona de Mediana Edad , Cognición/efectos de los fármacos , Hidroclorotiazida/administración & dosificación , Atenolol/administración & dosificación , Atenolol/uso terapéutico , Aspirina/administración & dosificación , Prevención Secundaria/métodos , Anciano , Simvastatina/administración & dosificación , Simvastatina/uso terapéutico , Ramipril/administración & dosificación , Ramipril/uso terapéutico , Accidente Cerebrovascular Isquémico , Resultado del Tratamiento , Accidente Cerebrovascular , Factores de TiempoRESUMEN
Purpose: Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ. Methods: This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated. Results: The 90% CI of the ratio of geometric means (combination: monotherapy) for AUCτ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80-1.25. For henagliflozin, co-administration increased Css, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased Css, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported. Conclusion: Although Css,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing. Trial Registration: ClinicalTrials.gov NCT06083116.
Asunto(s)
Interacciones Farmacológicas , Voluntarios Sanos , Hidroclorotiazida , Adulto , Femenino , Humanos , Masculino , Adulto Joven , Pueblo Asiatico , Relación Dosis-Respuesta a Droga , Pueblos del Este de Asia , Glucósidos/administración & dosificación , Glucósidos/farmacocinética , Glucósidos/farmacología , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/farmacocinética , Hidroclorotiazida/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/administración & dosificación , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacocinética , ChinaRESUMEN
Since 3D printing technology is an emerging field in pharmaceutical technology, the present study aimed at the development of a mixed-mode liquid chromatographic method for the separation and determination of hydrochlorothiazide, diltiazem, and propranolol to investigate their in-vitro release performance from 3D printed tablets. Due to the unique properties of the mixed-mode stationary phase, the three drugs were separated in less than 8â¯min under isocratic elution. Method development was accomplished following the Analytical Quality by Design principles and was evaluated using risk assessment and multivariate analysis. The influences of critical method parameters on critical method attributes (were screened using a 2-level fractional factorial design and subsequently optimized through a central composite design. The method operable design region was approved by the establishment of a robust zone using Monte Carlo simulation and capability analysis. The validation of the HPLC method was performed based on the total error concept. The relative bias was varied between â 11.6â¯% and 10.5â¯% and the RSD values for repeatability and intermediate precision were below 4.4â¯% in all cases. The limits of detection (LOD) ranged between 0.17 - 0.90⯵g/mL and were adequate for the specific application. The developed method was successfully applied to the analysis of the studied drugs in in-vitro drug release samples obtained from 3D-printed tablets combining the above-mentioned active pharmaceutical ingredients (APIs).
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Diltiazem , Liberación de Fármacos , Hidroclorotiazida , Límite de Detección , Impresión Tridimensional , Propranolol , Comprimidos , Hidroclorotiazida/análisis , Hidroclorotiazida/química , Cromatografía Líquida de Alta Presión/métodos , Diltiazem/análisis , Diltiazem/química , Propranolol/análisis , Propranolol/química , Reproducibilidad de los Resultados , Tecnología Farmacéutica/métodos , Método de Montecarlo , Química Farmacéutica/métodosRESUMEN
Diuretics have been used for decades in the treatment of hypertension. Its efficacy has been demonstrated in numerous clinical trials. It is well known that the reduction in cardiovascular risk is a consequence of the reduction in blood pressure levels regardless of the drug used, but thiazide diuretics continue to be first-line drugs, especially in low doses and combined with other drugs. The debate on the advantages of using chlorthalidone or hydrochlorothiazide continues, however hydrochlorothiazide is drug most used and for which there is greater availability. The association with potassium-sparing diuretics increases the effectiveness and reduces the adverse reactions of thiazides. A new group of drugs, close to potassium-sparing diuretics, that antagonise aldosterone synthase are showing promising results as antihypertensives. There are no significant differences between men and women regarding the antihypertensive effect of thiazide diuretics.
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Antihipertensivos , Diuréticos , Hipertensión , Humanos , Hipertensión/tratamiento farmacológico , Diuréticos/efectos adversos , Diuréticos/administración & dosificación , Diuréticos/uso terapéutico , Diuréticos/farmacología , Antihipertensivos/efectos adversos , Antihipertensivos/administración & dosificación , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversos , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Inhibidores de los Simportadores del Cloruro de Sodio/administración & dosificación , Inhibidores de los Simportadores del Cloruro de Sodio/farmacología , Hidroclorotiazida/efectos adversos , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/uso terapéutico , Clortalidona/administración & dosificación , Clortalidona/uso terapéutico , Clortalidona/efectos adversos , Femenino , Masculino , Quimioterapia CombinadaRESUMEN
Wet granulation, a particle size enlargement process, can significantly enhance the critical quality attributes of powders and improve the ability to form tablets in pharmaceutical manufacturing. In this study, a mechanistic-based population balance model is applied to twin screw wet granulation. This model incorporated a recently developed breakage kernel specifically designed for twin screw granulation, along with nucleation, layering, and consolidation. Calibration and validation were performed on Hydrochlorothiazide and Acetaminophen formulations, which exhibit different particle size and wettability characteristics. Utilizing a compartmental experimental dataset, a comprehensive global sensitivity analysis identified critical inputs impacting quality attributes. The study revealed that the nucleation rate process model, effectively represented particle size distributions for both formulations. Adjustments to nucleation and breakage rate parameters, influenced by material properties and screw configuration, improved the model's accuracy. A model-driven workflow was proposed, offering step-by-step guidelines and facilitating PBM model usage, providing essential details for future active pharmaceutical ingredient (API) formulations.
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Acetaminofén , Composición de Medicamentos , Hidroclorotiazida , Tamaño de la Partícula , Acetaminofén/química , Composición de Medicamentos/métodos , Calibración , Hidroclorotiazida/química , Flujo de Trabajo , Polvos , Humectabilidad , Química Farmacéutica/métodos , Comprimidos , Modelos TeóricosRESUMEN
BACKGROUND AND PURPOSE: This study analyses whether first-line antihypertensive drugs ameliorate the dysbiosis state in hypertension, and to test if this modification contributes to their blood pressure (BP) lowering properties in a genetic model of neurogenic hypertension. EXPERIMENTAL APPROACH: Twenty-week-old male Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were untreated or treated with captopril, amlodipine or hydrochlorothiazide. A faecal microbiota transplantation (FMT) experiment was also performed by gavage of faecal content from donor SHR-treated groups to SHR recipients for 3 weeks. KEY RESULTS: Faeces from SHR showed gut dysbiosis, characterized by lower acetate- and higher lactate-producing bacteria and lower strict anaerobic bacteria. All three drugs increased the anaerobic bacteria proportion, captopril and amlodipine restored the proportion of acetate-producing bacterial populations to WKY levels, whereas hydrochlorothiazide decreased butyrate-producing bacteria. Captopril and amlodipine decreased gut pathology and permeability and attenuated sympathetic drive in the gut. Both drugs decreased neuroinflammation and oxidative stress in the hypothalamic paraventricular nuclei. Hydrochlorothiazide was unable to reduce neuroinflammation, gut sympathetic tone and gut integrity. FMT from SHR-amlodipine to SHR decreased BP, ameliorated aortic endothelium-dependent relaxation to acetylcholine, lowered NADPH oxidase activity, aortic Th17 infiltration and reduced neuroinflammation, whereas FMT from SHR-hydrochlorothiazide did not have these effects. CONCLUSIONS AND IMPLICATIONS: First-line antihypertensive drugs induced different modifications of gut integrity and gut dysbiosis in SHR, which result in no contribution of microbiota in the BP lowering effects of hydrochlorothiazide, whereas the vasculo-protective effect induced by amlodipine involves gut microbiota reshaping and gut-immune system communication.
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Amlodipino , Antihipertensivos , Presión Sanguínea , Microbioma Gastrointestinal , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Antihipertensivos/farmacología , Masculino , Ratas , Presión Sanguínea/efectos de los fármacos , Amlodipino/farmacología , Captopril/farmacología , Hipertensión/tratamiento farmacológico , Hipertensión/microbiología , Hidroclorotiazida/farmacología , DisbiosisRESUMEN
Importance: Patients with prior myocardial infarction (MI) or stroke have a greater risk of recurrent cardiovascular (CV) events. Objective: To evaluate the association of chlorthalidone (CTD) vs hydrochlorothiazide (HCTZ) with CV outcomes and noncancer deaths in participants with and without prior MI or stroke. Design, Setting, and Participants: This was a prespecified secondary analysis of the Diuretic Comparison Project (DCP), a pragmatic randomized clinical trial conducted within 72 participating Veterans Affairs health care systems from June 2016 to June 2021, in which patients aged 65 years or older with hypertension taking HCTZ at baseline were randomized to continue HCTZ or switch to CTD at pharmacologically comparable doses. This secondary analysis was performed from January 3, 2023, to February 29, 2024. Exposures: Pharmacologically comparable daily dose of HCTZ or CTD and history of MI or stroke. Main Outcomes and Measures: Outcome ascertainment was performed from randomization to the end of the study. The primary outcome consisted of a composite of stroke, MI, urgent coronary revascularization because of unstable angina, acute heart failure hospitalization, or noncancer death. Additional outcomes included achieved blood pressure and hypokalemia (potassium level <3.1 mEq/L; to convert to mmol/L, multiply by 1.0). Results: The DCP randomized 13â¯523 participants to CTD or HCTZ, with a mean (SD) study duration of 2.4 (1.4) years. At baseline, median age was 72 years (IQR, 69-75 years), and 96.8% were male. Treatment effect was evaluated in subgroups of participants with (n = 1455) and without (n = 12â¯068) prior MI or stroke at baseline. There was a significant adjusted interaction between treatment group and history of MI or stroke. Participants with prior MI or stroke randomized to CTD had a lower risk of the primary outcome than those receiving HCTZ (105 of 733 [14.3%] vs 140 of 722 [19.4%]; hazard ratio [HR], 0.73; 95% CI, 0.57-0.94; P = .01) compared with participants without prior MI or stroke, among whom incidence of the primary outcome was slightly higher in the CTD arm compared with the HCTZ arm (597 of 6023 [9.9%] vs 535 of 6045 [8.9%]; HR, 1.12; 95% CI, 1.00-1.26; P = .054) (P = .01 for interaction). The incidence of a nadir potassium level less than 3.1 mEq/L and hospitalization for hypokalemia differed among those with and without prior MI or stroke when comparing those randomized to CTD vs HCTZ, with a difference only among those without prior MI or stroke (potassium level <3.1 mEq/L: prior MI or stroke, 43 of 733 [5.9%] vs 37 of 722 [5.1%] [P = .57]; no prior MI or stroke, 292 of 6023 [4.9%] vs 206 of 6045 [3.4%] [P < .001]; hospitalization for hypokalemia: prior MI or stroke, 14 of 733 [1.9%] vs 16 of 722 [2.2%] [P = .72]; no prior MI or stroke: 84 of 6023 [1.4%] vs 57 of 6045 [0.9%] [P = .02]). Conclusions and Relevance: Results of this secondary analysis of the DCP trial suggest that CTD may be associated with reduced major adverse CV events and noncancer deaths in patients with prior MI or stroke compared with HCTZ. Trial Registration: ClinicalTrials.gov Identifier: NCT02185417.
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Antihipertensivos , Clortalidona , Hidroclorotiazida , Hipertensión , Infarto del Miocardio , Accidente Cerebrovascular , Humanos , Clortalidona/uso terapéutico , Clortalidona/administración & dosificación , Masculino , Hidroclorotiazida/uso terapéutico , Hidroclorotiazida/administración & dosificación , Anciano , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/complicaciones , Femenino , Hipertensión/tratamiento farmacológico , Antihipertensivos/uso terapéutico , Resultado del TratamientoRESUMEN
Simultaneous determination of atenolol (ATN), losartan potassium (LOS), and hydrochlorothiazide (HCZ) in presence of HCZ impurity B was conducted by chemometric approaches and radial basis function network (RBFN) using UV-spectrophotometry without preliminary separation. Three chemometric models namely, classical least-squares (CLS), principal component regression (PCR), and partial least-squares (PLS) along with RBFN were utilized using the ternary mixtures of the three drugs. The multivariate calibrations were obtained by measuring the zero-order absorbance of the mixtures from 250 to 270 nm at the interval of 0.2 nm. The models were built covering the concentration range of (4.0 to 20.0), (3.8 to 20.2), and (0.9 to 50.1) µg mL-1 for ATN, LOS, and HCZ, respectively. The regression coefficient was calculated between the actual and predicted concentrations of the 3 drugs using CLS, PCR, PLS and RBFN. The accuracy of the developed models was evaluated using the root mean square error of prediction (RMSEP) giving satisfactory results. The proposed methods were simple, accurate, precise and were applied efficiently for the quantitation of the three components in laboratory-prepared mixtures, and in dosage form showing good recovery values. In addition, the obtained results were compared statistically with each other using ANOVA test showing non-significant difference between them.
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Atenolol , Hidroclorotiazida , Losartán , Espectrofotometría Ultravioleta , Hidroclorotiazida/análisis , Atenolol/análisis , Losartán/análisis , Espectrofotometría Ultravioleta/métodos , Análisis de los Mínimos Cuadrados , Análisis de Componente Principal , Formas de Dosificación , Reproducibilidad de los ResultadosRESUMEN
PURPOSE OF REVIEW: Kidney stones are the most common condition affecting the kidney, and characterized by a high rate of recurrence. Thiazide and thiazide-like diuretics (thiazides) are commonly prescribed to prevent the recurrence of kidney stones. This review offers a comprehensive up-to-date assessment of the evidence supporting the use of thiazides for kidney stone recurrence prevention, highlights potential harms associated with treatment, and identifies areas of knowledge that require further investigation. RECENT FINDINGS: The clinical routine to prescribe thiazides for kidney stone prevention has recently been challenged by the findings of the large NOSTONE trial that failed to show superiority of hydrochlorothiazide at doses up to 50âmg daily over placebo in preventing a composite of clinical or radiological recurrence in patients at high risk of recurrence. Yet, adverse events such as new onset diabetes mellitus and gout were more common in patients receiving hydrochlorothiazide compared to placebo. As demonstrated by a novel meta-analysis presented in this review encompassing all randomized placebo-controlled trials with thiazide monotherapy, current trial evidence does not indicate that thiazide monotherapy is significantly better than placebo in preventing kidney stone recurrence. SUMMARY: Given the limited efficacy and possible adverse effects, we advocate for a restrictive use of thiazides for kidney stone recurrence prevention. Clearly, there remains a high unmet medical need for effective, targeted therapies to prevent recurrence of kidney stones.
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Cálculos Renales , Recurrencia , Prevención Secundaria , Inhibidores de los Simportadores del Cloruro de Sodio , Humanos , Cálculos Renales/prevención & control , Prevención Secundaria/métodos , Inhibidores de los Simportadores del Cloruro de Sodio/uso terapéutico , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversos , Tiazidas/uso terapéutico , Tiazidas/efectos adversos , Resultado del Tratamiento , Hidroclorotiazida/uso terapéutico , Hidroclorotiazida/efectos adversosRESUMEN
PURPOSE: We aim to present a refined thin-film model describing the drug particle dissolution considering radial diffusion in spherical boundary layer, and to demonstrate the ability of the model to describe the dissolution behavior of bulk drug powders. METHODS: The dissolution model introduced in this study was refined from a radial diffusion-based model previously published by our laboratory (So et al. in Pharm Res. 39:907-17, 2022). The refined model was created to simulate the dissolution of bulk powders, and to account for the evolution of particle size and diffusion layer thickness during dissolution. In vitro dissolution testing, using fractionated hydrochlorothiazide powders, was employed to assess the performance of the model. RESULTS: Overall, there was a good agreement between the experimental dissolution data and the predicted dissolution profiles using the proposed model across all size fractions of hydrochlorothiazide. The model over-predicted the dissolution rate when the particles became smaller. Notably, the classic Nernst-Brunner formalism led to an under-estimation of the dissolution rate. Additionally, calculation based on the equivalent particle size derived from the specific surface area substantially over-predicted the dissolution rate. CONCLUSION: The study demonstrated the potential of the radial diffusion-based model to describe dissolution of drug powders. In contrast, the classic Nernst-Brunner equation could under-estimate drug dissolution rate, largely due to the underlying assumption of translational diffusion. Moreover, the study indicated that not all surfaces on a drug particle contribute to dissolution. Therefore, relying on the experimentally-determined specific surface area for predicting drug dissolution is not advisable.
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Liberación de Fármacos , Hidroclorotiazida , Tamaño de la Partícula , Polvos , Solubilidad , Polvos/química , Difusión , Hidroclorotiazida/química , Química Farmacéutica/métodos , Modelos Químicos , Simulación por ComputadorRESUMEN
Despite the fact that the pathogenesis of cutaneous melanoma is shrouded in mystery, factors that have been neglected or unnoticed until now have come to the attention in recent years, and in all likelihood, they could also be pivotal. These factors, known as nitrosamines or NDSRIs, are characterized by high carcinogenic and mutagenic potency, and some of them have demonstrated these properties to human DNA as well. Unfortunately, these ingredients also turn up as contaminants in about 300 of the most widely distributed drugs worldwide. According to the most recent literature, some of these ingredients are also identified as potent photocarcinogens, as well as human carcinogens. The intake of these carcinogens in the context of polycontamination of polymedication, has been associated for years with the occurrence of melanomas. The need for cataloguing of nitrosamines , as well as their accurate labelling on drug packaging, would help to classify them even more accurately as carcinogens affecting human DNA. We present once again a patient , who developed nodular melanoma within the context of the intake of 3 potentially nitrosamine/ NDSRIs contaminated antihypertensive drugs (valsartan/ Hydrochlorothiazide/ bisoprolol). Pathogenetic aspects concerning drug-induced nitrosogenesis, photocarcinogenesis and oncopharmacogenesis of skin cancer are discussed. Nitrosogenesis' of Cancer as concept in the medical literature has been known for decades, but in relation to other forms of human cancer. Exogenously mediated drug-mediated nitrosogenesis is a logically conditioned and newly defined concept whose significance with respect to the clinical manifestation of skin cancer is only beginning to grow.
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Melanoma , Nitrosaminas , Neoplasias Cutáneas , Humanos , Melanoma/inducido químicamente , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/inducido químicamente , Bisoprolol , Polifarmacia , Hidroclorotiazida/efectos adversos , Valsartán , Carcinógenos , Nitrosaminas/toxicidad , ADNRESUMEN
Oncopharmacogenesis and Drug-Induced Skin cancer related Nitrosogenesis are newly introduced concepts in the medical literature that owe their genesis or presence to the carcinogens/ mutagens, also known as nitrosamines/NDSRIs, which are present in a heterogeneous class of drugs. The contribution to the origin of these 2 concepts is entirely due to 1) the functions and efficacy of FDA in terms of control and identification of these carcinogens, and 2) the establishment of clinicopathological correlations by the dermatologists, occurring during drug intake. According to recent FDA data, the concentration of NDMA in just one metformin tablet could be up to more than 5-fold increased. The intake of 3 to 6 tablets per day should result in a carcinogen intake that is 15 to 30 times elevated within the day and within the monomedication alone. It is these circumstances that paraphrase/ ËbetonateË concepts such as Onco-Pharmacogenesis and Drug-mediated Nitrosogenesis of skin cancer. Although not officially declared, these mutagens are present and have been in forced tolerance mode for the last 30-40 years. And after their intake, multiple cancers have been found to develop. The concomitant use of other nitrosamine-contaminated drugs such as losartan/hydrochlorothiazide, metoprolol and nefidipine should certainly not be surprising when it could also be associated with the development of exactly 16 keratinocytic tumours as in the case presented by us. Recent evidence in medical literature has linked the nitrosamine N-nitrosomorpholine (NMOR) with the direct development of its subsequent mutagenic action in rodents following irradiation with UVA. This fact leaves open the question of the potentially available photocarcinogenic action of the other nitrosamines in humans found in medicinal preparations. This is what necessitates a clarification of the concept of Photo-Nitroso-Carcinogenesis/ Oncogenesis in humans and its relationship to skin cancer. The overlap of the mutational patterns of some of the nitrosamine-induced mutations in target genes such as p53 and RAS oncogenes, with those of UV light-induced mutations - or practically the same ones mentioned above, suggest a possible significant role of the Drug-Induced Photo-Nitroso-Carcinogenesis of keratinocyte cancer in the context of Onco-Pharmacogenesis. Future analyses should focus on elucidating the photocarcinogenic effect of nitrosamines in drug preparations and differentiating Skin cancer Nitrosogenesis from ËpureË Photo-Carcinogenesis and Nitroso-Photo-Carcinogenesis. The localization of the tumors in the area of the UV-exposed sites within the potential/actual contamination of the 4 preparations (simultaneously) in the described patient are indicative of a possible pathogenetic influence in the context of the already mentioned Nitroso-(Photo)carcinogenesis. Polycontamination of polymedication remains a so far unresolvable problem.
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Nitrosaminas , Neoplasias Cutáneas , Humanos , Metoprolol , Nifedipino/efectos adversos , Losartán , Dermatólogos , Queratinocitos , Neoplasias Cutáneas/inducido químicamente , Carcinogénesis/inducido químicamente , Carcinógenos/toxicidad , Hidroclorotiazida/efectos adversos , Nitrosaminas/toxicidad , MutágenosRESUMEN
BACKGROUND: Potassium (K+)-deficient diets, typical of modern processed foods, increase blood pressure (BP) and NaCl sensitivity. A K+-dependent signaling pathway in the kidney distal convoluted tubule, coined the K+ switch, that couples extracellular K+ sensing to activation of the thiazide-sensitive NaCl cotransporter (NCC) and NaCl retention has been implicated, but causality has not been established. METHODS: To test the hypothesis that small, physiological changes in plasma K+ (PK+) are translated to BP through the switch pathway, a genetic approach was used to activate the downstream switch kinase, SPAK (SPS1-related proline/alanine-rich kinase), within the distal convoluted tubule. The CA-SPAK (constitutively active SPS1-related proline/alanine-rich kinase mice) were compared with control mice over a 4-day PK+ titration (3.8-5.1 mmol) induced by changes in dietary K+. Arterial BP was monitored using radiotelemetry, and renal function measurements, NCC abundance, phosphorylation, and activity were made. RESULTS: As PK+ decreased in control mice, BP progressively increased and became sensitive to dietary NaCl and hydrochlorothiazide, coincident with increased NCC phosphorylation and urinary sodium retention. By contrast, BP in CA-SPAK mice was elevated, resistant to the PK+ titration, and sensitive to hydrochlorothiazide and salt at all PK+ levels, concomitant with sustained and elevated urinary sodium retention and NCC phosphorylation and activity. Thus, genetically locking the switch on drives NaCl sensitivity and prevents the response of BP to potassium. CONCLUSIONS: Low K+, common in modern ultraprocessed diets, presses the K+-switch pathway to turn on NCC activity, increasing sodium retention, BP, and salt sensitivity.