Application of electron paramagnetic resonance spectroscopy to examine free radicals formed in indapamide and torasemide storage under UV irradiation and at the higher temperatures which appear under light exposition.

Free radical formation in two diuretics: indapamide and torasemide was examined during UV irradiation and storage at higher temperatures using X-band (9.3 GHz) electron paramagnetic resonance spectroscopy (EPR). The aim of this study was to investigate the possibility of storing indapamide and torasemide under UV irradiation and at higher temperatures, which may occur during exposure to light. The diuretic samples were exposed to UVA irradiation for 15, 30 and 45 minutes, and stored at temperatures of 40 °C and 50 °C by 30 minutes. The EPR spectra were analyzed to determine the amplitudes (A), linewidths (ΔBpp), and integral intensities (I) and g factors. The concentrations of free radical (N) in the diuretic samples were also determined. The influence of microwave power on amplitudes, linewidths and the asymmetry parameter were evaluated. The result showed that the tested indapamide and torasemide samples exhibited high free radical concentrations in the range of 1018-1019 spin/g after UV irradiation and heat treatment. Therefore, due to the significant free radical formation indapamide and torasemide should not be stored under UV light and at temperatures of 40 °C and 50 °C. The complex character of free radical systems in the diuretic samples was proved as evidenced by the changes of the asymmetry parameters of the EPR lines with increasing microwave power. Fast spin-lattice relaxation processes were observed in all tested diuretic samples, regardless of the storage conditions. Electron paramagnetic resonance spectroscopy is proposed as a useful method in pharmacy to determine the appropriate storage conditions for diuretics.

Demonstrating the Benefits of Antihypertensive Nighttime Dosing and Indapamide Usage in Hypertension Management.

Background: Uncontrolled hypertension, specifically nocturnal hypertension, increases the risk for significant clinical outcomes. Evidence on the use of nighttime antihypertensives is scant and conflicting. In addition, hydrochlorothiazide continues to be the primary thiazide used despite being the least potent. Objective: The primary purpose of this study was to evaluate instituting nighttime dosing to control hypertension and compare the short-term effectiveness of blood pressure control with indapamide versus hydrochlorothiazide. Methods: This was a retrospective, observational study. Participant inclusion criteria consisted of patients 18 years of age or older, a current diagnosis of hypertension, and hypertension that required medical therapy. The investigator documented whether a patient was taking at least one antihypertensive at night versus all morning medications, as well as the use of indapamide versus hydrochlorothiazide. The patient's baseline and first follow-up blood pressure readings were documented. The primary outcome was to determine whether including nighttime dosing in antihypertensive regimens is more effective than all morning antihypertensive regimens. The secondary outcome was to determine whether indapamide was more effective than hydrochlorothiazide. Results: A total of 64 patients were included in the study. Twenty-eight patients were taking >1 nighttime antihypertensives versus 32 patients on all morning medications. Patients on at least one nighttime medication demonstrated greater systolic blood pressure reduction. There was no difference in blood pressure reduction between indapamide and hydrochlorothiazide. Conclusion: The study findings support the use of nighttime dosing to improve blood pressure management. The results on the effectiveness of indapamide versus hydrochlorothiazide conflict with previous research.

Diuretic Strategies in Acute Decompensated Heart Failure: A Narrative Review.

Background: Heart failure is a common condition with considerable associated costs, morbidity, and mortality. Patients often present to hospital with dyspnea and edema. Inadequate inpatient decongestion is an important contributor to high readmission rates. There is little evidence concerning diuresis to guide clinicians in caring for patients with acute decompensated heart failure. Contemporary diuretic strategies have been defined by expert opinion and older landmark clinical trials. Objective: To present a narrative review of contemporary recommendations, along with their underlying evidence and pharmacologic rationale, for diuretic strategies in inpatients with acute decompensated heart failure. Data Sources: PubMed, OVID, and Embase databases were searched from inception to December 22, 2022, with the following search terms: heart failure, acute heart failure, decompensated heart failure, furosemide, bumetanide, ethacrynic acid, hydrochlorothiazide, indapamide, metolazone, chlorthalidone, spironolactone, eplerenone, and acetazolamide. Study Selection: Randomized controlled trials and systematic reviews involving at least 100 adult patients (> 18 years) were included. Trials involving torsemide, chlorothiazide, and tolvaptan were excluded. Data Synthesis: Early, aggressive administration of a loop diuretic has been associated with expedited symptom resolution, shorter length of stay, and possibly reduced mortality. Guidelines make recommendations about dose and frequency but do not recommend any particular loop diuretic over another; however, furosemide is most commonly used. Guidelines recommend that the initial furosemide dose (on admission) be 2-2.5 times the patient's home dose. A satisfactory diuretic response can be defined as spot urine sodium content greater than 50-70 mmol/L at 2 hours; urine output greater than 100-150 mL/h in the first 6 hours or 3-5 L in 24 hours; or a change in weight of 0.5-1.5 kg in 24 hours. If congestion persists after the maximization of loop diuretic therapy over the first 24-48 hours, an adjunctive diuretic such as thiazide or acetazolamide should be added. If decongestion targets are not met, continuous infusion of furosemide may be considered. Conclusions: Heart failure with congestion can be managed with careful administration of high-dose loop diuretics, supported by thiazides and acetazolamide when necessary. Clinical trials are underway to further evaluate this strategy.

Contexte: L'insuffisance cardiaque est une maladie courante entraînant des coûts, une morbidité et une mortalité considérables. Les patients se présentent souvent à l'hôpital avec une dyspnée et un oedème. Une décongestion inadéquate des patients hospitalisés contribue largement aux taux élevés de réadmission. Il existe peu de données probantes concernant la diurèse pour guider les cliniciens dans la prise en charge des patients atteints d'insuffisance cardiaque aiguë décompensée. Les stratégies diurétiques contemporaines ont été définies par l'opinion d'experts et des essais cliniques de référence plus anciens. Objectif: Présenter une revue narrative des recommandations contemporaines, ainsi que leurs données probantes sous-jacentes et leur justification pharmacologique, pour les stratégies diurétiques chez les patients hospitalisés souffrant d'insuffisance cardiaque aiguë décompensée. Sources des données: Les bases de données PubMed, OVID et Embase ont été consultées depuis leur création jusqu'au 22 décembre 2022, avec les termes de recherche suivants: insuffisance cardiaque, insuffisance cardiaque aiguë, insuffisance cardiaque décompensée, furosémide, bumétanide, acide éthacrynique, hydrochlorothiazide, indapamide, métolazone, chlorthalidone, spironolactone, éplérénone et acétazolamide. Choix de l'étude: Les essais contrôlés randomisés et les revues systématiques portant sur au moins 100 patients adultes (plus de 18 ans) ont été inclus. Les essais impliquant le torsémide, le chlorothiazide et le tolvaptan ont été exclus. Synthèse des données: L'administration précoce et agressive d'un diurétique de l'anse a été associée à une résolution accélérée des symptômes, à une durée de séjour plus courte et éventuellement à une mortalité réduite. Les lignes directrices font des recommandations sur la dose et la fréquence, mais ne recommandent pas un diurétique de l'anse particulier plutôt qu'un autre; cependant, le furosémide est le plus couramment utilisé. Les lignes directrices recommandent que la dose initiale de furosémide à l'admission soit de 2 à 2,5 fois la dose à domicile du patient. Une réponse diurétique satisfaisante peut être définie comme une teneur ponctuelle en sodium dans l'urine supérieure à 50 à 70 mmol/L après 2 heures; débit urinaire supérieur à 100 à 150 mL/h au cours des 6 premières heures ou à 3 à 5 L en 24 heures; ou un changement de poids de 0,5 à 1,5 kg en 24 heures. Si la congestion persiste après la maximisation du traitement par diurétique de l'anse au cours des premières 24 à 48 heures, un diurétique d'appoint tel que le thiazidique ou l'acétazolamide doivent être ajoutés. Si les objectifs de décongestion ne sont pas atteints, une perfusion continue de furosémide peut être envisagée. Conclusions: L'insuffisance cardiaque accompagnée de congestion peut être gérée par l'administration prudente de diurétiques de l'anse à haute dose, appuyés par des thiazidiques et de l'acétazolamide si nécessaire. Des essais cliniques sont en cours pour évaluer davantage cette stratégie.

Comparison of Pharmacokinetics and Bioavailability of Fixed-Dose Combination Tablet and Monotherapy Combination of Allisartan Isoproxil and Indapamide Sustained-Release in Healthy Chinese Volunteers.

This study aimed to compare the pharmacokinetics and bioavailability of 2 formulations: a fixed-dose combination tablet containing allisartan isoproxil (AI) and indapamide sustained-release (SR), and a monotherapy combination of AI and indapamide SR, in healthy Chinese subjects. A monocentric, open-label, single-dose, randomized, 2-way crossover study design was implemented. A total of 38 healthy male and female volunteers were equally divided into 2 treatment sequences. The analysis of plasma concentrations was conducted using a nonstereospecific liquid chromatography/tandem mass spectrometric method. The primary pharmacokinetic parameters were calculated using a noncompartmental model. Safety assessments were performed throughout the study. For the fixed-dose combination and monotherapy combination, the mean values of EXP3174 (metabolite of AI) Cmax , AUC0-t , and AUC0-∞ were 987 and 999 ng/mL, 8059 and 7749 ng/mL h, and 8332 and 8007 ng/mL h, respectively. The corresponding values for indapamide were 27 and 32 ng/mL, 1002 and 1105 ng/mL h, and 1080 and 1172 ng/mL h. No serious adverse events were reported during the study. The combination tablet containing 240 mg of AI and 1.5 mg of indapamide SR met the bioequivalence standards. Additionally, both formulations were tolerated and had good safety profiles in the research.

Pharmacokinetics and Drug-Drug Interaction of Allisartan Isoproxil and Indapamide Sustained-Release Formulation.

Allisartan isoproxil (AI) is an angiotensin II type 1 receptor blocker and be converted into the active substance EXP3174 in vivo. We evaluated the drug-drug interactions of AI and an indapamide sustained-release (Ind SR) preparation, as well as the pharmacokinetic characteristics and safety of AI and Ind SR in healthy subjects. The trial was set up in 6 sequences and 3 cycles, and each cycle contained a 7-day washout period. Subjects received 3 different trial drugs (A, AI; B, Ind SR; C, AI + Ind SR) during 3 different cycles. Twenty-four subjects were enrolled in the clinical trial. Of these, 22 completed the study, 2 subjects dropped out due to adverse events (AEs). For subjects given AI alone or combined with Ind SR, the pharmacogenetic parameters Cmax and the geometric mean ratio of steady state (combined/single) of EXP3174 was 130%. The geometric mean ratio of area under the concentration-time curve over the dosing interval at steady state (combined/single use) was 144.5%. Therefore, the combination of Ind SR had an impact on the pharmacokinetics of AI. Then, the results indicated that the AI combination had no effect on the pharmacokinetics of Ind SR. Serious AEs did not occur. The AEs in this clinical trial were the same as those for AI and Ind SR. Combined administration resulted in 2 cases (2 subjects) of Grade 3 hypotension and 1 case of Grade 3 hypotension with AI alone. Considering that this trial included healthy volunteers, the risk of hypotension was expected to be manageable.

Diethyl 2,2'-[({2-chloro-5-[(2-eth-oxy-2-oxoeth-yl)(2-methyl-indolin-1-yl)carbamo-yl]phen-yl}sulfon-yl)aza-nedi-yl]di-acetate.

The majority of the title mol-ecule, C28H34ClN3O9S, is disordered over two closely spaced sets of sites; the site occupancy of the major component = 0.542 (3). The conformation of each component is approximately U-shaped with the chloro-benzene ring forming the base and the indolinyl and sulfamoyl groups the sides; an intra-molecular C-H⋯Cl hydrogen bond possibly contributes to the stabilization of the conformation. In the crystal, a corrugated layer structure parallel to the ab plane is formed by C-H⋯O and C-H⋯Cl hydrogen bonds together with C-H⋯π(ring) inter-actions.

Physical Ageing of Amorphous Poly(lactic acid)-Indapamide System Studied by Differential Scanning Calorimetry.

The process of isothermal and non-isothermal physical ageing of amorphous polylactide (PLA) with the active pharmaceutical ingredient, indapamide (IND), was investigated. A PLA-IND system with a 50/50 weight ratio was obtained and characterized using differential scanning calorimetry (DSC). In the 50/50 (w/w) mixture, two glass transitions were observed: the first at 64.1 ± 0.3 °C corresponding to the glass transition temperature (Tg) of PLA, and the second at 102.6 ± 1.1 °C corresponding to the Tg of IND, indicating a lack of molecular mixing between the two ingredients. The PLA-IND system was subjected to the isothermal physical ageing process at different ageing temperatures (Ta) for 2 h. It was observed that the highest effect of physical ageing (enthalpy relaxation change) on IND in the PLA-IND system occurred at Ta = 85 °C. Furthermore, the system was annealed for various ageing times at 85 °C. The relaxation enthalpies were estimated for each experiment and fitted to the Kohlrausch-Williams-Watts (KWW) equation. The KWW equation allowed for the estimation of the relaxation time and the parameter describing the distribution of relaxation times of the isothermal physical ageing process of IND in the PLA-IND system. The physical ageing of the PLA-IND mixture (50/50) was also discussed in the context of heat capacity. Moreover, the activation energy and fragility parameters were determined for the PLA-IND (50/50) system.

Not So Innocent Indapamide.

A 58-year-old asymptomatic man was referred by his general practitioner for abnormal blood results. Routine blood tests to monitor blood count and kidney functions showed neutropenia and hyponatremia. He was euvolemic on examination. A further detailed investigation did not reveal any cause of neutropenia and hyponatremia. After careful assessment of their drug history, it transpired he recently started Indapamide for uncontrolled hypertension. Hyponatraemia is a common side effect of Indapamide and in addition, it can rarely cause agranulocytosis and leukopenia. Indapamide was stopped and the blood counts started to improve and became normal after two weeks.

Association between Food/UGT2B7 Polymorphisms and Pharmacokinetics/Pharmacodynamics Properties of Indapamide in Healthy Humans.

Indapamide is an effective and safe antihypertensive medication showing a beneficial effect in combination with other antihypertensive agents regarding morbidity and mortality. A comparative study was performed under fasting and fed conditions to investigate the effect of food and selected single nucleotide polymorphisms in the uridine diphosphate glucuronyl transferase (UGT2B7) gene on the pharmacokinetics and pharmacodynamics behavior of indapamide 1.5 mg sustained release. Forty-nine healthy volunteers aged 18-55 years were randomized into two groups; 25 volunteers were administered indapamide under fasting conditions and 24 under fed conditions. Genotyping of the UGT2B7 rs7438135 and rs11740316 was done before commencing the study using predesigned TaqMan assays. Results showed that food independently decreased the value of indapamide' Tmax by 5.5 h and increased the value of Cmax by 8.7 ng/mL. On the other hand, all genetic variants of both UGT2B7 SNPs had no significant impact on the values of Tmax, Cmax, and AUC0-t; however, it was found that rs11740316 variant AG was correlated with a 2.8 h lower MRTinf. Finally, BMI positively correlated with longer MRTinf. It was concluded that none of rs7438135, rs11740316, or food had a significant impact on the pharmacodynamic properties. Food had a modest impact on indapamide Cmax and Tmax values, while there were unremarkable differences in safety and efficacy.

Adherence to Triple Single-Pill Combination of Perindopril/Indapamide/Amlodipine: Findings from Real-World Analysis in Italy.

INTRODUCTION: Single-pill combination therapy for hypertension is recognized to improve adherence to treatment. However, less is known about the benefits of triple single-pill combinations. This retrospective observational analysis aimed to assess changes in adherence when treatment was switched from perindopril (PER)/indapamide (IND) + amlodipine (AML) to PER/IND/AML single-pill combination, in Italian clinical practice. METHODS: This analysis used data extracted from administrative databases of Italian healthcare entities. Adult patients receiving PER/IND/AML were selected, and the prescription date was considered as the index date. Among them, those who had a prescription for PER/IND + AML during the 12 months before the index date and a prescription of PER/IND/AML during 6 months of follow-up were included. Adherence was calculated as the proportion of days covered (PDC: PDC < 40%, non-adherent; PDC = 40-79%, partially adherent; PDC ≥ 80%, adherent). RESULTS: Among the identified patients, 158 were exposed users and were included in the analysis. When patients were compared before and after switch to triple single-pill combination, the proportion of adherent patients was significantly higher with PER/IND/AML single-pill combination (75.3%) than with PER/IND + AML combination (44.3%) (P < 0.05). Conversely, the proportion of non-adherent patients was lower with the PER/IND/AML single-pill combination (14.6%) vs PER/IND + AML (17.7%) (P < 0.001). CONCLUSION: This real-world analysis showed that switching to a triple single-pill combination could offer an opportunity to improve adherence to antihypertensive treatment in real-life clinical practice.

Medication adherence is defined by the World Health Organization as the "extent to which a person's behavior (in taking medication) corresponds with agreed recommendations from a healthcare provider". Low levels of medication adherence in hypertension have been linked with increased disease burden and with higher costs for patients. Patients with hypertension whose blood pressure is poorly controlled often need to receive more than one pill. Nevertheless, having to take many pills may result in poor adherence, i.e., patients not taking their treatment as prescribed. Combining multiple drugs into a single pill for the management of hypertension is known to improve adherence; however, limited evidence exists about the benefits of triple single-pill combinations compared with equivalent free combinations in real clinical practice. This analysis evaluated changes in adherence before and after patients switched from a three-drug therapy of perindopril/indapamide single-pill + amlodipine (PER/IND + AML) to perindopril/indapamide/amlodipine (PER/IND/AML) taken as a single pill. In this analysis, real-world data from Italian administrative databases covering around 11% of the Italian population were used. Overall, 158 patients were included. More patients were found to be adherent after switch to PER/IND/AML single pill (75.3% vs 44.3% of PER/IND + AML combination). Partially adherent and poorly adherent patients were fewer with PER/IND/AML single-pill combination (10.1% and 14.6%, respectively) compared to PER/IND + AML combination (38.0% and 17.7%, respectively). These findings indicate that switching to a simplified therapy in which all three drugs are taken in one pill may offer an opportunity for increasing the number of patients that are adherent to their medication.

[Intraoperative management of potentially fatal arrhythmias after anesthesia induced by severe hypokalemia: A case report].

Severe hypokalemia is defined as the concentration of serum potassium lower than 2.5 mmol/L, which may lead to serious arrhythmias and cause mortality. We report an unusual case of potentially fatal ventricular arrhythmias induced by severe hypokalemia in a patient undergoing laparoscopic partial nephrectomy in Peking University Third Hospital due to irregular use of indapamide before operation. Indapamide is a sulfonamide diuretic with vasodilative and calcium antagonistic effects, which enhances sodium delivery to the renal distal tubules resulting in a dose-related increase in urinary potassium excretion and decreases serum potassium concentrations. The electrolyte disorder caused by the diuretic is more likely to occur in the elderly patients, especially those with malnutrition or long-term fasting. Hence, the serum potassium concentration of the patients under indapamide therapy, especially elderly patients, should be monitored carefully. Meanwhile, the potassium concentration measured by arterial blood gas analysis is different from that measured by venous blood or laboratory test. According to the previous research, the concentration of potassium in venous blood was slightly higher than that in arterial blood, and the difference value was 0.1-0.5 mmol/L. This error should be taken into account when rapid intravenous potassium supplementation or reduction of blood potassium level was carried out clinically. In the correction of severe hypokalemia, the standard approach often did not work well for treating severe hypokalemia. The tailored rapid potassium supplementation strategy shortened the time of hypokalemia and was a safe and better treatment option to remedy life-threatening arrhythmias caused by severe hypokalemia with a high success rate. Through the anesthesia management of this case, we conclude that for the elderly patients who take indapamide or other potassium excretion diuretics, the electrolyte concentration and the general volume state of the patients should be comprehensively measured and fully evaluated before operation. It may be necessary for us to reexamine the serum electrolyte concentration before anesthesia induction on the morning of surgery in patients with the history of hypokalemia. For severe hypokalemia detected after anesthesia, central venous cannulation access for individualized rapid potassium supplementation is an effective approach to reverse the life-threatening arrhythmias caused by severe hypokalemia and ensure the safety of the patients.

Incidence of severe hypokalaemia in patients taking indapamide.

BACKGROUND: Diuretics are commonly used for the treatment of hypertension. Yet, hypokalaemia is a well-recognised adverse effect. We conducted a retrospective study to evaluate the incidence of severe hypokalaemia, defined as requiring hospitalisation, among patients on indapamide. METHODS: We searched a territory-wide database, Clinical Data Analysis and Reporting System of the Hong Kong Hospital Authority. We traced all hypertensive patients who had been prescribed indapamide in 2007-2016 and all admissions due to hypokalaemia in 2007-2018. Factors associated with hospitalisation were studied using multivariable logistic regression. RESULTS: During the period studied, 62,881 patients were started on indapamide and 509 (0.8%) were hospitalised for hypokalaemia. 53% of these hospitalisations occurred within the first year of treatment, and half of those in the first year occurred during the first 16 weeks. Female sex (adjusted OR, 1.75; 95%CI, 1.45-2.12) and immediate-release formulation (adjusted OR, 1.41; 95%CI, 1.14-1.75) were associated with hospitalisation. In the multivariable model, advanced age was not a significant predictor. There were no deaths during hospitalisation and the median length of hospital stay was one day. CONCLUSIONS: In this large population-based study with 147,319 person-years of follow-up, severe hypokalaemia requiring hospitalisation was uncommon among hypertensive patients on indapamide. The risk is higher in women and in the initial weeks and months after starting therapy. The use of the sustained-release formulation reduces the risk. We conclude that using indapamide to treat hypertension is safe, even in the elderly, especially if the sustained-release formulation is used and electrolytes are monitored periodically.

Assessment of the genotoxic effects of antihypertensive drug active ingredient indapamide in human lymphocytes.

Hypertension is the most common cardiovascular disease and is also known as high blood pressure. The large majority of hypertensive patients need long-term administration of antihypertensive agents. Indapamide is an orally administered diuretic antihypertensive drug. The present work aimed to assess the possible genotoxic effects of indapamide using four different assays: chromosomal aberration (CA), sister chromatid exchange (SCE), micronucleus (MN), and comet. Lymphocytes from three different donors were exposed to 18.75, 37.50, 75.00, and 100.00 µg/ml indapamide. Additionally, a negative, a positive (mitomycin C = MMC, 0.20 µg/ml), and a solvent control (5.4 µl/ml methanol) were also applied. As a result, it was seen that indapamide did not cause a significant change in CAs and MN frequencies compared to the control. It caused significant damage only at the highest concentration in the comet assay. Similarly, while it did not affect the number of SCEs in the 24-h treatment, it increased the SCE frequency at the two highest concentrations in the 48-h. Mitotic index (MI) decreased at almost all concentrations. Considering all these results, this study revealed that indapamide did not have a significant genotoxic effect in these conditions. To the best of our knowledge, this is the first investigation about the genotoxic effect of indapamide in human lymphocytes in vitro.

Machine Learning Insights Into Uric Acid Elevation With Thiazide Therapy Commencement and Intensification.

Background Elevated serum uric acid, associated with cardiovascular conditions such as atherosclerotic heart disease, hypertension, and heart failure, can be elevated by thiazide or thiazide-like drugs (THZ), essential in hypertension management. Identifying clinical determinants affecting THZ-related uric acid elevation is critical. Methods In this retrospective cross-sectional study, we explored the clinical determinants influencing uric acid elevation related to THZ, focusing on patients where THZ was initiated or the dose escalated. A cohort of 143 patients was analyzed, collecting baseline and control uric acid levels, alongside basic biochemical studies and clinical data. Feature selection was conducted utilizing criteria based on mean squared error increase and enhancement in node purity. Four machine learning algorithms - Random Forest, Neural Network, Support Vector Machine, and Gradient Boosting regressions - were applied to pinpoint clinical influencers. Results Significant features include uncontrolled diabetes, index estimated Glomerular Filtration Rate (eGFR) level, absence of insulin, action of indapamide, and absence of statin treatment, with absence of Sodium-glucose cotransporter 2 inhibitors (SGLT2i), low dose aspirin exposure, and older age also being noteworthy. Among the applied models, the Gradient Boosting regression model outperformed the others, exhibiting the lowest Mean Absolute Error (MAE), Mean Squared Error (MSE), Root Mean Squared Error (RMSE) values, and the highest R2 value (0.779). While Random Forest and Neural Network regression models were able to fit the data adequately, the Support Vector Machine demonstrated inferior metrics. Conclusions Machine learning algorithms are adept at accurately identifying the factors linked to uric acid fluctuations caused by THZ. This proficiency aids in customizing treatments more effectively, reducing the need to unnecessarily avoid THZ, and providing guidance on its use to prevent instances where uric acid levels could become problematic.

Intraoperative management of potentially fatal arrhythmias after anesthesia induced by severe hypokalemia: A case report / 北京大学学报(医学版)

Severe hypokalemia is defined as the concentration of serum potassium lower than 2.5 mmol/L, which may lead to serious arrhythmias and cause mortality. We report an unusual case of potentially fatal ventricular arrhythmias induced by severe hypokalemia in a patient undergoing laparoscopic partial nephrectomy in Peking University Third Hospital due to irregular use of indapamide before operation. Indapamide is a sulfonamide diuretic with vasodilative and calcium antagonistic effects, which enhances sodium delivery to the renal distal tubules resulting in a dose-related increase in urinary potassium excretion and decreases serum potassium concentrations. The electrolyte disorder caused by the diuretic is more likely to occur in the elderly patients, especially those with malnutrition or long-term fasting. Hence, the serum potassium concentration of the patients under indapamide therapy, especially elderly patients, should be monitored carefully. Meanwhile, the potassium concentration measured by arterial blood gas analysis is different from that measured by venous blood or laboratory test. According to the previous research, the concentration of potassium in venous blood was slightly higher than that in arterial blood, and the difference value was 0.1-0.5 mmol/L. This error should be taken into account when rapid intravenous potassium supplementation or reduction of blood potassium level was carried out clinically. In the correction of severe hypokalemia, the standard approach often did not work well for treating severe hypokalemia. The tailored rapid potassium supplementation strategy shortened the time of hypokalemia and was a safe and better treatment option to remedy life-threatening arrhythmias caused by severe hypokalemia with a high success rate. Through the anesthesia management of this case, we conclude that for the elderly patients who take indapamide or other potassium excretion diuretics, the electrolyte concentration and the general volume state of the patients should be comprehensively measured and fully evaluated before operation. It may be necessary for us to reexamine the serum electrolyte concentration before anesthesia induction on the morning of surgery in patients with the history of hypokalemia. For severe hypokalemia detected after anesthesia, central venous cannulation access for individualized rapid potassium supplementation is an effective approach to reverse the life-threatening arrhythmias caused by severe hypokalemia and ensure the safety of the patients.

Impact of the COVID-19 pandemic on cardiovascular heart disease medication use: time-series analysis of England's prescription data during the COVID-19 pandemic (January 2019 to October 2020).

BACKGROUND: Management of high blood pressure (BP) typically requires adherence to medication regimes. However, it is known that the COVID-19 pandemic both interrupted access to some routine prescriptions and changed some patient health behaviours. AIM: This study, therefore, retrospectively investigated prescription reimbursement of cardiovascular (CVD) medicines as a proxy measure for patient adherence and access to medicines during the pandemic. METHODS: A cohort study of all primary care patients in England prescribed CVD medicines. The exposure was to the global pandemic. Prescriptions were compared before and after the pandemic's onset. Statistical variation was the outcome of interest. RESULTS: Descriptive statistics show changes to monthly prescriptions, with wide confidence intervals indicating varying underlying practice. Analysis of variance reveals statistically significant differences for bendroflumethiazide, potassium-sparing diuretics, nicorandil, ezetimibe, ivabradine, ranolazine, colesevelam and midodrine. After the pandemic began (March-October 2020), negative parameters are observed for ACE inhibitors, beta-blockers, calcium channel blockers, statins, antiplatelet, antithrombotics, ARBs, loop diuretics, doxazosin, bendroflumethiazide, nitrates and indapamide, indicating decelerating monthly prescription items (statistically significant declines of calcium channel blockers, antithrombotic, adrenoreceptor blockers and diuretics) of CVD medicines within the general population. Many data points are not statistically significant, but fluctuations remain clinically important for the large population of patients taking these medications. CONCLUSION: A concerning decline in uptake of CVD therapies for chronic heart disease was observed. Accessible screening and treatment alongside financial relief on prescription levies are needed. A video abstract is (4 min 51 s) available: https://bit.ly/39gvEHi.

Associations of thiazide use with skin cancers: a systematic review and meta-analysis.

BACKGROUND: Previous findings on the associations of thiazide use with skin cancers were conflicting. This study aimed to examine the associations of individual thiazide use with skin cancer risk, differentiated by subtypes of skin cancers, geographic regions, and cumulative doses of individual thiazides. METHODS: We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials for relevant studies on January 5, 2022, scanned the references of included studies, and consulted experts. We included case-control and cohort studies or randomized trials reporting the associations of individual thiazide or thiazide-like diuretics use with skin cancers. Non-melanoma skin cancer (NMSC) and melanoma were analysed separately. A random-effects model meta-analysis was conducted for pooled odds ratio (OR) and hazard ratio (HR) for skin cancers related to individual thiazide use. RESULTS: We included 15, 5, and 5 case-control or cohort studies reporting the risk for skin cancers associated with hydrochlorothiazide, bendroflumethiazide, and indapamide use, respectively, with 17,848,313 participants. The meta-analysis showed associations of hydrochlorothiazide use with increased risk of NMSC (OR 1.16, 95% CI 1.08-1.24; HR 1.26, 95% CI 1.04-1.54), squamous cell carcinoma (SCC) (OR 1.32, 95% CI 1.06-1.65; HR 1.61, 95% CI 0.97-2.67), and melanoma (OR 1.11, 95% CI 1.02-1.20; HR 1.03, 95% CI 0.93-1.14). The increased risks for SCC were associated with high cumulative doses of hydrochlorothiazide (OR 2.56, 95% CI 1.43-4.57; HR 1.20, 95% CI 1.00-1.45). Hydrochlorothiazide use was associated with different subtypes of melanoma including superficial spreading (OR 1.18, 95% CI 1.05-1.33), nodular (OR 1.23, 95% CI 1.08-1.39), and lentigo maligna melanoma (OR 1.33, 95% CI 1.08-1.65). Various cumulative doses of hydrochlorothiazide were associated with increased odds for melanoma. However, the associations of hydrochlorothiazide use with increased risk of NMSC and melanoma only appeared in non-Asian countries. No meaningful increase in the risk for skin cancers was associated with bendroflumethiazide and indapamide. CONCLUSIONS: Hydrochlorothiazide is associated with an increased risk for NMSC (especially SCC) and melanoma in non-Asian countries, whereas bendroflumethiazide and indapamide are not associated with a meaningful risk for skin cancers. Healthcare professionals and patients should be informed of the different risk profiles of skin cancers associated with different thiazides, cumulative doses, and regions. TRIAL REGISTRATION: PROSPERO CRD42021234317 .

Management of Diabetes and Hypertension within the Gulf Region: Updates on Treatment Practices and Therapies.

Cardiovascular disease (CVD) is a leading cause of death globally, driven by the high rates of risk factors, such as diabetes and hypertension. As the prevalence of these risk factors is particularly high in the Gulf region, better diagnosis and management of type 2 diabetes (T2D) and hypertension has the potential to dramatically reduce adverse cardiovascular outcomes for individuals in that part of the world. This article provides a summary of presentations made during the EVIDENT summit, a virtual symposium on Evidence in Diabetes and Hypertension, held in September 2021, including a review of the various guidelines for both T2D and hypertension, as well as recent findings relevant to the safety and efficacy for therapies relating to these conditions. Of relevance to the Gulf region, the risk of hypoglycaemia with sulfonylureas during Ramadan was reviewed. For the management of T2D, sulfonylureas have been a long-standing medication used to achieve glycaemic control; however, differences have emerged between early and later generations, with recent studies suggesting improvements in the safety profiles of late-generation sulfonylureas. For patients with hypertension, incremental therapy changes are recommended to reduce the risk of cardiovascular complications that are associated with increasing blood pressure. For first-line therapy, angiotensin-converting enzyme inhibitors (ACEi), such as perindopril, have been demonstrated to reduce the risk of cardiovascular and all-cause mortality. The addition of calcium channel blockers and diuretics to ACEi has been shown to be effective in patients with poorly controlled hypertension. The different renin-angiotensin-aldosterone system inhibitors are reviewed, and the benefit of combination therapies, including amlodipine and indapamide in patients with difficult-to-control hypertension, is investigated. The benefits of lifestyle modifications for these patients are also discussed, with important clinical considerations that are expected to inform patient management in daily clinical practice.

Development of Simple Dissolution Methods for Felodipine and Combined Amlodipine Besylate-Indapamide Extended Release Tablets without Stationary (Felodipine) Basket.

BACKGROUND: The dissolution method for certain drugs needs specialized conditions. Dissolution testing for felodipine extended release (ER) tablets (Plendil® 5 mg) and amlodipine-indapamide fixed dose (Natrilam®, 5/1.5 mg) ER tablets requires the use of a stationary (felodipine) basket in USP Apparatus II. OBJECTIVE: The study aimed to develop simple methods for Plendil® and Natrilam® without the use of a felodipine basket. METHODS: The dissolution profiles obtained from different media and paddle speeds were used to compute miscellaneous dissolution parameters and were compared to those obtained from standard (existing) methods using a felodipine basket. RESULTS: The f1, f2, and bootstrap f2 (5th % percentile) values for Plendil® 2.47, 88.17, and 54.62, respectively, and all other dissolution factors revealed similarity between standard and the selected test method with 1% Tween 20 at 50 rpm. For Natrilam®, f1 and f2 and bootstrap f2 5.13, 72.92, and 62.67, respectively, and all other dissolution parameters showed similarity of the standard and selected test method using 0.1N HCl media having 0.38 gm/L EDTA with a sinker at 100 rpm. Release of products assumed zero-order and Weibull model, respectively. CONCLUSION: Test dissolution methods for Plendil® and Natrilam® tablets produced equivalent dissolution profiles compared to their respective standard methods with stationary basket USP Apparatus II.