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.

Rationale for a New Low-Dose Triple Single Pill Combination for the Treatment of Hypertension.

Two recent large trials showed the potential of single pill combinations (SPCs) with ≥3 low-dose components among people with hypertension who were untreated or receiving monotherapy. In both trials, these 'hypertension polypills' were superior to usual care, achieving >80% BP control without increasing withdrawal due to side effects. However, there are no such products available for prescribers. To address this unmet need, George Medicines developed GMRx2 with telmisartan/amlodipine/indapamide in three strengths (mg): 10/1.25/0.625, 20/2.5/1.25; 40/5/2.5. Two pivotal trials are ongoing to support FDA submission for the treatment of hypertension, including initial treatment. These assess efficacy and safety of GMRx2 compared to: placebo, and each of the three possible dual combinations. Regulatory submissions are planned for 2024, with the aim of providing access to GMRx2 in developed and developing regions. Wider implementation of GMRx2-based treatment strategies will be guided by further research to inform access and appropriate scale up.

In Silico Prediction of N-Nitrosamine Formation Pathways of Pharmaceutical Products.

The recent discovery of N-nitrosodimethylamine (NDMA), a mutagenic N-nitrosamine, in pharmaceuticals has adversely impacted the global supply of relevant pharmaceutical products. Contamination by N-nitrosamines diverts resources and time from research and development or pharmaceutical production, representing a bottleneck in drug development. Therefore, predicting the risk of N-nitrosamine contamination is an important step in preventing pharmaceutical contamination by DNA-reactive impurities for the production of high-quality pharmaceuticals. In this study, we first predicted the degradation pathways and impurities of model pharmaceuticals, namely gliclazide and indapamide, in silico using an expert-knowledge software. Second, we verified the prediction results with a demonstration test, which confirmed that N-nitrosamines formed from the degradation of gliclazide and indapamide in the presence of hydrogen peroxide, especially under alkaline conditions. Furthermore, the pathways by which degradation products formed were determined using ranitidine, a compound previously demonstrated to generate NDMA. The prediction indicated that a ranitidine-related compound served as a potential source of nitroso groups for NDMA formation. In silico software is expected to be useful for developing methods to assess the risk of N-nitrosamine formation from pharmaceuticals.

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.

A real-world analysis of outcomes and healthcare costs of patients on perindopril/indapamide/amlodipine single-pill vs. multiple-pill combination in Italy.

OBJECTIVES: This analysis compared adherence, cardiovascular (CV) events and all-cause mortality incidence, and healthcare costs among hypertensive patients treated with perindopril (PER)/indapamide (IND)/amlodipine (AML) in single-pill combination (SPC) vs. multiple-pill combination, in a real-world setting in Italy. METHODS: In this observational retrospective analysis of Italian administrative databases, adult patients treated with PER/IND/AML between 2010 and 2020 were divided into two cohorts: single-pill vs. multiple-pill. Patient data were available for at least one year before and after index date. Propensity score matching (PSM) was applied to reduce selection bias. Adherence was defined as proportion of days covered: non-adherence, <40%; partial adherence, 40-79%, and adherence ≥80%. Mortality incidence and CV events as single, or composite, endpoints were evaluated after first year of follow-up. Healthcare cost analyses were performed from the perspective of the Italian National Health Service. RESULTS: Following PSM, the single-pill cohort included 12 150 patients, and the multiple-pill cohort, 6105. The SPC cohort had a significantly higher percentage of adherent patients vs. the multiple-pill cohort (59.9% vs. 26.9%, P  < 0.001). Following the first year of follow-up, incidence of all-cause mortality, and combined endpoint of all-cause mortality and CV events were lower in the SPC cohort compared with multiple-pill cohort. Average annual direct healthcare costs were lower in the single-pill cohort (€2970) vs. multiple-pill cohort (€3642); cost of all drugs and all-cause hospitalizations were major contributors. CONCLUSION: The SPC of PER/IND/AML, compared with multiple-pill combination, is associated with higher adherence to medication, lower incidence of CV events and mortality, and reduced healthcare costs.

[Efficacy and Organoprotection of Triple Combinations in the Treatment of Arterial Hypertension].

The 2022 draft Russian guidelines on arterial hypertension recommend initiation of antihypertensive therapy with a combination of drugs in most patients with blood pressure above 150 / 90 mm Hg and / or in the presence of high-risk criteria. In 2021, the results of a 12-year analysis of the Brisighella Heart Study (BHS) were published. The aim of this study was to compare the use of different triple antihypertensive drug combinations in an Italian cohort of patients in real-life clinical practice. Combination antihypertensive therapy with a renin-angiotensin-aldosterone system inhibitor, amlodipine, and thiazide/thiazide-like diuretics provides a better blood pressure control compared to other antihypertensive drug combinations. The use of the triple combination of amlodipine/indapamide/perindopril is associated with a better metabolic profile than any other considered combination of antihypertensive drugs and a more pronounced organ-protective effect.

A Spanish Family with Gordon Syndrome Due to a Variant in the Acidic Motif of WNK1.

(1) Background: Gordon syndrome (GS) or familial hyperkalemic hypertension is caused by pathogenic variants in the genes WNK1, WNK4, KLHL3, and CUL3. Patients presented with hypertension, hyperkalemia despite average glomerular filtration rate, hyperchloremic metabolic acidosis, and suppressed plasma renin (PR) activity with normal plasma aldosterone (PA) and sometimes failure to thrive. GS is a heterogeneous genetic syndrome, ranging from severe cases in childhood to mild and sometimes asymptomatic cases in mid-adulthood. (2) Methods: We report here a sizeable Spanish family of six patients (four adults and two children) with GS. (3) Results: They carry a novel heterozygous missense variant in exon 7 of WNK1 (p.Glu630Gly). The clinical presentation in the four adults consisted of hypertension (superimposed pre-eclampsia in two cases), hyperkalemia, short stature with low body weight, and isolated hyperkalemia in both children. All patients also presented mild hyperchloremic metabolic acidosis and low PR activity with normal PA levels. Abnormal laboratory findings and hypertension were normalized by dietary salt restriction and low doses of thiazide or indapamide retard. (4) Conclusions: This is the first Spanish family with GS with a novel heterozygous missense variant in WNK1 (p.Glu630Gly) in the region containing the highly conserved acidic motif, which is showing a relatively mild phenotype, and adults diagnosed in mild adulthood. These data support the importance of missense variants in the WNK1 acidic domain in electrolyte balance/metabolism. In addition, findings in this family also suggest that indapamide retard or thiazide may be an adequate long-standing treatment for GS.

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.

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.

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.

Benefit of treatment based on indapamide mostly combined with perindopril on mortality and cardiovascular outcomes: a pooled analysis of four trials.

OBJECTIVE: The aim of this study was to assess the reduction in all-cause death and cardiovascular outcomes associated with the administration of the thiazide-like diuretic indapamide monotherapy or in combination with perindopril as a blood pressure lowering drug in randomized controlled trials (RCTs). METHOD: Aggregate data from four published RCTs conducted versus matching placebo were pooled: PATS, a 2-year study (indapamide), and PROGRESS, a 4-year study (indapamide and perindopril), both in patients with a history of stroke or transient ischemic attack; ADVANCE, a 4-year study in patients with type 2 diabetes and cardiovascular risk factor (single-pill combination perindopril/indapamide) and HYVET, a 2-year study in very elderly hypertensive individuals (indapamide and an option of perindopril). The pooled effect (fixed and random) estimate (hazard ratio) was reported with corresponding 95% confidence intervals and P values. Treatment discontinuations were also analysed to assess the net benefit of the treatment. RESULTS: The population involved 24 194 patients (active: 12 113, placebo: 12 081). The fixed-effects meta-analysis of the three mortality endpoints found low statistical heterogeneity ( I2  = 0). Statistically significant risk reductions in the indapamide with or without perindopril-treated patients as compared to placebo were observed for all-cause death (-15%), cardiovascular death (-21%), fatal stroke (-36%) and all strokes (-27%). Other cardiovascular outcomes were improved (risk reduction, 22 to 36%). As expected, discontinuation rates for safety (two studies) were higher in the active group (6.4 vs. 3.9%), while they were similar when discontinuation for any reason is concerned (18.4 vs. 18.0%). CONCLUSION: Across medium to high cardiovascular risk population, long-term indapamide, mostly combined with perindopril-based treatment, provided evidence of benefit on mortality and morbidity.

[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.

Analysis of Fixed-Dose Combination of Three Antihypertensive Drugs by a Green and Quality by Design Approach.

This paper presents the result of a combined employment of Analytical Quality-by-Design and Green Analytical Chemistry principles for the development of a robust high-performance liquid chromatography method for simultaneous determination of fixed-dose combination of three drugs, perindopril tert-butylamine, amlodipine besylate and indapamide. Optimum conditions were achieved on ZORBAX Eclipse XDB-C18 column (150 mm × 4.6 mm, 5 µm particle size), the mobile phase comprising acetonitrile and phosphate buffer (30 mM, pH 2.7) in the ratio 34:66 (v/v), the flow rate of 1 mL min-1, injection volume of 10 µL and UV detection at 210 nm. By assigning the design space from the overlay plot, the regions within which the robustness of the method is achieved were defined and confirmed by Dong's algorithm calculations. The proposed method was validated and shown to be applicable for the determination of the three drugs in commercially available tablets. In addition, the impact of the method on the environment was assessed through four different analytical tools: National Environmental Methods Index, Analytical Eco-Scale, Green Analytical Procedure Index and Assessment of Green Profile. The proposed method was determined to be greener, with minimal impact on the environment with regard to waste production, energy consumption and use of hazardous chemicals.

The impact of different diuretics on regression of myocardial reperfusion injury in spontaneously hypertensive rats.

The study's objective was to ascertain the results of sub-chronic therapy of various diuretics on the ischemia/reperfusion dysfunction of the heart in hypertensive rats by a global ischemia in an isolated rat heart model. The research included 40 spontaneously hypertensive male rats (Wistar Kyoto strain, body mass 250 ± 30 g, 8 weeks old) grouped into four groups. The animals were treated for 4 weeks with 10 mg/kg of hydrochlorothiazide, indapamide, or spironolactone per os. After a period of sub-chronic treatment, we analyzed hemodynamic measurements, echocardiography, and myocardial function according to the Langendorff retrograde perfusion method. The hearts were subjected to 20 min of global ischemia and then reperfused for 30 min (I20:R30). Cardiovascular parameters that depict the left ventricle functions were continuously monitored, while flowmetry was used to determine coronary flow values. Markers of oxidative stress were estimated from coronary venous effluent using spectrophotometry. All three examined diuretics (hydrochlorothiazide, spironolactone, indapamide) lowered the production of the majority of the detected prooxidants, reducing myocardial oxidative damage. The cardiological examination of heart function in vivo demonstrated that treatment with indapamide and spironolactone mitigates left ventricular hypertrophy but without significant lowering of blood pressure or increment in ejection fraction. Additionally, monitoring of cardiac function ex vivo indicated the cardiodepressant effect of spironolactone in spontaneously hypertensive rats.

In Vitro Dissolution Profile of Antihypertensive Mixture: Comparison Between Multivariate Methods and Statistical and Graphical Representation of Different Univariate Spectrophotometric Data.

BACKGROUND: Triplixam® is a new antihypertensive drug combination consisting of perindopril, amlodipine, and indapamide, which have a synergistic mechanism of action in combination with each other. OBJECTIVE: Comparative study of different spectrophotometric approaches used for the simultaneous determination of perindopril, indapamide, and amlodipine in bulk powder and in dosage form Triplixam. METHOD: The methods include univariate and multivariate spectrophotometric methods depending on either mathematical calculation or graphical representation of data. For the univariate methods: perindopril was resolved from other components using constant multiplication followed by spectrum subtraction resolution technique, and then two base point, AUC, constant value, and concentration value (CNV) methods were applied. For both amlodipine and indapamide: constant multiplication resolution technique was used, and then constant value and CNV methods were applied. CNV depends on graphical representation of data rather than statistical data. PLS and PCR chemometric assisted spectrophotometric techniques were also applied. The proposed methods are considered a green alternative to the reported methods as the greenness of the proposed methods was evaluated qualitatively and quantitatively by four green analytical evaluation tools. RESULTS: The methods were applied for the analysis of the mixture in the pharmaceutical dosage form Triplixam and in vitro release at intestinal pH (7.4) using a USP dissolution tester. CONCLUSIONS: The proposed green analytical methods are considered to be greener than the reported methods and simpler, so they could be used as an alternative for routine analysis of the mixture in quality control laboratories for the reason of their accurate results beside minimum manipulation steps that reduced the error and time required of the analysis with no harmful effect on analyst health as well as the environment. HIGHLIGHTS: The study was the first in vitro dissolution profiling of perindopril, amlodipine, and indapamide. The developed methods were excellent green methods without compromising the analytical criteria.

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.