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Purpose: Toxicological screenings for identifying antihypertensive drugs proved to be a useful tool for assessing adherence. However, misinterpretation may occur in case of highly metabolised drugs with low renal excretion, as well as for drugs with a prolonged detectability. The aim of the present study was to compare a recently developed therapeutic drug monitoring (TDM) method based on serum concentrations to an urine drug detection method for assessing adherence in outpatients. Materials and methods: Corresponding urine and blood samples were obtained at the same time from 26 outpatients without supervised medication. Urine and serum analyses were performed using established high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodologies. Adherence was assumed if drugs were detectable in urine or if serum concentrations were above individually calculated lower dose-related concentrations (DRC) or literature-based therapeutic reference ranges (TRR) used as cut-off, respectively. Results: The identification of analytes in urine as well as the quantitative serum assay were performed for atenolol ( n  = 6 patients), bisoprolol ( n  = 8), nebivolol ( n  = 6), canrenone ( n  = 6, metabolite of spironolactone), hydrochlorothiazide ( n  = 12) and furosemide ( n  = 2). On the basis of drug detectability in urine, adherence was assumed in 88% of prescriptions. In 81% (DRC) and 50% (TRR) of the serum analyses the cut-off value was exceeded, which confirms patients' adherence in a lower number. Differences in adherence rates were found in five patients, mainly for β-blockers. Conclusion: This study suggests that assessment of adherence can be performed more precisely on the basis of serum drug concentrations with individually calculated lower DRC than by using the TRR or qualitative urinalysis.

Confirmation of medication adherence is a challenge in clinical practice and essential for the accurate diagnosis of resistant hypertension. Although it is well established that drug adherence is critical for controlling blood pressure, there are still difficulties applying a simple, inexpensive, and reliable assessment of adherence in the clinical setting. We aimed to test a simple method to assess adherence in resistant hypertensive (RH) patients. A pilot study with normotensives or mild/moderate hypertensive subjects was performed to provide a fluorescence cutoff point for adherence. After that, 21 patients referred to the Resistant Hypertension Clinic had triamterene prescribed and were monitored for a 30-day period. We conducted two unannounced randomly selected home visits for urine collection to test drug intake that day. Office, home and 24-hour ambulatory blood pressure, biochemical data, and the 8-item Morisky Medication Adherence Scale (MMAS-8) were systematically acquired. According to adherence indicated by urine fluorescence, subjects were divided into adherent and nonadherent groups. We found 57% of nonadherence. No differences were found between groups regarding baseline characteristics or prescribed medications; Kappa's test showed concordance between adherence through MMAS-8 items and fluorescence (kappa = 0.61; 95% confidence interval: 0.28-0.94; P = .005). Nonadherent patients had higher office (81 ± 11 vs. 73 ± 6 mm Hg, P = .03), 24-hour ambulatory blood pressure monitoring (75 ± 9 vs. 66 ± 7 mm Hg, P = .01), and home blood pressure measurement (77 ± 9 vs. 67 ± 8 mm Hg, P = .01) diastolic blood pressure than their counterparts. Nonadherence to antihypertensive therapy is high in patients with RH, even when assessed in clinics specialized in this condition. Fluorometry to detect a drug in the urine of RH patients is safe, easy, and reliable method to assess adherence., (Copyright © 2016 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

An alternative method for analysis of aliskiren (ALI) and hydrochlorothiazde (HCT) in combined dosage forms by ion-pair reversed phase high performance liquid chromatography was developed and validated. The pharmaceutical preparations were analyzed using a C18 column (250 mm x 4.6 mm, 3 microm) with a mobile phase consisting of 25% methanol, 50% sodium monobasic phosphate aqueous solution containing 6 mM tetrabutylammonium bromide and 25% water at pH 7.2. Isocratic analysis was performed at a flow rate of 1 mL/min and a column temperature of 30 degrees C under direct UV detection at 210 nm. Paracetamol was used as internal standard. The validation was performed according to the ICH guidelines. The proposed method was linear over the concentration range of 0.250 to 60 and 0.1 to 10 microg/mL for ALI and HCT, respectively. The limits of detection and quantitation (LOD and LOQ) were 0.075 and 0.198 microg/mL, respectively, for ALI and 0.04 and 0.062 microg/mL, respectively, for HCT. The method proved to be specific, sensitive, precise and accurate with mean recovery values of 101.1 +/- 0.32% and 100.9 +/- 0.41% for ALI and HCT, respectively. The method robustness was evaluated by means of an experimental design. The proposed method was applied successfully to spiked human urine samples with mean recoveries of 98.8 +/- 0.36% and 98.1 +/- 0.21% for ALI and HCT, respectively.

Hydrochlorothiazide (HCTZ) is a thiazide diuretic used for the treatment of hypertension and edema associated with fluid overload conditions such as congestive heart failure (CHF). A population-based meta-analysis approach in NONMEM® was used to develop a PK model to characterize the time-course of HCTZ concentrations in plasma and excretion into the urine for healthy subjects and CHF patients. Data from healthy subjects receiving 100 mg of oral HCTZ were supplemented with additional plasma concentration and urinary excretion versus time data published in the literature following administration of oral HCTZ doses ranging from 10 to 500 mg to healthy subjects or patients with renal failure, CHF or hypertension. A two-compartment model with first-order oral absorption, using a Weibull function, and first-order elimination best described HCTZ PK. Creatinine clearance (CLCR ) was a statistically significant predictor of renal clearance (CLR ). Non-renal clearance was estimated to be 2.44 l/h, CLR was 18.3 l/h and T1/2,α was 1.6 h and T1/2,β was 14.8 h for a typical individual with normal renal function (CLCR  = 120 ml/min). However, CLR was reduced to 10.5, 5.47 and 2.70 l/h in mild (CLCR  = 80 ml/min), moderate (CLCR  = 50 ml/min) and severe (CLCR  = 30 ml/min) renal impairment, respectively. Model diagnostics helped to demonstrate that the population PK model reasonably predicts the rate of urinary HCTZ excretion over time using dosing history and estimated CLCR , allowing for the convenient assessment of PK-PD relationships for HCTZ when given alone or in combination with other agents used to treat fluid overload conditions., (Copyright © 2013 John Wiley & Sons, Ltd.)

A novel fluorescence quenching method for the determination of torasemide (TOR) with some dihalogenated fluorescein dyes as fluorescence probes was developed. In acidulous medium, TOR could interact with some dihalogenated fluorescein dyes such as dichlorofluorescein (DCF), dibromofluorescein (DBF) and diiodofluorescein (DIF) to form binary complexes, which could lead to fluorescence quenching of above dihalogenated fluorescein dyes. The maximum fluorescence emission wavelengths were located at 532 nm (TOR-DCF), 535 nm (TOR-DBF) and 554 nm (TOR-DIF). The relative fluorescence intensities (ΔF=F0-F) were proportional to the concentration of TOR in certain ranges. The detection limits were 4.8 ng mL(-1) for TOR-DCF system, 9.8 ng mL(-1) for TOR-DBF system and 35.1 ng mL(-1) for TOR-DIF system. The optimum reaction conditions, influencing factors were studied; and the effect of coexisting substances was investigated owing to the highest sensitivity of TOR-DCF system. In addition, the reaction mechanism, composition and structure of the complex were discussed by quantum chemical calculation and Job's method. The fluorescence quenching of dihalogenated fluorescein dyes by TOR was a static quenching process judging from the effect of temperature and the Stern-Volmer plots. The method was satisfactorily applied to the determination of TOR in tablets and human urine samples., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To investigate the diuretic, natriuretic and kaliuretic effects of the antihypertensive Ayurveda drug Karavi Panchaka decoction and compare it with the diuretic frusemide., Design: An animal study using Sprague-Dawley rats. The volume of urine and the total sodium and potassium excreted in the urine by rats in response to orally fed Karavi Panchaka decoction were compared with rats fed with frusemide. Control experiments were done with rats receiving similar volumes of distilled water orally. The Ayurveda drug was prepared in accordance with the traditional method in the laboratory using medicinal plant specimens individually collected and identified., Measurements: The volume of urine excreted during a 24-hour period following administration of the Ayurveda drug, frusemide or water was measured. The total sodium and potassium ion concentrations in the urine samples were determined using flame photometry., Results: The Karavi Panchaka decoction clearly showed a statistically significant increase in urine excretion when compared with the control group that received only distilled water. The potassium ion excretion was significantly increased in the Karavi Panchaka decoction treated group when compared to the control group. This increase was statistically similar to that caused by frusemide. Neither drug had a significant effect on sodium ion excretion at the dosages used., Conclusion: Our results show that the Karavi Panchaka decoction significantly increases urine and potassium ion excretion in rats, but has no effect on sodium ion excretion at the dosage used. The effect of the Ayurveda drug on urine output as well as the sodium and potassium ion excretion is similar to that of frusemide administered at the dose used in our study.

A simple direct injection chromatographic procedure with fluorimetric detection is successfully applied to the determination of mixtures of 4 diuretics (amiloride, bendroflumethiazide, piretanide, and triamterene) and 6 beta-blockers (acebutolol, atenolol, labetalol, metoprolol, nadolol, and propranolol), which are usually administered in combinations for the treatment of hypertension, in urine samples. The procedure makes use of C18 columns and micellar mobile phases of sodium dodecyl sulphate (SDS), propanol, and phosphate buffer at pH 3. The adequate resolution of most drugs is obtained with a chemometrics approach where the retention is modeled as a first step using the retention factors in only 5 mobile phases. Afterward, an optimization criterion that takes into account the position and shape of the chromatographic peaks is applied. A mobile phase of 0.11M SDS--8% propanol could resolve mixtures of 8 drugs and was adequate for the analysis of the combinations of diuretic and beta-blocker usually prescribed. However, a mobile phase of larger elution strength, such as 0.15M SDS--15% propanol, is preferred for the analysis of mixtures of amiloride-metoprolol, amiloride-labetalol, and triameterene-propranolol. The method is sensitive enough for the routine analysis of diuretics and beta-blockers at therapeutic urine levels with limits of detection in the 0.5-28-ng/mL range. Urinary excretion studies show that the detection of most drugs is possible up to 24-72 h after their ingestion.

A simple and rapid on-line method for the determination of chlorthalidone in urine is proposed. The sample containing the internal standard is injected in a CN precolumn. After a 2-ml water rinsing, the precolumn is coupled for 30 s to the HPLC column via a switching, valve, allowing the on-line elution of the compounds of interest. Analysis is carried out by reversed-phase chromatography with an acetonitrile-0.01 M phosphate buffer pH 7 (20:80, v/v) eluent, using UV detection at 214 nm. While the LC separation is performed, the precolumn is regenerated and conditioned, and is ready to receive the next sample at the end of the run. Accurate (> 95%) and precise (< 10%) analyses, in the range of 0.1-20 micrograms/ml of chlorthalidone in urine, have been achieved using this method.

1. Enantiomer-enantiomer interaction of 5-dimethylsulphamoyl-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxyl ic acid (DBCA), a uricosuric, diuretic and antihypertensive agent, was studied from the pharmacokinetics of the enantiomers following intravenous injection of individual enantiomers and racemate into male cynomolgus monkeys. Also studied was the involvement of the anion transport system in the renal excretion of DBCA by comparison of the pharmacokinetics in probenecid-treated and non-treated animals. 2. Separate administration of individual enantiomers showed higher plasma concentrations of (S)(-)-DBCA than those of the antipode, at an early period after dosing. Both enantiomers disappeared rapidly from plasma with an elimination half-life (t1/2 beta) of 0.35-0.38 h. Unbound fractions were 18.9% for the (R)(+)-enantiomer and 10.2% for the (S)(-)-enantiomer. The major portion of both enantiomers was excreted by 6 h after dosing and 77-78% of the dose was recovered within 48 h, principally as the unchanged drug. Tubular secretion contributed significantly to the renal excretion of DBCA, because tubular secretion clearance values of unbound drug (CLrf,s) were 14- to 29-fold greater than creatinine clearance. 3. The presence of the antipode decreased the tubular secretion clearance (CLrf,s) value of unbound (S)(-)-enantiomer by 30%, and tended to decrease that for the unbound (R)(+)-enantiomer, although not significantly. This indicates the occurrence of enantiomer-enantiomer interaction in the process of renal tubular secretion, and the inhibition of (S)(-)-DBCA renal excretion in the presence of the antipode. 4. Probenecid treatment significantly decreased the CLrf,s of both enantiomers, and the extent of inhibition for the (S)(-)-enantiomer (53%) was significantly higher than that for the antipode (14%). These results show that renal tubular secretion of DBCA involves an anion transport system which prefers the (S)(-)-enantiomer, and that probenecid can preferentially inhibit (S)(-)-enantiomer secretion.

A pharmacokinetic study of cicletanine, a new class of antihypertensive drugs was performed in ten healthy volunteers after administration of 50 mg single oral dose. Cicletanine plasma and urine concentrations were measured using the HPLC technique. The main pharmacokinetic parameters were estimated applying a non-compartmental approach. The half-life ranged between 4.76 to 17.76 h; the mean oral and renal clearance were 7.3 +/- 2.5 l/h and 0.026 +/- 0.012 l/h, respectively. The urinary excretion of the product ranged between 37.5 and 64.6% of the administered dose, the amount of unchanged drug being negligible (0.4 +/- 0.3%). Both metabolic conjugation pathways glucuronidation and sulphation occurred in a similar extent 23.7 +/- 6.7% and 23.0 +/- 7% respectively. The overall pharmacokinetic parameters obtained in this study agree with those previously reported after the administration of higher doses (75-300 mg) and is in favour of a linear pharmacokinetic behaviour of cicletanine over the dose range of 50 mg to 300 mg.

A method for the measurement of a potential diuretic-antihypertensive agent, (+/-)-[[6,7-dichloro-2-(4-fluorophenyl)-2-methyl-1-oxo-5-indanyl] oxy]acetic acid, in biological fluids is described. The procedure involves the addition of a related internal standard to the specimens followed by extraction of the acids into toluene at pH 1. The indanyloxyacetic acids, following back-extraction into base and reextraction into methylene chloride at an acidic pH, are converted to methyl esters by reaction with ethereal diazomethane for subsequent gas chromatographic analysis. The sensitivity of the method is such that 5 ng of drug in 1 mL of biological specimen can be quantitated using a 63Ni electron-capture detector. The recovery from plasma in the 5-2000-ng/mL range (n = 53) was 97.0 +/- 16.3%. Differences were noted in the disposition of the enantiomers of this agent in dogs following a pharmacologically active dose.