Hydrochlorothiazide Concentrations Research Articles

Developed and Validated RP-HPLC Method for Concurrent Analysis of Some Cardiovascular Drugs

Objective: An ICH-compliant RP-HPLC approach was created and validated in order to measure the concentrations of HCTZ and LIS in bulk and mixed medicinal dosage forms. This procedure was subsequently submitted for certification. Methods: Column, a Phenomenex Luna C18(2) (250 x 4.6 mm, 5μ) with a Methanol: Formic acid (30:70) mobile phase, a flow rate is kept as 01 mL/min, the wavelength of detection was 215 nm, and a used detector was PDA. Results: Hydrochlorothiazide (HCTZ)) and lisinopril (LIS) both had linear calibration curves (r2 = 0.9973 and 0.9983, respectively) for the ranges of concentration 4.0 to 6.0 and 10.0 to 15.0 μg/mL. The proposed technique eluted LIS in 3.97 minutes and hydrochlorothiazide in 4.53 minutes. Lisinopril had a recovery rate of 99.31 to 99.83%, whereas hydrochlorothiazide had a recovery rate of 100.75 to 101.16%. At 1.22 and 0.31 μg/mL, respectively, HCTZ as well as LIS had the lowest detectable values. It was found that the LoQs for lisinopril and hydrochlorothiazide were 0.97 and 3.75 μg/mL, respectively. Conclusion: It was found that the current RP-HPLC technique is reliable, simple to use, accurate, linear, efficient, and rapid. With a shorter analysis period, this method offers better resolution between the two compounds. Therefore, there is sufficient evidence to include the approach in regular lisinopril and hydrochlorothiazide analysis in a variety of pharmaceutical companies and academic institutions.

Voltammetric determination of hydrochlorothiazide at a modified carbon paste electrode with polypyrrole nanotubes.

In this paper, the electrochemical behavior of hydrochlorothiazide (HCTZ) is described using carbon paste electrodes modified with polypyrrole nanotubes (PPy-NTs/CPEs) at pH value 7. Experiments revealed that the presence of HCTZ greatly impacts the electrochemical behavior of modified CPEs. The synthesized PPy-NTs were utilized as a sensing material for the electrochemical detection of HCTZ and were investigated by cyclic voltammetry (CV), differential pulse voltammetry (DPV) and chronoamperometry. The key experiment conditions, including supporting electrolyte and electrolyte pH, were studied and optimized. Under optimized conditions, the prepared sensor displayed the linear relationships for the concentrations of HCTZ from 5.0 to 400.0 μM (R2 = 0.9984). The detection limit of the PPy-NTs/CPEs sensor was found to be 1.5 μM using the DPV method. The PPy-NTs is highly selective, stable and sensitive for the determination of HCT. Therefore, we believe the newly prepared PPy-NTs material can be useful for different electrochemical applications.

Pharmacokinetic and bioequivalence study of Telzap® Plus fixed-dose combination compared with MikardisPlus® in healthy volunteers after single administration

Introduction. A fixed dose combination of telmisartan and hydrochlorothiazide is indicated for treatment of in the treatment of arterial hypertension. The combination of these substances causes an additive effect that helps to reduce blood pressure. A bioequivalence study of Telzap® Plus compared with MikardisPlus® was conducted with 63 volunteers.Aim. The purpose of the bioequivalence trial was a comparative study of the pharmacokinetics and evidence of the bioequivalence of the fixed dose combination drug product Telzap® Plus (tablets 80 mg + 12,5 mg, Zentiva KS company, Czech Republic) compared with drug products MikardisPlus® (telmisartan+hydrochlorothiazide, tablets 80 mg + 12,5 mg, Boehringer Ingelheim Pharma GmbH & Co. KG, Germany) in healthy volunteers after a single administration under fasting.Materials and methods. To prove bioequivalence, an open label, comparative, randomized, crossover fourperiod replicate single-center clinical trial was conducted. The concentrations of hydrochlorothiazide and telmisartan in plasma samples were determined with a validated HPLC-MS/MS method. A pharmacokinetic and statistical analysis was performed and confidence intervals for the pharmacokinetic parameters Cmax and AUC0-72 were calculated.Results and discussion. It can be concluded that the studied formulations are bioequivalent in terms of pharmacokinetic parameters of hydrochlorothiazide and telmisartan. All 90 % confidence intervals for the estimated pharmacokinetic parameters of hydrochlorothiazide were in the range of 80–125 %, 90 % confidence intervals for telmisartan were within the bioequivalence range of 80–125 % for AUC0-72, and 79,30–126,11 % for Cmax.Conclusion. Thus, according to the criteria used in the study, the formulations are proved to be bioequivalent.

Fluorescent molecularly imprinted polymer nanocomposite for solid-phase extraction and fluorimetric determination of hydrochlorothiazide.

We report herein a fluorescent molecularly imprinted polymer (FMIP) for the solid-phase extraction (SPE) and fluorimetric determination of hydrochlorothiazide (HCTZ) in water. The FMIP is based on fluorescent polystyrene nanoparticles embedded within a molecularly imprinted polyaniline (PANI) matrix. The operational adsorption parameters such as the initial HCTZ concentration, incubation time and the solution pH were found to influence the removal efficiency. At optimum conditions, a high adsorption capacity of the FMIP was found (2.08 mg g-1). Evidence of the adsorption process was confirmed by the change in the FMIP physicochemical properties measured by FTIR absorption spectroscopy and electron microscopy. Based on the regression R2 values and the consistently low values of the adsorption statistical error functions, equilibrium data were best fitted to both Freundlich and Temkin isotherms. Moreover, the pseudo-second-order kinetic model described the adsorption kinetics, and the mechanism of the adsorption process was explained by the intraparticle diffusion model. Upon studying adsorption thermodynamics, negative ΔG values (-26.18 kJ mol-1 at room temperature) were obtained revealing that the adsorption process is spontaneous. Interestingly, the maximum adsorption capacity was obtained at 298 K, pH 7.0, and using a high HCTZ concentration, thus revealing the suitability of the proposed FMIP for easy and fast SPE of HCTZ. The FMIP showed an imprinting factor of 1.19 implying the selectivity over the corresponding FNIP. Eventually, the proposed FMIP was successfully applied to the spectrofluorimetric determination of HCTZ in aqueous samples with %recovery values close to 100%.

Hydrochlorothiazide use is associated with the risk of cutaneous and lip squamous cell carcinoma: A systematic review and meta-analysis.

The aim of this study is to investigate the association between hydrochlorothiazide (HCTZ) use and the risk of cutaneous and lip squamous cell carcinoma development. We performed a systematic review and meta-analysis of case-control studies. We searched the Cochrane Library, PubMed, Scopus, Web of Science and LILACS. This study was registered in PROSPERO under protocol CRD42019129710. The meta-analysis was performed using the software Stata (version 12.0). A total of 2181 published studies referring to the theme were identified, from which six were included in this systematic review. Men were more frequently affected by cutaneous and lip squamous cell carcinoma than women, with a 1.42:1 ratio. The mean age for cutaneous and lip squamous cell carcinoma development was 73.7 years. This meta-analysis demonstrated a chance of developing cutaneous and lip squamous cell carcinoma in any region of the body in hydrochlorothiazide users of 1.76-fold higher than in non-users. In addition, a risk factor of 1.80 higher (CI 95% = 1.71-1.89) of cutaneous squamous cell carcinoma in the head and neck region was observed in HCTZ users. Moreover, in the analysis of the dose used, the chance of developing squamous cell carcinoma was 3.37-fold lower when the concentration of HCTZ used was less than 50,000 mg. Our results confirm the association between the use of hydrochlorothiazide and the cutaneous and lip squamous cell carcinoma development.

Development of a multivariate model with desirability-based optimization for determination of atenolol and hydrochlorothiazide by eco-friendly HPLC method with fluorescence detection.

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

Simultaneous Determination of Hydrochlorothiazide and Losartan Potassium in Pharmaceutical Product by UV-Vis Spectrophotometric Method with Kalman Filter Algorithm.

In this paper, hydrochlorothiazide (HCT) and losartan potassium (LSP) in tablets are simultaneously determined with UV-Vis spectrophotometry and chemometrics without separation. The spectra of standard and sample solutions were recorded in the wavelength from 220 to 300 nm at 1.0 nm intervals. The concentrations of HCT and LSP in the sample solutions were computed with the Kalman filter algorithm written on the Microsoft Excel 2016 and Visual Basic for Applications (VBA) platform. The method validation was determined via the accuracy and repeatability of measurements when analyzing HCT and LSP in the Splozarsin Plus tablet and comparing the mean values of their contents in the sample with those analyzed with HPLC. The proposed method is simple with a low cost compared with the standard HPLC method.

Efficacy of ARB/HCTZ Combination Therapy in Uncontrolled Hypertensive Patients Compared with ARB Monotherapy: A Meta-Analysis.

Objective To evaluate the efficacy of combination of angiotensin receptor blocker (ARB) with hydrochlorothiazide (HCTZ) compared to ARB alone in patients with uncontrolled hypertension via a systematic review and meta-analysis. Methods We searched databases till July 2019 using relevant search terms. We included articles that were randomised controlled trials (RCTs) comparing ARB/HCTZ with ARB for a duration of at least 4 weeks and reported on the efficacy or safety. Meta-analyses for efficacy outcomes were performed. In addition, groups given different concentrations of HCTZ (12.5 and 25 mg) were analysed separately. Results Sixteen RCTs (12,055 participants) were included. Overall, ARB/HCTZ combination therapy (both 12.5 and 25 mg HCTZ combination) resulted in better sitting systolic and diastolic blood pressure control than ARB alone (mean difference (95% confidence interval (CI): −5.69 [−6.66, −4.73] for 12.5 mg and −9.10 [−11.78, −6.42] for 25 mg and mean difference (95% CI): −2.91 [−3.31, −2.51] for 12.5 mg and −4.16 [−4.75, −3.58] for 25 mg). ARB/HCTZ combination therapy resulted in a higher rate of target blood pressure achievement compared to ARB alone (risk ratio (95% CI): 1.50 [1.42, 1.59]). ARB/HCTZ combination therapy had similar rates of total adverse events (AEs) and severe AEs compared to ARB alone. Conclusion ARB/HCTZ combination therapy is more efficacious for controlling blood pressure, and combination with a low concentration of HCTZ has similar AEs compared to ARB alone. Clinicians should consider adding HCTZ in the medication regime of patients with uncontrolled hypertension using ARB, if their clinical profile allows.

Hydrochlorothiazide Use and Risk of Nonmelanoma Skin Cancers: A Biological Plausibility Study

Recent studies reported the association between increased risk of nonmelanoma skin cancers (NMSCs) and the use of hydrochlorothiazide (HCTZ), one of the most commonly prescribed diuretic, antihypertensive drug, over the world. Although HCTZ is known to be photosensitizing, the mechanisms involved in its potential prophotocarcinogenic effects remain unclear. Under acute exposure, therapeutically relevant concentrations of HCTZ (70, 140, and 370 ng/mL) amplified UVA-induced double-strand breaks, oxidative DNA, and protein damage in HaCaT human keratinocytes, and this effect was associated to a defective activity of the DNA repair enzyme, OGG1. Oxidative damage to DNA, but not that to proteins, was reversible within few hours. After chronic, combined exposure to HCTZ (70 ng/mL) and UVA (10 J/cm2), for 9 weeks, keratinocytes acquired a dysplastic-like phenotype characterized by a multilayered morphology and alterations in cell size, shape, and contacts. At the ultrastructural level, several atypical and enlarged nuclei and evident nucleoli were also observed. These transformed keratinocytes were apoptosis resistant, exhibited enhanced clonogenicity capacity, increased DNA damage and inflammation, defective DNA repair ability, and increased expression of the oncogene ΔNp63α and intranuclear β-catenin accumulation (a hallmark of Wnt pathway activation), compared to those treated with UVA alone. None of these molecular, morphological, or functional effects were observed in cells treated with HCTZ alone. All these features resemble in part those of preneoplastic lesions and NMSCs and provide evidence of a biological plausibility for the association among exposure to UVA, use of HCTZ, and increased risk of NMSCs. These results are of translational relevance since we used environmentally relevant UVA doses and tested HCTZ at concentrations that reflect the plasma levels of doses used in clinical practice. This study also highlights that drug safety data should be followed by experimental evaluations to clarify the mechanistic aspects of adverse events.

Plasma Trough Concentrations of Antihypertensive Drugs for the Assessment of Treatment Adherence: A Meta-Analysis.

Biochemical drug screening by liquid chromatography-tandem mass spectrometry in plasma is an accurate method for the quantification of plasma concentrations of antihypertensive medications in patients with hypertension. Trough concentrations could possibly be used as drug-specific cutoff values in the biochemical assessment of (non-)adherence. We performed a literature review and meta-analysis of pharmacokinetic studies to determine plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan. PubMed was searched for pharmacokinetic studies up to September 2020. Eligible studies reported steady-state mean trough concentration and their variance. Pooled trough concentrations were estimated using a three-level random effects meta-analytic model. Moderator analyses were performed to explore sources of heterogeneity. One thousand three hundred eighteen potentially relevant articles were identified of which 45 were eligible for inclusion. The pooled mean trough concentration was 9.2 ng/mL (95% CI, 7.5-10.8) for amlodipine, 41.0 ng/mL (95% CI, 17.4-64.7) for hydrochlorothiazide, and 352.9 ng/mL (95% CI, 243.5-462.3) for valsartan. Substantial heterogeneity was present for all 3 pooled estimates. Moderator analyses identified dosage as a significant moderator for the pooled trough concentration of amlodipine (β1=0.9; P<0.05), mean age, and mean body weight for the mean trough concentration of hydrochlorothiazide (β1=2.2, P<0.05, respectively, β1=-4.0, P<0.05) and no significant moderators for valsartan. Plasma trough concentrations of amlodipine, hydrochlorothiazide, and valsartan, measured with liquid chromatography-tandem mass spectrometry, are highly heterogeneous over the different studies. Use of the pooled trough concentration as a cutoff in the biochemical assessment of adherence can result in inaccurate diagnosis of (non-)adherence, which may seriously harm the patient-physician relationship, and is therefore not recommended.

Pharmacokinetics of Hydrochlorothiazide in Children: A Potential Surrogate for Renal Secretion Maturation.

Hydrochlorothiazide (HCTZ) is a thiazide diuretic used in adults and children for the treatment of hypertension and edema. The pharmacokinetic (PK) properties of HCTZ in children are not well characterized, particularly among children with obesity who frequently suffer from hypertension and may, therefore, benefit from HCTZ therapy. HCTZ is excreted in the kidney via organic anion transporters 1 and 3 (OAT1 and OAT3). The ontogeny of OAT1 and OAT3 remain unknown, but HCTZ clearance may serve as a surrogate marker of OAT1 and OAT3 maturation. Population PK modeling was performed in NONMEM, and the model was leveraged to conduct dose-exposure simulations. This study examined 83 plasma samples from 49 participants (69% male) taking enteral HCTZ. The median (range) postnatal age was 6.7 years (0.03-19.5 years), and 17 (34%) participants were obese or morbidly obese. The median (range) dose of HCTZ was 0.654 mg/kg (0.11-1.8 kg) and the median number of doses recorded per participant was 5 (1-8). HCTZ PK was well characterized by a 1-compartment PK model. Body weight and a maturation model based on postmenstrual age were significant covariates for apparent clearance, but the presence of obesity was not. Dosing simulations were performed with a standardized 1mg/kg. Simulated exposure (area under the curve and maximum HCTZ concentrations) decreased with age and was likely due to older children receiving the maximum absolute doses of HCTZ. Further studies with more patients in each age group are required to confirm these PK findings of HCTZ in the children.

In-Vitro Incompatibility Study of Valsartan and Hydrochlorothiazide by Spectroscopic and RP-HPLC Method

The present investigation was based on an in-vitro incompatibility study between valsartan and hydrochlorothiazide by spectroscopic and reverse-phase high-pressure liquid chromatography (RP-HPLC) methods. The method was developed and validated by UltraViolet-Spectroscopic (UV-Spectroscopic) method using water and methanol (4:1) as the solvent. The RP-HPLC study was carried out using Acetonitrile, methanol, and 50Mm phosphate buffer (20:50:30%) adjusted to pH-3 with orthophosphoric acid. The methods showed linearity at the concentration range of 1-5μg/ml with correlation coefficient 0.9994 for valsartan and 0.9978 for hydrochlorothiazide in the method and 5-25 μg/ml in. Both the methods were shown a percentage relative standard deviation (%RSD) values less than 2. The in-vitro incompatibility study was carried out by UV-Spectroscopic and RP-HPLC methods. The result of the study shown that there is a change in the concentration level of both drugs in combination. The structure of the interacting compound was determined by spectral analysis using IR, 1 HNMR and LC-MS study. The spectral analysis confirmed the formation of the new complex between valsartan and hydrochlorothiazide. The result obtained from the LC-MS study also correlates the reason behind an increase in the concentration of valsartan and decreases the concentration of hydrochlorothiazide during recovery study by spectroscopic and RP-HPLC method.

Development of a stable oral pediatric solution of hydrochlorothiazide by the combined use of cyclodextrins and hydrophilic polymers.

Hydrochlorothiazide (HCT) is widely used in pediatrics for hypertension management. Due to the lack of pediatric commercial forms, community or hospital pharmacies generally prepare HCT extemporaneous pediatric suspensions by dispersing in water a portion of a crushed tablet or the drug powder; however, any dose or stability control is usually done on these preparations. Obtaining stable HCT solutions is very challenging, due to its low water-solubility and pH-dependent degradation. The aim of this work was to develop a stable 2mg/mL-HCT oral pediatric solution without using co-solvents. Combined use of cyclodextrins (CD) and hydrophilic polymers was exploited to improve poor HCT solubility and stability. HPβCD and SBEβCD were selected, considering their safe toxicological profiles, while PVP resulted the best among the tested polymers. Low PVP concentrations (0.2-1.0%) improved the solubilizing efficiency of both CDs, allowing to reach the prefixed HCT concentration. Different CD-PVP concentrations were used to prepare several 2mg/mL-HCT solutions in pH 5.5 buffer. The best stability was shown by solutions containing the highest SBEβCD concentration (25mM), which allowed a 3-months stability at 4°C. In vivo studies on rats showed that such formulation allowed a more pronounced and more reproducible diuretic effect than the corresponding HCT suspension.

Spectrophotometric Simultaneous Determination of Benazepril and Hydrochlorothiazide in Commercial Pharmaceutical by Chemometric Methods

In this study, models were developed for the simultaneous determination of Benazepril (BEN) and hydrochlorothiazide (HCT) in drug samples using chemometric approaches using UV spectrophotometry. It was used to calculate the calibration mixes between 200 and 360 nm wavelengths at 5 nm intervals for the spectra of BEN and HCT at various concentrations. The least squares calibration method and principal component regression were used for chemometric analysis of the data and the parameters of the chemometric procedures were optimized. The analytical performances of this chemometric method were compared by characterizing the sum of the residual errors' squares (PRESS), estimated standard error (SEP) and recoveries (%). A series of synthetic mixtures containing different concentrations of BEN and HCT were studied to control the predictive ability of the chemometric methods applied. This method was successfully applied to real samples, it was not affected by excipients as stated in the recovery study results. The results obtained in this review encourage these chemometric methods to apply these strategies for standard research and quality control of two active ingredients. Keywords: Benazepril, Hydrochlorothiazide, Partial Least Squares Calibration, Principal Component Regression. DOI: 10.7176/JSTR/6-04-04

A Smart Green Spectrophotometric Method for Simultaneous Determination of Severely Overlapped Binary Mixtures Using Normalized Spectrum and Isosbestic Point as Resolving Tools

Background: The ability of the normalized spectra when used as a divisor and in combination with isosbestic point to resolve complex binary or ternary mixtures, Candesartan and Hydrochlorthiazide binary mixture was taken as a model. Introduction: A green simple smart and accurate method using ethanol as a solvent namely simultaneous derivative ratio (SIDD) was applied to prove the power of normalized spectra and isosbestic point as spectrophotometric resolving tools. Methods: In the proposed SIDD method, the zero order spectra of drugs were simply manipulated using the normalized spectra of CAN as divisor to obtain the ratio and first derivative spectra in two successive steps. Firstly, the total amplitude at isosbestic point 255.4 nm of the ratio spectra of the mixture was measured representing the total actual concentration of both drugs in the mixture. Then, the first derivative of the ratio spectra was obtained to determine Hydrochlorothiazide concentration at 233 nm. While the concentration of Candesartan was determined subsequently by subtracting the Hydrochlorothiazide concentration calculated after derivatization from the total concentration of both drugs obtained at the ratio spectra before the derivatization step. Results: The SIDD was successfully applied for simultaneous determination of both drugs in their pure form or in their binary mixture either in synthetic prepared mixtures or in combined dosage form the adopted method was validated according to the ICH guidelines and the results were found to be within the acceptable limits. Conclusion: The adopted method highlighted the important role of normalized spectrum when used as a divisor in addition to the importance of isosbestic point to resolve severely overlapped spectra. All the measurements were carried using ethanol which is considered one of the greenest solvents making the method an environmentally friendly one. the adopted method was validated according to the ICH guidelines and the results were found to be within the acceptable limits.

Degradation of the diuretic hydrochlorothiazide by UV/Solar radiation assisted oxidation processes

The objective of this study was to analyse the effectiveness of advanced oxidation processes (AOPs) with Solar and UV radiation (UV/H2O2, UV/K2S2O8) for the degradation of hydrochlorothiazide (HCTZ), a widely used diuretic drug, in aqueous solution focusing on the influence of four experimental parameters: initial concentration of HCTZ, solution pH, nature of the water matrix, and initial concentration of radicals. The obtained results showed that using both kinds of direct photolysis (UV and Solar), the percentage of degraded HCTZ was low, but there was a decrease in the degradation rate favored by the increase of the initial concentration of this pollutant. In addition, the degradation rates were higher at acid pHs. With regard to the nature of water, the degradation rate varied in the order: ultrapure > superficial > tap water. This is due to the presence of organic and inorganic matter (bicarbonates, nitrates, and chlorides) in surface and tap water, that react with the radicals generated, which reduces the availability of radical species, generating competitive kinetics. The presence of radical-promoter species increased the degradation rate of the pollutant, reaching a degradation of 100% of HCTZ after 20 min of treatment. The results obtained point out that the degradation rate was higher in the presence of HO radicals. This behavior was attributed to the higher oxidation power of HO versus ▪ radicals. The determination of the degradation by-products led to structures very similar to the parent compound. For example, the corresponding hydroxylated dechlorinated derivative of HCTZ was found in all the systems used. The cytotoxicity test showed that these byproducts have a lower toxicity than the original product. Finally, the economic viability study confirmed that the UV/K2S2O8 system has the lowest cost.

Spectrophotometric and Principal Component Regression Chemometric Method for Simultaneous Determination of Hypertension Drug's in Commercial Pharmaceutical

In this study, the simultaneous determination of Lisinopril (LIS) and Hydrochlorothiazide (HCT) in drug samples by chemometric approaches using UV spectrophotometry has been reported as a simple alternative to using separate models for each component. Spectra of LIS and HCT were recorded at several concentrations within their ranges and were used to compute the calibration mixture between wavelengths 200 and 350 nm at an interval of 5 nm was used for data acquisition. Principal component regression was used for chemometric analysis of data and the parameters of the chemometric procedures were optimized. The analytical performances of this chemometric method was characterized by predicted residual error sum of squares (PRESS), standard error of prediction (SEP) and recoveries (%) and were compared with each other. A series of synthetic solution containing different concentrations of LIS and HCT were used to check the prediction ability of the principal component regression. This method was successfully applied to real samples, with no interference from excipients as indicated by recovery study results. The outcomes acquired in this examination firmly urge us to apply these strategies for a standard investigation and quality control of the two medications. Keywords : Lisinopril, Hydrochlorothiazide, Principal Component Regression DOI : 10.7176/JSTR/5-4-03

Two smart spectrophotometric methods for simultaneous determination of Lisinopril and Hydrochlorothiazide in binary mixtures

Two new, simple, fast and sensitive spectrophotometric methods were developed for analysis of binary mixtures of Lisinopril (LIS) and hydrochlorothiazide (HCT). These methods were absorptivity factor method and ratio subtraction method. In the first method, calculations were made using the absorbance of the mixtures at 211 nm where LIS absorptivity is half HCT absorptivity. On the other hand, the second method was based on reobtaining the original spectrum of LIS from the zero order spectrum of the binary mixture then determining the concentration of LIS from its linear regression equation. HCT concentration in both methods was determined from the absorbance at 270 nm where a lack of interference of LIS occurs. The methods were validated according to ICH and applied successfully on different ratios of laboratory mixtures and on pharmaceutical tablets with excellent accuracy and precision.

Multiple incidence of the prescription diuretic hydrochlorothiazide in compounded nutritional supplements.

Diuretic agents are prohibited in sports in- and out-of-competition according to the regulations of the World Anti-Doping Agency (WADA) because of their possible masking effects on other doping agents in urine samples, and their ability to produce fast acute weight losses. Despite previous studies reported adverse analytical findings (AAFs) resulting from contaminations at ppm level (μg/g) of medicinal products, and recommended to introduce reporting limits for diuretics in doping controls, these are not adopted in analyses performed by WADA-accredited laboratories. We report the case of an athlete with two AAFs for hydrochlorothiazide (HCTZ) at low urinary concentrations (<10ng/mL), who declared the use of nutritional supplements prepared in a compounding pharmacy. His nutritional supplements were analyzed revealing HCTZ presence in different concentrations, at the ppm level (μg/g and ng/mL). With the aim of testing the plausibility of the observed urinary HCTZ concentrations with the nutritional supplement ingestion, a urinary excretion study with three healthy volunteers was performed. HCTZ-contaminated powder (6.4μg/g of HCTZ) was administered to each subject in different dosages, reproducing the possible ingestion pattern occurred. Urine specimens were collected before and after ingestion of the powder, up to 24hours, and underwent liquid-liquid extraction and liquid chromatography-tandem mass spectrometry determination. Post-administration specimens were found to contain HCTZ at concentrations of 5-230ng/mL, which supported the accidental inadvertent intake of the prohibited substance by the athlete. This study makes the argument that the introduction of reporting limits for diuretics are warranted in doping control samples, in order to protect against inadvertent AAFs due to contaminated products.

Quantification of Hydrochlorothiazide and Ramipril/Ramiprilate in Blood Serum and Cerebrospinal Fluid: A Pharmacokinetic Assessment of Central Nervous System Adverse Effects

Background: A drug must reach the central nervous system (CNS) in order to directly cause CNS adverse effects (AEs). Our current study addressed the pharmacokinetic (PK) background of the assumption that CNS concentrations of hydrochlorothiazide (HCT) and ramiprilate may directly cause CNS AEs such as headache and drowsiness. Methods: In neurological patients, paired serum and cerebrospinal fluid (CSF) samples were withdrawn simultaneously. Some of them were treated with HCT (n = 15, daily chronic doses 7.5–25 mg) or ramipril (n = 9, 2.5–10 mg). Total concentrations of HCT and ramiprilate were quantified in these samples. To this end, sensitive liquid chromatography/tandem mass spectrometry methods were developed. Results: CSF reached 4.1% (interquartile ranges 2.5–5%) of total serum concentrations for HCT and 2.3% (1.7–5.7%) for ramiprilate, corresponding to about 11.3% and 5.5% of respective unbound serum concentrations. Conclusion: The PK/Pharmacodynamic characteristics of HCT and ramiprilate in the CNS are unknown. However, since the CSF levels of these agents, both free and bound, were much lower than the corresponding concentrations in serum, it is unlikely that the observed CNS AEs are mediated primarily via direct effects in the brain.