Escaping the cohort of concern: in vitro experimental evidence supports non-mutagenicity of N-nitroso-hydrochlorothiazide.

In recent years, nitrosamine impurities in pharmaceuticals have been subject to intense regulatory scrutiny, with nitrosamine drug substance-related impurities (NDSRIs) treated as cohort of concern impurities, regardless of predicted mutagenic potential. Here, we describe a case study of the NDSRI N-nitroso-hydrochlorothiazide (NO-HCTZ), which was positive in the bacterial reverse mutation (Ames) test but is unstable under the test conditions, generating formaldehyde among other products. The mutagenic profile of NO-HCTZ was inconsistent with that expected of a mutagenic nitrosamine, exhibiting mutagenicity in the absence of metabolic activation, and instead aligned well with that of formaldehyde. To assess further, a modified Ames system including glutathione (3.3 mg/plate) to remove formaldehyde was developed. Strains used were S. typhimurium TA98, TA100, TA1535, and TA1537, and E. coli WP2 uvrA/pKM101. In this system, formaldehyde levels were considerably lower, with a concomitant increase in levels of S-(hydroxymethyl)glutathione (the adduct formed between glutathione and formaldehyde). Upon retesting NO-HCTZ in the modified system (1.6-5000 µg/plate), a clear decrease in the mutagenic response was observed in the strains in which NO-HCTZ was mutagenic in the original system (TA98, TA100, and WP2 uvrA/pKM101), indicating that formaldehyde drives the response, not NO-HCTZ. In strain TA1535, an increase in revertant colonies was observed in the modified system, likely due to a thiatriazine degradation product formed from NO-HCTZ under Ames test conditions. Overall, these data support a non-mutagenic designation for NO-HCTZ and demonstrate the value of further investigation when a positive Ames result does not align with the expected profile.

Sex difference in kidney electrolyte transport III: Impact of low K intake on thiazide-sensitive cation excretion in male and female mice.

We compared the regulation of the NaCl cotransporter (NCC) in adaptation to a low-K (LK) diet in male and female mice. We measured hydrochlorothiazide (HCTZ)-induced changes in urine volume (UV), glomerular filtration rate (GFR), absolute (ENa, EK), and fractional (FENa, FEK) excretion in male and female mice on control-K (CK, 1% KCl) and LK (0.1% KCl) diets for 7 days. With CK, NCC-dependent ENa and FENa were larger in females than males as observed previously. However, with LK, HCTZ-induced ENa and FENa increased in males but not in females, abolishing the sex differences in NCC function as observed in CK group. Despite large diuretic and natriuretic responses to HCTZ, EK was only slightly increased in response to the drug when animals were on LK. This suggests that the K-secretory apparatus in the distal nephron is strongly suppressed under these conditions. We also examined LK-induced changes in Na transport protein expression by Western blotting. Under CK conditions females expressed more NCC protein, as previously reported. LK doubled both total (tNCC) and phosphorylated NCC (pNCC) abundance in males but had more modest effects in females. The larger effect in males abolished the sex-dependence of NCC expression, consistent with the measurements of function by renal clearance. LK intake did not change NHE3, NHE2, or NKCC2 expression, but reduced the amount of the cleaved (presumably active) form of γENaC. LK reduced plasma K to lower levels in females than males. These results indicated that males had a stronger NCC-mediated adaptation to LK intake than females.

Use of hydrochlorothiazide and risk of skin cancer in a large nested case-control study in Spain.

PURPOSE: Hydrochlorothiazide (HCTZ) use has been linked to skin cancer in northern European countries. We assessed the association between HCTZ exposure and risk of malignant melanoma (MM) and keratinocyte carcinoma (KC) in a European Mediterranean population. METHODS: Two parallel nested case-control studies were conducted in Spain using two electronic primary healthcare databases, each one providing data on both exposure and outcomes: SIDIAP and BIFAP. Cancer cases were matched to 10 controls by age and gender through risk-set sampling. The ORs and 95% CI for MM and KC associated with previous HCTZ use were estimated using conditional logistic regression. In BIFAP, KC cases were further identified as basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). RESULTS: In adjusted analyses, both ever and cumulative high (≥50,000 mg) use of HCTZ were associated with an increased risk of KC. The risk estimates for high use were 1.30 (1.26-1.34) in SIDIAP and 1.20 (1.12-1.30) in BIFAP, with a lower risk for BCC (1.11 [1.02-1.21]) than for SCC (1.71 [1.45-2.02]). A dose-response relationship was observed between cumulative doses of HCTZ and KC risk. Inconsistent results were found for high use of HCTZ and risk of MM: 1.25 (1.09-1.43) in SIDIAP and 0.85 (0.64-1.13) in BIFAP. CONCLUSIONS: In this European Mediterranean population, a high cumulative use of HCTZ was related to an increased risk of KC with a clear dose-response pattern.

Na restriction activates epithelial Na channels in rat kidney through two mechanisms and decreases distal Na+ delivery.

KEY POINTS: Dietary Na restriction, through the mineralocorticoid aldosterone, acts on epithelial Na channels via both fast (24 h) and slow (5-7 days) mechanisms in the kidney. The fast effect entails increased proteolytic processing and trafficking of channel protein to the apical membrane. It is rapidly reversible by the mineralocorticoid receptor antagonist eplerenone and is largely lost when tubules are studied ex vivo. The slow effect does not require increased processing or surface expression, is refractory to acute eplerenone treatment, and is preserved ex vivo. Both slow and fast effects contribute to Na retention in vivo. Increased Na+ reabsorption in the proximal tubule also promotes Na conservation under conditions of chronic dietary Na restriction, reducing Na+ delivery to the distal nephron. ABSTRACT: Changes in the activity of the epithelial Na channel (ENaC) help to conserve extracellular fluid volume. In rats fed a low-salt diet, proteolytic processing of ENaC increased within 1 day, and was almost maximal after 3 days. The rapid increase in the abundance of cleaved αENaC and γENaC correlated with decreased urinary Na+ excretion and with increased ENaC surface expression. By contrast, ENaC activity, measured ex vivo in isolated cortical collecting ducts, increased modestly after 3 days and required 5 days to reach maximal levels. The mineralocorticoid receptor antagonist eplerenone reversed the increase in cleaved γENaC and induced natriuresis after 1 or 3 days but failed to alter either ENaC currents or Na+ excretion after 7 days of Na restriction. We conclude that Na depletion, through aldosterone, stimulates ENaC via independent fast and slow mechanisms. In vivo, amiloride-induced natriuresis increased after 1 day of Na depletion. By contrast, hydrochlorothiazide (HCTZ)-induced natriuresis decreased gradually over 7 days, consistent with increased ability of ENaC activity to compensate for decreased Na+ reabsorption in the distal convoluted tubule. Administration of amiloride and HCTZ together increased Na+ excretion less in Na-depleted compared to control animals, indicating decreased delivery of Na+ to the distal nephron when dietary Na is restricted. Measurements of creatinine and Li+ clearances indicated that increased Na reabsorption by the proximal tubules is responsible for the decreased delivery. Thus, Na conservation during chronic dietary salt restriction entails enhanced transport by both proximal and distal nephron segments.

Effect of obstructive sleep apnea on the response to hypertension therapy.

Obstructive sleep apnea (OSA) often precedes cardiovascular disease, partly due to treatment resistant hypertension. The nocturnal apneas of OSA trigger increased sympathetic nervous discharge during both sleep and wakefulness. Apneas also trigger cardiac release of the endogenous diuretic atrial natriuretic peptide. We hypothesized that treatment of the excess sympathetic nervous activity of OSA with a ß1 blocker would lower 24 h blood pressure (BP) more than diuretic therapy. Subjects with OSA associated hypertension received 2 weeks of placebo followed by the ß1 blocker nebivolol or hydrochlorothiazide (HCTZ) for 6 weeks in a blinded crossover study. BP, baroreflex sensitivity (BRS), heart rate variability (HRV), arterial reactivity, and stiffness were measured after placebo and each treatment. The ß1 blocker lowered clinic BP by -11/-8 mmHg, more than the -3/-1 effect of HCTZ (P < 0.01). The ß1 blocker lowered 24 h diastolic blood pressure (DBP) more than HCTZ. Although given at bedtime, neither drug increased BP dipping. Nebivolol increased HRV in the high-frequency band. Nebivolol did not alter BRS while HCTZ significantly diminished BRS compared to nebivolol (P < 0.01). Nebivolol increased flow-mediated brachial artery dilation when compared to HCTZ and slowed pulse wave velocity, indicating a decrease in arterial stiffness. Diuretic therapy failed to lower BP in OSA subjects and this might account for the frequent association of OSA with treatment resistant hypertension. However, blockade of the excess sympathetic nervous activity of OSA with a ß1 blocker lowered both clinic and 24 h DBP.

A Rapid, Sensitive, and High-throughput Method for the Simultaneous Determination of Antihypertensive Drug Combinations in Dog Plasma by UHPLC-MS/MS: The Assessment of Predicable Bioequivalence of In-vitro Dissolution Condition.

BACKGROUND: Essential hypertension is a common clinical disease and a risk factor for cardiovascular and cerebrovascular diseases. Olmesartan medoxomil, amlodipine, and hydrochlorothiazide are commonly used antihypertensive drugs. The aim of this study was to establish a robust UPLC-MS/MS method for the simultaneous determination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide in dog plasma. At the same time, the release in vivo and in vitro studies were conducted, and a preliminary in vitro-in vivo correlation (IVIVC) evaluation was performed. METHODS: The bioequivalence experiment was conducted with a double-crossed design. Three major components were extracted and analyzed by UHPLC-MS/MS. With the MRM scan, olmesartan and amlodipine were quantified by fragment conversion (m/z 447.10→190.10) and (m/z 408.95→294.00) under positive ESI mode, while hydrochlorothiazide was quantified with fragment conversion (m/z 295.90→268.90) under negative ESI mode. The in vitro release studies were performed using a USP paddle, and the dissolution medium was chosen from pH 6.0 to pH 6.8 according to the BCS classification of compounds. The IVIVC was calculated using the Wagner-Nelson equation. RESULTS: The linear ranges of olmesartan, amlodipine, and hydrochlorothiazide in the plasma were 5.0-2500, 0.1-50, and 3.0-1500 ng/mL, respectively. All accuracies were within 3.8% of the target values, and the findings revealed that intra-day and inter-day accuracy was less than 12.1%. Moreover, the recoveries exceeded 88.3%, the matrix effect tests were positive, and the stability tests were positive. With the establishment of correlation, the distinguishable dissolution condition (pH 6.8) was selected as the predictable condition. CONCLUSION: The established method was suitable for the preclinical pharmacokinetic study of tripartite drugs with strong specificity and high sensitivity. Through the evaluation of IVIVC, the connection between in vivo and in vitro drug testing was initially established.

A First Report of HCTZ and Dicyclomine Induced Uncharacteristic Contraction Alkalosis.

Background: Contraction alkalosis is characterized by low serum sodium and chloride and high serum carbon dioxide and bicarbonate levels. Case Report: A 28-year-old Caucasian active-duty male with a history of autosomal dominant polycystic kidney disease and diarrhea-predominant Irritable Bowel Syndrome (D-IBS) presented to his primary care provider (PCP) with elevated blood pressure (136/96 mmHg), was diagnosed with stage-2 hypertension, and started oral HCTZ (25 mg/day). His medications included dicyclomine (10 mg oral three times daily). Subsequently, (Visit 1), his blood pressure was 130/91 mmHg and he was started on telmisartan (20 mg/day). At Visit 2, 4 weeks later, his blood pressure improved (121/73 mmHg); however, blood chemistry revealed elevated serum CO2 (32 mEq/L) and chloride (94 mmol/L). Four days later, the patient presented to the Emergency Department with dyspnea and swallowing difficulty. The patient returned to his PCP 3 days later complaining of cough, congestion, vomiting, and mild dyspnea, blood pressure of 124/84 mmHg. Two months later, sudden onset of projectile vomiting and abdominal pain while running was reported, resolved by rehydration and a single oral dose of prochlorperazine 25 mg. Three months later, (Visit 3), he complained of lightheadedness and cloudy judgment, suggesting contraction alkalosis. HCTZ was discontinued and telmisartan was increased to 20 mg twice daily. A follow-up blood chemistry panel 2 weeks later revealed serum chloride and CO2 levels within normal limits and blood pressure under 130/80 mmHg. Conclusion: This is the first known report of contraction alkalosis driven by drug-drug interaction between dicyclomine and HCTZ.

Exploring the Effectiveness and Safety of Azilsartan-Medoxomil/Chlorthalidone Versus Olmesartan-Medoxomil/Hydrochlorothiazide in Hypertensive Patients: A Meta-Analysis.

This study aims to assess the effectiveness and safety of azilsartan-medoxomil/chlorthalidone (AZI-M/CT) compared to olmesartan-medoxomil/hydrochlorothiazide (OLM/HCTZ) in patients with hypertension. Systematic searches were conducted on PubMed, Google Scholar, and ClinicalTrials.gov, starting from their establishment until March 15, 2023. The purpose of these searches was to locate original reports that compare the effectiveness of AZI-M/CT and OLM/HCTZ in treating hypertension. Data on various characteristics at the beginning and end of the studies were gathered. The analyses were carried out using Review Manager 5.4.1 (The Nordic Cochrane Center, The Cochrane Collaboration, 2014, Odense, Denmark) and STATA 16.0 software (Stata Corp. LP, College Station, TX, USA). Risk ratios (RRs) and weighted mean differences (WMDs) with 95% confidence intervals (CIs) were calculated as part of the study. A total of 3,146 individuals from four separate investigations were included in the study, with 1,931 individuals receiving AZI-M/CT and 1,215 individuals receiving OLM/HCTZ. The combined analysis revealed that the average diastolic blood pressure (DBP) was significantly lower in the AZI-M/CT group compared to the OLM/HCTZ group (WMD -2.64 [-2.78, -2.51]; P = 0.00001; I2 = 1%). However, there were no significant differences in mean systolic blood pressure (SBP; WMD -2.95 [-6.64, 0.73]; P = 0). Furthermore, the AZI-M/CT group had a notably higher incidence of major adverse events (RR 1.58 [1.20, 2.08]; P = 0.001; I2 = 11%) and any treatment-emergent adverse events (RR 1.11 [1.03, 1.20]; P = 0.007; I2 = 51%). However, there was no significant difference in the mortality risk between the two groups (RR 0.74 [0.14, 3.91]; P = 0.72; I2 = 0%). Based on the results of our meta-analysis, AZI-M/CT is more effective than OLM/HCTZ at reducing blood pressure in elderly hypertensive patients. However, because of the small sample size, favorable results must be carefully reevaluated, and more studies are needed.

Mineralocorticoid receptor blockade improves pulmonary hypertension and right ventricular function in bronchopulmonary dysplasia: a case report.

Bronchopulmonary dysplasia (BPD) is a combined pulmonary vascular and parenchymal disease, representing the most common cause of chronic lung disease (CLD) in infancy. Pulmonary hypertension (PH) is frequently associated with BPD and-if persistent-substantially increases mortality. We report on a 4-month-old, former preterm infant with BPD, severe PH and right heart failure who greatly and rapidly improved clinical status and right ventricular (RV) function by means of blood biomarkers [N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP), cardiac troponin T] and transthoracic echocardiography, following the addition of spironolactone and hydrochlorothiazide to the treatment regimen.

Interamerican Society of Cardiology (IASC) position statement: Chlorthalidone vs. thiazide-type diuretics.

The Interamerican Society of Cardiology (IASC) Position Statement for hypertension management in Latin America is a practical and useful review of five different hypertension guidelines. Though, thiazide diuretics have been recommended as firstline option, the position statement needs to highlight differences within the thiazide class. Chlorthalidone is structurally and pharmacokinetically distinct from thiazide-type iuretics like hydrochlorothiazide with a longer half-life and 24-h anti-hypertensive effect. It has been shown to reduce cardiovascular morbidity and mortality in several landmark studies evaluating anti-hypertensives.

Lack of thiazide diuretic inhibition of agonist constriction of mouse mesenteric arterioles ex vivo.

The chronic reduction of arterial blood pressure by thiazide diuretics (TZD) in hypertensive patients is mediated through an extra-renal mechanism. It is widely held that this extra-renal mechanism is a direct TZD inhibition of vasoconstriction. This study tested whether the TZD, hydrochlorothiazide (HCTZ), inhibited agonist constriction of mesenteric arterioles ex vivo. Mice deficient in the kidney distal convoluted tubule Na+/Cl- cotransporter (NCC), i.e., the target of thiazide inhibition-mediated diuresis, and wild type (WT), were subjected to Na+-restricted diet. Mesenteric arterioles from NCC knockout and WT mice were then isolated, placed under constant pressure, and the inhibitory effects of HCTZ (100 µM) on phenylephrine constriction determined. HCTZ did not inhibit phenylephrine constriction of arterioles from NCC knockout and wild type (WT) mice subjected to Na+-restricted diet. This study suggests that future investigations to identify the extra-renal site of chronic TZD treatment should (1) focus on indirect inhibition of vascular constriction and (2) be determined under clinically relevant conditions. These conditions include chronic TZD at relevant concentrations in hypertensive animals.

A pilot study evaluating biomarker development for drug-induced chronic eczematous eruptions of aging individuals.

BACKGROUND: Identifying the drug(s) responsible for drug-induced chronic eczematous eruptions of aging individuals (CEEA) is a clinical challenge in patients on multiple medications. Reliable in vitro testing methods and biomarkers are needed to identify the causative agent and allow simultaneous assessment of T-cell responses to multiple drugs being taken concurrently. This study examined the feasibility of using in vitro, drug-specific T cell activation responses as a biomarker for drug-induced CEEA. METHODS: This was a single center, proof-of-concept pilot study at the University of Utah Hospital, Salt Lake City, Utah. Eight aging study subjects having a history suggestive of chronic eczematous drug eruptions suspected to have resulted from calcium channel blocker (CCB) and/or hydrochlorothiazide (HCTZ) hypersensitivity plus three matched aging control subjects were identified. Drug patch testing for CCB and/or HCTZ, in vitro drug antigen-induced lymphocyte proliferation assays, and multianalyte-determined cytokine release assays were performed before and after HCTZ and/or CCB incubation. RESULTS: All study and control subject blood samples tested failed to demonstrate detectable enhanced lymphocyte proliferation or cytokine release to in vitro CCBs or HCTZ challenge when tested with a fairly wide range of drug concentrations. Additionally, none of the enrolled patients developed a positive patch test to CCBs and/or HCTZ. CONCLUSIONS: This pilot study aimed to correlate in vitro drug-induced T lymphocyte transformation and cytokine production with the presence of drug-induced CEEA. Failure to identify T cell proliferative responses to CCB drug antigens in our in vitro studies could have, in part, resulted from a pharmacologic inhibiting effect of CCB on T cell activation.

Effect of food on the oral bioavailability of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide fixed dose combination tablets in healthy subjects.

A double fixed dose combination of amlodipine/valsartan and triple fixed dose combination of amlodipine/valsartan/HCTZ tablets have been developed to treat patients with moderate-to-severe hypertension. Here, we present the effect of food on the oral bioavailability of these two fixed dose combination tablets from two separate clinical studies in healthy subjects. Single oral doses of amlodipine/valsartan (10/160 mg) and amlodipine/valsartan/HCTZ (10/320/25 mg were administered under fasted or fed conditions. Blood samples were collected in both studies to determine the pharmacokinetic parameters of amlodipine, valsartan, and/or HCTZ using non-compartmental analysis. Following amlodipine/valsartan administration, the geometric mean ratios (GMRs, 90% CI) of AUC0-∞ and Cmax were 1.09 (1.05-1.13) and 1.03 (0.97-1.09) for amlodipine, and 0.94 (0.81-1.10) and 0.86 (0.73-1.02) for valsartan, respectively. Following amlodipine/valsartan/HCTZ administration, the GMRs (90%CI) of AUC0-∞ and Cmax were 1.09 (1.04-1.15) and 1.11 (1.05-1.08) for amlodipine, 1.14 (0.99-1.31) and 1.12 (0.98-1.29) for valsartan, and 1.09 (1.02-1.16) and 0.86 (0.79-0.93) for HCTZ, respectively. Considering the sample size and pharmacokinetic variability associated with analytes, these study results indicate that food effect is minimal or none when fixed dose combination tablets are administered with food. In conclusion, both fixed dose combination tablets can be administered without regards to meals.

Aliskiren/amlodipine vs. aliskiren/hydrochlorothiazide in hypertension: indirect meta-analysis of trials comparing the two combinations vs. monotherapy.

BACKGROUND: Aliskiren, a direct renin inhibitor, is effective for reducing blood pressure (BP) in patients with hypertension when combined with amlodipine or hydrochlorothiazide (HCTZ). However, the efficacy and tolerability of the 2 combinations are unclear. We performed a meta-analysis of randomized controlled trials of aliskiren/amlodpine and aliskiren/HCTZ for hypertension. METHODS: The Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and the Novartis clinical trial database were searched through December 2012 for reports of randomized controlled trials of aliskiren/amlodpine and aliskiren/HCTZ vs. monotherapy in patients with hypertension. The main outcome measures were reduction in systolic BP and diastolic BP from baseline and rates of therapeutic response and BP control. Tolerance of aliskiren/amlodipine and aliskiren/HCTZ was also analyzed. Outcomes were initially pooled by standard random-effects methods, producing a weighted mean difference (WMD) or risk ratio (RR) and 95% confidence intervals (CIs). The pooled estimates were then used for adjusted indirect comparisons. RESULTS: We selected 19 reports of trials involving 13,614 participants. Aliskiren/amlodpine and aliskiren/HCTZ were more effective than monotherapy in controlling BP. Aliskiren/amlodipine was significantly more effective than aliskiren/HCTZ in reducing systolic BP (WMD = -3.36 mm Hg; 95% CI = -4.64 to 2.07 mm Hg) and diastolic BP (WMD = -3.49 mm Hg; 95% CI = -4.34 to 2.63 mm Hg). As compared with aliskiren/HCTZ, alikiren/amlodipine was associated with higher rate of therapeutic response (RR = 1.23; 95% CI = 1.14-1.33) and BP control (RR = 1.24; 95% CI = 1.11-1.39). Number of adverse events and withdrawals due to adverse events were similar with aliskiren/amlodipine and aliskiren/HCTZ. CONCLUSIONS: BP control is better with aliskiren combined with amlodipine or HCTZ than with monotherapy, with aliskiren/amlodipine being more effective than aliskiren/HCTZ.

Considerations for dofetilide use in the elderly.

This case describes an 85-year-old African-American female with atrial arrhythmias on dofetilide maintenance therapy who presented to an ambulatory cardiology clinic with hypotension. The pharmacist identified a potential major drug-drug interaction between dofetilide and the thiazide diuretic, chlorthalidone. Because of the patient's hypotension, it was decided to discontinue chlorthalidone to avoid the potential drug interaction with dofetilide. A systolic BP goal of 140-145 mmHg was later achieved and maintained with the addition of low-dose amlodipine, in addition to her lisinopril. This case highlights important considerations for prescribing and monitoring dofetilide and reviews hypertension management in the elderly population.

Phase quantification of antihypertensive drugs - Chlorthalidone, Hydrochlorothiazide, Losartan and combinations, Losartan/Chlorthalidone and Losartan/Hydrochlorothiazide - by the Rietveld method.

The identification and quantification of crystalline phases of antihypertensive drugs - Losartan potassium (LOS-K), Hydrochlorothiazide (HCTZ) and Chlorthalidone (CTD) were carried out by means of X-ray powder diffraction data and the Rietveld method. Quantitative phase analyses of Losartan potassium/Chlorthalidone (LOS-K/CTD) and Losartan potassium/Hydrochlorothiazide (LOS-K/HCTZ) combinations were also evaluated. The results indicated that for diuretics (HCTZ and CTD) only one crystalline phase was found in samples, and for LOS-K the crystal structure showed similarity between the Bragg peaks to the phase described as monoclinic and space group P21/c. After one year storage, the orthorhombic one was also observed in this sample.

Clinical characteristics, treatment patterns and outcomes of Hispanic hypertensive patients.

Hispanics are the largest and fastest-growing minority population in the United States, currently comprising about 16.3% (52 million) of the total population. With an increased prevalence of metabolic risk factors in this population, the rate of uncontrolled hypertension (HTN) in Hispanics significantly exceeds the rates observed among non-Hispanic blacks and whites. Unfortunately, data on HTN in Hispanics remains limited due to the under-representation of Hispanics in clinical trials; with most of the data primarily restricted to observational and retrospective subgroup analyses. This article aims to review the available data on prevalence, awareness and control of HTN, risk factors and some of the challenges unique to the Hispanics population. We also discuss treatment strategies derived from large HTN trials that included Hispanics.

Involvement of bradykinin and prostaglandins in the diuretic effects of Achillea millefolium L. (Asteraceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Achillea millefolium L. (Asteraceae), popularly known as "mil-folhas", is well recognized and widely used in Brazilian folk medicine to treat heart and kidney disorders. Among its popularly described effects are diuretic and hypotensive actions. AIM OF THE STUDY: The diuretic activity of Achillea millefolium L. extracts and its semi-purified fractions, as well as the mechanisms involved, were evaluated in male Wistar rats. MATERIAL AND METHODS: An aqueous extract (AEAM, 125-500 mg/kg), hydroethanolic extract (HEAM, 30-300 mg/kg), dichloromethane subfractions (DCM-2, 10 and 30 mg/kg), or hydrochlorothiazide (10mg/kg), were orally administered and the animals were kept in metabolic cages for 8h for urine collection. To evaluate the involvement of bradykinin and prostaglandins in the diuretic action of Achillea millefolium, selected groups of rats received HOE-140 (1.5mg/kg, i.p.) or indomethacin (5mg/kg, p.o.), before treatment with a DCM-2 subfraction (30 mg/kg). The urinary volume, conductivity, pH, density and electrolyte excretion were measured. RESULTS: Similar to hydrochlorothiazide, both HEAM and DCM-2, but not AEAM, increased urinary volume and the excretion of Na(+) and K(+) when compared with the control group (vehicle). The diuretic effect of DCM-2 was abolished by HOE-140 (a bradykinin B2 receptor antagonist), as well as by indomethacin (a cyclooxygenase inhibitor). CONCLUSION: The present study reveals that extracts obtained from Achillea millefolium are able to effectively increase diuresis when orally administered in rats. This effect depends on both the activation of bradykinin B2 receptors and the activity of cyclooxygenases.