Treatment Patterns and Blood Pressure Control With Initiation of Combination Versus Monotherapy Antihypertensive Regimens.

Many patients with hypertension require 2 or more drug classes to achieve their blood pressure (BP) goal. We compared antihypertensive medication treatment patterns and BP control between patients who initiated combination therapy versus monotherapy. We identified adults with hypertension enrolled in a US integrated healthcare system who initiated antihypertensive medication between 2008 and 2014. Patient demographics, clinical characteristics, antihypertensive medication, and BP were extracted from electronic health records. Antihypertensive medication patterns and multivariable adjusted prevalence ratios (PRs) of achieving the 2017 American College of Cardiology/American Heart Association guideline-recommended BP <130/80 mm Hg were evaluated for 2 years following treatment initiation. Of 135 971 patients, 43% initiated antihypertensive combination therapy (35% ACE [angiotensin converting enzyme] inhibitor (ACEI)-thiazide diuretics; 8% with other combinations) and 57% initiated monotherapy (22% ACEIs; 16% thiazide diuretics; 11% ß blockers; 8% calcium channel blockers). After multivariable adjustment including premedication BP levels, patients who initiated ACEI-thiazide diuretic combination therapy were more likely to achieve BP <130/80 mm Hg compared with their counterparts who initiated monotherapy with ACEI (PR, 1.10 [95% CI, 1.08-1.12]), thiazide diuretic (PR, 1.21 [95% CI, 1.18-1.24]), ß blocker (PR, 1.17 [95% CI, 1.14-1.20]), or calcium channel blocker (PR, 1.25 [95% CI, 1.22-1.29]). Compared with initiating monotherapy, patients initiating ACEI-thiazide diuretic combination therapy were more likely to achieve BP goals.

Conventional Treatment of Hypoparathyroidism.

The treatment of hypoparathyroidism depends on the severity of hypocalcemia, how rapidly the hypocalcemia developed, and the symptomatology. Chronic hypoparathyroidism is usually treated with oral supplementations, including calcium, calcitriol, or other active vitamin D analogs, and at times, thiazide diuretics. Although the standard therapy can adequately control patients with this disease, sometimes very high doses are required to maintain serum calcium levels in the normal range, with poor compliance and risk of long-term complications.

Outcomes Associated With a Strategy of Adjuvant Metolazone or High-Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis.

Background In acute decompensated heart failure, guidelines recommend increasing loop diuretic dose or adding a thiazide diuretic when diuresis is inadequate. We set out to determine the adverse events associated with a diuretic strategy relying on metolazone or high-dose loop diuretics. Methods and Results Patients admitted to 3 hospitals using a common electronic medical record with a heart failure discharge diagnosis who received intravenous loop diuretics were studied in a propensity-adjusted analysis of all-cause mortality. Secondary outcomes included hyponatremia (sodium <135 mE q/L), hypokalemia (potassium <3.5 mE q/L) and worsening renal function (a ≥20% decrease in estimated glomerular filtration rate). Of 13 898 admissions, 1048 (7.5%) used adjuvant metolazone. Metolazone was strongly associated with hyponatremia, hypokalemia, and worsening renal function ( P<0.0001 for all) with minimal effect attenuation following covariate and propensity adjustment. Metolazone remained associated with increased mortality after multivariate and propensity adjustment (hazard ratio=1.20, 95% confidence interval 1.04-1.39, P=0.01). High-dose loop diuretics were associated with hypokalemia and hyponatremia ( P<0.002) but only worsening renal function retained significance ( P<0.001) after propensity adjustment. High-dose loop diuretics were not associated with reduced survival after multivariate and propensity adjustment (hazard ratio=0.97 per 100 mg of IV furosemide, 95% confidence interval 0.90-1.06, P=0.52). Conclusions During acute decompensated heart failure, metolazone was independently associated with hypokalemia, hyponatremia, worsening renal function and increased mortality after controlling for the propensity to receive metolazone and baseline characteristics. However, under the same experimental conditions, high-dose loop diuretics were not associated with hypokalemia, hyponatremia, or reduced survival. The current findings suggest that until randomized control trial data prove otherwise, uptitration of loop diuretics may be a preferred strategy over routine early addition of thiazide type diuretics when diuresis is inadequate.

Thiazide diuretics and the risk of hip fracture after stroke: a population-based propensity-matched cohort study using Taiwan's National Health Insurance Research Database.

OBJECTIVES: This study aimed to investigate the association between thiazide use and the risk of hip fracture after stroke. SETTING: A population-based, propensity-matched cohort study was conducted on the basis of Taiwan's National Health Insurance Research Database. PARTICIPANTS: Patients with newly diagnosed ischaemic stroke between 2000 and 2011 were included. After propensity score matching, 7470 patients were included, of whom 3735 received thiazides and 3735 did not. OUTCOME MEASURES: HRs for developing hip fractures within 2 years after stroke were calculated using Cox proportional hazards regression model with adjustments for sociodemographic and coexisting medical conditions. RESULTS: Overall, patients using thiazides after stroke had a lower risk of hip fracture than those not using thiazides (8.5 vs 13.9 per 1000 person-years, adjusted HR=0.64, 95% CI 0.46 to 0.89, p=0.007). Further sensitivity analysis based on the duration of thiazide use revealed that the risk of hip fracture tended to decrease as the duration of exposure of thiazides increased. However, the effect was significant only in patients with long-term use of thiazides (using thiazides for >365 days within 2 years after stroke), with a 59% reduction in the risk of hip fracture when compared with patients not using thiazide (adjusted HR=0.41, 95% CI 0.22 to 0.79, p=0.008). CONCLUSIONS: The long-term use of thiazides is associated with a decreased risk of hip fracture after stroke.

Continuous and long-term treatment is more important than dosage for the protective effect of thiazide use on bone metabolism and fracture risk.

BACKGROUND: Data from observational studies have suggested that thiazide diuretics protect against fractures. Few studies have investigated time frames from initiation of treatment to fracture occurrence. OBJECTIVE: To evaluate the time to spinal, hip, femur, wrist and upper extremity fracture occurrence before and after thiazide exposure. METHODS: A matched retrospective cohort study of patient information from national Danish patient databases was conducted. Patients with reimbursed prescriptions for noncompounded thiazide diuretics with potassium supplementation (Anatomical Therapeutic Chemical classification system code C03AB) between 1996 and 2011 were matched with nonexposed control subjects by date of birth and gender. Weekly odds ratios (ORs) of fracture occurrence and total incidence rates (IRs) and incidence rate ratios (IRRs) of fracture risk were calculated for the periods before treatment initiation, weeks 1-42 and weeks 43-780. RESULTS: A total of 1,602,141 'thiazide exposure periods' (46,8271 individuals) and 1,530,233 'nonexposure periods' (655,399 individuals) were included in the analysis. Thiazide use was associated with factors of increased de novo fracture risk. Weekly adjusted fracture risk between exposure and nonexposure was increased prior to commencing thiazide therapy, further increasing from weeks 1-42 weeks and then decreasing gradually from weeks 43-780. There was a decreasing trend in total age-adjusted risk during these periods: IRR [95% confidence interval 1.44 [1.42; 1.47], 1.27 [1.24; 1.29] and 1.14 [1.11; 1.18], respectively. Prescription patterns showed several treatment breaks amongst thiazide users. CONCLUSIONS: It appears that thiazides reduce the background risk of fracture that is increased prior to commencing therapy. Long duration and continuity of thiazide exposure seems to be important to obtain this protective effect on fracture risk, but we have found in this study that this approach is not always used in clinical practice.

[Diuretic therapy in acute heart failure]. / Tratamiento con diuréticos en la insuficiencia cardíaca aguda.

Diuretics are widely recommended in patients with acute heart failure (AHF). Unfortunately, despite their widespread use, limited data are available from randomized clinical trials to guide clinicians on the appropriate management of diuretic therapy. Loop diuretics are considered the first-line diuretic therapy, especially intravenous furosemide, but the best mode of administration (high-dose versus low-dose and continuous infusion versus bolus) is unclear. When diuretic resistance develops, different therapeutic strategies can be adopted, including combined diuretic therapy with thiazide diuretics and/or aldosterone antagonists. Low or "non-diuretic" doses (25-50mg QD) of aldosterone antagonists have been demonstrated to confer a survival benefit in patients with heart failure and reduced ejection fraction and consequently should be prescribed in all such patients, unless contraindicated by potassium and/or renal function values. There is less evidence on the use of aldosterone antagonists at higher or "diuretic" doses (≥ 100mg QD) but these drugs could be useful in relieving congestive symptoms in combination with furosemide. Thiazide diuretics can also be helpful as they have synergic effects with loop diuretics by inhibiting sodium reabsorption in distal parts of the nephron. The effect of diuretic therapy in AHF should be monitored with careful observation of clinical signs and symptoms of congestion. Serum electrolytes and kidney function should also be monitored during the use of intravenous diuretics.

Tratamiento con diuréticos en la insuficiencia cardíaca aguda / Diuretic therapy in acute heart failure

El tratamiento diurético es ampliamente recomendado y utilizado en pacientes con insuficiencia cardíaca aguda. A pesar de su amplio uso, existen pocas evidencias sobre el tratamiento con diuréticos en insuficiencia cardíaca que provengan de ensayos clínicos aleatorizados. Los diuréticos de asa son los más utilizados, en especial furosemida por vía intravenosa, pero todavía no está claro cuál es su mejor forma de administración, ni las dosis (altas frente a bajas), ni la vía de administración (en forma de bolo o en perfusión continua). Cuando aparece resistencia a diuréticos de asa hay diferentes estrategias de tratamiento diurético, siendo una de ellas el tratamiento diurético combinado con diuréticos tiacídicos y/o antagonistas de la aldosterona. Los antagonistas de la aldosterona en dosis bajas o no diuréticas (25-50 mg/día) han demostrado mejorar la supervivencia en pacientes con insuficiencia cardíaca y fracción de eyección deprimida, por lo que todos los pacientes deberían recibirlos, siempre que las cifras de potasio y/o la función renal lo permitan. Hay menos evidencia sobre su uso en dosis altas o diuréticas (≥ 100 mg/día), pero también podrían ser útiles para aliviar de forma precoz los síntomas congestivos en combinación con furosemida. Los diuréticos tiacídicos pueden ser también útiles utilizados de forma sinérgica con los diuréticos de asa al inhibir la reabsorción de sodio en porciones más distales de la nefrona. Durante el tratamiento diurético es importante monitorizar los signos y síntomas de congestión, así como vigilar la aparición de efectos adversos, sobre todo deterioro de la función renal y alteraciones electrolíticas (AU)

Diuretics are widely recommended in patients with acute heart failure (AHF). Unfortunately, despite their widespread use, limited data are available from randomized clinical trials to guide clinicians on the appropriate management of diuretic therapy. Loop diuretics are considered the first-line diuretic therapy, especially intravenous furosemide, but the best mode of administration (high-dose versus low-dose and continuous infusion versus bolus) is unclear. When diuretic resistance develops, different therapeutic strategies can be adopted, including combined diuretic therapy with thiazide diuretics and/or aldosterone antagonists. Low or "non-diuretic" doses (25-50 mg QD) of aldosterone antagonists have been demonstrated to confer a survival benefit in patients with heart failure and reduced ejection fraction and consequently should be prescribed in all such patients, unless contraindicated by potassium and/or renal function values. There is less evidence on the use of aldosterone antagonists at higher or "diuretic" doses (≥ 100 mg QD) but these drugs could be useful in relieving congestive symptoms in combination with furosemide. Thiazide diuretics can also be helpful as they have synergic effects with loop diuretics by inhibiting sodium reabsorption in distal parts of the nephron. The effect of diuretic therapy in AHF should be monitored with careful observation of clinical signs and symptoms of congestion. Serum electrolytes and kidney function should also be monitored during the use of intravenous diuretics (AU)

Pattern analysis and variations in the utilization of antihypertensive drugs in Taiwan: a six-year study.

BACKGROUND: In the last few years there have been changed in the pattern of consumption of antihypertensive drugs in other countries. Factors causing this variability include differences in the effectiveness of detection, guidelines for the management of hypertension, and differences in national health insurance systems among countries. AIM: The aim of this study was to reveal patterns in the use of antihypertensive drugs in Taiwan over a six year period (2001 to 2006) and compare these results with data from other countries. MATERIALS AND METHODS: This study performed descriptive analysis of data from the National Health Insurance Research Database (NHIRD) of Taiwan, and compared these findings with similar findings from around the world. Quantities were standardized using the defined daily dose (DDD) per 1000 inhabitants per day (DID) in accordance with WHO anatomical therapeutic classification and DDD measurement methodology. RESULTS: The total number of DDDs prescribed in Taiwan increased from 0.66 billion in 2001 to 1.08 billion in 2006, representing 80.6 and 129.2 DID in 2001 and 2006, respectively. This indicates a significant increase in the prescription of antihypertensive drugs in Taiwan over this period. The average annual increase ranged from 10.7% for calcium channel blockers (CCBs) to 22.1% for angiotensin II receptor blockers (ARBs). All of these patterns were statistically significant (p < 0.05). The rapid increase in the use of ARBs resulted in its surpassing ACEIs with the second highest DID (21.9) in 2006. Though the proportional use of CCBs and ARBs has increased significantly, the use of thiazide diuretics remains low. CONCLUSIONS: The consumption of antihypertension drugs in Taiwan increased during the period studied and the highest average annual increases were for ARBs and CCBs. Overall consumption of antihypertension drugs also increased in other countries, but differences in the relative increase for each class of drug suggest that further study may be required to clarify the origins and causes.

Hypertension management: rationale for triple therapy based on mechanisms of action.

An estimated 25% of patients will require 3 antihypertensive agents to achieve blood pressure (BP) control; combination therapy is thus an important strategy in hypertension treatment. This review discusses the triple-therapy combination of an angiotensin receptor blocker (ARB) or direct renin antagonist (DRI) with a calcium channel blocker (CCB) and a diuretic, with a focus on mechanisms of action. Multiple physiologic pathways contribute to hypertension. Combining antihypertensive agents not only better targets the underlying pathways, but also helps blunt compensatory responses that may be triggered by single-agent therapy. DRIs and ARBs target the renin-angiotensin-aldosterone system (RAAS) at the initial and final steps, respectively, and both classes lower BP by reducing the effects of angiotensin-2; however, ARBs may trigger a compensatory increase in renin activity. Dihydropyridine CCBs target L-type calcium channels and lower BP through potent vasodilation, but can trigger compensatory activation of the sympathetic nervous system (SNS) and RAAS. Thiazide diuretics lower BP initially through sodium depletion and plasma volume reduction, followed by total peripheral resistance reduction, but can also trigger compensatory activation of the SNS and RAAS. The combination of an agent targeting the RAAS with a CCB and diuretic is rational, and triple combinations of valsartan/amlodipine/hydrochlorothiazide, olmesartan/amlodipine/hydrochlorothiazide, and aliskiren/amlodipine/hydrochlorothiazide have demonstrated greater effectiveness compared with their respective dual-component combinations. In addition, single-pill, fixed-dose combinations can address barriers to BP control including clinical inertia and poor adherence. Fixed-dose antihypertensive combination products capitalize on complementary mechanisms of action and have been shown to result in improved BP control.

Thiazides diuretics in the treatment of nephrolithiasis: are we using them in an evidence-based fashion?

In the 1980s a change occurred in hydrochlorothiazide prescribing practices for hypertension from high-dose (50 mg/day) to low-dose (12.5-25 mg/day) therapy. However, randomized controlled trials (RCT) for prevention of calcium-containing kidney stones (CCKS) employed only high doses (≥ 50 mg/day). We hypothesized that these practices have resulted in underdosing of hydrochlorothiazide for prevention of CCKS. Patients with a filled prescription for thiazide diuretics that underwent a 24-h urine stone risk factor analysis were eligible. Those with evidence that thiazide was prescribed for CCKS were further analyzed. Of 107 patients, 102 were treated with hydrochlorothiazide, 4 with indapamide, and one with chlorthalidone. Only 35% of hydrochlorothiazide-treated patients received 50 mg/day; a dose previously shown to reduce stone recurrence. Fifty-two percent were prescribed 25 mg and 13% 12.5 mg daily, doses that were not studied in RCT. Evidence-based hydrochlorothiazide use was suboptimal regardless of where the patient received care (Nephrology or Endocrinology clinic). In a small subset of patients (n = 6) with 24-h urinary calcium excretion measured at baseline and after 2 hydrochlorothiazide doses (25 and ≥ 50 mg), there was a trend toward decreased urinary calcium excretion as the dose was increased from 25 to ≥ 50 mg/day (p = 0.051). Low-dose hydrochlorothiazide was often used for prevention of CCKS despite the fact that there is no evidence that it is effective in this setting. This may have resulted from a practice pattern of using lower doses for hypertension therapy or a lack of knowledge of RCT results in treatment of CCKS.

Combination therapy for hypertension: focus on high-dose olmesartan medoxomil (40 mg) plus hydrochlorothiazide.

IMPORTANCE OF THE FIELD: Cardiovascular disease is a major cause of premature death and disability worldwide, and effective blood pressure (BP) control is crucial for the reduction of cardiovascular risk in patients with hypertension. Despite this, many will fail to attain recommended BP goals. A reappraisal of European guidelines led to revised recommendations for BP reduction to values within the SBP/DBP range of 130 - 139/80 - 85 mmHg in all patients with hypertension, including higher-risk groups such as those with diabetes. AREAS COVERED IN THIS REVIEW: The majority of hypertensive patients will require the enhanced blood-pressure-lowering effects of at least two antihypertensive drugs with complementary mechanisms of action to achieve these goals. WHAT THE READER WILL GAIN: The angiotensin II receptor blocker (ARB) olmesartan medoxomil and the thiazide diuretic hydrochlorothiazide (HCTZ) provide greater antihypertensive efficacy when used in combination than as monotherapy with either component, with a similar tolerability profile. In addition, there is evidence that higher doses of olmesartan may prolong the antihypertensive effect of this ARB, and a number of US 'treat-to-target' and European add-on clinical trials have been conducted to assess the efficacy and safety of high-dose olmesartan plus HCTZ in a wide range of patients with mild-to-severe hypertension. TAKE HOME MESSAGE: Combination therapy with olmesartan, including the high 40-mg dose, plus HCTZ is an effective and safe treatment option for controlling BP in patients with mild-to-severe hypertension, particularly those who fail to achieve recommended BP goals with monotherapy.

The role of fixed-dose combination therapy with drugs that target the renin-angiotensin system in the hypertension paradigm.

Most patients with hypertension require two or more agents from different classes to achieve BP control. Several fixed-dose combinations are available, often combining agents that target the renin angiotensin system (angiotensin-converting enzyme [ACE] inhibitors or an angiotensin receptor blockers [ARBs]) plus either thiazide diuretics or calcium channel blockers (CCBs). At low doses, these combinations may have greater efficacy and better tolerability than the respective high dose monotherapies. Combining an ARB (instead of an ACE inhibitor) with the CCB amlodipine offers efficacy with improved tolerability. This review aims to highlight the simplicity, tolerability, and convenience of fixed-dose combinations targeting the renin-angiotensin system, which can lead to improved compliance and more patients achieving BP goals.

Treatment of resistant hypertension.

AIM: Resistant hypertension (RH) is a common clinical problem. Patients with RH have increased cardiovascular risk. These patients also have high risk for having reversible causes of hypertension and may potentially benefit from special diagnostic or therapeutic considerations. The purpose of this review was to discuss RH, its definition, recognition, evaluation and treatment. METHODS: Authors define RH and the implications of this definition. They present latest data on its prevalence, prognostic implications, genetics, and patient characteristics. Elements of pseudoresistance and possible etiologies of treatment resistance are also identified. Lastly, diagnostic and therapeutic approaches to RH are discussed, focusing on antihypertensive medication classes that have proven benefit in patients with RH, and also on novel therapeutic approaches in these patients. CONCLUSION: RH is a common clinical problem and carries an increased risk for cardiovascular morbidity and mortality, as well as target organ damage. Patients with RH are aat high risk for reversible causes of hypertension and may benefit from special diagnostic or therapeutic considerations. Elements of pseudoresistance, intake of interfering substances and secondary causes of hypertension should be searched for and corrected, if possible. Therapeutic lifestyle modifications should be emphasized. Medical therapy includes optimizing diuretic use and considering the use of mineralocorticoid antagonists as add on antihypertensive agents. Novel approaches include surgical and transcatheter techniques, chronotherapy, and new classes of antihypertensive agents.

Effects of low-dose liquorice alone or in combination with hydrochlorothiazide on the plasma potassium in healthy volunteers.

Both liquorice and thiazide diuretics have hypokalaemic effects. In spite of their prevalent use, there are no studies on hypokalaemia caused by the combination of liquorice and thiazides. We recruited 10 healthy volunteers in order to study the effects of 32 g liquorice alone or in combination with 25mg hydrochlorothiazide a day for 2 weeks. The trial had a randomized, open and crossover design. During the liquorice phase, there were no changes in plasma potassium, sodium, creatinine, renin activity, serum aldosterone, blood pressure or heart rate. Weight tended to increase by 0.4 kg (70.2 to 70.6 kg; p=0.056). During the liquorice-hydrochlorothiazide phase, the plasma potassium decreased by 0.32 mmol/l (p=0.0015), plasma renin activity increased by 1.6 microg/l/h (p=0.0064) and the weight decreased by 0.9 kg (70.5 to 69.6 kg, p=0.0065). Twenty per cent of the subjects (2/10) became hypokalaemic during the combined liquorice-hydrochlorothiazide treatment. Furthermore, both subjects developed hypokalaemia within the first week of the combined treatment leading to premature discontinuation. The evaluation of liquorice consumption habits is warranted when initiating thiazide medications to avoid the excessive risk of hypokalaemia associated with the combined use of low-dose liquorice and thiazide diuretics.

Risk factors associated with the occurrence of fractures in U.S. nursing homes: resident and facility characteristics and prescription medications.

OBJECTIVES: To determine whether resident and facility characteristics and prescription medications influence the occurrence of fractures in nursing homes (NHs). DESIGN: Panel study with 1-year follow-up. SETTING: A nationally representative sample of NHs from the Medical Expenditure Panel Survey (MEPS). PARTICIPANTS: Residents aged 65 and older who were in sample NHs on January 1, 1996. MEASUREMENTS: Health status measures were collected from facility records and abstracted using a computer-assisted personal interview instrument. Fracture and drug data were updated every 4 months to provide a full year of information. Drug data were obtained from monthly medication administration records. The occurrences of fractures were obtained from medical records. Administered medications were classified using the Department of Veterans Affairs medication classification system. Facility characteristics were based on MEPS survey data collected from NH sources. RESULTS: In 1996, 6% of residents in a NH at the beginning of the year experienced a fracture during their NH stay(s). Resident risk factors included aged 85 and older, admitted from the community, exhibited agitated behaviors, and used both wheelchair and cane or walker. Use of anticonvulsants, antidepressants, opioid analgesics, iron supplements, bisphosphonates, thiazides, and laxatives were associated with fractures. A high certified nurse aide ratio was negatively associated with fractures. CONCLUSION: The findings indicate that fractures are associated with resident and facility characteristics and prescribing practices. It reaffirms the importance of medication review with special attention on opioid analgesics, antidepressants, and anticonvulsants to reduce the risk of fractures.

[Hypercalciuria with severe hypocalcaemia in association with distal renal tubular acidosis--case report and differential diagnostics]. / Hiperkalcjuria z ciezka hipokalcemia w przebiegu kwasicy cewkowej dystalnej--opis przypadku i diagnostyka róznicowa.

Neither severe distal renal tubular acidosis nor hypercalciuria have been recognized to cause severe hypocalcaemia. We describe a 53 years old woman with distal renal tubular acidosis and hypercalciuria who demonstrated severe hypocalcemia, normalized after calcium and vitamin D supplementation and treatment with thiazide.

Renal effects of 26-week administration of olmesartan medoxomil/hydrochlorothiazide in rats.

The combination of an angiotensin II type 1 receptor blocker (ARB) and a diuretic is effective clinically in treatment of hypertension. As a non-clinical safety evaluation of a combination of the ARB olmesartan medoxomil (OM) and the diuretic hydrochlorothiazide (HCTZ), male and female normotensive rats were administered OM/HCTZ (fixed ratio of 8 : 5) orally by gavage for 26 weeks at dose levels of 0, 4.88, 16.25, 48.75, 162.5, 487.5, or 1625 mg/kg/day. Additional groups were given 1000 mg/ kg/day OM or 625 mg/kg/day HCTZ. Statistically significant and marked decreases in urinary protein excretion were observed in males and females given doses of 16.25 mg/kg/day or higher compared to vehicle-control groups. Increases in blood urinary nitrogen (BUN) were observed in males and females given doses of 16.25 and 162.5 mg/kg/day or higher, respectively. Increased incidence of chronic progressive nephropathy (CPN), a rat-specific spontaneous renal lesion, was observed in males and females given doses of 48.75 mg/kg/day or higher. An additional mechanistic study, consisting of male and female rats given 0, or 162.5 mg/kg/day OM/HCTZ, was conducted to clarify the toxicological significance of the increases in BUN and the increased incidence of CPN described above. This additional study clearly demonstrated that saline-supplementation through free access to saline in the drinking water ameliorated the elevation in BUN and also ameliorated the incidence of CPN. Consequently, the effects on BUN and CPN observed in the first study can be explained by the hemodynamic disturbances caused by the large doses and an exaggerated pharmacological action in volume-depleted normotensive animals. Importantly, the marked decreases in urinary protein were not affected by the saline-supplementation, and indicated that OM/HCTZ elicited a renoprotective effect, probably by an effect on the glomeruli. An additional toxicokinetic study revealed no drug interactions between OM and HCTZ. In conclusion, OM/HCTZ induced a renoprotective effect as well as changes probably attributed to the exaggerated pharmacological action of the ARB with diuretic in normotensive rats. These results suggest that OM/HCTZ may have renoprotective effects in clinical treatment of hypertensive patients.

Angiotensin converting enzyme inhibition and dihydropyridine calcium channel blockade in the treatment of left ventricular hypertrophy in arterial hypertension.

In arterial hypertension, left ventricular (LV) hypertrophy (H) is a prognostically relevant target organ damage associated with systolic and diastolic LV dysfunction. The level of LV dysfunction seems to be related to the degree of myocardial fibrosis. Prognosis of hypertensive patients who have LVH regression appears to be improved. Therefore, LVH regression is an important antihypertensive treatment goal. The renin-angiotensin-aldosterone system is implicated in LVH development and myocardial fibrosis in essential arterial hypertension. Early studies in the 80s and 90s have led expectations that angiotensin converting enzyme (ACE) inhibitors could induce greater LVH regression than other antihypertensive drugs at similar blood pressure reduction. In the late 90s, the double-blind randomized controlled PRESERVE trial (Prospective Randomize Enalapril Study Evaluating Reversal of Ventricular Enlargement) has been designed to evaluate whether the ACE inhibitor enalapril was more effective than nifedipine GITS in regressing LVH and improving LV diastolic dysfunction. The PRESERVE study demonstrated a mildly higher antihypertensive effect of nifedipine GITS than enalapril, which required more frequently association with hydrochlorothiazide to control blood pressure. However, at similar level of blood pressure reduction achieved with enalapril and long-acting nifedipine in association with hydrochlorothiazide or atenolol, both antihypertensive treatments showed similar efficacy in LVH regression and LV diastolic filling improvement.