Hypokalaemia associated with hydrochlorothiazide used in the treatment of hypertension in NHANES 1999-2018.

Hydrochlorothiazide is the most common thiazide diuretic used for hypertension in the US. Yet, hypokalaemia is a well-recognised adverse effect. To evaluate the prevalence and factors associated with hypokalaemia (serum potassium < 3.5 mmol/L) among hydrochlorothiazide users, we included US adults aged ≥20 years in the 1999-2018 National Health and Nutrition Examination Survey. Participants were categorised according to the use of hydrochlorothiazide and other antihypertensive agents. Factors associated with hypokalaemia, including demographics and prescription patterns (monotherapy vs single-pill fixed-dose combination vs polytherapy) were studied using multivariable logistic regression. Hypokalaemia was present in 12.6% of the hydrochlorothiazide users, equivalent to ~2.0 million US adults. Women (adjusted OR, 2.22; 95% CI, 1.74-2.83), non-Hispanic blacks (adjusted OR, 1.65; 95% CI, 1.31-2.08), underweight (adjusted OR, 4.33; 95% CI, 1.34-13.95), and participants taking hydrochlorothiazide for five years or more (adjusted OR, 1.47; 95% CI, 1.06-2.04) had a higher risk of hypokalaemia. Compared to monotherapy, fixed-dose combination therapy (adjusted OR, 0.32; 95% CI, 0.21-0.48) was associated with the lowest risk. Among those taking potassium supplements, hypokalaemia was found in 27.2% of participants on monotherapy and 17.9% on polytherapy. The prevalence of hypokalaemia among hydrochlorothiazide users was considerable, even among participants who also took potassium supplements. Women, ethnic minorities, underweight, monotherapy, and participants with long-term therapy are more likely to have hypokalaemia. Regular monitoring of potassium and combination with potassium-sparing drugs are needed.

Pairwise comparison of hydrochlorothiazide and chlorthalidone responses among hypertensive patients.

This study conducted a pairwise comparison of antihypertensive and metabolic effects of hydrochlorothiazide (HCTZ) and chlorthalidone (CTD) at 25 mg/day in the same individuals to address the clinical dilemma on preferred thiazide for hypertension (HTN) management. We included 15 African American (AA) and 35 European American (EA) patients with HTN treated with HCTZ and CTD as part of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) and PEAR-2 trials, respectively. Mean reduction in systolic/diastolic blood pressure (SBP/DBP) with HCTZ versus CTD was 8/5 versus 16/8 mmHg among EA patients (p < 1.0e-5 SBP, p = 0.002 DBP) and 11/8 versus 20/11 mmHg among AA patients (p = 0.03 SBP, p = 0.22 DBP). While CTD showed clinically meaningful benefit over HCTZ in two-thirds of participants with respect to SBP reduction and half of EA patients with respect to DBP reduction, a majority of AA patients (53%) showed similar DBP reduction with both thiazides. Sixty percent of AA patients and 29% of EA patients attained blood pressure (BP) <140/90 mmHg with both thiazides. Mean potassium (K+) reduction was greater with CTD compared to HCTZ both in EA patients (mean difference = 0.35, p = 0.0002) and AA patients (0.49, p = 0.043). While 31% of AA patients developed severe hypokalemia on CTD, <5% of others developed severe hypokalemia. Although 46% of AA patients on CTD required K+ supplementation, only 6%-11% of others required supplementation. Overall, in the majority of EA patients, CTD was superior to HCTZ, whereas among AA patients, it was superior in a minority, and was associated with significant potassium-related risk, suggesting that guideline preferences for CTD over HCTZ are reasonable in EA patients but may be less reasonable in AA patients, particularly if the target is <140/90 mmHg.

Dyskalemia risk associated with fixed-dose anti-hypertensive medication combinations.

A model-based meta-analysis quantified comparative dyskalemia risk (hyper- or hypo-kalemia) in hypertensive patients treated with angiotensin receptor blockers (ARBs), a calcium channel blocker (CCB) and/or a thiazide diuretic (hydrochlorothiazide; HCTZ) as monotherapy or as fixed-dose combinations. Among 15 randomized controlled trials in a US Food and Drug Administration regulatory review database, dyskalemia events were reported by five trials (24 treatment arms, 11,030 subjects, 8-week median follow up time). The five trials evaluated monotherapy (ARB or HCTZ) alongside dual (ARB + HCTZ, ARB + CCB, or HCTZ + CCB) or triple fixed-dose combinations (ARB + CCB + HCTZ). Hypo- and hyper-kalemia rates were analyzed jointly to account for correlation. Significant drug class, drug, or dose effects were included in the final model. Effect on various drug- and dose combinations on dyskalemia risk were simulated and compared with model-estimated placebo arm dyskalemia risk. After a typical follow-up of 8 weeks, fixed-dose combinations of ARB with a high dose (25 mg) of HCTZ were associated with a higher hypokalemia risk difference (RD) from placebo (e.g.,Valsartan + HCTZ: 2.52%[95%CIs:1.17, 4.38%]). However, when ARB was combined with a lower, 12.5 mg dose of HCTZ, hypokalemia RD from placebo was not significant (Valsartan + HCTZ: -0.03%[-0.80, 0.71%]). ARB monotherapy raised hyperkalemia RD from placebo (1.3%[0.3, 3.6%]). Hyperkalemia risk was not appreciably higher than placebo for any FDC that combined ARB with HCTZ (Valsartan + HCTZ: 0.06%[-1.48, 1.64%]). In uncomplicated hypertensive patients, ARB + 12.5 mg HCTZ fixed-dose combinations are safer with respect to dyskalemia than either ARB or HCTZ monotherapy for initial antihypertensive treatment.

Race-Specific Comparisons of Antihypertensive and Metabolic Effects of Hydrochlorothiazide and Chlorthalidone.

BACKGROUND: Chlorthalidone is recommended over hydrochlorothiazide (HCTZ) as the preferred thiazide, but the supporting evidence is not robust at routinely used doses, or in whites vs blacks, in whom differences in response to thiazides are well known. We compare the efficacy and safety of HCTZ and chlorthalidone as first-line therapies for white and black hypertensive patients. METHODS: We compared treatment-related outcomes between the HCTZ arm (12.5 mg for 2-3 weeks; 25 mg for additional 6 weeks) of the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR, n = 376) and chlorthalidone arm (15 mg for 2 weeks; 25 mg for additional 6 weeks) of PEAR-2 (n = 326) clinical trials, in 17-65-year-old mild-moderate uncomplicated hypertensive whites and blacks. RESULTS: Mean systolic/diastolic blood pressure (SBP/DBP) reduction with HCTZ vs chlorthalidone: 8 ± 8/4 ± 5 vs 12 ± 9/7 ± 5 mm Hg in whites (P < 10-6 SBP and DBP); 12 ± 10/7 ± 6 vs 15 ± 10/9 ± 6 in blacks (P = .008 SBP, P = .054 DBP). Treatment with HCTZ vs chlorthalidone in whites resulted in significantly fewer patients achieving target BP (<140/90 mm Hg) (44% vs 57%, P = .018) and clinical response rate (≥10 mm Hg DBP reduction); and significantly higher nonresponse rate (<6 mm Hg DBP reduction); but no significant differences in rates among blacks (eg, target-BP rate: 56% vs 63%, P = .31). HCTZ treatment led to significantly lower rates of hypokalemia and hyperuricemia in whites and blacks, vs chlorthalidone, and significantly lower odds of requiring potassium supplementation among blacks (odds ratio 0.16; 95% confidence interval, 0.07-0.37; P = 3.4e-7). CONCLUSION: Compared with HCTZ, chlorthalidone showed greater blood pressure lowering and adverse metabolic effects in whites, but similar blood pressure lowering and greater adverse effects in blacks; suggesting that the recent guideline recommendations to choose chlorthalidone over HCTZ may not be warranted in blacks.

Clinical efficacy of various anti-hypertensive regimens in hypertensive women of Punjab; a longitudinal cohort study.

BACKGROUND: Gender wise differences exist in anti-hypertensive treatment outcomes, yet still un-explored in Pakistan. Thus, we aimed to estimate the clinical efficacy of four different anti-hypertensive regimens in hypertensive women of Punjab, Pakistan. METHODS: A longitudinal cohort study of 12 months duration was conducted by enrolling 300 hypertensive women on four anti-hypertensive regimens. Chi-square for significance, logistic regression for association and multilevel regression for changes in outcomes were used. RESULTS: Majority of subjects were < 60 years of age, weighing > 65 Kg, having family history, married and hailing from urban areas, with diabetes as the most common comorbidity. Hypertension, adjusted for covariates, was significantly associated with salt intake (OR:2.27, p <  0.01) and physical activity (OR;2.16, p <  0.01). High-risk subjects, compared to low-risk, were consuming more fat (OR;1.54), meat (OR; 2), salt (OR; 2.48) and even vegetables/fruits (OR;3.43). Compared to baseline, the maximum reduction in BP was observed with combination therapy, N-GITS+LTN + HCT (SBP; - 50.17, p <  0.01, DBP; - 16.55, p <  0.01), followed by N-GITS alone (SBP; - 28.89, p <  0.01, DBP; - 12.21, p <  0.01). Compared to baseline, adjusted for treatment effects, significant reductions in SBP (low-risk; - 17.92, p <  0.01 high-risk; - 19.48, p <  0.01) and DBP (low-risk; - 17.92, p <  0.01, high-risk; - 19.48, p <  0.01) were observed in low and high risk patients. Among all four cohorts, orthostatic hypotension and edema were common in N-GITS+LTN + HCT only, but variable effects were observed on biochemical values; urea, BSR and creatinine. CONCLUSION: In conclusion, compared to a single agent, combination therapy conferred improved BP controls followed by N-GITS alone in low and high risk women with manageable side effects.

Vitamin A and Hydrochlorothiazide Causing Severe Hypercalcemia in a Patient With Primary Hyperparathyroidism.

OBJECTIVE: To report a case of severe hypercalcemia, exacerbated by vitamin A supplementation and hydrochlorothiazide, in a patient with primary hyperparathyroidism. METHODS: Clinical and laboratory findings are presented along with response to therapy. RESULTS: A 68-year-old white female presented to the emergency department complaining of nausea, vomiting, and altered mental status. Laboratory findings revealed calcium 15.8 mg/dL (8.4-10.2), albumin 4.1 g/dL (3.8-4.8), and parathyroid hormone 62 pg/mL (14-64). Serum calcium improved after intravenous hydration with normal saline. Prior to this hospitalization, over-the-counter medications were significant for calcium (600 mg daily), vitamin A (11 000 IU daily), and vitamin D (800 IU daily).The patient's prescription medications were significant for hydrochlorothiazide (12.5 mg daily). Twenty-four-hour urine calcium was subsequently found to be 146 mg (35-250). Myeloma, lymphoma, and sarcoidosis were ruled out as the etiology for hypercalcemia. The diagnosis of primary hyperparathyroidism was confirmed. She was treated surgically for primary hyperparathyroidism. The right and left superior parathyroid showed hypercellular parathyroid on pathology. The patient was normocalcemic after surgery. CONCLUSION: Previous reports suggest that very high doses of vitamin A is required to cause hypercalcemia. This case suggests that in a setting of primary hyperparathyroidism and hydrochlorothiazide therapy, vitamin A may contribute to the development of severe hypercalcemia in patients who are on calcium and vitamin D supplements. Given their biologic effects, public awareness needs to be created regarding the injudicious use of vitamins.

Losartan/hydrochlorothiazide combination is safe and effective for morning hypertension in Very-Elderly patients.

Morning hypertension is an independent risk for cerebrovascular and cardiovascular events. Although the prevalence of morning hypertension increases with age, treatment of morning hypertension has not been established, particularly in Very-Elderly patients. We compared the safety and efficacy of a losartan/hydrochlorothiazide (HCTZ) combination in controlling morning hypertension between Very-Elderly (≥75 years) and Young/Elderly patients (<75 years). This study was a subanalysis of the Morning Hypertension and Angiotensin Receptor Blocker/Hydrochlorothiazide Combination Therapy study, in which patients with morning hypertension (≥135/85 mmHg) received a 50-mg losartan/12.5-mg HCTZ combination tablet (combination therapy) or 100-mg losartan (high-dose therapy) for 3 months. High adherence rates and few adverse effects were observed in Very-Elderly patients receiving combination (n = 32) and high-dose (n = 34) therapies and in Young/Elderly patients receiving combination (n = 69) and high-dose (n = 66) therapies. Baseline morning systolic BP (SBP) was similar in both age groups receiving either therapy. Morning SBP was reduced by 20.2 and 18.1 mmHg with combination therapy and by 7.1 and 9.1 mmHg with high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Morning BP target (<135/85 mmHg) was achieved in 40.6% and 55.1% by combination therapy and in 14.7% and 24.2% by high-dose therapy in the Very-Elderly and Young/Elderly patients, respectively. Neither therapy changed renal function and serum potassium in Very-Elderly patients. In conclusion, the losartan/HCTZ combination was safe and effective in controlling morning hypertension in Very-Elderly as well as Young/Elderly patients. In addition, combination therapy was also superior to high-dose therapy for lowering morning SBP in Very-Elderly patients.

Efficacy and safety of combination therapy of high-dose losartan and hydrochlorothiazide in patients with hypertension.

OBJECTIVE: We analyzed the efficacy and safety of combination therapy of high-dose losartan (100 mg/day) and hydrochlorothiazide (HCTZ, 12.5 mg/day) compared with those of the combination of high-dose telmisartan (80 mg/day) and HCTZ (12.5 mg/day). METHODS: Forty hypertensive patients who received a combination of high-dose telmisartan and HCTZ were enrolled. We applied a changeover strategy with switching from a combination of high-dose telmisartan and HCTZ to high-dose losartan and HCTZ. We divided the patients into two groups; those who achieved the target blood pressure (controlled group) and those who did not reach the target blood pressure (uncontrolled group) before the changeover and performed further analysis. RESULTS: The uncontrolled group showed a significant decrease in systolic blood pressure (SBP) (143±12 mmHg to 126±11 mmHg at three months). In addition, serum uric acid significantly decreased in all subjects, and in each of the controlled and uncontrolled groups. There were no significant changes in other biochemical parameters, such as potassium and hemoglobin A1c, at three months after the changeover in all subjects. CONCLUSION: Combination therapy with high-dose losartan and HCTZ was superior to the combination of telmisartan and HCTZ with respect to significant decreases in systolic blood pressure and serum uric acid in hypertensive patients.

Risk of hypercalcemia in blacks taking hydrochlorothiazide and vitamin D.

INTRODUCTION: Hydrochlorothiazide, an effective antihypertensive medication commonly prescribed to blacks, decreases urinary calcium excretion. Blacks have significantly higher rates of hypertension and lower levels of 25-hydroxyvitamin D. Thus, they are more likely to be exposed to vitamin D supplementation and thiazide diuretics. The risk for hypercalcemia among blacks using vitamin D and hydrochlorothiazide is undefined. METHODS: We assessed the frequency of hypercalcemia in hydrochlorothiazide users in a post hoc analysis of a randomized, double-blind, dose-finding trial of 328 blacks (median age 51 years) assigned to either placebo, or 1000, 2000, or 4000 international units of cholecalciferol (vitamin D3) daily for 3 months during the winter (2007-2010). RESULTS: Of the 328 participants, 84 reported hydrochlorothiazide use and had serum calcium levels assessed. Additionally, a comparison convenience group of 44 enrolled participants who were not taking hydrochlorothiazide had serum calcium measurements at 3 months, but not at baseline. At 3 months, hydrochlorothiazide participants had higher calcium levels (0.2 mg/dL, P <.001) than nonhydrochlorothiazide participants, but only one participant in the hydrochlorothiazide group had hypercalcemia. In contrast, none of the nonhydrochlorothiazide participants had hypercalcemia. In a linear regression model adjusted for age, sex, 25-hydroxyvitamin D at 3 months, and other covariates, only hydrochlorothiazide use (Estimate [SE]: 0.05 [0.01], P = .01) predicted serum calcium at 3 months. CONCLUSION: In summary, vitamin D3 supplementation up to 4000 IU in hydrochlorothiazide users is associated with an increase in serum calcium but a low frequency of hypercalcemia. These findings suggest that participants of this population can use hydrochlorothiazide with up to 4000 IU of vitamin D3 daily and experience a low frequency of hypercalcemia.

Effectiveness of the fixed-dose combination of olmesartan/amlodipine/hydrochlorothiazide for the treatment of hypertension in patients stratified by age, race and diabetes, CKD and chronic CVD.

The prevalence of hypertension is high in patients with diabetes mellitus (DM), chronic kidney disease (CKD) and chronic cardiovascular disease (CVD), as well as in black and elderly subjects. In addition, these subjects have the lowest control of blood pressure (BP) among the hypertensive population, and also the risk of having a morbid or fatal cardiovascular event >20% in 10 years. For these reasons, aggressive control of BP to <130/80 mm Hg for these subjects is strongly recommended by National and International guidelines. To accomplish this goal, combination therapy with two or more antihypertensive drugs with a complementary mechanism of action is necessary. Drugs that block the renin-angiotensin system (RAS) in combination with a calcium channel blocker (CCB) and a diuretic have been shown to be the most effective combinations to accomplish this goal. However, this will require the administration of multiple drugs given separately, which will decrease the patient compliance and adherence to treatment. Poor patient compliance and adherence to treatment is a major factor for poor BP control. Several studies have shown that patient compliance is inversely related to the number of drugs being administered. To overcome this problem, several dual and triple-drug, fixed-dose combinations with a RAS blocker, a CCB and a diuretic have been developed and marketed, which are easier to administer, and have been shown to increase patient compliance and adherence to treatment. In this concise review, the effectiveness and safety of the fixed-dose, triple-combination of the RAS blocker olmesartan medoxomil, the CCB amlodipine besylate and the diuretic hydrochlorothiazide, as well as other similar combinations for the treatment of hypertension, will be discussed. These drug combinations have been shown to be effective, safe and well tolerated by most patients.

The single pill triple combination of aliskiren, amlodipine, and hydrochlorothiazide in the treatment of hypertension.

INTRODUCTION: Hypertension is a leading cause of cardiovascular morbidity and mortality, and uncontrolled hypertension remains common despite the availability of several classes of effective antihypertensive medications. Combination therapy with antihypertensive agents of complementary actions has been advocated in the management of hypertension to maximize efficacy and minimize side effects. AREAS COVERED: This review summarizes the current data on the triple combination therapy of aliskiren with amlodipine and hydrochlorothiazide, and discusses the clinical use of single pill triple combination of aliskiren, amlodipine and hydrochlorothiazide in the treatment of hypertension and associated cardiovascular conditions. EXPERT OPINION: Combination therapy with antihypertensive agents of complementary actions is more effective than monotherapy in the management of hypertension. Combining an agent in renin-angiotensin blockade with a dihydropyridine calcium channel blocker (CCB) and a thiazide diuretic has plausibility in maximizing blood pressure reduction and minimizing side effects. The combination of aliskiren with amlodipine and hydrochlorothiazide has shown effective blood pressure lowering and noteworthy tolerability. The single pill triple combination of aliskiren, amlodipine, and hydrochlorothiazide offers five different formulations of escalating dosages of the three agents, allowing dosing flexibility. The decreased pill burden and simplified treatment options with the single pill triple combination provide an opportunity to improve blood pressure control through improved adherence and reduced treatment inertia.

Efficacy and safety of a single-pill fixed-dose combination of high-dose telmisartan/hydrochlorothiazide in patients with uncontrolled hypertension.

OBJECTIVE: Many patients still have high blood pressure (BP) after treatment with high-dose angiotensin II type 1 receptor blockers (ARBs) or Preminent® (medium-dose of losartan (50 mg/day)/hydrochlorothiazide (HCTZ) (12.5 mg/day)). Therefore, we analyzed whether Micombi®BP (high-dose telmisartan (80 mg/day)/HCTZ (12.5 mg/day)) could provide better results with regard to efficacy and safety for patients with uncontrolled hypertension. METHODS: In total, 44 hypertensive patients (22 males, age 71±14 years) who showed uncontrolled BP despite the use of high-dose ARBs or Preminent® were enrolled in this study. We used a changeover design in which the patients were switched from high-dose ARBs or Preminent® to Micombi®BP. We analyzed BP, heart rate (HR), and biochemical parameters before and after treatment for 3 months. RESULTS: Systolic BP and diastolic BP significantly decreased (125±15/69±11 mmHg) and 85% of the patients achieved their target BP at 3 months after changeover. Patients who switched from ARBs and those who switched from Preminent® showed similar BP-lowering effects. In addition, the reductions in BP after 3 months in patients with or without chronic kidney disease and in those with or without metabolic syndrome (MetS) were also similar. There were no significant changes in HR during the study period. Although blood levels of potassium, hemoglobin A1c and uric acid (UA) significantly increased after 3 months for all of the patients, none of the patients showed serious adverse effects. CONCLUSION: High-dose telmisartan/HCTZ therapy was associated with a significant reduction in BP and helped patients achieve their target BP.

Herb-drug interaction between the extract of Hibiscus sabdariffa L. and hydrochlorothiazide in experimental animals.

Decoctions of Hibiscus sabdariffa L. (Family Malvaceae) are very popular for the preparation of homemade refreshing drinks and are also used medicinally for a variety of ailments. Particularly remarkable are the various scientific reports supporting diuretic and antihypertensive potentials. It is therefore not unusual for patients who are on orthodox antihypertensive medications to use medicinal H. sabdariffa drinks concomitantly without regard to the possibility of herb-drug interactions. This possibility necessitated this study in which the pharmacokinetic and pharmacodynamic interactions of H. sabdariffa extract (HSE) and hydrochlorothiazide (HCT), a commonly prescribed diuretic drug, were examined. The effects of concomitant administration of HSE on urine volume, urine pH, and urinary concentrations of sodium, bicarbonate, and chloride ions, as well as on the pharmacokinetic parameters of HCT, were determined in experimental rats and rabbits. Co-administration of HSE with HCT caused a significant increase in the volume of urine excreted and resulted in a decrease in the pH of urine and the concentrations of sodium, bicarbonate, and chloride ions. Co-administration of HSE (20-40 mg/kg) with HCT (10 mg/kg) increased and prolonged the plasma concentration, the mean area under the concentration-time curve, and the volume of distribution of HCT achieved over the 24-hour sampling period. The plasma clearance and the elimination rate constant of HCT decreased with increasing dose of HSE co-administered with the HCT. The results of this study reveal a possible herb-drug interaction involving HCT and HSE, used as an ingredient in medicinal or refreshing drinks in many countries.

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.

Photoallergenic potential testing by online irradiation and HPLC.

A simple screening method was developed for testing the photoallergenic potential of drugs. The photolysis of the drugs under UV-A irradiation was investigated in aqueous buffer solution alone and in combination with a model dipeptide. As an useful tool for this, high performance liquid chromatography (HPLC) based on an automated column-switching system with aqueous online UV-A irradiation was used. For testing the system, hydrochlorothiazide (HC) with well-known photoallergenic properties was used as a drug and alanyltryptophane (ALATRP) as a model for proteins. Promethazine (PMZ) as a second drug was investigated by the developed screening system. The screening was performed at pH 3 and pH 7. Both cleavage of the peptide binding and formation of new products could indicate a photoallergenic potential.

Thiazide-induced severe hypercalcemia: a case report and review of literature.

Most common causes of hypercalcemia are hyperparathyroidism, malignancy, vitamin D-mediated conditions such as sarcoidosis, and vitamin D toxicity. Less commonly, hypercalcemia can be caused by drugs such as thiazide diuretics and lithium. Mild hypercalcemia is usually asymptomatic but severe hypercalcemia is associated with nausea, vomiting, abdominal pain, excessive thirst, muscle weakness, lethargy, confusion, and fatigue. We are reporting a case of abdominal pain and altered mental status caused by thiazide-induced severe hypercalcemia of 19.8 mg/dL. This is the most severe case of thiazide-induced hypercalcemia that we have seen reported. Patients on thiazide diuretics should have their electrolytes frequently checked, especially patients on calcium supplements. Management usually includes hydration and discontinuation of drugs causing hypercalcemia.

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.

Sex differences in blood pressure response to antihypertensive therapy in Chinese patients with hypertension.

BACKGROUND: Sex-specific responses to antihypertensive drugs are not very well understood. OBJECTIVE: To investigate sex-related differences in blood pressure response to antihypertensive drugs in a community-based prospective clinical trial. METHODS: We recruited 3535 untreated hypertensive patients (2326 women), aged 40-75 years, from 7 rural communities in China. Subjects were randomized to 1 of 4 drug groups: atenolol, hydrochlorothiazide (HCTZ), captopril, or sustained-released nifedipine; duration of the study was 8 weeks. Mean blood pressure reduction, blood pressure control rates, and frequency of adverse events were compared between men and women. RESULTS: Women had a better response to HCTZ in relation to diastolic blood pressure (1.8 mm Hg lower) than did men (p < 0.05) and were 57% more likely to reach the control goal of diastolic blood pressure than were men (p < 0.05). In the atenolol group, mean systolic blood pressure decreased 3.9 mm Hg more in women than in men (p < 0.05), and women were 65% more likely to reach the control goal of systolic blood pressure and 57% more likely to reach the control goal of diastolic blood pressure than were men (p < 0.05). Significant sex-related differences were also found in drug-related adverse events in the nifedipine group (15.8% in women vs 9.8% in men; p = 0.017) and in the captopril group (14.3% in women vs 8.4% in men; p = 0.005), but no differences were seen with HCTZ or atenolol. CONCLUSIONS: Women have better blood pressure responses to HCTZ and atenolol and experience more adverse effects with sustained-release nifedipine and captopril than do men, indicating that sex should be taken into account when selecting antihypertensive drugs.

Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study.

In this randomized, double-blind, multicenter study, patients whose blood pressure (BP) was uncontrolled by monotherapy were switched directly to amlodipine/valsartan 5/160 mg (n=443) or 10/160 mg (n=451). After 16 weeks, BP control (levels <140/90 mm Hg or <130/80 mm Hg for diabetics) was achieved in 72.7% (95% confidence interval [CI], 68.6-76.9) of patients receiving amlodipine/valsartan 5/160 mg and in 74.8% (95% CI, 70.8-78.9) receiving amlodipine/valsartan 10/160 mg. Incremental reductions from baseline in mean sitting systolic and diastolic BP were significantly greater with the higher dose (20.0+/-0.7 vs 17.5+/-0.7 mm Hg; P=.0003 and 11.6+/-0.4 vs 10.4+/-0.4 mm Hg; P=.0046). Incremental BP reductions were also achieved with both regimens irrespective of previous monotherapy, hypertension severity, diabetic status, body mass index, and age. Peripheral edema was the most frequent adverse event. These results provide support for the BP-lowering benefits of complementary antihypertensive therapy with amlodipine and valsartan in patients with hypertension uncontrolled by previous monotherapy.