Comparison of Azelnidipine and Trichlormethiazide in Japanese Type 2 Diabetic Patients with Hypertension: The COAT Randomized Controlled Trial.

OBJECTIVE: This study compared the efficacy and safety of azelnidipine with that of trichlormethiazide in Japanese type 2 diabetic patients with hypertension. METHODS: In a multicenter, open-label trial, 240 patients with adequately controlled diabetes (HbA1c ≤ 7.0%) under lifestyle modification and/or administration of hypoglycemic agents and inadequately controlled hypertension (systolic blood pressure [sBP] ≥ 130 mmHg or diastolic blood pressure [dBP] ≥ 80 mmHg) who were being treated with olmesartan were enrolled. Participants were randomly assigned to an azelnidipine group or a trichlormethiazide group and were followed up for 48 weeks. Main outcome measure was the difference in the change in HbA1c levels from the baseline values at 48 weeks between these two groups. RESULTS: Of the 240 subjects that were enrolled, 209 subjects (azelnidipine group: 103 patients, trichlormethiazide group: 106 patients) completed this trial. At 48 weeks, the following changes were observed in the azelnidipine and trichlormethiazide groups, respectively: HbA1c levels, 0.19 ± 0.52% and 0.19 ± 0.54%; sBP/dBP, -10.7 ± 9.6/-6.6 ± 6.6 mmHg and -7.1 ± 7.7/-3.3 ± 6.1 mmHg (P < 0.001 for both sBP and dBP). In both groups, dizziness (12 patients [11.7%] and 16 patients [15.1%]) and edema (16 patients [15.5%] and 7 patients [6.6%], P = 0.047) were observed during the 48-week follow-up period. CONCLUSIONS: Azelnidipine was more effective for controlling blood pressure than trichlormethiazide in Japanese type 2 diabetes patients, whereas trichlormethiazide was more effective for reducing albuminuria than azelnidipine. Both of these agents, however, similarly exacerbated glycemic control in type 2 diabetic patients with hypertension. TRIAL REGISTRATION: UMIN 000006081.

Successful conversion from thiazide to tolvaptan in a patient with stage d heart failure and chronic kidney disease before heart transplantation.

Chronic kidney disease (CKD) is often complicated with advanced heart failure because of not only renal congestion and decreased renal perfusion but also prolonged use of diuretics at higher doses, which sometimes results in hyponatremia. Preoperative CKD is known to be associated with poor prognosis after heart transplantation (HTx). We experienced a stage D heart failure patient with CKD and hyponatremia who was switched from trichlormethiazide to tolvaptan. His hyponatremia was normalized, and his renal function was improved after conversion to tolvaptan. In patients with stage D heart failure, it may be useful to administer tolvaptan with a concomitant reduction in the dose of diuretics in order to preserve renal function and avoid hyponatremia before HTx.

Adverse effect profile of trichlormethiazide: a retrospective observational study.

BACKGROUND: Trichlormethiazide, a thiazide diuretic, was introduced in 1960 and remains one of the most frequently used diuretics for treating hypertension in Japan. While numerous clinical trials have indicated important side effects of thiazides, e.g., adverse effects on electrolytes and uric acid, very few data exist on serum electrolyte levels in patients with trichlormethiazide treatment. We performed a retrospective cohort study to assess the adverse effects of trichlormethiazide, focusing on serum electrolyte and uric acid levels. METHODS: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and July 31, 2010, to identify cohorts of new trichlormethiazide users (n = 99 for 1 mg, n = 61 for 2 mg daily dosage) and an equal number of non-users (control). We used propensity-score matching to adjust for differences between users and control for each dosage, and compared serum chemical data including serum sodium, potassium, uric acid, creatinine and urea nitrogen. The mean exposure of trichlormethiazide of 1 mg and 2 mg users was 58 days and 64 days, respectively. RESULTS: The mean age was 66 years, and 55% of trichlormethiazide users of the 1 mg dose were female. In trichlormethiazide users of the 2 mg dose, the mean age was 68 years, and 43% of users were female. There were no statistically significant differences in all covariates (age, sex, comorbid diseases, past drugs, and current antihypertensive drugs) between trichlormethiazide users and controls for both doses. In trichlormethiazide users of the 2 mg dose, the reduction of serum potassium level and the elevation of serum uric acid level were significant compared with control, whereas changes of mean serum sodium, creatinine and urea nitrogen levels were not significant. In trichlormethiazide users of the 1 mg dose, all tests showed no statistically significant change from baseline to during the exposure period in comparison with control. CONCLUSIONS: Our study showed adverse effects of decreased serum potassium and increased serum uric acid with trichlormethiazide treatment, and suggested that a lower dose of trichlormethiazide may minimize these adverse effects. These findings support the current trend in hypertension therapeutics to shift towards lower doses of thiazides.

A case of exercise-induced acute renal failure in a patient with idiopathic renal hypouricemia developed during antihypertensive therapy with losartan and trichlormethiazide.

Exercise-induced acute renal failure (ARF) developed in a 45-year-old man during antihypertensive therapy with losartan and trichlormethiazide. The antihypertensive therapy was stopped and marked hypouricemia became apparent during improvement of his renal function. The daily urinary excretion of uric acid was normal and an increased fractional excretion of uric acid was observed. Renal biopsy revealed that the kidney was recovering from acute tubular necrosis with interstitial fibrosis. Based on the results of pyrazinamide and benzbromarone tests, we classified this case as one of presecretory reabsorption defect of uric acid. Antihypertesive therapy with benidipine and candesartan was initiated, and the patient has not had any ARF episodes since. Because idiopathic renal hypouricemia can be associated with exercise-induced ARF and chronic renal dysfunction, careful antihypertensive therapy and follow-up evaluation of renal function might be necessary for hypertensive patients with idiopathic renal hypouricemia.

Randomized double-blind comparison of a calcium antagonist and a diuretic in elderly hypertensives. National Intervention Cooperative Study in Elderly Hypertensives Study Group.

Although diuretics are recommended for the treatment of hypertension, decreased diuretic use and increased calcium antagonist use necessitate a comparison of the efficacy of these drugs in preventing cardiovascular events. Patients >/=60 years of age with systolic blood pressure of 160 to 220 mm Hg and diastolic blood pressure <115 mm Hg were enrolled. Patients were randomly assigned to 20 mg of sustained-release nicardipine hydrochloride twice daily or 2 mg of trichlormethiazide once daily by the double-dummy method and followed up for 5 years. A total of 414 patients were analyzed: 204 in the nicardipine group and 210 in the diuretic group. Blood pressure at entry was 172/94 mm Hg and 173/93 mm Hg, respectively, and decreased to 147/81 mm Hg and 147/79 mm Hg, respectively. Cardiovascular morbidity rates per 1000 persons per year were similar in the nicardipine and diuretic groups (27.8 and 26.8, respectively; P=0.923). The sex- and age-adjusted risk ratio for the nicardipine group was 0.973 (95% confidence interval, 0.514 to 1.839, P=0.932). The calcium antagonist and diuretic groups had a similarly decreased rate of cardiovascular events.

Phototoxicity to sulphonamide-derived oral antidiabetics and diuretics: investigations in hairless mice.

The oral antidiabetics glibenclamide, glipizide, glymidine, tolazamide and tolbutamide and the diuretics bemetizide, bendroflumethiazide, benzylhydrochlorothiazide, bumetanide, butizide, furosemide, hydrochlorothiazide, hydroflumethiazide and trichlormethiazide were investigated for phototoxic effects in hairless mice. The back of the animals (hr/hr-c3H/TifBom) was covered with Duoderm dressing, and at the site of two punched out holes 0.05 ml of the test substances at 0.25 mol/l concentration and the solvent alone as control were injected intradermally, respectively. Both test and control sites were irradiated with 6-12 J/cm2 of longwave UVA light from a "Bluelight 2000" apparatus (Hönle, Martinsried, Germany). Skin reactions were read at 24 and 48 h. Compared to the solvent alone, all of the test substances induced reactions (necrosis or oedema)--most frequently seen by macroscopic and histologic investigation and by measurements with a thickness gage. Injection of the test substance or solvent alone without or with subsequent UVA irradiation, as well as UVA alone, did not induce measurable skin changes in this model. Three oral antidiabetics and four diuretics, not yet described to induce photosensitivity in vitro nor in vivo, were detected as potential photosensitizers using our animal model.

Crossover trial comparison of enalapril maleate and trichlormethiazide in the treatment of essential hypertension: emphasis on the quality of life.

Enalapril and trichlormethiazide were compared with respect to effects on the quality of life in a crossover study of 36 patients with hypertension. Multiple-choice 34-item questionnaires with three possible answers (severe, mild and none) per question were used to assess symptoms and mood. Twenty patients were initially given enalapril and 16 were initially given trichlormethiazide. There was no significant difference in the antihypertensive efficacy of the 2 drugs. Treatment with enalapril resulted in significant improvement in 11 of the 34 items, and a tendency for another 4 items to improve. Treatment with trichlormethiazide resulted in significant improvement in only 5 items and a tendency to improve in 2. When enalapril and trichlormethiazide were compared, significantly greater improvement in 2 items and a tendency toward greater improvement in 4 items was seen with enalapril treatment. Thus, enalapril was found to be more efficacious than trichlormethiazide with respect to quality of life in patients with hypertension.

Effects of first-line antihypertensive agents on sexual function and sex hormones.

We studied sexual dysfunction induced by antihypertensive agents in 156 male hypertensive patients. The antihypertensive agents were: trichloromethiazide, 2-4 mg; atenolol, 50-100 mg; captopril 37.5-75 mg; and slow release nifedipine 40-80 mg, administered every day for 1 year after a 2-4-week placebo period. Sexual dysfunction was checked by both a self-reporting questionnaire and a test for serum sex hormones. In the self-reporting questionnaire, the following items were requested: reduction of sexual desire, problems in obtaining and maintaining an erection, problems in ejaculation and the number of occasions of sexual intercourse. The sex hormones measured were testosterone, follicular stimulating hormone, luteinizing hormone and oestradiol. During the placebo period, 5% of the hypertensive patients complained of some sexual disturbance without any significant changes in the plasma levels of the sex hormones. In the short term (1-4 weeks) after the initiation of the antihypertensive therapy, all antihypertensive agents except captopril caused sexual dysfunction. Patients on atenolol or trichloromethiazide complained of every item listed. Those on slow-release nifedipine complained mainly about problems in ejaculation. Serum levels of both testosterone and follicular stimulating hormone were significantly decreased while there was mild elevation of oestradiol in patients on atenolol. In the long term (1 year), only patients taking atenolol experienced sexual dysfunction and mild reduction of serum levels of testosterone. Our findings show that first-line antihypertensive agents have different effects on sexual function and that only captopril may have some advantages over the other agents in terms of the quality of sexual life.

Depression after treatment with thiazide diuretics for hypertension.

The authors reports eight cases of depression induced by thiazide diuretics prescribed for hypertension and discusses possible mechanisms behind this action. The side effects of thiazide diuretics may be overlooked when they are used with other hypertensives known to cause depression.

[Combined treatment with beta-receptor blocker pindolol and diureticum trichlormethiazidum in patients with essential hypertony in stadium II WHO (author's transl))]. / Die Anwendung des Betarezeptorenhemmers Pindolol mit dem Diuretikum Trichlormethiazidum) bei Kranken mit essentieller Hypertonie im Standium II WHO.

A double blind study was performed concerning effects and endurance of a combined therapy with beta-receptor blocker Pindolol (LB 46 Visken Sandoz/2 X 2 tabletes per 5 mg daily and Trichlormethiazidum Eurinol Spofa 3-dicholor-methyl-6-chlor-7-sulfamoyl 3,4-dihydro-1,2, 4-benzothiadiazin-1, 1-dyoxydum) 1 X1 tablet per 4 mg daily in 74 patients with essential hypertony in stadium II WHO. Reduction of the systolic as well as the diastolic blood pressure was already highly significant after the first two weeks of treatment (p less than 0.05). Heart frequency dropped from the average of 86,6 +/-8,6 per minute to 74 +/-16.8 per minute. All patients endured the medication very well.

Sinus arrest following diuretic therapy in a patient with myxedema and hypertension.

A 65-year-old female patient suffering from hypertension and myxedema due to chronic thyroiditis developed anginal attacks under trichlormethiazide therapy. The ECG revealed a SA block with reciprocal beats and aberrant ventricular conduction in a form of bigeminy. Upon substitution of desiccated thyroid for the antihypertensive drug, the anginal attacks subsided, the conduction disturbances disappeared and the blood pressure returned to normal without hypotensive treatment. This observation suggests that replacement therapy should precede diuretics in hypertensive patients with myxedema.