Efficacy and effects on lipid metabolism of combination treatment with losartan + hydrochlorothiazide versus losartan + amlodipine: a 48-week prospective, multicenter, randomized, open-label trial.

BACKGROUND: Both combination therapies of an angiotensin II receptor blocker (ARB) with the thiazide diuretic hydrochlorothiazide (HCTZ) and an ARB with a calcium channel blocker (CCB) are recommended to achieve blood pressure (BP) goals in antihypertensive treatment. However, although HCTZ is known to have unfavorable effects on lipid metabolism, the effects of HCTZ in the ARB + HCTZ combination on lipid metabolism have not been fully elucidated. OBJECTIVE: The aim of this study was to compare the effects on lipid metabolism of combination treatment with the ARB losartan + HCTZ and losartan + the CCB amlodipine and to assess the efficacy in BP lowering of these 2 combination therapies. The metabolism of glucose, uric acid (UA), and high-sensitivity C-reactive protein (hs-CRP), an inflammation marker of atherosclerosis, were also assessed in association with lipid metabolism. METHODS: This 48-week, prospective, randomized, open-label trial was conducted at 2 clinics and 2 hospitals in Tokorozawa City (Saitama, Japan) and Shinjuku-ku Ward (Tokyo, Japan). Eligible patients had a systolic BP (SBP) >140 mm Hg and/or diastolic BP (DBP) >90 mm Hg despite a >1-month history of monotherapy with an ARB. Patients were randomly assigned to receive losartan 50 mg/d + HCTZ 12.5 mg/d (LOS + HCTZ) or losartan 50 mg/d + amlodipine 5 mg/d (LOS + CCB) for 48 weeks. Follow-up visits were scheduled at 4, 8, 12, 24, and 48 weeks. Biochemical measurements were centrally measured at a single institute. Tolerability and treatment compliance were assessed by physicians every 4 weeks. RESULTS: A total of 112 patients were enrolled; 26 were excluded from the final analysis, leaving 42 and 44 patients in the LOS + HCTZ and LOS + CCB groups, respectively, included in the final analysis. At 48 weeks, SBP and DBP were significantly decreased in the 2 treatment groups (both, P < 0.0001). The decrease in SBP was significantly greater in the LOS + HCTZ group than in the LOS + CCB group (P < 0.001). The difference in the decrease in DBP between the 2 groups was nonsignificant. There were no significant differences in the changes from baseline (Δ) in any of the lipid parameters between the 2 groups. The decreases at 8 and 12 weeks in LDL-C, TC, and apolipoprotein (apo) B were significantly greater in the LOS + CCB group compared with those in the LOS + HCTZ group. The between-group differences in ΔTG, ΔHDL-C, ΔapoA-1, and ΔapoE throughout the study were nonsignificant. Changes in fasting plasma glucose (FPG), hemoglobin A1c, and hs-CRP were not significantly different between the 2 groups. The between-group difference in ΔUA in men was not significant, but a significant difference was found in women (LOS + HCTZ, 0.74 mg/dL; LOS + CCB, 0.28 mg/dL [P = 0.0017]). No clinically significant adverse events were reported with either treatment throughout the study. CONCLUSIONS: The findings from the present study suggest that LOS + HCTZ was more efficacious in decreasing SBP than was LOS + CCB in the management of hypertension refractory to ARB monotherapy. Unfavorable effects on lipid metabolism were not observed with either combination therapy.

Associations between headache and stress, alcohol drinking, exercise, sleep, and comorbid health conditions in a Japanese population.

We conducted a cross-sectional survey of 12,988 subjects aged 20-79 years (5,908 men and 7,090 women) receiving health checkups at a Tokyo clinic. They filled out a self-administered structured questionnaire, and 5.4% of the men and 15.4% of the women reported having headaches. Younger subjects were more prone to having headaches. The likelihood of having headaches increased with stress level and decreased ability to relieve stress in both genders. There was an inverse dose-response relationship between having headaches and alcohol consumption, and less walking/exercise and sleep problems increased the likelihood of headaches in both genders. Headache sufferers of both genders were more likely to report multiple additional poor health conditions. A multivariate stepwise logistic analysis showed that age, self-estimated degree of stress, reported number of additional poor health conditions, and less alcohol consumption were independently correlated with having headaches. In conclusion, although women were more susceptible to headache, Japanese men and women in Tokyo shared factors associated with headache, including age, stress, having other poor health conditions, alcohol consumption, sleep, and exercise.

A short-term admission improved brachial-ankle pulse wave velocity in type 2 diabetic patients.

Brachial-ankle pulse wave velocity (baPWV) is a non-invasive method for assessing arterial stiffness associated with atherosclerosis. We examined whether baPWV could improve during a 2-week hospital-based education program in patients with type 2 diabetes and whether improvement associates with changes in known atherogenic risk factors. Body mass index (BMI), blood pressure (BP), fasting plasma glucose (FPG), insulin, lipid profiles and baPWV were measured in 32 type 2 diabetic patients before and after an educational program that included advice about nutrition and exercise. Relationship between the changes in baPWV and additional parameters, 24h-urinary excretion of C-peptide, visceral and subcutaneous fat area by abdominal computer tomography and intima-medial thickness (IMT) of the carotid artery by ultrasonography, were also evaluated. Baseline values of baPWV significantly correlated with age, duration of diabetes, BP, IMT and FPG. BaPWV significantly decreased after the program (-120+/-108.4 cm/s, P<0.0001) and this change significantly correlated with that of systolic BP (r=0.697, P<0.0001) and FPG (r=0.452, P<0.05). These results indicate that short-term hospitalization with an educational program can improve arterial wall stiffness, perhaps due to improvements in BP and glycemic control.

Methimazole-induced aplastic anemia caused by hypocellular bone marrow with plasmacytosis.

Aplastic anemia is a rare but severe complication of methimazole (MMI) treatment for Graves' disease. We present a case of a 53-year-old Japanese female who had been treated with 30 mg/d of MMI for 30 days for Graves' disease and was subsequently admitted to the Japan Self Defense Forces (JSDF) Central Hospital with a mild sore throat and high-grade fever that began the previous day. The patient had a reduced white blood cell count (WBC) count of 0.9 x 10(3) per microliter with severe granulocytopenia and increased lymphocytes, a platelet count of 49 x 10(3) per microliter, and hemoglobin of 10.6 g/dL. Bone marrow (BM) aspirates showed hypocellular bone marrow with plasmacytosis. Because of poor recovery of her peripheral blood values after withdrawal of MMI, she was given transfusions of platelets and erythrocytes thereafter. This is the second report of plasmacytosis in bone marrow of MMI-induced aplastic anemia, and suggests that immunogenic mechanisms may cause this rare complication.

The renin-angiotensin system is involved in the production of plasminogen activator inhibitor type 1 by cultured endothelial cells in response to chylomicron remnants.

Triglyceride-rich lipoproteins have been suggested to promote atherosclerosis. Plasminogen activator inhibitor type 1 (PAI-1) plays an important role in the events of cardiovascular pathophysiology. The renin-angiotensin system influences various vascular functions, including PAI-1 production. We examined whether or not chylomicron remnants increased PAI-1 mRNA and protein production in endothelial cells and whether or not an inhibition of the renin-angiotensin system interfered with this effect. Chylomicron remnants were isolated from functionally hepatectomized rats injected with chylomicrons. Human umbilical vein endothelial cell cultures (HUVECs) were incubated with chylomicron remnants with or without an angiotensin-converting enzyme inhibitor (temocaprilat), an angiotensin II receptor type 1 antagonist (RNH-6270), or an angiotensin II receptor type 2 antagonist (PD123319). Chylomicron remnants increased PAI-1 secretion in HUVECs (0.5 microg/ml; 128.3 +/- 6.1%, the mean +/- SEM) as well as angiotensin II (10 nmol/l; 130.7 +/- 9.5%) in 18 h, as compared with the controls, as well as stimulated PAI-1 mRNA expression to a maximum level at 4 h. Temocaprilat and RNH-6270, but not PD123319, attenuated all of these effects. Chylomicron remnants enhanced nuclear extract binding to a very low-density lipoprotein response element in the PAI-1 promoter region and activated nuclear factor-kappaB. Extracellular signal-regulated kinase (ERK 1/2) was phosphorylated in response to chylomicron remnants. These effects were inhibited by temocaprilat or RNH-6270. In conclusion, chylomicron remnants increased protein secretion and mRNA expression of PAI-1 in HUVECs. Inhibition of the renin-angiotensin system reduced this stimulation.