Antihypertensive and metabolic effects of hydrochlorothiazide versus amlodipine when added to losartan in patients with type 2 diabetes.

We performed a prospective, randomized, multicenter, parallel-group, per-protocol study to compare the effects of hydrochlorothiazide (HCTZ) and amlodipine as add-on to losartan treatment in hypertensive type 2 diabetic patients. A total of 49 Japanese type 2 diabetic patients with inadequate control of blood pressure while receiving losartan 50 mg were randomly allocated to receive a fixed-dose single-pill combination of HCTZ 12.5 mg plus losartan (N = 26) or a free combination of amlodipine 5 mg plus losartan (N = 23). During 8 weeks of follow-up, changes in blood pressure and laboratory data including HbA1c, uric acid, and potassium were compared between the groups using analysis of covariance. Systolic and diastolic blood pressure decreased in both groups, the reductions of which were greater in the amlodipine group. However, the least square mean (95 % CI) differences between groups were not statistically significant [2.3 (-6.8 to 11.4) mmHg, p = 0.618 and 2.7 (-2.4-7.9) mmHg, p = 0.293, respectively]. HbA1c increased in patients receiving HCTZ but not in the amlodipine group. Uric acid also increased in patients receiving HCTZ but decreased in patients receiving amlodipine, yielding a significant between-group difference of 1.0 (0.5-1.5) mg/dl (p < 0.001). No intra- or intergroup change was observed in serum potassium levels. This pilot study suggests that HCTZ and amlodipine result in nonsignificant effects on systolic and diastolic blood pressure reduction when administrated as add-on therapy to losartan in hypertensive patients with type 2 diabetes; however, addition of HCTZ may be associated with less favorable effects on metabolic profiles than amlodipine.

Effects of pravastatin sodium on mevalonate metabolism in common marmosets.

In experimental animals and humans, the concentration of serum mevalonate (MVA), a direct product of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, is considered to reflect the activity of whole-body sterol synthesis. The relationship between the concentration of serum MVA and the activity of sterol synthesis in tissues, however, has not been fully clarified. In the present study, we examined MVA metabolism by using pravastatin, a liver-selective inhibitor of HMG-CoA reductase, and common marmosets, a good model animal for studying lipid metabolism. In the time course study, the maximal reduction in the concentration of serum MVA was observed 2 h after a single oral administration of 30 mg/kg pravastatin to common marmosets. We, therefore, examined the relationship between the concentrations of serum and hepatic MVA, and sterol synthesis in some tissues at this time point. Sterol synthesis was determined ex vivo in tissue slices by measuring the incorporation of [14C]acetate into digitonin-precipitable [14C]sterols. Pravastatin at 0.03-30 mg/kg reduced dose-dependently the activity of hepatic sterol synthesis, whereas no significant reduction of sterol synthesis was observed in other tissues such as intestine, kidney, testis and spleen, even with the highest dose (30 mg/kg). The liver-specific inhibition of sterol synthesis caused parallel reductions in the concentrations of both serum and liver MVA. In addition, there were good correlations between the concentration of either serum or hepatic MVA and the activity of hepatic sterol synthesis. These data indicate that the major origin of serum MVA is the liver, and that the concentration of serum MVA reflects the concentration of hepatic MVA and the activity of hepatic sterol synthesis 2 h after a single oral administration of pravastatin in common marmosets.

Pravastatin sodium, an inhibitor of HMG-CoA reductase, decreases HDL cholesterol by transfer of cholesteryl ester from HDL to VLDL in Japanese white rabbits.

In a recent paper, we reported that pravastatin sodium (pravastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme. A reductase, decreases the concentrations of low density lipoprotein (LDL) cholesterol through an LDL receptor pathway in Japanese White (JW) rabbits, whereas this agent lowers high density lipoprotein (HDL) cholesterol in a manner correlated with a reduction of very low density lipoprotein (VLDL) cholesterol secretion from the liver. In the present study, we administered pravastatin to JW rabbits at 30 mg/kg for 14 days and examined further the mechanisms for the reduction of HDL cholesterol. A striking finding was that the 4-day administration of pravastatin at 30 mg/kg selectively decreased the concentration of HDL cholesterol. Since 4-day administration of pravastatin to JW rabbits did not change the concentrations of hepatic LDL receptor proteins, these receptors were not likely to be involved in the reduction of HDL cholesterol. Another important finding was that pravastatin suppressed VLDL cholesteryl ester (CE) secretion from the liver, but not that of other VLDL lipids and VLDL proteins, indicating that the CE-poor VLDL particles were secreted by the consecutive administration of pravastatin. There were, however, no differences in the levels of VLDL cholesterol between the control and pravastatin-treated groups over the experimental period of 14 days. These observations raised the possibility that the reduction of HDL cholesterol in the pravastatin-treated group was due to the transfer of CE molecules from HDL particles to these CE-poor VLDL particles. Molecular species analysis supported this notion that the VLDL-CE in the pravastatin-treated group was rich in cholesteryl linoleate, indicating that the CE in this group mainly originated from HDL, whereas the VLDL-CE in the control group was rich in cholesteryl oleate, indicating that the CE in this group originated from the liver. The present study suggests that pravastatin lowers HDL cholesterol by transferring CE from these lipoproteins to VLDL in JW rabbits.

Temporal increase in the gastric colonization of Helicobacter pylori after healing of acetic acid-induced gastric ulcer in a miniature pig.

While the eradication of Helicobacter pylori has been reported to reduce the frequency of ulcer relapse, the preventative mechanism remains unknown. We investigated the changes in the level of gastric colonization 140 days after inducing gastric ulcer by acetic acid in the antral mucosa of a miniature pig infected with H. pylori. The gastric ulcer was induced endoscopically with 1 mL of 40% acetic acid 12 days after inoculation of H. pylori in a 3-month-old miniature pig. Gastric ulcer was healed by 30 days after ulcer induction and the levels of H. pylori in cardiac and antral mucosa increased gradually from 30 to 71 days. The peak bacterial counts in the cardia and antrum were 6.1 and 6.6 log10 cfu/g, respectively, or about 100-fold higher than the initial levels. The levels of H. pylori in cardiac and antral mucosa steadily decreased until reaching the initial levels at 127 days, while that in the fundic mucosa remained constant throughout the observation period. No ulcer recurrence was detected by endoscopy. These results suggested that the levels of H. pylori colonization increased temporally after healing of the acetic acid-induced gastric ulcer in the miniature pig.

Essential role of magnesium ion in water for colonization of Helicobacter pylori in 2-week-old miniature pigs.

This study was designed to determine whether magnesium ion in water would influence the colonization of Helicobacter pylori in 2-week-old miniature pigs. Groups A (2 pigs) and B (1 pig) were both fed a milk diet dissolved in drinking water, Group C (2 pigs) was fed a milk diet dissolved in deionized distilled water (DDW), and Group D (1 pig) was fed a milk diet dissolved in DDW supplemented with MgCl2. Groups B, C, and D were all challenged with H. pylori, and Group A was not. Necropsy was performed on the pigs on postinfection Day 5, and biopsy specimens were taken from 16 sites of the stomach. H. pylori were recovered from 11 of 16 sites in Group B, 1 of 32 sites in Group C, and 13 of 16 sites in Group D. On the other hand, the degree of lymphocyte infiltration increased in the order of Group A < Group B < Group C < Group D. These observations suggest that magnesium ion in drinking water is essential for the colonization of H. pylori in the pig stomach. Possible mechanisms for the lymphocyte infiltration are discussed.

Contribution of ferrous iron to maintenance of the gastric colonization of Helicobacter pylori in miniature pigs.

Our previous study showed that the colonization levels of Helicobacter pylori were higher in the stomachs of 5-day-old miniature pigs than in 2-week-old ones. As dietary factors can cause these differences, we compared two diets, i.e., Weanymilk and a similar formula with a higher concentration of Fe(II), Weanylobulin. The colonization levels in the fundic mucosa were significantly higher in 2-week-old pigs fed Weanylobulin than in those fed Weanymilk. Supplementing Weanylobulin with an iron chelator, deferoxamine mesylate, significantly lowered the bacteria counts in the gastric mucosa. Normal diets supplemented with Fe(II) in 2-month-old pigs caused significantly more sites of bacteria in the antrum compared with normal diets alone. In addition, ranitidine, an inhibitor of gastric acid secretion that reduces Fe(III) to Fe(II) in the stomach, decreased the bacteria counts in 10-month-old pigs. These results suggested that Fe(II) maintained the colonization levels of H. pylori in the stomach of the miniature pigs.

Combination therapy with losartan/hydrochlorothiazide for blood pressure reduction and goal attainment in a real-world clinical setting in Japan.

OBJECTIVE: When physicians prescribe a new antihypertensive drug, they do not know the extent of the drug's effect on lowering blood pressure. To resolve this dilemma, a Web-based program was constructed for real-time entry and analysis of treatment. This observational study evaluated the efficacy of losartan/hydrochlorothiazide (Lo/HCTZ) in lowering blood pressure (BP) and achieving BP target values. METHODS: Physicians prescribed Lo/HCTZ for patients with hypertension who failed to achieve target BP values of < 140/90 mmHg and < 130/80 mmHg in patients with diabetes or chronic kidney disease, respectively, with antihypertensive drugs including an angiotensin receptor blocker. RESULTS: From December 2006 to December 2009, the data of 88,254 patients were entered into this database, and the data of 24,825 subjects were analyzed. At the first visit, a total of 88,254 patients received a first prescription of Lo/HCTZ daily. Among these, at the end of the present analysis, 24,825 (28%) outpatients had a follow-up visit at 1 month and 20,726 (23%) outpatients had a follow-up visit at 6 months. The prevalence of hypertensive patients achieving systolic blood pressure (SBP) control (< 140 mmHg) increased over time from 6.9% to 54.3% in females and 6.1% to 52.3% in males (p < 0.05). At the start of the study, the levels of SBP were significantly highest in the eldest patients (≥ 75 years) followed by the group of 65-75 years and lowest in the youngest patients (≤ 64 years). However, at the end of the study, there were no differences in levels of SBP among the three groups. CONCLUSIONS: This Web-based system may provide useful information when a new drug is first released into the market. Treatment with Lo/HCTZ enabled a substantial proportion of hypertensive patients to achieve the recommended goal of < 140/90 mmHg.