15-Hydroxyeicosatrienoic acid induces nasal congestion by changing vascular functions in mice.

BACKGROUND: Nasal congestion in allergic rhinitis (AR) is caused by vascular hyperpermeability and vascular relaxation of the nasal mucosa. We previously detected high levels of a lipoxygenation metabolite of dihomogammalinolenic acid, 15-hydroxy-8Z,11Z,13E-eicosatrienoic acid (15-HETrE) in the nasal lavage fluid of AR model mice. Here, we investigated the effects of 15-HETrE on vascular functions associated with nasal congestion. METHODS: We measured 15-HETrE levels in the nasal lavage fluid of ovalbumin-induced AR model mice and nasal discharge of patients with AR. We also assessed nasal congestion and vascular relaxation in mice. Vascular contractility was investigated using isolated mouse aortas. RESULTS: Five ovalbumin challenges increased 15-HETrE levels in AR model mice. 15-HETrE was also detected in patients who exhibiting AR-related symptoms. Intranasal administration of 15-HETrE elicited dyspnea-related behavior and decreased the nasal cavity volume in mice. Miles assay and whole-mount immunostaining revealed that 15-HETrE administration caused vascular hyperpermeability and relaxation of the nasal mucosa. Intravital imaging demonstrated that 15-HETrE relaxed the ear vessels that were precontracted via thromboxane receptor stimulation. Moreover, 15-HETrE dilated the isolated mouse aortas, and this effect was attenuated by K+ channel inhibitors and prostaglandin D2 (DP) and prostacyclin (IP) receptor antagonists. Additionally, vasodilatory effects of 15-HETrE were accompanied by an increase in intracellular cAMP levels. CONCLUSIONS: Our results indicate that 15-HETrE, whose levels are elevated in the nasal cavity upon AR, can be a novel lipid mediator that exacerbates nasal congestion. Moreover, it can stimulate DP and IP receptors and downstream K+ channels to dilate the nasal mucosal vasculature.

Analysis of Patient Narratives in Disease Blogs on the Internet: An Exploratory Study of Social Pharmacovigilance.

BACKGROUND: Although several reports have suggested that patient-generated data from Internet sources could be used to improve drug safety and pharmacovigilance, few studies have identified such data sources in Japan. We introduce a unique Japanese data source: tobyoki, which translates literally as "an account of a struggle with disease." OBJECTIVE: The objective of this study was to evaluate the basic characteristics of the TOBYO database, a collection of tobyoki blogs on the Internet, and discuss potential applications for pharmacovigilance. METHODS: We analyzed the overall gender and age distribution of the patient-generated TOBYO database and compared this with other external databases generated by health care professionals. For detailed analysis, we prepared separate datasets for blogs written by patients with depression and blogs written by patients with rheumatoid arthritis (RA), because these conditions were expected to entail subjective patient symptoms such as discomfort, insomnia, and pain. Frequently appearing medical terms were counted, and their variations were compared with those in an external adverse drug reaction (ADR) reporting database. Frequently appearing words regarding patients with depression and patients with RA were visualized using word clouds and word cooccurrence networks. RESULTS: As of June 4, 2016, the TOBYO database comprised 54,010 blogs representing 1405 disorders. Overall, more entries were written by female bloggers (68.8%) than by male bloggers (30.8%). The most frequently observed disorders were breast cancer (4983 blogs), depression (3556), infertility (2430), RA (1118), and panic disorder (1090). Comparison of medical terms observed in tobyoki blogs with those in an external ADR reporting database showed that subjective and symptomatic events and general terms tended to be frequently observed in tobyoki blogs (eg, anxiety, headache, and pain), whereas events using more technical medical terms (eg, syndrome and abnormal laboratory test result) tended to be observed frequently in the ADR database. We also confirmed the feasibility of using visualization techniques to obtain insights from unstructured text-based tobyoki blog data. Word clouds described the characteristics of each disorder, such as "sleeping" and "anxiety" in depression and "pain" and "painful" in RA. CONCLUSIONS: Pharmacovigilance should maintain a strong focus on patients' actual experiences, concerns, and outcomes, and this approach can be expected to uncover hidden adverse event signals earlier and to help us understand adverse events in a patient-centered way. Patient-generated tobyoki blogs in the TOBYO database showed unique characteristics that were different from the data in existing sources generated by health care professionals. Analysis of tobyoki blogs would add value to the assessment of disorders with a high prevalence in women, psychiatric disorders in which subjective symptoms have important clinical meaning, refractory disorders, and other chronic disorders.

Effectiveness of using long-acting angiotensin II type 1 receptor blocker in Japanese obese patients with metabolic syndrome on morning hypertension monitoring by using telemedicine system (FUJIYAMA study).

AIM: Recently, obesity patients have been diagnosed as metabolic syndrome. The aim of this study was to evaluate which angiotensin type 1 receptor blockers (ARBs), telmisartan or candesartan, is superior for the control of home blood pressure (BP) in the morning when the outpatient clinic BP was well controlled in the patients with metabolic syndrome. METHODS: The patients with metabolic syndrome were enrolled. Home BP was monitored by using a telemedicine system. After a 2- to 4-week control period to establish baseline home BP values, these patients were randomly divided into telmisartan (20-80 mg) and candesartan (4-12 mg) groups. These end points were evaluated by using the telemedicine system during steady-state active therapy. A total of 356 patients attending 60 outpatient Japanese centers were recruited. RESULTS: On a day of active therapy, telmisartan significantly lowered both systolic and diastolic home BP in the morning to a greater extent compared to candesartan. At the end of the study, reductions in systolic and diastolic home BP in the morning, in telmisartan group were significantly larger compared to the changes in the candesartan group (systolic; Tel: 12.0 ± 8.9 versus Can: 8.1 ± 17.1 mmHg, p = 0.0292, diastolic; Tel: 7.4 ± 6.1 versus Can: 3.7 ± 6.8 mmHg, p = 0.0053). Additionally in the telmisartan treated group, LDL-cholesterol showed significant reduction (p = 0.037), but candesartan did not. CONCLUSION: The present study by using the telemedicine system clearly demonstrated that telmisartan has a strong effect on reducing morning home BP, and a good effect on lipid metabolism in patients with metabolic syndrome.

Beneficial cardiometabolic actions of telmisartan plus amlodipine therapy in elderly patients with poorly controlled hypertension.

BACKGROUND: There is a growing body of evidence that blood pressure (BP) level is one of the major determinants of cardiovascular morbidity and mortality in individuals, including elderly people. However, to achieve a target BP level in the elderly is more difficult compared with patients aged <65 years. Current guidelines recommend combination drug therapy with different modes of action for the treatment of elderly patients with moderate hypertension (HT). However, the optimal combination regimen is not well established in elderly HT. HYPOTHESIS: We hypothesized that combination therapy of telmisartan plus amlodipine would exert favorable cardiometabolic actions in elderly HT. METHODS: Seventeen elderly patients with essential HT who failed to achieve a target home BP level with treatment of 5 mg amlodipine plus 80 mg valsartan or 8 mg candesartan for at least 2 months were enrolled. Then the patients were assigned to replace their valsartan or candesartan with 40 mg telmisartan. The subjects were instructed to measure their own BP at home every day during the study periods. RESULTS: Replacement of valsartan or candesartan by telmisartan in amlodipine-treated elderly hypertensive patients showed a significant reduction in morning home systolic BP and evening home systolic and diastolic BP at 12 weeks. Switching to telmisartan significantly increased serum adiponectin level. CONCLUSIONS: Our present study suggests that combination therapy with telmisartan plus amlodipine may exert more beneficial cardiometabolic effects in elderly patients with HT compared with valsartan or candesartan plus amlodipine treatment.

Efficacy of combination therapy with telmisartan plus amlodipine in patients with poorly controlled hypertension.

There is accumulating evidence that blood pressure (BP) control significantly reduces the risk of future cardiovascular events in patients with essential hypertension. However, strict BP control is often difficult to maintain, and half of hypertensive patients fail to attain BP goals on single-drug therapy. Therefore, current guidelines recommend combinations of drugs that have complimentary mode of actions for treatment of patients with moderate hypertension. In this study, we examined in hypertensive patients uncontrolled by the combination treatment with 5 mg amlodipine plus 80 mg valsartan or 8 mg candesartan whether additional BP lowering could be achieved by switching to 5 mg amlodipine plus 40 mg telmisartan. Forty-seven patients with essential hypertension who failed to achieve a target BP level by the treatment of 5 mg amlodipine plus 80 mg valsartan or 8 mg candesartan for at least 2 months were enrolled. Replacement of valsartan or candesartan by telmisartan showed a significant reduction in both mean clinic systolic and diastolic BP at 4, 8 and 12 weeks; BP level decreased from 143.7/82.3 mmHg at baseline to 135.4/77.5 mmHg at 12 weeks. Furthermore, in 8 patients of valsartan group, switching to telmisartan significantly reduced central BP by 11.8 mmHg. Our present study suggests that combination therapy with telmisartan plus amlodipine may be more beneficial than valsartan or candesartan plus amlodipine treatment for controlling brachial and central BP, which could lead to more favorable cardiovascular outcomes with this drug combinations.

Effect of telmisartan and amlodipine on home blood pressure by monitoring newly developed telemedicine system: monitoring test by using telemedicine. Telmisartan's effect on home blood pressure (TelTelbosu).

We have developed a new home blood pressure (BP) monitoring system by using cellular telephone and the Internet. All data of home BP and pulse rate were directly collected by I-converter date collecting system and sent online to a main server constructed in a central data center. The home doctor can monitor the exercise data of each patient by using this system. This home BP monitoring system was directly connected to the Internet by using application service provider technology (ASP). Anytime and anywhere, each patient can check the changes of these parameters by themselves by using cellular telephone and/or the Internet. The average of the data was calculated and demonstrated online. In real time, all data were monitored and sent to the home doctor's office. In the present study, we tried to use this monitoring system to compare the effect of some antihypertensive drugs on home BP. To compare the effects of telmisartan (TEL) and amlodipine (AM) on home BP, home BP was monitored for eight weeks using this telemedicine system. The target point of office BP was 140/90 mmHg or less. After two weeks control period, telmisartan (TEL group: 20-80 mg/day, n = 21) or amlodipine (AM group: 2.5-10 mg/day, n = 19) was orally administrated once a day in the morning. There was no significant difference of office BP between these two groups. Systolic home BP was significantly decreased from 144 +/- 4 to 134 +/- 3 mmHg (TEL group) and from 143 +/- 4 to 135 +/- 3 mmHg (AM group), respectively. There was no significant difference in the changes of home BP in the morning between groups (eight weeks home systolic BP reduction, TEL: 15 +/- 2 mmHg, AM: 13 +/- 2 mmHg). However the reduction of home BP in the evening in TEL group was significantly bigger than AM group (eight weeks home systolic BP reduction, TEL: 13 +/- 3 vs. AM: 6 +/- 3 mmHg). From these data, we concluded that there is a big difference on the effects of antihypertensive agents on diurnal variation and 24hr overall BP variability in home BP. TEL has a good effect on home BP for 24 hours compared to AM. This telemedicine system has a great advantage in monitoriong home BP correctly in hypertensive patients.

Crossover study of amlodipine versus nifedipine CR with home blood pressure monitoring via cellular phone: internet-mediated open-label crossover trial of calcium channel blockers for hypertension (i-TECHO trial).

OBJECTIVE: We developed a new data collection system named i-converter that could transmit data to a website via cellular phone. Using the system, we compared the effects of two calcium channel blockers on the home blood pressure. METHODS: Amlodipine and nifedipine CR were administered to 41 patients with essential hypertension for more than 6 weeks each in a randomized open-label crossover study. The dose of each drug was increased until the home blood pressure reached the target level of under 135/85 mmHg. RESULTS: The morning home systolic and diastolic blood pressures were significantly lower during nifedipine CR treatment: 133 +/- 10/81 +/- 8 mmHg with amlodipine versus 131 +/- 8/80 +/- 8 mmHg with nifedipine CR, P < 0.05. The morning pulse rate was significantly higher during nifedipine CR treatment (69 +/- 9 beats/min with amlodipine versus 70 +/- 9 beats/min with nifedipine CR, P < 0.05). The evening home blood pressure and pulse rate, however, showed no significant differences between the two drugs (128 +/- 11/74 +/- 7 mmHg and 74 +/- 10 beats/min with amlodipine versus 128 +/- 10/75 +/- 7 mmHg and 74 +/- 9 beats/min with nifedipine CR, all not significant). CONCLUSIONS: Nifedipine CR had a stronger antihypertensive effect than amlodipine during the critical morning period, but the morning pulse rate was higher. Our new data transmission system was effective for collecting precise data on the blood pressure and pulse rate via the internet.

Blood pressure monitoring by cellular telephone in patients on continuous ambulatory peritoneal dialysis.

We have developed a new telemedicine system that uses a cellular telephone and Internet Web site to monitor changes of blood pressure (BP) in patients on continuous ambulatory peritoneal dialysis (CAPD). An I-converter data collection system directly transmits all data on BP and heart rate (HR) measured by a fully automatic device (HEM-705IT: Omron Life Science, Tokyo, Japan) to a cellular telephone. The cellular telephone then sends the data directly to the main server at the NTT DoCoMo data center. All data, including BP and HR from each patient, are accumulated in the server. Application service provider technology (ASP) connects that system directly to the Internet. Any time and anywhere, each patient can use a cellular telephone or the Internet Web site to monitor, in graph form, changes in their data. The average data at each collection point are calculated and shown on the Web site. All data collected by cellular telephone are also calculated and sent directly, in real time, to the physician's office. Currently, we are using this telemedicine system for 44 hypertensive patients on CAPD at our center. In the present study, we used the telemedicine system to evaluate changes in 24-hour BP. We followed 20 CAPD patients, monitoring changes in BP for 3 months. At the end of study, we found that the average daytime home BP was 137 +/- 8 mmHg over 80 +/- 4 mmHg and that the average nighttime BP was 128 +/- 7 mmHg over 72 +/- 4 mmHg. The overall average home BP was 132 +/- 7 mmHg over 76 +/- 3 mmHg. The average outpatient clinic BP was 155 +/- 9 mmHg over 86 +/- 5 mmHg. The measured systolic and diastolic BP at the out-patient clinic were significantly higher than those measured at home. As measured at the outpatient clinic, BP indicated that 7 CAPD patients (35%) were hypertensive (> 160/95 mmHg). However, as measured at home, BP indicated that only 4 CAPD patients (20%) were truly hypertensive (> 135/85 mmHg). We were therefore able to determine that 43% of our hypertensive patients had "white coat" hypertension. Our new telemedicine system that monitors BP by cellular telephone provides great advantages in monitoring BP at home in patients on CAPD.

[Suppressive effect of angiotensin converting enzyme inhibitor (ACEI) on the progression of renal insufficiency: a propensity score analysis].

To clarify the renal protection conferred by angiotensin II converting enzyme inhibitor(ACEI), we compared an ACEI group and a conventional therapy (control) group with matched propensity scores. The propensity score is used to control imbalances in the conditional probability of a subject receiving a particular exposure given a set of defined confounders. To calculate the propensity score, the confounders are used in a logistic regression to predict the exposure of interest, without including the outcome. We used a database of the characteristics and clinical data for 1,309 renal insufficiency cases who visited our out-patient clinic between 1986 and 2001. The major contributing factors in the patient characteristics were primary disease, blood pressure, renal function(serum creatinine levels; sCr), urinary protein excretion (UP), and gender. The primary end-point was the doubling of the baseline sCr noted at the time of enrollment or endstage renal failure. The major characteristics of the two groups were not statistically different. An incidence of 90% was obtained at 95 months in the control group and at 183 months in the ACEI group. Using a Kaplan-Meier survival analysis, the survival rates of the two groups were found to be significantly different (p < 0.001 by log-rank test), with ACEI having a beneficial effect on the survival rate and renal function. Using a sub-analysis, neither the starting point of ACEI treatment, based on an sCr above or below 2 mg/dl, nor the amount of UP, more or less than 1 g/day, affected the superiority of ACEI in the prevention of renal failure progression. The ACEI treatment was superior to conventional therapy in patients with renal insufficiency, and this superiority was independent of blood pressure, renal function and the amount of UP, based on the analysis of an observational database of renal insufficiency cases with matched propensity scores.