Tolerability and safety of a calcium channel blocker in comparison with a diuretic in the treatment of elderly patients with hypertension: secondary analysis of the NICS-EH.

A randomized prospective controlled study, the National Interventional Cooperative Study in Elderly Hypertensives (NICS-EH), previously demonstrated that the preventive effect of the long-acting calcium channel blocker nicardipine on the cardiovascular endpoint was similar to that of the diuretic, trichlormethiazide. The present report is a sub-analysis in which we compare the tolerability and safety of the calcium channel blocker with that of a diuretic in the long-term treatment of elderly hypertensives. A total of 429 elderly patients with hypertension were assigned to the nicardipine group or the diuretic group by the double-dummy method and were followed up for 5 years. Two hundred four patients in the nicardipine group and 210 patients in the diuretic group were analyzed. The incidences of fatal and nonfatal cardiovascular (CV) events in the two groups were comparable, and there was no significant difference in the cumulative event-free rate. However, the total incidence of adverse reactions, including non-CV events and unfavorable BP changes, was 31 cases (15.2%) in the nicardipine group, which was significantly lower than the 47 cases (22.4%) in the diuretic group (log-rank: p=0.026, G. Wilcoxon: p=0.01). The total number of medical endpoints, including CV events, the withdrawal of the patient from the study, was 52 (25.5%) in the nicardipine group, which was significantly lower than the 65 (31.0%) in the diuretic group (log-rank: p=0.078, G. Wilcoxon: p=0.044). It was concluded that sustained-release nicardipine is better tolerated, as it exhibits a lower incidence of medical-related withdrawals such as adverse drug reactions, non-cardiovascular events and unfavorable BP responses during the treatment.

Measurement of plasma brain natriuretic peptide level as a guide for cardiac overload.

OBJECTIVES: We examined whether measurement of the plasma BNP concentrations might be useful for the early diagnosis of the existence and severity of disease in patients with heart disease in daily clinical practice. METHODS AND RESULTS: The plasma BNP and ANP concentrations in 415 patients with heart disease and hypertension and 65 control subjects were measured. Patients with heart disease had higher plasma BNP and ANP concentrations than did those with hypertension or control subjects. Among the etiology of cardiac diseases, specifically dilated cardiomyopathy and hypertrophic cardiomyopathy, was associated with the highest plasma BNP concentrations, whereas dilated cardiomyopathy was associated with the highest plasma ANP concentrations. Plasma BNP concentrations showed an increase as the severity of the heart disease, as graded according to the NYHA classification of cardiac function, increased. In both patients with heart disease and hypertension, the plasma BNP values were higher in those who had abnormalities in their echocardiogram and electrocardiogram as compared to those without any abnormalities. The plasma BNP levels also showed a significant correlation with left ventricular wall thickness and left ventricular mass. On the other hand, the plasma ANP levels showed significant correlations with left ventricular dimension. Receiver operative characteristic analysis revealed that plasma BNP levels showed substantially high sensitivity and specificity to detect the existence of heart diseases. CONCLUSION: Measurements of the plasma BNP concentrations is useful to detect the existence of the diseases, and abnormalities of left ventricular function and hypertrophy in patients with heart disease in daily clinical practice.

Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor.

[structure: see text] Total synthesis of nafuredin, a selective NADH-fumarate reductase inhibitor, has been accomplished by a convergent approach. The C1-C8 and C9-C18 segments were derived efficiently from D-glucose and (S)-(-)-2-methyl-1-butanol, respectively, coupled by stereoselective Julia olefination, and converted to nafuredin.

[Antihypertensive therapy in patients with stroke].

Most patients with acute ischemic stroke do not need antihypertensive therapy, because the rapid lowering of blood pressure (BP) may reduce cerebral blood flow due to impaired cerebral autoregulation. In patients with severe hypertension, or associated with other complications (hemorrhagic transformation, myocardial infarction, renal failure or dissection of the aorta), antihypertensive therapy should be done cautiously. In chronic phase, the optimal BP level for the prevention of stroke recurrence remains unclear. The presence of the J-curve phenomenon is still controversial. The several large scale trials are now in progress to determine the optimal BP level for the secondary prevention in stroke patients.

The effects of short-term blood pressure variability and nighttime blood pressure levels on cognitive function.

We investigated the relationship between 24-h blood pressure (BP) and cognitive function. We performed the Hasegawa Dementia Scale Revised (HDSR), the Mini-Mental State Examination (MMSE), and the Raven's Coloured Progressive Matrices Test (RCPM) in 88 subjects (71+/-9 years) with no history of stroke. Ambulatory BP was non-invasively measured using a TM2421 for 24 h in all patients. Whereas 90% of the scores converged into a narrow range between 25 and 30 points in the HDSR and the MMSE tests, the RCPM score was widely distributed, ranging from 9 to 36 points. The subjects were therefore divided into three groups of > or =25, 26-30, and 31-36 according to their RCPM scores. Subjects with lower scores were significantly associated with increased short-term BP variability during the daytime (p<0.05) and had a tendency toward higher nighttime SBP (p=0.05) compared with those with higher scores. Increased short-term variability of daytime BP and high nighttime systolic BP were associated with cognitive impairment as assessed by the RCPM. The RCPM, which can assess the capacity for judgment through visual information processing, may detect earlier stages of cognitive impairment related to high BP. To prevent a deterioration of cognitive function, strict control of nighttime BP and suppression of short-term BP variability are thus necessary.

Control of blood pressure and lifestyle-related risk factors in elderly Japanese hypertensive subjects.

The aim of this study was to analyze the treatment of elderly hypertensive patients by Japanese physicians specializing in hypertension. We enrolled 939 patients with hypertension who were treated in the outpatient clinics of 11 hospitals in 1995; 793 of these patients (388 men and 405 women; mean age, 66.6+/-9.0 years) received follow-up examinations in 1996, and the data on these patients was used for the present analysis. Blood pressure (BP), body mass index, lifestyle, and laboratory data were analyzed in all patients. The average BP was 143+/-16/81+/-10 mmHg in 1995 and 142+/-15/80+/-10 mmHg in 1996. The patients whose baseline BP was at the level of Grade 2 or 3 in the WHO-ISH classification (n=117) were characterized by a higher women-to-men ratio, higher age, a higher serum total cholesterol concentration, and higher QRS voltage. In these patients, from 1995 to 1996, the average BP significantly decreased, whereas fasting plasma glucose, serum total cholesterol and serum creatinine concentrations showed only negligible changes. In 220 patients (28%), BP was <140/<90 mmHg at both the initial and the follow-up examinations, whereas 351 patients (44%) were hypertensive in both 1995 and 1996. Thirty-three percent of the patients were smokers. More smokers than nonsmokers had had prior cardiovascular events, diabetes mellitus, or overt proteinuria. In conclusion, the average BP level among the patients treated by Japanese physicians specializing in hypertension was somewhat higher than that recommended by WHO-ISH Guidelines (1999). Patient education to control lifestyle-related risk factors, particularly to stop smoking, should be emphasized.

Prognostic value of nighttime blood pressure in the elderly: a prospective study of 24-hour blood pressure.

Although it has been suggested in several reports that 24-h ambulatory blood pressure (BP) is a better predictor than casual BP measured in a clinician's office of the incidence of cardiovascular (CV) events, little information is available concerning the prognostic value of nighttime BP in the elderly population. Therefore, to evaluate the clinical implications of the nighttime BP in the elderly, we prospectively followed-up 324 elderly individuals (mean age, 77.2 +/- 7.0 years) who had undergone ambulatory BP monitoring at an annual health examination over a mean follow-up period of 51.5 +/- 22.0 months, and the relationship between BP and CV events was analyzed using Cox's proportional hazard model. For the analysis, 310 participants, excluding 14 subjects who were withdrawn due to non-CV events, were classed into two groups, one consisting of 134 individuals who were undergoing treatment with an anti-hypertensive drug (medicated group) and another consisting of 176 who were not medicated (nonmedicated group). New cardiovascular events developed in 43 cases in the medicated group and in 14 cases in the non-medicated group during the follow-up period. In the medicated group, a linear relationship was observed between BP and the event rates. The hazard ratio for CV events adjusted for age, sex, and other cardiovascular risks was 1.28 (95% confidence interval [CI], 1.05 to 1.54, p< 0.05) for a 10 mmHg increase of 24-h systolic BP. Corresponding values in 24-h diastolic BP, nighttime systolic BP, and nighttime diastolic BP were 1.71 (1.19 to 2.46, p< 0.01), 1.34 (1.13 to 1.58, p< 0.01), and 1.67 (1.20 to 2.31, p< 0.01), respectively. In the non-medicated group, the event rate was least in the subgroup in the second-lowest quartile for nighttime systolic BP, with a slight non-significant increase in the subgroup of the lowest quartile. It was shown that insufficient control of nighttime BP in the elderly with hypertension is associated with the development of CV complications.

Factors related to impairment of activities of daily living.

OBJECTIVE: We examined the factors related to the impairment of activities of daily living (ADL). METHODS: ADL was evaluated by using ADL-20, which consists of 20 items from 4 major categories of activities; mobility, self-care, instrumental, and communication. The patients' gender, birth date, clinical diagnosis, past history, life styles, physical findings, laboratory data, and details of therapy were also recorded. Patients A total of 1,163 outpatients aged 50 years or older were included. Data from 1,093 patients were analyzed. RESULTS: We divided the subjects into two groups; Group I having full marks of ADL-20 (n=582) and group II exhibiting an impairment of ADL (n=511). Multiple logistic analysis revealed that in both sexes age and stroke were common independent factors related to the impairment of ADL. Other factors associated with impairment of ADL were smoking in men and presence of proteinuria in women. The presence of hyperlipidemia was associated with preservation of the ADL in women. CONCLUSION: The results demonstrated significant associations of smoking in men and the presence of proteinuria in women with the impairment of ADL in elderly Japanese outpatients. There appears to be a sex difference in the risk factors of impairment of ADL.

[An autopsy case of elderly idiopathic enlargement of the right atrium].

We report an autopsy case of an 88-year-old man with idiopathic enlargement of the right atrium which is considered to be the oldest case reported. The patient was given a diagnosis of atrial fibrillation at the age of 75 years, when he developed congestive heart failure. Bradycardia associated with partial atrial standstill was detected and, the patient underwent implantation of a pacemaker at age 77. An echocardiogram revealed marked enlargement of the right atrium and moderate enlargement of the left atrium. Thus, idiopathic enlargement of the right atrium was diagnosed. He had recurrent congestive heart failure before admission to our hospital because of malnutrition and anemia. Although he was treated with high calorie intravenous infusion and blood transfusion, he died of pneumonia and heart failure. Postmortem examination revealed that the heart weighed 430 g, and there was marked dilatation of the right atrium which had an extremely thin wall. The annular circumference of the tricuspid valve was markedly dilated, 170 mm, resulting in tricuspid regurgitation. The left atrium was moderately dilated and the right and left ventricles were slightly dilated. Histologically, the free wall of the right atrium was totally replaced by fibrous tissue and atrioventricular valves did not reveal any rheumatic changes. These pathological findings were compatible with idiopathic enlargement of the right atrium. There has been no previous case report of idiopathic enlargement of the right atrium in a patient aged 80 years of age or over.

[Usefulness and safety of intravenous thrombolytic therapy for elderly patients with acute myocardial infarction: relationship with cardiac rupture].

The usefulness and safety of intravenous thrombolytic therapy were investigated in 298 patients older than 65 years (145 males, 153 females, mean age 78 years) with acute myocardial infarction from 1984 to 1993. These patients were divided into 2 groups of 88 patients younger than 74 years (Group A) and 210 patients older than 75 years (Group B). Seventy patients received thrombolytic therapy with urokinase (UK) or tissue-plasminogen activator [t-PA (UK96 X 10(4)U: 57 patients, t-PA 30-40 X 10(4)U/kg: 12, UK + t-PA: 1)] within 6 hours after the onset of acute myocardial infarction (Group TL). Two hundred twenty-eight patients received conventional therapy (Group C). There were no differences in the frequencies of the site of myocardial infarction, Killip class, admission within 6 hours after the onset of acute myocardial infarction or thrombolytic therapy between the 2 age groups. In-hospital mortality was significantly higher in Group B than in Group A (43% vs 24%, p < 0.01). In Groups A and B, in-hospital mortality was 20% lower in Group TL compared with Group C (20% vs 25% in Group A, 36% vs 45% in Group B). In Group B, the mortality from pump failure including shock and congestive heart failure was half in Group TL compared with Group C (13% vs 30%). Cardiac rupture was found in 11 patients of Group TL and 7 patients of Group C. Therefore, the mortality from cardiac rupture was fivefold higher in Group TL compared with Group C (8% vs. 1.6% in Group A, 20% vs 3.6% in Group B). Of 11 patients with cardiac rupture in Group TL, 8 patients suffered rupture in the early phase within 12 hours after the onset of acute myocardial infarction and the tear was present near the center of infarcted area in all 7 autopsy cases. The case of recanalization of the infarct-related coronary artery in Group TL revealed moderate to massive hemorrhagic infarction at autopsy. This indicates that the mechanisms involved in cardiac rupture are different in thrombolytic therapy and conventional therapy. Intravenous thrombolytic therapy is effective for the reduction of mortality from pump failure in elderly patients with acute myocardial infarction older than 75 years. However, it must be evaluated as one of the risk factors of cardiac rupture in elderly patients.

The accuracy and clinical performance of a new compact ambulatory blood pressure monitoring device, the ES-H531.

The validity and clinical performance of the ES-H531, a newly developed ambulatory blood pressure (BP) monitoring device, were evaluated. The validity was assessed by simultaneous comparisons (total of 223 measurements) with the measurements made by two experienced observers using standard mercury column sphygmomanometers in 121 subjects. The clinical performance was evaluated through the number of measurement failures by observation of the cuff equipped site, and tolerability was assessed by administering a questionnaire to 30 of the subjects following completion of 24-h BP monitoring. The differences in systolic and in diastolic BP measured by the standard auscultation method and that measured with the ES-H531 by the Korotkoff method (K method) was 0.9+/-3.7 mm Hg (mean+/-standard deviation) and 0.1+/-3.2 mm Hg, respectively. These values satisfy the accuracy criteria of the American Association of Medical Instruments (AAMI) and accord with the grade of A in the accuracy criteria of the British Hypertension Society (BHS). The mean difference in systolic and in diastolic BP as assessed by the standard auscultation method and with the ES-H531 by the oscillometric method (O method) was 1.1+/-4.6 mm Hg and 2.7+/-5.4 mm Hg, respectively. This accords with grade B in the BHS accuracy criteria. Failures or errors in measurement occurred in 4.4% of the readings. A few subjects experienced discomfort because of noise or pain during measurements. The ES-H 531, a new compact and light weight ambulatory BP monitoring device, offers acceptable validity and sufficient comfort for clinical use.

Synthesis of C-ring aromatic taxoids and evaluation of their multi-drug resistance reversing activity.

The C-aromatic taxoids were synthesized to develop effective inhibitors against drug efflux mediated by p-glycoproteins. Among those tested using multi-drug resistant tumor cells (2780AD), the benzoate 11 exhibited significant activity as potent as verapamil, a well-established MDR reversing agent.

Synthesis and evaluation of artificial taxoids with antitumor and multi-drug resistance reversing activities.

Artificial taxoids were synthesized and subjected to evaluation of their ability of multi-drug resistance reversing and antitumor activities. While the taxoid 4 could not increase cellular accumulation of vincristine in multi-drug resistant tumor cells, the C4-hydroxy analog 15 showed significant effect. However, these compounds showed weak activities on growth inhibition of cancer cells.

What are the normal levels for ambulatory blood pressure measurement?

With acceptance of ambulatory blood pressure measurement as a useful technique in the management of hypertension, the question of what constitutes the upper limit of normality for 24 h blood pressures has been the subject of a number of reviews [1,2]. In fact, there has been remarkable similarity in a number of large population studies [3-10]. For example, taking the 95th percentile as the upper limit of the distribution of daytime blood pressure in various studies in different countries (Internation Database 141/88 mmHg [3,4], Ireland 138/89 mmHg [5], Belgium 137/88 mmHg [6], Japan 138/83 mmHg [7], Denmark 139/88 mmHg [8] and Italy 134/88 mmHg [9,10] gave variations of less than 7/6 mmHg for systolic and diastolic blood pressures, respectively, the average for all studies being 138/87 mmHg (for review, [6]). A review of the literature carried out independently by the American Society of Hypertension [11] and our group [1,2,6] produced an identical recommendation for the levels of daytime blood pressure that may be regarded as normal and abnormal, namely, that blood pressures above 140/90 mmHg are probably abnormal and that blood pressures below 135/85 mmHg are probably normal. Moreover, the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure in its recent communication takes blood pressures of awake subjects below 135/85 mmHg to be normal [12].

[Antihypertensive therapy of patients with cerebrovascular disease].

In the acute phase of the stroke, it must be prudent to reduce blood pressure (BP) because the rapid reduction might cause the exacerbation of the perfusion pressure to the brain. The target BP level should be higher than the level of primary prevention as the blood pressure regulatory function is disturbed in acute phase. In chronic phase, BP should be reduced so slowly through the several months so as not to cause the ischemia of the brain by rapid reduction of BP. However, the optimal target BP level should be the same degree as the primary prevention level as far as the speed of reduction is taken into consideration. The several large scale trials, are now in progress to determine the optimal BP level for the secondary prevention in the patients with prion stroke.

Relation between left ventricular remodeling and nocturnal blood pressure in the elderly with systemic hypertension.

Elderly hypertensive patients with concentric left ventricular (LV) hypertrophy had larger LV mass, more impaired diastolic LV function, higher nocturnal blood pressure (BP), and smaller nocturnal BP reduction than those of patients with other geometric patterns. Patients with concentric LV hypertrophy might have more severe hypertensive cardiac involvement and greater risk for cardiovascular events than those patients with other geometric patterns.

Current status of antihypertensive therapy for elderly patients in Japan.

To assess how elderly Japanese hypertensive patients are treated by specialists, we conducted a cross-sectional survey. A total of 1,163 outpatients aged 50 years or older were studied. Hypertension was diagnosed in 939 of these patients, and 827 were receiving drug therapy. The average blood pressure during therapy was 143 +/- 16/81 +/- 10 mmHg. In patients aged 70 years or older, systolic blood pressure during antihypertensive therapy was significantly higher (p < 0.01) and diastolic blood pressure was significantly lower (p < 0.01) than the corresponding values in those aged 50 to 59 years or 60 to 69 years. The calculated mean blood pressures were similar in the different age groups. The rate of monotherapy in the patients aged 70 years or older was 58.8%, which was significantly higher (p < 0.01) than the rates of monotherapy in the other age groups. Calcium channel blockers were prescribed in about 80% of patients, irrespective of age or comorbidity. Of the patients receiving calcium channel blockers, 43.5% were treated with monotherapy. This rate significantly (p < 0.01) increased with advancing age. Diastolic blood pressures were significantly lower (p < 0.05) in patients with stroke and in those with ischemic heart disease, diabetes mellitus, or dyslipidemia, as compared with patients with no comorbidity. Among patients aged 70 years or older, the difference in systolic blood pressure between those with ischemic heart disease and those with no comorbidity was not significant. Blood pressure in elderly hypertensive patients was reduced to a level similar to that in younger patients. The target blood pressure was influenced by the presence of comorbidity. Furthermore, specialists showed a high preference for the use of calcium channel blockers in the management of hypertension.