Improvement of accessory symptoms of hypertension by TSUMURA Orengedokuto Extract, a four herbal drugs containing Kampo-Medicine Granules for ethical use: a double-blind, placebo-controlled study.

A double-blind, placebo-controlled study was conducted to evaluate the efficacy, safety, and utility of TSUMURA Orengedokuto Extract Granules for Ethical Use (TJ-15) as a treatment for the accessory symptoms of hypertension. Two capsules of the study drug were administered orally 3 times daily (i.e., before meals) for 8 weeks. Among 265 patients enrolled in the study, 134 were assigned to the TJ-15 group and 131 were assigned to the placebo group, of whom 204 patients (103 in the TJ-15 group and 101 in the placebo group) were included in the efficacy and utility analyze and 251 patients (128 in the TJ-15 group and 123 in the placebo group) were included in the safety analysis. Efficacy was significantly higher in the TJ-15 group based on the total score for the accessory symptoms of hypertensions which was the primary efficacy endpoint (Wilcoxon's rank sum test, p=0.013). When each accessory symptom of hypertension was assessed separately, efficacy was higher for hot flushes and facial suffusion in the TJ-15 group (Wilcoxon's rank sum test, p=0.034, and 0.022, respectively). There were no significant differences between the TJ-15 and the placebo groups with respect to the decrease of blood pressure or the antihypertensive effect. There was also no significant difference between the two groups with regard to the overall safety rating. The utility rating was significantly higher in the TJ-15 group than in the placebo group (Wilcoxon's rank sum test, p=0.016). In conclusion, TJ-15 was superior to placebo with respect to efficacy, safety, and utility for the treatment of accessory symptoms of hypertension.

Magnesium decreases arterial pressure and inhibits cardiovascular responses induced by N-methyl-D-aspartate and metabotropic glutamate receptors stimulation in rostral ventrolateral medulla.

OBJECTIVE: Magnesium sulfate (MgSO4) is widely used for the treatment of eclampsia. However, effects of Mg2+ in central cardiovascular regulation remain unclear. In the present study, the role of Mg2+ on cardiovascular regulation in the rostral ventrolateral medulla (RVLM) of rats was examined. METHODS: Adult male Wistar rats were anesthetized with urethane, and artificially ventilated. The ventral surface of the medulla was exposed, and the RVLM was identified by microinjection (50 nl) of l-glutamate (l-Glu; 2 nmol). Then, MgSO4 (1, 3, 10 nmol, n = 7 for each dose) and magnesium chloride (MgCl2; 10 nmol, n = 7) were microinjected into the RVLM. l-Glu (2 nmol), N-methyl-D-aspartate (NMDA; 20 pmol), alpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid (AMPA; 5 pmol) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD, metabotropic glutamate receptor agonist; 1 nmol] were also microinjected with or without pretreatment of MgSO4 (10 nmol; n = 7 for each drug). RESULTS: MgSO4 dose-dependently decreased mean arterial pressure (MAP) and heart rate (HR). The high dose of MgSO4 (10 nmol) significantly decreased MAP and HR (-25 +/- 4 mmHg and -43 +/- 6 bpm). Similarly, MgCl2 decreased MAP and HR (-27 +/- 4 mmHg and -30 +/- 6 bpm). The pressor response evoked by NMDA or (1S,3R)-ACPD was significantly attenuated by the pretreatment with MgSO4. In contrast, pressor response caused by l-Glu or AMPA was not affected by pretreatment with MgSO4. CONCLUSIONS: These results suggest that Mg2+ has an inhibitory role on the RVLM neurons, and inhibits cardiovascular responses induced by NMDA and metabotropic glutamate receptor agonists.

Crohn's disease of aphthous type: serial changes in intestinal lesions.

In Crohn's disease (CD), aphthous lesions are regarded as possible precursors of typical intestinal involvement. To determine the natural course of intestinal lesions in CD of aphthous type, the clinical course of 10 patients was retrospectively investigated during a period ranging from 6 to 16 years after diagnosis. The criterion for inclusion was confirmed aphthous lesions within the gastrointestinal tract with histologically verified epithelioid granuloma. The degrees of aphthous lesions in the small intestine and the colon were graded by small bowel radiography, barium enema examination and colonoscopy. Five patients developed typical CD during a period ranging from 0.8-3.3 years. The site of involvement was the ileum in three patients, the colon in one patient and both the ileum and the colon in one patient. Typical small intestinal CD occurred in four of seven patients with marked aphthous lesions of the small intestine, whereas colonic CD occurred in two of eight patients with such aphthous lesions of the colon. These findings suggest that CD of aphthous type is not necessarily a precursor of clinically overt disease. This may especially be the case for colonic aphthous lesions.

[Serum immunoglobulin concentrations and autoantibodies in patients with Yusho].

To evaluate chronic immune effects of polychlorinated biphenyl (PCB), serum immunoglobulin concentrations and autoantibodies were studied in 79 patients with Yusho in 1997. Serum levels of immunoglobulin A (IgA), immunoglobulin G (IgG) and immunoglobulin M (IgM) were elevated in 10 cases (12.7%), 19 cases (24.1%) and 7 cases (8.9%), respectively. Autoatibodies were present in some patients of Yusho; 10 cases (12.7%) for rheumatoid factor and 36 cases (45.6%) for antinuclear antibody. LE factor was not detected. There were no significant correlations between blood PCB concentrations and serum immunoglobulin concentrations, or presence of autoantibodies. We conclude that antinuclear antibody in patients with Yusho is frequent, although it may not be associated with blood PCB concentration.

Long-term treatment of portosystemic encephalopathy with oral branched-chain amino acids--a case report.

We treated a 68-year-old male patient of hepatic encephalopathy with oral branched chain amino acids-enriched formula (Aminoleban EN) in addition to lactulose. His encephalopathy was successfully controlled with this therapy for more than a year despite the high blood ammonia levels. Repeated amino acids analyses demonstrated that the deranged branched chain to aromatic amino acids ratio was attenuated with long-term Aminoleban EN administration both in plasma and in cerebrospinal fluid. Oral branched-chain amino acid supplement was very useful in improving the chronic portosystemic or hepatic encephalopathy in this patient.

Comparative efficacies of a calcium antagonist and an alpha1 blocker in elderly hypertensive patients with stroke.

We compared the effects of nilvadipine, a calcium antagonist, and terazosin. an alpha1 blocker, on the hemodynamics and quality of life (QOL) in 12 elderly hypertensive patients with stroke. Following a washout period of 2 weeks. nilvadipine or terazosin was administered for 2 weeks in a randomized crossover manner. At the end of control and treatment periods, we measured the 24-hour-ambulatory blood pressure (BP) and postural change of BP, and interviewed QOL. Terazosin treatment did not show consistent decrease of casual BP, but was associated with a transient decrease of systolic BP and an increase of pulse rate after standing, and enhanced postprandial decrease in BP. Nilvadipine decreased casual BP in a dose-dependent manner, but showed neither postural nor postprandial change of BP. There was no difference in QOL scores with either treatment. Results suggest that nilvadipine is preferable to terazosin for the treatment of elderly hypertensive patients with stroke.

Central and peripheral mechanisms involved in hypertension induced by chronic inhibition of nitric oxide synthase in rats.

OBJECTIVE: To study the possible central and peripheral mechanisms involved in hypertension induced by chronic inhibition of nitric oxide synthase. METHODS: We evaluated neurohormonal and renal responses of Wistar rats to chronic oral administration of 20 and 100 mg/kg per day NG-nitro-L-arginine methyl ester (L-NAME). Effects of intracerebroventricular and intravenous injections of NO donors (NOC-18 and FK-409) and an angiotensin II type 1 receptor antagonist CV-11974, and intravenous injection of alpha-adrenergic receptor antagonist phentolamine after chronic treatment with 100 mg/kg per day L-NAME were also studied. RESULTS: The chronic treatment with L-NAME induced a sustained dose-dependent hypertension with a decrease in heart rate. Urinary levels of norepinephrine and epinephrine decreased with no changes in plasma catecholamine levels, renin activity, and vasopressin level. Serum nitrate/nitrite levels in the rats treated with the high dose of L-NAME decreased. The intracerebroventricular and intravenous injections of the NO donors reduced arterial pressure in L-NAME-treated rats to a significantly greater extent than they did that in control rats. The intravenous but not intracerebroventricular injection of CV-11974 produced a sustained decrease in arterial pressure of L-NAME-treated rats. The depressor responses to intravenous injection of phentolamine of L-NAME-treated and control rats were similar. CONCLUSIONS: Results indicate that L-NAME-induced hypertension is associated with a deficiency of nitric oxide, both peripherally and centrally. Circulating angiotensin II could contribute to the maintenance of hypertension via angiotensin II type 1 receptor while the sympathetic nervous system seems to be suppressed.

Effects of high atmospheric pressure and oxygen on middle cerebral blood flow velocity in humans measured by transcranial Doppler.

BACKGROUND AND PURPOSE: There are several reports that have studied the effects of hyperbaric oxygen (HBO) on cerebral blood flow (CBF). However, most of the reports have been of animal experiments, and human studies are few so far. The aim of this study is to clarify the relationship between HBO and CBF in humans. METHODS: Middle cerebral arterial blood flow velocity (MCV) was measured using transcranial Doppler (TCD) technique in a multiplace hyperbaric chamber. The Doppler probe was fixed on the temporal region by a head belt, and the transcutaneous gas measurement apparatus (tcPO2 and tcPCO2) was fixed on the chest wall. MCV and transcutaneous gas were measured continuously in eight healthy volunteers under four various conditions: 1 atmosphere absolute (ATA) air, 1 ATA oxygen (O2), 2 ATA air, and 2 ATA O2. On the next step, the effect of environmental pressure was studied in another eight healthy volunteers, in whom the tcPO2 was kept at almost the same level under conditions of both 1 ATA and 4 ATA by inhaling oxygen at 1 ATA. RESULTS: MCV of 1 ATA O2, 2 ATA air, and 2 ATA O2 decreased, and tcPO2 increased significantly in comparison with that of 1 ATA air. A significant difference in MCV was observed between the O2 group and the air group under the same pressure circumstance. On the other hand, there were no differences in MCV or tcPO2 between 4 ATA air and 1 ATA plus O2, and the influence for the MCV of the environmental pressure was not observed. CONCLUSIONS: We conclude that hyperoxemia caused by HBO reduces the CBF, but the high atmospheric pressure per se does not influence the CBF in humans.

Serum n3 polyunsaturated fatty acids are depleted in Crohn's disease.

To determine fatty acid patterns in Crohn's disease, we measured various serum fatty acids by gas chromatography in 20 patients with the disease and compared them with those in 18 healthy controls. All the patients had been free from any nutritional supplementation during preceding six months or had no history of intestinal resection. Eight of the patients were affected in the small bowel only, three in the large bowel only, and the remaining nine in both the small and large bowel. Both serum concentrations and percentages of C20:4n6, C20:5n3, C22:0, C22:6n3, total n3 polyunsaturated fatty acids, and total polyunsaturated fatty acids were lower in the patients than in the controls. Both essential fatty acids (C18:2n6, C18:3n3) and C20:3n9 levels were not different between the two groups. Among nine fatty acids that correlated with the Crohn's disease activity index, C20:5n3 and total n3 polyunsaturated fatty acids showed the most significant negative correlations. These findings suggest that essential fatty acid deficiency rarely occurs in Crohn's disease and also that n3 polyunsaturated fatty acids may be relevant to the activity of the disease.

[Thyroid function in patients with Yusho: 28 year follow-up study].

To evaluate chronic effect of polychlorinated biphenyl (PCB) on thyroid functions, thyroid hormone levels and thyroidal autoantibodies were studied in 81 patients with Yusho in 1996. Serum level of thyroid stimulating hormone (TSH) was elevated in 7 cases (8.6%). All of them showed normal triiodothyronine (T3), thyroxine (T4) and free T4 levels, and regarded as latent hypothyroidism. There were no significant correlations between blood PCB concentrations and TSH levels, T2 levels, T4 levels or free T4 levels. Thyroglobulin antibodies were detected in 8 cases (19.5%) of 41 Yusho patients with high PBC concentration (higher than 3.0 ppb), and in only one case (2.5%) of 40 patients with low PBC concentration (lower than 2.9 ppb). We conclude that thyroglobulin antibody in patients with Yusho is not frequent and it may be associated with blood PCB concentration.

AMPA receptor antagonist, YM90K, reduces infarct volume in thrombotic distal middle cerebral artery occlusion in spontaneously hypertensive rats.

We examined the effects of a potent and selective antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) subtype of glutamate receptor, YM90K, on brain infarction using a newly developed stroke model of thrombotic distal middle cerebral artery occlusion. Male spontaneously hypertensive rats (5-7 months old) were subjected to photochemically-induced distal middle cerebral artery occlusion as previously described [Stroke 26 (1996) 333-336]. Intravenous infusion of YM90K (n = 8) (5 mg/kg per h for 1 h) or the same amount of vehicle (n = 8) (alkaline saline) was started 5 min after distal middle cerebral artery occlusion. Penumbral cerebral blood flow was determined with laser-Doppler flowmetry. Three days after the ischemic insult, brains were stained with 2,3,5-triphenyltetrazolium chloride and infarct volumes were determined. One hour infusion of YM90K significantly reduced infarct volume by 34% (93 +/- 23 mm3 in control group vs. 61 +/- 25 mm3 in YM90K-treated group, P = 0.017). There were no significant differences in the degrees of cerebral blood flow reduction after distal middle cerebral artery occlusion between the YM90K treated and control groups. YM90K reduces infarct volume in experimental ischemia produced by photothrombotic distal middle cerebral artery occlusion in rats. The present results demonstrated beneficial effects of AMPA receptor blockade on acute ischemic stroke.

[Guidelines on treatment of hypertension in the elderly, 1995--a tentative plan for comprehensive research projects on aging and health-- Members of the Research Group for "Guidelines on Treatment of Hypertension in the Elderly", Comprehensive Research Projects on Aging and Health, the Ministry of Health and Welfare of Japan].

We propose the following guidelines for treatment of hypertension in the elderly. 1. Indications for Treatment. 1) Age: Lifestyle modification is recommended for patients aged 85 years and older. Antihypertensive therapy should be limited to patients in whom the merit of the treatment is obvious. 2) Blood pressure: Systolic BP > 160 mmHg, diastolic BP > 90 approximately 10 mmHg. Systolic BP < age + 100 mmHg for those aged 70 years and older. Patients with mild hypertension (140-160/ 90-95 mmHg) associated with cardiovascular disease should be considered for antihypertensive drug therapy. 2. Goal of Therapy for BP: The goal BP in elderly patients is higher than that in younger patients (BP reduction of 10-20 mmHg for systolic BP and 5-10 mmHg for diastolic BP). In general, 140-160/< 90 mmHg is recommended as the goal. However, lowering the BP below 150/85 should be done with caution. 3. Rate of Lowering BP: Start with half the usual dose, observe at the same dose for at least four weeks, and reach the target BP over two months. Increasing the dose of antihypertensive drugs should be done very slowly. 4. Lifestyle Modification: 1) Dietary modification: (1) Reduction of sodium intake is highly effective in elderly patients due to their high salt-sensitivity. NaCl intake of less than 10 g/day is recommended. Serum Na+ should be occasionally measured. (2) Potassium supplementation is recommended, but with caution in patients with renal insufficiency. (3) Sufficient intake of calcium and magnesium is recommended. (4) Reduce saturated fatty acids. Intake of fish is recommended. (2) Regular physical activity: Recommended exercise for patients aged 60 years and older: peak heart rate 110/minute, for 30-40 minutes a day, 3-5 days a week. (3) Weight reduction. (4) Moderation of alcohol intake, smoking cessation. 5. Pharmacologic Treatment: 1) Initial drug therapy. First choice: Long-acting (once or twice a day) Ca antagonists or ACE inhibitors. Second choice: Thiazide diuretics (combined with potassium-sparing diuretic). 2) Combination therapy. (1) For patients without complications, either of the following is recommended. i) Ca antagoinst + ACE inhibitor, ii) ACE inhibitor + Ca antagonist (or low-dose diuretics), iii) diuretic + Ca antagonist (or ACE inhibitor), iv) beta-blockers, alpha 1-blockers, alpha + beta blockers can be used according to the patho-physiological state of the patient. (2) For patients with complications. Drug(s) should be selected according to each complication. 3) Relatively contraindicated drugs. beta-Blockers and alpha 1-blockers are relatively contraindicated in elderly patients with hypertension in Japan. Centrally acting agents such as reserpine, methyldopa and clonidine are also relatively contraindicated beta-Blockers are contraindicated in patients with congestive heart failure, arteriosclerosis obliterans, chronic obstructive pulmonary disease, diabetes mellitus (or glucose intolerance), or bradycardia. These conditions are often present in elderly subjects. Elderly subjects are susceptible to alpha 1-blocker-induced orthostatic hypotension, since their baroreceptor reflex is diminished. Orthostatic hypotension may cause falls and bone fractures in the elderly.

Dysplasia in ulcerative colitis: is radiography adequate for diagnosis?

PURPOSE: To determine to usefulness of barium enema examination in detecting dysplasia in patients with ulcerative colitis. MATERIALS AND METHODS: Radiographic findings of 22 areas of dysplasia in 10 patients (seven men, three women; aged 34-81 years at diagnosis) were reviewed. Serial changes in radiographic features of four areas of dysplasia in three patients were retrospectively investigated. RESULTS: Fourteen of 22 areas of dysplasia were shown on radiographs. Dysplasia in the rectum or sigmoid colon was depicted less frequently than that in other segments of the colon. Radiographic features were classified as obvious nodular protrusions (seven lesions), irregular mucosa (five lesions), or nodular protrusions with irregular mucosa (two lesions). Six of the seven areas of dysplasia shown as irregular mucosa were accompanied by minute spiculations in the margin of the colonic lumen. There was no correlation between radiologic features and histologic grade of dysplasia. CONCLUSION: Barium enema examination may be used as a complementary method of cancer surveillance with endoscopy. These methods show about two-thirds of lesions associated with dysplasia.

[Laboratory findings in patients with Yusho: 26 year follow-up study].

To evaluate chronic effect of PCBs on laboratory findings, peripheral blood cells and biochemical parameters were studied in 74 patients with Yusho in 1994. Serum level of triglyceride was elevated in 21 cases (28.4%) of these patients. Serum triglyceride levels showed statistically significant correlation with body mass index (Quetelet Index) and blood PCB concentration. We conclude that hypertriglyceridemia in patients with Yusho is not frequent and it may be associated with both obesity and blood PCB concentration.

Posttraumatic intestinal stenosis: clinical and radiographic features in four patients.

PURPOSE: To characterize posttraumatic intestinal stenosis clinically and radiographically. MATERIALS AND METHODS: The clinical records and radiographic and pathologic findings were reviewed in four patients with posttraumatic stenosis. RESULTS: The patients experienced abdominal symptoms from 1 to 18 weeks after the trauma. While the small intestine was affected in two patients with ileus, the colon was involved in the other two patients with rectal bleeding or diarrhea. Barium studies showed an irregular contour within the severely narrowed intestine in three patients, even 25 weeks after the trauma. In these three patients, pathologic examinations of the resected specimens revealed a circumferential, open ulcer, whereas a scarred ulcer was present in the other patient. CONCLUSION: Posttraumatic intestinal stenosis is clinically characterized by a delayed onset of symptoms that differ according to the site of involvement. This condition should be included in the differential diagnosis of intestinal stenosis.

Clinical features in young adult patients with ischaemic colitis.

The clinical, radiographic and endoscopic findings in 16 patients with ischaemic colitis, all of whom were < 45 years of age, were analysed. The clinical features were characterized by an acute onset of abdominal pain and rectal bleeding, and persistent constipation prior to the onset of symptoms. Twelve of the 16 patients did not have any known predisposing factors. Barium enema examination and colonoscopy revealed longitudinal ulcers and oedema of the left side of the colon of these patients. These features were then compared with those found in patients with ischaemic colitis, who were > 70 years of age. Although the clinical symptoms, the site of involvement and the initial radiographic or endoscopic findings were similar between the two groups, the transient form of ischaemic colitis and constipation prior to the onset of symptoms were more frequently present in the young patients than in the old patients. These findings suggest that ischaemic colitis, which is not a rare condition even in young adults, is less severe in young patients than in old patients, and that constipation may be related to the pathogenesis of this disease in young adults.

Progressive encephalopathy in a Crohn's disease patient on long-term total parenteral nutrition: possible relationship to selenium deficiency.

The case of a patient with Crohn's disease complicated by progressive and irreversible encephalopathy, who had been on long-term total parenteral nutrition due to short bowel syndrome, is described. He initially experienced a disturbance of his vision, which was followed by various neurological symptoms during the next 3 years. These symptoms rapidly progressed until he finally developed consciousness disturbance. He also manifested erythrocytic macrocytosis, a low serum level of tri-iodothyronine and a high level of thyroxine. His blood levels of various trace minerals and vitamins were normal, except for selenium, which showed extremely low values. In addition, impaired plasma glutathione peroxidase activity was confirmed. After intravenous supplementation of selenium, macrocytosis, tri-iodothyronine and thyroxine values, and glutathione peroxidase activity all became normalized, yet he improved little neurologically. Our case suggests that long-term selenium deficiency may cause progressive and irreversible encephalopathy, and that careful monitoring of this mineral is necessary when an excessive period of total parenteral nutrition is being considered in the clinical setting.

Crohn disease: early recognition and progress of aphthous lesions.

PURPOSE: To clarify the radiographic appearance of the initial change an dprogression in Crohn disease. MATERIALS AND METHODS: Between 1984 and 1992, nine patients (seven men and two women, aged 16-34 years; mean, 20 years) with Crohn disease, who had evidence of only aphthous erosions or ulcers at the initial examination, underwent repeated radiography for up to 7 years 11 months (median, 4 years). RESULTS: In all patients, the stomach, duodenum, small intestine, and colorectum were involved, and the esophagus was affected in three patients. Subsequently, four of the nine patients had lesions that progressed from aphthous lesions to overt Crohn disease, including ileitis in two patients, colitis in one, and ileocolitis in one. Time intervals between the first visit and the progression varied from 9 months to 3 years 6 months. In all eight patients who underwent nutritional treatment, regression of the lesions was recognized, but three of the lesions progressed during interruption of the nutritional diet. CONCLUSION: Crohn disease may initially appear as diffuse aphthous lesions in the gastrointestinal mucosa.

Postoperative recurrence in patients with intestinal Behçet's disease.

PURPOSE: The postoperative course of intestinal Behçet's disease was studied in nine patients who had undergone a total of 15 operations due to intestinal ulcers. METHODS: These patients were followed up for an average of 6.0 years (range, 1 year, 3 months to 13 years, 10 months) after each operation and they were repeatedly examined by double-contrast radiography and/or colonofiberscopy. RESULTS: Recurrence of intestinal ulcers was observed in 12 (80 percent) of the 15 surgical cases. The incidence (50 percent) of postoperative recurrence in six cases in which intraoperative endoscopy revealed no abnormality in the retained intestine was lower than that (100 percent) in nine cases without this examination. Recurrent intestinal lesions in most cases were demonstrated as multiple aphthoid ulcers in the ileum near the ileocolectomy, or as one or two deep ulcers at the ileocolectomy site. The recurrent ulcers were successfully treated by various medical therapies, but the effectiveness of these therapies was only temporary. CONCLUSION: In the case of this disease, intraoperative endoscopy may be useful for preventing postoperative recurrence and periodic follow-up examination with radiography and endoscopy should be performed, even after surgery.

Gastrointestinal manifestations of Cowden's disease. Report of four cases.

Four patients with an established diagnosis of Cowden's disease underwent barium meal study, upper gastrointestinal endoscopy, barium enema examination, and colonoscopy. In three, the esophagus was affected by small protrusions, which were diagnosed as glycogenic acanthosis. Numerous hyperplastic polyps were found in the stomach in three patients, and in one an inflammatory fibroid polyp was also detected. Either lymphangiectasia or lymphoid polyps were found in the duodenum in two patients. In all patients, the colon showed polyps that varied in histology and included adenoma, hamartomatous polyp, and ganglioneurofibroma. In addition, jejunal lymphangiomas were found in one of the three patients in whom the small intestine could be precisely evaluated. These findings suggest that the gastrointestinal involvement in Cowden's disease is characterized by various benign lesions, especially esophageal glycogenic acanthosis, numerous gastric hyperplastic polyps, and multiple hamartomatous polyps in the rectosigmoid colon. Detection of these gastrointestinal manifestations may lead to early diagnosis of this potentially malignant disease.