A multicenter clinical open trial of FK 506 in refractory uveitis, including Behçet's disease. Japanese FK 506 Study Group on Refractory Uveitis.
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Biomedical subjects
Publications and source records attributed to M Kogure.
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After lobectomy, it is recognized that functional as well as absolute reduction occurs in residual lobes of the operated side. So whether lobectomy is indicated or not is determined by the same criteria as those for pneumonectomy, namely, by the unilateral pulmonary artery occlusion (UPAO) test. However, is it really appropriate to use the same criteria for both lobectomy and pneumonectomy? To answer to this question, in patients with lung cancer we compared the hemodynamics after lobectomy (13 cases) and pneumonectomy (14 cases) with that at the UPAO test. After pneumonectomy, the mean pulmonary arterial wedge pressure (mPWP) was significantly lower than that on the preoperative day and at the test. It seemed that hypovolemic change occurred in the hemodynamics after pneumonectomy. After pneumonectomy, the pulmonary arteriolar resistance index (PARI) was significantly higher than the preoperative value. It was the same as that as at the time of the UPAO test. The total pulmonary vascular resistance index (TPVRI) at the time of the test was significantly higher than the preoperative value, but the TPVRI after pneumonectomy was not significantly higher. The TPVRI tended to decrease after pneumonectomy, compared to the value predicated by the test. These results indicated that some of the cases judged inoperable on the basis of the UPAO test might be operable. On the day of lobectomy, the PARI was significantly higher than the preoperative value, but significantly lower than that at the time of the test. The cardiac index (CI) was significantly higher and the mPWP was significantly lower than each preoperative value.(ABSTRACT TRUNCATED AT 250 WORDS)
The spontaneously hypertensive rat (SHR) maintained a higher blood pressure level at and after 8 weeks old than the genetical control Wistar-Kyoto strain (WKY). At 10 weeks old, the turnover rate of 5-hydroxytryptamine (5-HT) was lower in the hypothalamus of SHR than of WKY. Following portacaval anastomosis (PCA) in SHR, the blood pressure was significantly decreased in comparison with that of sham-operated control SHR. In WKY, no significant change in the blood pressure response was observed. PCA treatment increased the 5-HT turnover including that in SHR. If the SHR with PCA was bred with food pellets containing higher concentrations of leucine and isoleucine, the blood pressure increased and the 5-HT turnover decreased. These findings suggest that the central serotonergic system is involved in the development of hypertension.
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A mutant mouse (wriggle mouse sagami, WMS) with neurological disorders was found in a colony of the BALB/c strain. The clinical signs included tremor, dystonia and involuntary movements. The concentrations of the neurotransmitter substances, noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and acetylcholine (ACh), were measured simultaneously with their metabolites in dissected brain regions by high-performance liquid chromatography with electrochemical detection. The turnover of 5-HT was significantly higher in the cerebral cortex, hippocampus, hypothalamus, midbrain and pons-medulla of WMS than of the genetic control, BALB/c. The intrastriatal DA and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid were increased. However, there was no evidence to suggest an increase in turnover rate of this neurotransmitter. An increase in concentration of and decrease in turnover rate of NA were observed in the cerebellum of this mutant. These findings suggest that multiple disturbance of the neurotransmitter system was largely responsible for the manifestation of the clinical signs of WMS.
The efficacy and safety of oral cyclosporin 10 mg/kg per day in Behçet's disease were compared in a randomised double-masked study with those of colchicine, 1 mg orally per day, and were also investigated in a long-term open study. The double-masked study showed that cyclosporin was effective in treating not only the ocular manifestations of Behçet's disease but also oral aphthous ulcer, dermal lesions, and genital ulceration. Efficacy did not weaken during long-term treatment.
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In Caucasians, there is close correlation between acute anterior uveitis and histocompatibility antigen HLA-B27. But in Japanese, this is not clear. Therefore, we examined 58 patients with non-granulomatous anterior uveitis (NGAU) about HLA typing in our uveitis clinic at Tokyo Women's Medical College Hospital. HLA-B27 was identified in 20 out of 58 patients (34.5%) with NGAU and it was statistically significant. We also studied the clinical features of patients with HLA-B27 positive NGAU. We found that in HLA-B27-positive NGAU, the visual acuity was more strongly affected during the attack and the duration of inflammation was longer than HLA-B27 negative NGAU patients. The duration of the first attack was longer than re-attack, and the duration of the first attack was longer than HLA-B27 negative NGAU patients. It was less commonly associated with systemic disorders in Japanese HLA-B27 positive anterior uveitis than in Caucasian. However, in Japanese NGAU patients without systemic disorders, there was the same tendency concerning the HLA-B27 positive rate as in Caucasians.
SMS 201-995 (SMS), a synthetic analogue of somatostatin (SRIF) has been shown to be effective in the treatment of the hypersecretion of hormones such as in acromegaly. However, little is known about the effects of SMS on the secretion of thyroid-stimulating hormone (TSH) in normal subjects. In this study, plasma TSH was determined with a highly sensitive immunoradiometric assay, in addition to the concentration of SMS in plasma and urine with a radioimmunoassay, following subcutaneous injection of 25, 50, 100 micrograms of SMS (4 subjects/dose) or a placebo (6 subjects) to normal male subjects, at 0900 h after an overnight fast. The plasma concentrations of SMS were dose-responsive and the peak levels were 1.61 +/- 0.09, 4.91 +/- 0.30 and 8.52 +/- 1.18 ng/ml, which were observed at 30, 15 and 45 min after the injection of 25, 50 and 100 micrograms of SMS, respectively. Mean plasma disappearance half-time of SMS was estimated to be 110 +/- 3 min. Plasma TSH was suppressed in a dose dependent manner and the suppression lasted for at least 8 hours. At 8 hours after the injection of 25, 50 and 100 micrograms of SMS, the plasma TSH levels were 43.8 +/- 19.4, 33.9 +/- 9.4 and 24.9 +/- 3.2%, respectively, of the basal values. The results suggest that SMS suppresses secretion of TSH from the normal thyrotrophs in man and thus also that attention should be paid to possible hypothyroidism during the long-term treatment of patients such as those with acromegaly with this potent analogue of SRIF.
We examined the interrelationships between the pressor response to the administration of norepinephrine and arginine vasopressin and baroreflex function in rats with hypertension of two days' duration induced by heminephrectomy and a clip placed on the right renal artery (2-day clipped rats). Mean arterial pressure was higher in the 2-day clipped rats than in heminephrectomized rats without clips (sham-operated rats). The pressor response in the 2-day clipped rats to both agents increased as compared to the sham-operated rats. This hyperresponsiveness was attenuated by administering an angiotensin II antagonist, [1-Sar, 8-Ile] angiotensin II. Baroreflex sensitivity was studied by measuring changes in arterial pressure and pulse interval in response to the injection of phenylephrine. Baroreflex sensitivity was not decreased but markedly increased in the 2-day clipped rats and unaffected by infusing the angiotensin II antagonist. These results provide evidence that 1) in the 2-day clipped rats there are exaggerated pressor responses to vasoconstrictors; 2) the hyperresponsiveness is not causally related to the change of baroreflex sensitivity; and 3) angiotensin II plays a significant role in the increased pressor responses; however, the baroreflex mechanism is not involved in attenuation of the hyperresponsiveness by the angiotensin II antagonist.
Exogenously administered vasopressin (VP) augments ACTH secretion stimulated by CRH. This study was performed to elucidate the role of endogenous VP in potentiating CRH-induced ACTH secretion in man. Synthetic human CRH (100 micrograms) was injected iv into seven normal men after they had been water loaded (20 mL/kg; 60 and 30 min before CRH injection; WL-CRH test) and water deprived (water restriction for 18 h before CRH injection; WD-CRH test). Blood samples were obtained before and 5, 15, 30, 60, 90, and 120 min after CRH injection at 0900 h for determination of plasma ACTH, cortisol, arginine vasopressin (AVP), CRH, and catecholamine levels and osmolality. Urine was obtained immediately before and 120 min after CRH injection for determination of osmolality. The mean plasma AVP levels were significantly higher during the WD-CRH test [1.8 +/- 0.4 (+/- SE) to 1.9 +/- 0.4 pmol/L] than during the WL-CRH test (0.6 +/- 0.1 to 0.9 +/- 0.1 pmol/L). The mean plasma ACTH and cortisol levels rose significantly from basal (4.5 +/- 0.6 pmol/L and 320 +/- 20 nmol/L, respectively) to peak values of 14.0 +/- 2.1 pmol/L at 30 min and 700 +/- 50 nmol/L at 60 min, respectively, during the WD-CRH test. During the WL-CRH test, mean basal plasma ACTH and cortisol levels were 3.5 +/- 0.7 pmol/L and 420 +/- 50 nmol/L, respectively, and reached peak values of 7.7 +/- 1.1 pmol/L at 60 min and 550 +/- 40 nmol/L at 30 min, respectively. Both the mean peak levels and integrated ACTH and cortisol responses were significantly higher during the WD-CRH than during the WL-CRH test. There was no significant difference between the plasma CRH and catecholamine concentrations in both tests. These results suggest that endogenous AVP potentiates CRH-stimulated ACTH secretion and, thus, plays a physiologically significant role in regulating CRH-stimulated ACTH and cortisol secretion in man.
A severe case of Vogt-Koyanagi-Haradi's disease was treated with a combination therapy of cyclosporin A and steroid. The therapy was successful and showed no side effects.
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The role of prostaglandins (PGs) in the pressor response to norepinephrine (NE) was examined in one-kidney, one clip rabbits with renal artery stenosis for 3-day's duration (3-day clipped rabbits) and in sham operated rabbits with one-kidney without renal artery stenosis. An exaggerated pressor response to NE, 800 ng/kg/min, was observed in the 3-day clipped rabbits, and it was abolished by angiotensin II antagonist, [Sar1, Ile8] angiotensin II (AIIA). Treatment with indomethacin, 10 mg/kg, induced hyperresponsiveness to NE in the sham operated rabbits and also produced a further increase in the response in the 3-day clipped rabbits: the enhanced responses with similar levels were not attenuated by AIIA in both groups. A subdepressor dose of PGE2, 800 ng/kg/min, abolished the hyperresponsiveness in the 3-day clipped rabbits, while subdepressor or depressor dose of PGI2, 10 or 20 ng/kg/min did not, but the concurrent infusion of AIIA with PGI2 attenuated it. These results indicate that PGs, in particular PGE2 might be involved in the enhanced pressor response to NE in the 3-day clipped rabbits in addition to the altered renin-angiotensin system.
The effects of guanabenz, guanfacine and clonidine on alpha-adrenoceptors were investigated in isolated rat vas deferens and rabbit aortic strip. All 3 drugs at low concentrations (10(-9)-10(-8) M) caused inhibition of twitch responses of the rat vas deferens induced by nerve stimulation. These effects were competitively antagonized by yohimbine. Guanfacine and clonidine at relatively high concentrations (10(-6)-10(-4) M) produced contractions of the rat vas deferens which were antagonized by prazosin. These contractile responses were not much affected by denervation. Prazosin-sensitive contractions by guanfacine and clonidine were also observed in the rabbit aortic strip, which were not affected by reserpine pretreatment. In both tissues, the intrinsic activity of guanfacine was almost identical to that of norepinephrine, whereas that of clonidine was less than one half. Guanabenz and clonidine showed a competitive antagonistic effect against norepinephrine and phenylephrine in both the rat vas deferens and rabbit aorta, the antagonisms being similar in potency. The results indicate that all 3 drugs are potent agonists on the presynaptic alpha 2-adrenoceptor. In contrast, on the postsynaptic alpha 1-adrenoceptor, guanfacine and guanabenz showed only agonistic and antagonistic actions, respectively, whereas clonidine exhibited partial agonistic characteristics.
An open-labeled study of once-daily administration of 40 mg famotidine was conducted in 24 patients with endoscopically confirmed reflux esophagitis. The mean age of the patients was 62.8 years. Most had stage I or stage II esophagitis of 1 years' duration or less. After 4, 8, 12, and 16 weeks of treatment, endoscopically documented healing was reported in 50%, 75%, 82%, and 83% of patients, respectively. Among specific endoscopic findings documented at the start of the study there was clearing of white exudate in 83% of patients, and redness cleared in 50% of patients after 16 weeks of treatment. Symptomatic improvement was observed in 73% of patients after 2 weeks, and this increased to 81% and 85% after 4 and 8 weeks of treatment, respectively. Painful symptoms cleared within 2 weeks in 68% of patients, and this increased to 77% after 8 weeks of once-daily therapy. Famotidine was well tolerated. Historically, reflux esophagitis has not responded satisfactorily to drug treatment. The reported symptomatic response and the response documented by endoscopy after therapy with 40 mg famotidine once daily at bedtime are encouraging. Further studies should be conducted to define the role of famotidine in the treatment of reflux esophagitis.
The withdrawal effect of spironolactone treatment on natriuresis was studied in relation to atrial natriuretic peptide (ANP) in five patients with primary aldosteronism due to adenoma. The patients had been treated with spironolactone for 2-3 months before they were admitted. After admission, blood pressure, body weight, and urinary excretion of sodium were measured daily. Venous samples were obtained twice a week for measurements of plasma levels of ANP, plasma renin activity (PRA), and plasma concentrations of aldosterone (PAC), cortisol, and deoxycorticosterone. The study was performed for 7 days during the treatment with spironolactone and for 18 days after stopping the administration. Plasma volume was determined two times, during the control period and on the 13th day after stopping spironolactone. Urinary sodium excretion decreased initially and returned to the control levels successively. Body weight and plasma volume increased, and blood pressure rose steadily. PRA and the plasma concentrations of cortisol and deoxycorticosterone decreased significantly (P less than 0.05); however, high levels of PAC did not alter significantly. Plasma ANP levels increased significantly (P less than 0.05) from 26 +/- 4 pg/ml during the control period to 195 +/- 47 pg/ml on the 13th day after stopping spironolactone. The data of the urinary sodium excretion showed the escape from sodium-retaining effect of aldosterone, and this escape could be explained by the increase in plasma ANP. Furthermore, ANP might contribute to the decrease in cortisol and deoxycorticosterone in plasma because of the direct inhibitory action of ANP on steroidogenesis.