Azulene derivatives: new non-prostanoid thromboxane A2 receptor antagonists.
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Biomedical subjects
Publications and source records attributed to T Tomiyama.
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Renal effects of 4-week fixed maintenance doses of bunazosin three times daily (2.0 mg t.i.d., n = 8) and propranolol (40 mg t.i.d., n = 8) were evaluated in patients with mild-to-moderate essential hypertension [World Health Organization (WHO) stages I and II]. Both bunazosin and propranolol decreased blood pressure (BP) significantly (p less than 0.05), but the magnitude of reduction in diastolic BP (DBP) was greater with bunazosin (p less than 0.05) than with propranolol. Bunazosin produced a nonsignificant increase in renal blood flow (RBF) by 14%, a significant increase in glomerular filtration rate (GFR) 11% (p less than 0.05), and a decrease in total renal vascular resistance (TRR) by 15% (p less than 0.05), whereas propranolol caused no significant changes in these parameters. Urinary sodium excretion rate and the fractional excretion of sodium were unchanged by either of the drugs. The results of this short-term study suggest that bunazosin may be a drug that will increase RBF and GFR and decrease TRR with a concomitant hypotensive action in patients with mild-to-moderate essential hypertension. Whether these renal functional effects of the drug would benefit such patients must be determined in long-term studies.
The possibility of an impaired hepatic de-esterification of enalapril to enalaprilat due to hepatic dysfunction was assessed in seven patients with compensated liver cirrhosis and 10 normal control subjects. The peak serum concentration and time to the peak serum concentration of enalaprilat, as well as the suppression of serum angiotensin converting enzyme activity, following a single oral dose of enalapril maleate (10 mg) were not different in the two groups. The elimination half-life of enalaprilat was related to renal function. The results suggest that hepatic biotransformation of the drug may not be disturbed in a clinically significant manner in patients with moderate hepatic dysfunction due to compensated liver cirrhosis.
A series of alkylazulene-1-sodium sulfonate derivatives which has an isopropyl group at 6-position were synthesized, and their anti-ulcer activities were examined in Shay pylorus-ligated rats. The values of lipophilicity (log P) as a parameter of these new azulene derivatives were also examined in reference to the structure-activity relationship. The optimum value of log P, which showed maximal anti-ulcer activity, was about -0.46. Among the derivatives of azulene examined, 3-ethyl-6-isopropylazulene-1-sodium sulfonate (compound IXb:XT1-785) exhibited the most potent inhibitory action against Shay ulcer, and its anti-peptic activity was similar to that of 3-ethyl-7-isopropylazulene-1-sodium sulfonate (KT1-32). It also had more activity than guaiazulene sodium sulfonate (GAS). Furthermore, KT1-785 was extremely stable under heating as compared to GAS.
The relationship between blood pressure and progression of nephropathy was studied (the mean follow-up period of 32.6 +/- 17.9 (S.D.) months in 20 Type 2 (non-insulin-dependent) diabetic patients with clinical nephropathy (proteinuria greater than 0.5 g/day) and preserved renal function (serum creatinine level less than 150 mumol/liter). Fifteen hypertensive patients under antihypertensive treatment were divided into 2 groups: those with the mean diastolic blood pressure greater than or equal to 90 mmHg and/or the mean systolic blood pressure greater than or equal to 150 mmHg during the follow-up period were designated as Group A (n = 6) and the remainders as Group B (n = 9). Five normotensive patients without any anti-hypertensive treatment throughout the follow-up period served as a control group (Group C). The decline rate in GFR was significantly greater (p less than 0.05) in Group A (1.15 +/- 0.39 (S.E.) ml/min/month) than those in Groups B (0.33 +/- 0.08 ml/min/month) and C (0.40 +/- 0.09 ml/min/month), respectively. The decline rate in GFR showed significant positive correlations both with systolic (rS = 0.553, p less than 0.05) and diastolic (rS = 0.493, p less than 0.05) blood pressures in the 15 hypertensive patients. The age, initial glomerular filtration rate, duration of diabetes and mean HbA1c level during the observation period were comparable in Groups A, B and C, respectively. The results indicate that an uncontrolled hypertension is associated with a rapid progression of kidney impairment in Type 2 diabetic patients with overt nephropathy, as has been suggested in Type 1 (insulin-dependent) diabetic patients.
Human anti-cytomegalovirus (CMV) monoclonal antibody designated C23 was purified from the culture fluid of hybridoma cells which were generated by cell fusion of human lymphocytes and mouse myeloma cells. The purified C23 was found to be identical to human gammaglobulin (HGG) in sodium dodecyl sulfate-polyacrylamide gel electrophoresis under both reducing and non-reducing conditions and in gel filtration chromatography. C23 was not contaminated with either aggregated IgG molecules or mouse immunoglobulin chains. In addition, the formulated C23 preparation showed an anti-complement activity low enough to permit its use as a biologic. A virus neutralization titer of C23 was about 1,000 times higher than the titers of HGG preparations. All the tested CMV strains were susceptible to neutralization by C23 and this neutralization was not affected by addition of either beta 2 microglobulin or fresh human serum. These results suggest that human monoclonal antibody C23 is as safe as conventional HGG preparations which have been used in humans, and much more effective in providing host protection against CMV infection.
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A woman was operated on for a nonepithelial malignant tumor of the left leg and subsequently, for an epithelial carcinoma of the right breast and a borderline malignant tumor of the right ovary. She also developed a giant cavernous hemangioma that caused disseminated intravascular coagulation syndrome, which necessitated a left trisegmentectomy of the liver. Her family history suggested a hereditary predisposition to diverse malignant neoplasms, and also to giant cavernous hemangioma of the liver. Immunological evaluation disclosed selective inhibition of natural killer cell activity. Hormonal and hereditary factors are discussed in relation to the development of multiple primary tumors and giant cavernous hemangioma of the liver.
A number of carbacyclins having bicyclic substituents on the omega-chain have been synthesized and tested for antiplatelet aggregation activity in vitro (against collagen-induced aggregation of rat platelet), for reduction of systemic blood pressure in vivo (ability to reduce the blood pressure in anesthetized rat by iv injection), and for cytoprotective activity (protection against ethanol-induced rat gastric lesion). The most effective compound for each activity was [3aS-[2E,3a alpha,4 alpha (3R),5 beta,6a alpha]]-5-[hexahydro-5- hydroxy-4-[3-hydroxy-3-(2-indanyl)-1-propynyl]-2(1H)-pentalenylidene+ ++] pentanoic acid (compound 11a), while some 1,4-benzodioxan analogues had selectivity for organ-protective activity, and indan analogues showed selectivity in their antiaggregation activity.
We measured the urinary excretions of dopamine, noradrenaline and adrenaline, their conjugated metabolites, urinary excretion of sodium and creatinine clearance simultaneously in 21 patients with Type 2 (non-insulin-dependent) diabetes and 6 normal subjects. The mean (+/- SEM) value for urinary excretion of dopamine (52.4 +/- 8.8 micrograms/day) in diabetic patients with nephropathy (Group C, n = 12) was significantly lower (P less than 0.01) than in the normal subjects (Group A, 179.7 +/- 15.5 micrograms/day) and in diabetic patients without nephropathy (Group B, n = 9, 131.5 +/- 16.5 micrograms/day). The mean values for the urinary excretions of noradrenaline and adrenaline were also significantly lower (P less than 0.01) in Group C than in Groups A and B. In addition, the mean urinary excretion of conjugated metabolite of dopamine in Group C was significantly lower (P less than 0.05) than in Group A. There was a trend toward the observation that the mean 24-h urinary excretion of sodium in Group C (121.6 less than 12.9 mEq) was lower as compared with that in Group A (140.8 +/- 8.9 mEq) or B (150.7 +/- 17.9 mEq). A multiple regression analysis revealed that the 24-h urinary excretion of dopamine correlated significantly with creatinine clearance, systolic (P less than 0.01) and diastolic (P less than 0.05) blood pressures. The results indicate that synthesis or secretion of renal dopamine might decrease with a progression of diabetic nephropathy.(ABSTRACT TRUNCATED AT 250 WORDS)
Bovine leukaemia virus (BLV) induces syncytia in productively infected ovine and bovine monolayer cells. Expression of the env gene directly determines the syncytium-forming activity, since the expression of a cloned env gene directed by the simian virus 40 (SV40) early promoter efficiently induced syncytia in transfected ovine embryonic (OE) cells. However a BLV long terminal repeat (LTR)-directed expression plasmid (pLTRenv) failed to induce syncytia in transfected OE cells, suggesting insufficient promoter activity of the LTR sequences. To assess the role of the XBL genes, which are located in the 3' distal region of the genome, in viral gene expression we constructed SV40 early promoter-directed expression plasmids. These contained open reading frames (ORFs) in the XBL region, and were examined for syncytium-inducing activity by cotransfection with pLTRenv. The results suggest that both XBL-I (the longest ORF: x-lor) and XBL-II (a shorter overlapping ORF: x-sor) are trans-acting genes which cooperatively activate LTR-directed viral gene expression.
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Discharges of neurons in the midpontine dorsal tegmental field (DTF neurons) were recorded and analyzed during locomotion and were compared with those of reticulospinal neurons (RS neurons) located lateral to the DTF area. The conduction velocity of the descending axon of the DTF neurons was significantly smaller than that of the RS neurons. During locomotion, the DTF neurons showed a tonic increase in the discharge rate. In contrast, the discharge rate of the RS neurons showed cyclic modulation in step with locomotion.
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