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Biomedical subjects

K Takeyama

Publications and source records attributed to K Takeyama.

At least 127 records · Page 7Linked to original sources
PubMed1990

Angiotensin-converting enzyme inhibitors: synthesis and biological activity of N-substituted tripeptide inhibitors.

A new series of highly potent angiotensin-converting enzyme (ACE) inhibitors, 1-(N2-substituted L-lysyl-gamma-D-glutamyl)octahydro-1H-indole-2-carboxylic acids, was synthesized; various acyl groups were introduced at the alpha-amino group of the N-terminal P1 Lys. The effect of the N2-acyl groups on in vitro inhibitory activity and oral antihypertensive effect was examined. All of the synthesized N-acyl tripeptides were found to have in vitro inhibitory activity at an approximately nanomolar level, and showed antihypertensive potency in renal hypertensive rats at a dose of 10 mg/kg, when administered orally. Among them, compounds 7e, g and 9f, i, m showed potent and long-lasting antihypertensive effects compared with enalapril (2a). Their structure-activity relationships are also discussed.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Effect of the anti-asthmatic agent KC-404 on the contractile responses of rabbit airway smooth muscle to tachykinins.

To characterize the antagonistic action of KC-404, an anti-asthmatic agent, against the tachykinin-mediated bronchoconstriction, we studied the effect of this drug on the contractile responses of rabbit tracheal smooth muscle to neurokinin A (NKA) and substance P (SP) under isometric conditions in vitro. Addition of KC-404 relaxed the tracheal rings precontracted with NKA and SP in a dose-dependent fashion but had only a small effect on the contractile responses to acetylcholine and histamine. This inhibitory action of KC-404 was likewise noted even in the presence of atropine. In addition, each of NKA and SP at a concentration insufficient to alter the resting tone enhanced the contractile response to electrical filed stimulation, an effect that was dose-dependently attenuated by the subsequent application of KC-404. These results suggest that KC-404 may antagonize the bronchoconstrictor actions of tachykinins by interacting with their specific receptors on smooth muscle cells as well as on cholinergic nerve terminals in the airway.

Animals↗
PubMed1989

Angiotensin-converting enzyme inhibitors: synthesis and structure-activity relationships of potent N-benzyloxycarbonyl tripeptide inhibitors.

A new series of gamma-D-Glu-containing N-benzyloxycarbonyl (Z) tripeptide inhibitors of angiotensin-converting enzyme (ACE) was synthesized. The effect of varying the antepenultimate amino acid residue in this series on the biological activity was studied. Introduction of Lys and Orn residues at the P1 position provided the most potent inhibitors, 25a and 25b (IC50: 3.5 and 4.9 x 10(-9) M, respectively), which exhibited an oral antihypertensive activity. This result suggests that basic amino acid residues at the P1 position play an important role in binding with the S1 subsite of ACE in this series. Oral antihypertensive activity of selected compounds was evaluated.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Hemorrhagic cystitis associated with urinary excretion of adenovirus type 11 following allogeneic bone marrow transplantation.

We studied a total of 50 recipients who had received allogeneic bone marrow transplantation (BMT) and evaluated both the presence of hemorrhagic cystitis (HC) and the urinary excretion of adenovirus. Twelve recipients developed HC and eight of these 12 patients excreted adenovirus type 11 at the onset of cystitis. Urine for virus isolation was attempted 30, 60 and 100 days after BMT. Among 137 specimens examined, eight were positive for adenovirus type 11. Of these eight samples, six were collected during HC; while in the 129 samples which were negative for adenovirus, only three specimens was collected during HC. Female patients, seropositivity for the antibody to adenovirus prior to BMT and acute graft-versus-host disease (grade 2-4) showed a significant impact on the risk of adenovirus HC. It may be said that adenovirus type 11 is one of the causative agents of HC in BMT recipients.

Adenoviridae Infections↗
PubMed1989

[Prolonged thrombocytopenia after autologous bone marrow transplantation].

Thirty two patients with hematologic malignancies and solid tumors were treated with intensive therapy and autologous bone marrow transplantation. In nine out of 32 patients, it took more than 50 days to achieve a sustained platelet count of 50,000/microliter or greater. Significant associations with poor platelet recovery were found for patient age, diseases, period of cryopreservation, the kinds of eradicative therapy and in vitro purging. But most of these factors overlapped each other in the same patients. No correlation was found between platelet recovery and number of cells or CFU-GM infused.

Adolescent↗
PubMed1989

[Cyclosporine as prophylaxis for graft versus host disease in adults undergoing allogeneic bone marrow transplantation].

Fifteen adult patients undergoing allogeneic bone marrow transplantation (BMT) received cyclosporine (CSP) as prophylaxis of graft versus host disease (GVHD). In our patients eleven were hematologic malignancies, and four were severe aplastic anemia. Twelve patients were HLA-matched, and three were one locus mismatched. Three patients received CSP only, twelve received CSP and short term methotrexate. Seven patients had acute GVHD, but GVHD over Grade II were seen in only 3 patients who were transplanted from HLA-one locus mismatched donor. 7 patients had chronic GVHD. CSP were given intravenously at 3-5 mg/kg, starting 1 day before BMT. From about day 30, CSP was given orally. CSP concentrations when patients were given orally were lower in patients who had chronic GVHD. Although hypertension and water retention were seen in 8 patients, and renal dysfunction was seen in 3 patients, the side effects of CSP were mild and transient. There were no correlations between serum concentrations and the side effects of CSP. Three patients had the disturbance of hematopoiesis. Ten of fifteen patients are alive at median follow-up of 18.5 months (8-41 months) after BMT.

Adolescent↗
PubMed1989

[Severe aplastic anemia remarkably improved by a treatment with antilymphocyte globulin, high-dose methylprednisolone and danazol].

Sixteen-years-old female with severe aplastic anemia received a therapy combined with antilymphocyte globulin (ALG), high-dose methylprednisolone (m-PSL) and danazol. At the hospitalization, hematological examination demonstrated as follows; reticulocyte 21,000/microliters, granulocyte 350/microliters, platelet 10,000/microliters and hypocellular bone marrow. Treatment schedule were 1) m-PSL 1,000 mg (day 1-4), 500 mg (5-8)--then tapered. 2) ALG lg/day (day 4-8) 3) danazol 600 mg/day. During ALG administration, leukocytopenia and thrombocytopenia appeared but thereafter hematological recovery was obtained and the patient was free from supportive care. She developed mild diabetes mellitus and moderate liver dysfunction, nevertheless, both of which were controlled. At 3 months after the beginning of the treatment, hematological examination demonstrated as follows; reticulocyte 236,000/microliters, granulocyte 1,900/microliters, platelet 56,000/microliters and normocellular bone marrow. Although this immunosuppressive therapy was remarkably effective to this patient, immunological relation to the onset of aplastic anemia was not demonstrated in in vitro examination. This combined therapy seems to be effective one for patients with severe aplastic anemia.

Adolescent↗
PubMed1988

Use of cyclophosphamide and total lymphoid irradiation combined with cyclosporine in bone marrow transplantation for transfused severe aplastic anemia.

Between February 1984 and August 1987, 10 patients with severe aplastic anemia were treated with bone marrow transplantation from HLA-identical sibling donors after preparation with cyclophosphamide (CY) 200 mg/kg and total lymphoid irradiation (TLI) 750 cGy. Ages ranged from 5 to 28 years (median 14 years). All patients were previously transfused. Median number of transfusions was 16 (range, 3-886). For post-transplant immunosuppression all patients were given cyclosporine and the last three patients received additional immunosuppression with short-term methotrexate. All patients had initial engraftment and survived for more than 3-46 months after transplantation. One patient developed significant acute graft-versus-host disease (GVHD) and three of nine recipients who survived more than 100 days developed chronic GVHD. One male patient who had received 21 transfusions from his marrow donor before transplantation suffered from persistent granulocytopenia. Otherwise all have Karnofsky performance scores of 90-100%. Although the number of patients is small, it appears that allogeneic bone marrow transplantation with the regimen of CY + TLI for preparation combined with cyclosporine (+ short-term methotrexate) for post-transplant immunosuppression is a promising modality for treatment of previously transfused patients with severe aplastic anemia.

Adolescent↗
PubMed1988

Pharmacokinetics of an active cadralazine metabolite in plasma and blood vessels of spontaneously hypertensive rats.

The plasma and blood vessel (aorta and mesenteric artery) levels of (+/-)-6-[ethyl(2-hydroxypropyl)amino]-3-hydrazinopyridazine (ISF-2405), an active metabolite of cadralazine, were determined and compared with the changes in blood pressure in spontaneously hypertensive rats after single oral administration of cadralazine. The mean plasma level of ISF-2405 reached a maximum at 0.5 h after oral administration of 3 mg/kg of cadralazine, followed by a rapid elimination with a half-life of 1.0 h, whereas the mean aorta level of ISF-2405 reached a maximum at 4 h after dosing, followed by a slow elimination with a half-life of 6.5 h. The mean mesenteric artery levels of ISF-2405 were almost the same as the mean aorta levels over the time investigated. Both patterns of aorta and mesenteric artery levels of ISF-2405 were in good agreement with those of the hypotensive effects. These findings substantiate the assumption that the slow onset and long duration of the pharmacological effect of cadralazine is closely related to the distribution pattern of the active metabolite ISF-2405 in blood vessels, a target tissue of antihypertensive vasodilator drugs.

Animals↗
PubMed1986

Tissue levels, tissue angiotensin converting enzyme inhibition and antihypertensive effect of the novel antihypertensive agent alacepril in renal hypertensive rats.

Tissue levels, tissue angiotensin I converting enzyme (ACE) inhibition and hypotension were examined 20 min, 1, 5 and 14 h after oral administration of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) (37.5 mg (92 mumol)/kg) or 1-[(S)-3-mercapto-2-methylpropanoyl]-L-proline (captopril) (20.0 mg (92 mumol)/kg) in renal hypertensive rats, using 14C-labeled compounds. Alacepril exerted a more gradual and more sustained antihypertensive effect than captopril. The maximal hypotension was observed 1 and 5 h after administration of captopril and alacepril, respectively. After administration of [14C]captopril, serum level reached the maximum at 20 min and then decreased rapidly. After administration of [14C]alacepril, serum level reached the maximum at 1 h and decreased more slowly than after [14C]captopril. Time course patterns of tissue levels were essentially in parallel with those of serum levels. Captopril exerted the maximal reduction of ACE activity in tissues 20 min after oral administration and thereafter, the reduction was diminished with time rapidly. [14C]Alacepril showed gradual reduction (the maximum at 1 h) and recovery of ACE activity relative to captopril. After oral administration of [14C]alacepril, tissue unbound fractions contained captopril and its derived metabolites while serum unbound fraction contained the intermediate metabolite desacetyl-alacepril (DU-1227) as well. Correlations between ACE inhibition and tissue levels and between changes in tissue ACE inhibition and in blood pressure with time after oral administration of the two agents were discussed. Furthermore, the direct comparison of alacepril and captopril was attempted by the difference in blood pressures and in ACE inhibitions induced after oral administration of the agents.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

Metabolism of protein conjugate of desacetyl-alacepril and its effect on angiotensin converting enzyme in renal hypertensive rats.

The fate of protein conjugate of desacetyl-alacepril (DU-1227) and its effect on angiotensin I converting enzyme (ACE) activity in renal hypertensive rats were studied. [14C]DU-1227-protein conjugate was prepared by ultrafiltration method and administered intravenously in rats. Elimination of radioactivity of [14C]DU-1227-protein from plasma after injection seemed much slower than that reported of [14C]alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine, DU-1219) given orally. In the plasma unbound fraction, captopril and captopril-cysteine were detected. Most tissue levels were higher than plasma levels. Significant reduction of tissue ACE activity was seen after administration of the conjugate. Radioactivity was mostly excreted in feces. Captopril, captopril disulfide and captopril-cysteine were found as urinary metabolites. These findings indicate that protein-bound DU-1227 readily dissociated and released DU-1227 was converted to captopril in vivo and can therefore participate in prolonged hypotensive effect exerted by alacepril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1986

Effect of alacepril on renin-angiotensin-aldosterone system and kallikrein-kinin-prostaglandin system in experimental animals.

The effects of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219), an orally active angiotensin converting enzyme (ACE) inhibitor, on humoral factors which participated in the blood pressure control were examined with various experimental animals. In conscious renal hypertensive dogs, alacepril (3 mg/kg p.o.) showed decreases in plasma ACE activity and plasma aldosterone concentration, and increases in plasma renin activity and plasma angiotensin I concentration accompanied by a significant reduction in blood pressure. In conscious normotensive dogs, alacepril (1 and 3 mg/kg p.o.) showed an increase in urinary excretion of bradykinin accompanied by increases in urinary water and sodium excretion. In spontaneously hypertensive rats, alacepril (30 and 100 mg/kg p.o.) showed increases in urinary excretion of bradykinin and 6-keto-prostaglandin Fl alpha, and a decrease in that of aldosterone accompanied by increased in excretion of water and sodium. These results indicate that the antihypertensive activity of alacepril is due to the suppression of renin-angiotensin-aldosterone system and the enhancement of kallikrein-kinin-prostaglandin system through the inhibition of ACE (kininase II) activity in vivo.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Effect of the novel orally active angiotensin converting enzyme inhibitor alacepril on cardiovascular system in experimental animals.

Effects of 1-[(S)-3-acetylthio-2-methylpropanoyl]-L-prolyl-L-phenylalanine (alacepril, DU-1219) a new orally active angiotensin converting enzyme (ACE) inhibitor, on cardiovascular system in experimental animals were examined. In conscious renal hypertensive dogs, alacepril (3 mg/kg p.o.) caused a marked reduction in systolic and diastolic blood pressure (SBP and DBP) and total peripheral vascular resistance (TPR), but did not change significantly heart rate (HR), cardiac output (CO), stroke volume (SV), cardiac work (CW) and electrocardiogram (ECG). Captopril (3 mg/kg, p.o.) showed similar changes in cardiovascular parameters as alacepril. In anesthetized open-chest normotensive dogs, alacepril (3-100 micrograms/kg/min for 10 min, i.v. infusion) tended to decrease DBP and TPR, but did not change significantly CO, stroke work (SW), left ventricular end diastolic pressure (LVEDP), dp/dt and HR. Captopril also showed similar effects but these changes were greater in extent than those of alacepril. In conscious renal hypertensive rats, alacepril did not affect the regional cerebral blood flow in the frontal cortex and the dorsal hippocampus after single (3 and 10 mg/kg) and successive (3 mg/kg/d for 7 days) oral administration. Captopril (10 mg/kg) significantly decreased blood flow in the frontal cortex after single oral administration. In conscious normotensive dogs, alacepril (3 and 30 mg/kg p.o.) increased renal plasma flow (RPF), urine volume (UV), urinary sodium excretion (UNaV) and urinary Na+/k+ ratio, but did not change glomerular filtration rate (GFR) and urinary potassium excretion (UKV). Captopril (3 and 30 mg/kg p.o.) also showed similar changes as alacepril. These effects of alacepril on cardiovascular system resemble those of captopril and might be considered as a favourable profile for the antihypertensive agent.

Animals↗