Biomedical subjects

T Kawahara

Publications and source records attributed to T Kawahara.

At least 19 recordsLinked to original sources

PubMed1994

Novel dual inhibitors of 5-lipoxygenase and thromboxane A2 synthetase: synthesis and structure-activity relationships of 3-pyridylmethyl-substituted 2-amino-6-hydroxybenzothiazole derivatives.

As part of our search for novel antiinflammatory drug candidates, we have designed and synthesized a series of 3-pyridylmethyl-substituted 2-amino-6- hydroxybenzothiazoles. Introduction of a 3-pyridylmethyl group into the 2-amino group (type-A) or the benzene ring (type-B) of 2-amino-6-hydroxybenzothiazoles imparted dual inhibitory activity against the production by glycogen-induced peritoneal cells of rat (in vitro) of leukotriene B4 (LTB4) and thromboxane A2 (TXA2), while not significantly inhibiting that of prostaglandin E2 (PGE2). The observed inhibition of the former two arachidonic acid metabolites was indicated to be the result of a direct action on 5-lipoxygenase and TXA2 synthetase by a cell-free in vitro assay. On the other hand, the inhibitory activities against PGE2 production were for most compounds very weak, indicating that they did not inhibit cyclooxygenase. Structure-activity relationship studies concerning the position of the 3-pyridylmethyl group revealed that type-B compounds generally showed about 10-fold stronger inhibitory activity against TXA2 synthetase than type-A compounds. The position of the 3-pyridylmethyl group played an important role in TXA2 synthetase inhibition. When some of these compounds (8, 13a, 26a (E3040), 26b, 27b, and 28b) were orally administered in the rat TNB/ethanol-induced chronic colitis model (100 mg/kg), the production of both LTB4 and TXB2 in the rat colon was reduced (ex vivo). In addition, one type-B compound, 6-hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl)benzothiazole (26a), demonstrated a therapeutic effect at treatments of 100 mg/kg po once daily for 11 days and showed almost comparable activity to sulfasalazine at a dose of 500 mg/kg, the reference drug for inflammatory bowel diseases, in this in vivo model.

Animals↗

PubMed1994

Malignant fibrous histiocytoma of the larynx.

Malignant fibrous histiocytoma of the upper respiratory tract is rare. We report a case of a glottic malignant fibrous histiocytoma in a 46-year-old man. Ultrastructural findings demonstrated that tumor cells were composed of fibroblast-like cells with abundant rough endoplasmic reticulum, histiocyte-like cells with numerous lysosomes and transitional cells with characteristics of both the fibroblast-like and histiocyte-like cells. Laryngeal microsurgery was performed as surgery and the patient has done well without recurrence to date (8 months after surgery).

Endoplasmic Reticulum↗

PubMed1994

A correlation of argyrophilic nucleolar organizer regions with prognoses in patients with maxillary sinus squamous cell carcinoma.

Argyrophilic nucleolar organizer regions (AgNORs) were determined by a semiautomatic image analyzer in a group of 28 patients with T2 or T3 maxillary sinus squamous cell carcinoma. The group was separated into recurrent and non-recurrent groups, metastatic and non-metastatic groups, as well as groups strongly or weakly positive for epidermal growth factor receptor (EGFR). The mean number and area of AgNOR dots per nucleus and the mean size of each dot were calculated. The mean number and area were significantly greater than those in normal cells (P < 0.001), but not in recurrent and non-recurrent groups, metastatic and non-metastatic groups and groups separated by EGFR. There was also no difference found in the mean sizes of tumor and normal cells. These results suggest that AgNOR is related to malignant transformation, but not prognosis.

Aged↗

PubMed1994

[Experimental studies on effect on nitric oxide on the internal urethral relaxation in anesthetized rats].

Effects of L-arginine and the inhibitors of nitric oxide/cyclic GMP pathway on the internal urethral relaxation were examined in anesthetized rats. The bladder pressure and internal urethral pressure were continuously recorded during the rhythmic bladder contractions before and after intraarterial administration of the following drugs. Used drugs were L-arginine from which nitric oxide is synthesized, NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginine methyl ester (L-NAME) which inhibit the synthesis of nitric oxide from L-arginine, and methylene blue which inhibits the activation of soluble guanylyl cyclase. In anesthetized rats, rhythmic bladder contractions with concomitant urethral relaxations were occurred. Administration of L-arginine (30 mg/kg, i.a.) produced a decrease in the internal urethral pressure. Administration of L-NMMA (3-30 mg/kg, i.a.), L-NAME (3-10 mg/kg, i.a.), and methylene blue (3-30 mg/kg, i.a.) produced an inhibition of the relaxations of the internal urethral sphincter during rhythmic bladder contractions. Present study suggests that nitric oxide/cyclic GMP pathway takes an important role for the relaxation of the internal urethral sphincter during rhythmic bladder contractions.

Animals↗

PubMed1994

[Pre-operative autologous blood collection in neurosurgical patients].

Homologous transfusion has been known to cause viral infections and other complications. Recently, autologous transfusion has been adopted widely as a safer and more effective procedure to prevent these complications. The authors report the experiences of 29 patients who had been operated on after preparation of autologous blood. Furthermore, the authors report a study concerning maximum surgical blood order schedule (MSBOS) of these operations. 212 patients operated on between January, 1991 and June, 1993 were used for this study of MSBOS. Although intraoperative transfusion was performed on 14 of 29 patients, the need for homologous transfusion was avoided in 12 of these 14 patients by the use of autologous blood. The frequency of homologous transfusion was reduced significantly after the introduction of pre-operative autologous blood collection in our clinic. The patients' value of hemoglobin fell after the collection of blood but these levels were not so seriously low as to impede the performance of operations. 212 cases of operated patients were divided according to the operative methods and diagnosis for calculation of MSBOS. The results were as follows; Craniotomy and removal of glioma 5u, meningioma 11u, neurinoma 7u, AVM 5u, transsphenoidal surgery 3u, Moyamoya disease 2u and V-P or S-P shunt 0u. Pre-operative autologous blood collection is easy to achieve for scheduled neurosurgical operations, and autologous transfusion is a beneficial procedure which should be used more widely.

Blood Loss, Surgical↗

PubMed1993

Effect of local administration of lymphokine-activated killer cells and interleukin-2 on malignant brain tumor patients.

Nine patients with malignant brain tumors were treated with intratumoral infusion of lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2). LAK cells were generated from macrophage-depleted peripheral blood lymphocytes by culturing with IL-2 for 4 days. The resulting LAK cells showed strong cytotoxic activity against tumor target cells. Three patients received sufficient LAK cells (> or = 5.76 x 10(8)) to show partial tumor response by computed tomography and clinical signs. No severe neurological side effects occurred in any patient. Intratumoral administration of LAK cells and IL-2 can be effective in patients with malignant brain tumors.

Adult↗

PubMed1992

Characterization of a Xenopus laevis skin peptidylglycine alpha-hydroxylating monooxygenase expressed in insect-cell culture.

The C-terminal amide structure of peptide hormones and neurotransmitters is synthesized via a two-step reaction catalyzed by peptidylglycine alpha-hydroxylating monooxygenase (PHM) and peptidylhydroxyglycine N-C lyase. A Xenopus laevis PHM expressed in insect-cell culture by the baculovirus-expression-vector system was purified to homogeneity and characterized. Using a newly established assay system for PHM, the kinetic features of this enzyme were investigated. As expected, the enzyme required copper ions, L-ascorbate and molecular oxygen for turnover. Salts like KI and KCl, and catalase stabilized the enzyme in the presence of L-ascorbate. The optimum pH value for the enzyme reaction was around six when Mes buffer was used and around seven when phosphate buffer was used under the same assay condition. Below pH 6, acetate, iodide and chloride ions activated the reaction. The kinetic analysis is consistent with a ping-pong mechanism with respect to peptide and L-ascorbate, and the peptide showed substrate inhibition. The substrate specificity of the enzyme at the penultimate position was examined by competitive assay using tripeptides with glycine at the C-termini and the inhibitory potency of these peptides in descending order was methionine > aromatic > non-polar amino acids.

Acetates↗

PubMed1992

Synergistic inhibition of human gastric carcinoma cell growth by 1-beta-D-arabinofuranosylcytosine and hydroxyurea or 2'-deoxyguanosine in vitro.

The cytotoxicity of 1-beta-D-arabinofuranosylcytosine (ara-C) in combination with hydroxyurea (HU) or 2'-deoxyguanosine (GdR) on human gastric carcinoma MK-1 cells and colon carcinoma HT-15 cells was studied. Synergistic interaction between ara-C and HU on MK-1 cells and HT-15 cells, or ara-C and GdR on MK-1 cells was shown using the combination index method. HU increased the accumulation of ara-C triphosphate (ara-CTP) in the acid-soluble pool and diminished the cellular deoxyCTP (dCTP) pool. HU had no effect on the incorporation of ara-C into DNA and RNA. These results indicate that HU-induced elevation in ara-CTP and decrease in dCTP are the basis for synergy among ara-C and HU in MK-1 cells. GdR diminished cellular dCTP slightly, but it decreased the accumulation of ara-CTP in the acid-soluble pool and did not increase the incorporation of ara-C into DNA. On the other hand, ara-C increased cellular deoxyGTP (dGTP) level in the presence of GdR. These results indicate that synergy between ara-C and GdR is mediated through increased cellular dGTP which might inhibit DNA synthesis directly.

Carcinoma↗

PubMed1992

Evaluation of three hepatitis C virus-related antibodies C100, KCL-163, JCC. Tests for screening blood donors.

To evaluate the most effective method for detecting hepatitis C virus (HCV) carriers in a large population of blood donors, HCV-related antibodies were measured in 919 donor serum samples using three different enzyme-linked immunosorbent assays. The antibodies were C100 and KCL-163, nonstructural proteins of HCV, as well as JCC, a translation product of the presumptive HCV core gene. Fourteen (1.5%), 12 (1.3%), and 13 (1.4%) specimens were positive for anti-C100, anti-KCL-163, and anti-JCC, respectively. HCV RNA was detected by the polymerase chain reaction in seven (25.0%) of the 28 specimens that were anti-HCV-positive by at least one of the three assays. Four of the seven specimens were detected by anti-C100 screening, while the remaining three were not. All seven specimens were positive for KCL-163 and/or JCC antibodies. These findings suggest that screening for both KCL-163 and JCC antibodies may be of particular use in accurately identifying HCV-positive blood.

Adult↗

PubMed1992

Clinical evaluation of three anti-HCV ELISAs in patients with various liver diseases.

We measured antibodies to hepatitis C virus (HCV) in 380 patients with various liver diseases by three enzyme-linked immunosorbent assays (ELISAs): HCV antibody ELISA test (C100), KCL-163 (KCL) corresponding to the nonstructural protein of HCV, and JCC based on the translation product of the presumptive HCV core gene. Of 233 cases of non-A, non-B (NANB) liver disease, 63.9% were anti-C100 positive, 69.1% were anti-KCL positive, and 79.8% were anti-JCC positive. Detection of serum HCV-RNA in 213 cases of chronic NANB liver disease revealed that the concordance was 80.3% for C100, 86.4% for KCL, 94.8% for JCC, and 95.3% for all three ELISAs. Overall, 85.4% of chronic NANB cases were considered to have type C disease with HCV infection. The most reliable assays for diagnosing chronic NANB liver disease as type C appeared to be the KCL and JCC ELISAs.

Adolescent↗

PubMed1992

A case of an undifferentiated small cell carcinoma of the esophagus with a primary abdominal mass.

This paper reports a case with an undifferentiated carcinoma of the esophagus which primarily developed symptoms due to metastatic lesions. The case was a 59-year-old woman with a primary manifestation of an abdominal mass and with subsequent dysphagia. A protruding lesion with ulceration was found at the lower third of the thoracic esophagus by endoscopic examination and was histologically proved to be an undifferentiated carcinoma by biopsy. The abdominal mass was initially thought to be due to metastasis to an abdominal lymph node based on the diagnosis image finding at admission, but it was consequently found by autopsy to be a metastatic tumor in the liver. Therefore, undifferentiated carcinoma of the esophagus should be take into account for differential diagnosis of an abdominal mass.

Abdominal Neoplasms↗

PubMed1992

Hapten synthesis for (+)-6-(2-chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tet rahydro-8H-pyrido[4',3':4,5]thieno[3,2-f] triazolo[4,3-a][1,4]diazepine (E6123).

(+)-6-(2-Chlorophenyl)-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4, 5-tetrahydro-8H-pyrido[4',3':4,5]thieno[3,2-f]triazolo[4,3-a] [1,4]diazepine (E6123) is a very potent platelet-activating factor (PAF) receptor antagonist and shows potent anti-PAF activities at the microgram level in a variety of animal models. In order to examine the pharmacokinetics of E6123 at low doses, establishment of a radioimmunoassay is required. On the basis of the metabolic pattern of E6123, we synthesized 6-[2-chloro-4-(3-carboxypropyl) phenyl]-3-cyclopropanecarbonyl-8,11-dimethyl-2,3,4,5-tetrahydro-8H -pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine 22 as a potential hapten. In the synthesis of 22, we developed butynyl carbamate as a piperidine ring N-protecting group to prevent possible side reaction, namely oxidation of the methylene at position 2. This protecting group is stable under usual basic and acidic conditions.

Azepines↗

PubMed1992

Effect of methylene blue on the vesicourethral function in the rats.

The bladder and urethral activities during the rhythmic bladder contractions were evaluated before and after the intraarterial administration of methylene blue, which prevents the activation of soluble guanylate cyclase. The methylene blue produced an increase in the bladder activity and a decrease in the urethral smooth muscle relaxant response induced with bladder contraction. The L-arginine/nitric oxide pathway seems to modulate the vesicourethral function.

Anesthesia↗

PubMed1992

[Enophthalmos following radical operation of the maxillary sinus and ethmoidal sinus].

Enophthalmos is usually a consequence of orbital trauma resulting in a blowout fracture of the orbital floor. We report here the case of a 35-year-old male who had a radical operation of the maxillary sinus and the ethmoidal sinus, and 2 months after the operation, developed spontaneous enophthalmos and ocular pain. The left orbit was enophthalmic by 5mm according to Hertel enophthalmometry. Surgical correction was performed under general anesthesia. The left orbit was explored through a transcutaneous incision of the left lower lid which revealed marked periosteal adhesions and absence of the bony floor of the orbit. A rib cartilage graft was used to reconstruct the floor of the orbit, and the globe was brought forward by means of retrobulbar placement. Enophthalmos and ocular pain disappeared postoperatively.

Adult↗

PubMed1992

Ribozymes for specific inhibition of mRNA function in the nematode Caenorhabditis elegans.

Nine different hammerhead ribozymes were designed for three specific sites of unc-22 mRNA in C. elegans, which carry the common catalytic core and 12, 16 or 20 flanking nucleotides for base pairing with the mRNA, and tested for cleavage of short substrate RNA in vitro. All the ribozymes cleaved the substrate RNA catalytically at 37 degrees C and the activities at 37 degrees C were higher for all the ribozymes than those at 20 degrees C, the nematode growth temperature. Plasmids carrying each of a few different promoters and lacZ reporter gene were prepared and tested in the nematode as a test of vectors for the expression of ribozymes in vivo.

Animals↗

PubMed1992

Prevalence of hepatitis C virus antibodies in hemodialysis patients and dialysis staff.

To estimate the prevalence of hepatitis C virus (HCV) infection in dialysis patients, serum anti-HCV antibodies were evaluated in 489 Japanese patients undergoing hemodialysis, and 152 members of the hospital dialysis staff by enzyme-linked immunosorbent assays for anti-C100, anti-KCL-163 (HCV nonstructural protein), and anti-JCC (translation product of the presumptive HCV core gene). Of the 489 hemodialysis patients, 100 (20.4%) were positive for anti-C100, 107 (21.9%) for anti-KCL-163, and 168 cases (34.4%) for anti-JCC. These rates were significantly higher than those for either the hospital staff or the healthy blood donors. Forty-two per cent of the dialysis patients were anti-HCV positive by at least one assay, suggesting that HCV infection is more common among this population than previously thought. Positivity for anti-HCV was related to the duration of hemodialysis. Elevated alanine aminotransferase levels were present in 12.5% of the dialysis patients, 77% of whom were also anti-HCV positive. The positivity rates among the 152 members of the hospital staff were 0.7% for anti-C100, 2.6% for anti-KCL-163, and 8.6% for anti-JCC, with the anti-JCC rate of positivity exceeding that of the healthy blood donors.

Adult↗

PubMed1992

[Combination therapy of doxifluridine (5'-DFUR) + cyclophosphamide (CPA) + tamoxifen (TAM) for advanced or recurrent breast cancer. Joint Research Group in the Osaka Area for Combination Therapy of 5'-DFUR with Other Drugs].

Outpatients with advanced and recurrent breast cancer were treated by a combination therapy of the following drugs: doxifluridine (5'-DFUR) orally administered at a dose of 1200 mg/day; cyclophosphamide (CPA) orally given at dose of 100 mg/day; and tamoxifen (TAM) orally given at dose of 20 mg daily. 5'-DFUR and CPA were administered on consecutive days 1-14, then discontinued for 14 days. The response rate was 44.8% including five CR and eight PR out of 29 complete cases. As for response cases in terms of the subject lesions, corresponding cases were chiefly found in soft tissue and the lung. As for the response rate with or without pretreatment, cases previously treated showed a higher response rate such as 42.9% indicating that the present therapy was effective in pretreatment cases. The main side effect was leukopenia, but not so severe. Few cases with diarrhea were found. Based on the above findings, the present treatment is conceivably a highly useful therapy, on an outpatient basis, for advanced and recurrent breast cancer, especially metastatic lesions of soft tissue and the lung.

Administration, Oral↗

PubMed1992

[Locoregional therapy in patients with malignant pleural effusion--two different types of "BAC therapy"].

We used fibrin clot (FC) as a carrier of anticancer drug (AD) to provide a novel therapy for patients with serious malignant pleural effusion. After evacuating the pleural fluid, we enhanced an "FC-AD" formation in the pleural cavity of the patient to prevent this kind of effusion from reaccumulating. In an attempt to enhance FC-AD formation, we used two different procedures; either, fibrinogen/AD/G.T.XIII (procedure I) or fibrin glue/AD (procedure II). G.T.XIII is our newly devised compound drug, composed of biodegradable gelatin (G), thrombin (T) and a blood coagulation factor XIII (XIII). This therapy was termed "Bio-Adhesio-Chemo (BAC) therapy." We conducted BAC therapy 52 times on 44 patients using procedure I and 4 times on 4 patients using procedure II. Complete remission of the effusion was obtained, overall, in 83%, partial remission in 17%, and no non-effective case. The improvement of PS of the patients treated was 73%. Nineteen patients could be discharged with this therapy. Toxic effects with BAC therapy were within Grade 2 in all cases. We could favorably enhance FC-AD formation, in every case, by both procedure I and II. BAC therapy is very promising as a novel cancer chemopleurodesis for patients with malignant pleural effusion.

Antineoplastic Combined Chemotherapy Protocols↗