Effects of mitiglinide on glucose-induced insulin release into the portal vein and fat-induced triglyceride elevation in prediabetic and diabetic OLETF rats.

OBJECTIVE: The effect of single-dose mitiglinide on glucose and lipid metabolism was examined in OLETF rats with spontaneous type 2 diabetes in which the early insulin response following glucose challenge is known to diminish over time and become lost with aging. METHODS: (1) With catheters inserted into the portal veins, 12-wk-old prediabetic OLETF rats were given an OGTT of 1 g/kg after 17 h of fasting. Eight rats each were orally given mitiglinide 1 mg/kg, nateglinide 50 mg/kg, or glibenclamide 1 mg/kg, vs 0.5% carboxymethylcellulose (CMC) as control, and were given an OGTT immediately afterward. Following oral administration of mitiglinide, nateglinide, glibenclamide, or 0.5% CMC, the 24-wk-old overt-diabetic OLETF rats were immediately given an OGTT of 1g/kg. (2) After 17 h of fasting, 24-wk-old OLETF rats were subjected to a fat-loading test. Eight rats each were given mitiglinide 3 mg/kg, glibenclamide 1 mg/kg, or glimepiride 1 mg/kg, vs 0.5% CMC, and were given soy oil 2 g/kg immediately afterward. They were also given mitiglinide orally and examined for LPL mRNA expression in their adipose tissue. RESULTS: (1) After OGTT, mitiglinide produced a significant increase in portal insulin levels 15 min after its administration, as well as a significant decrease in peripheral glucose levels 15-120 min after its administration in the OLETF rats. Likewise, nateglinide produced an increase in portal insulin levels and a decrease in peripheral glucose levels shortly after its administration in these rats. Glibenclamide increased portal insulin levels for an extended time after its administration, and significantly decreased peripheral glucose levels in the rats 120-300 min after its administration in the rats. In contrast, as in the 12-wk-old rats, a precipitous rise in insulin secretion was seen in the portal vein of 24-wk-old rats given mitiglinide, which peaked 15 min after mitiglinide administration, but the insulin levels continued to increase for 120 min or longer in the 24-wk-old rats given glibenclamide. In addition, as in the 12-wk-old rats, a significant decrease in glucose levels in peripheral blood was noted 30 and 60 min after mitiglinide administration and 300 min after glibenclamide administration in the 24-wk-old rats. (2) Mitiglinide increased LPL mRNA expression 120 min after its administration, and significantly decreased peripheral TG and chylomicron- TG levels after fat challenge in the 24-wk-old OLETF rats. CONCLUSION: Mitiglinide exhibited fast-onset and short-acting insulin-secretagogic effects, inhibiting post-glucose challenge increases in glucose levels and post-fat challenge increases in TG levels.

Absence of exacerbation of myocardial stunning in anesthetized dogs treated with KAD-1229, a novel hypoglycemic agent.

The effect of (+)-momocalcium bis[(2S,3a,7a-cis)-alpha-benzylhexahydro-gamma-oxo-2-isoindolinebutyrate]dihydrate (KAD-1229), a novel hypoglycemic agent with a chemical structure different from that of the sulfonylureas, on myocardial stunning was assessed in anesthetized dogs by comparison with that of glibenclamide, a sulfonylurea. Even though their hypoglycemic effects were of similar magnitude, glibenclamide (1 mg/kg, i.v.), but not KAD-1229, exacerbated the myocardial stunning induced by occlusion/reperfusion of the descending coronary artery. In a receptor-binding experiment, unlabeled glibenclamide completely inhibited [(3)H]glibenclamide binding to the myocardium, but KAD-1229 did not. These results suggest that the difference in binding properties of KAD-1229 and glibenclamide toward cardiac sulfonylurea receptors is one of the causes of their different effects on myocardial stunning. It is likely that KAD-1229 is highly specific for pancreatic sulfonylurea receptors and is speculated to be a safer hypoglycemic agent than, at least, glibenclamide.

The effects of mitiglinide (KAD-1229), a new anti-diabetic drug, on ATP-sensitive K+ channels and insulin secretion: comparison with the sulfonylureas and nateglinide.

Mitiglinide (KAD-1229), a new anti-diabetic drug, is thought to stimulate insulin secretion by closing the ATP-sensitive K+ (K(ATP)) channels in pancreatic beta-cells. However, its selectivity for the various K(ATP) channels is not known. In this study, we examined the effects of mitiglinide on various cloned K(ATP) channels (Kir6.2/SUR1, Kir6.2/SUR2A, and Kir6.2/SUR2B) reconstituted in COS-1 cells, and compared them to another meglitinide-related compound, nateglinide. Patch-clamp analysis using inside-out recording configuration showed that mitiglinide inhibits the Kir6.2/SUR1 channel currents in a dose-dependent manner (IC50 value, 100 nM) but does not significantly inhibit either Kir6.2/SUR2A or Kir6.2/SUR2B channel currents even at high doses (more than 10 microM). Nateglinide inhibits Kir6.2/SUR1 and Kir6.2/SUR2B channels at 100 nM, and inhibits Kir6.2/SUR2A channels at high concentrations (1 microM). Binding experiments on mitiglinide, nateglinide, and repaglinide to SUR1 expressed in COS-1 cells revealed that they inhibit the binding of [3H]glibenclamide to SUR1 (IC50 values: mitiglinide, 280 nM; nateglinide, 8 microM; repaglinide, 1.6 microM), suggesting that they all share a glibenclamide binding site. The insulin responses to glucose, mitiglinide, tolbutamide, and glibenclamide in MIN6 cells after chronic mitiglinide, nateglinide, or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment. These results indicate that, similar to the sulfonylureas, mitiglinide is highly specific to the Kir6.2/SUR1 complex, i.e., the pancreatic beta-cell K(ATP) channel, and suggest that mitiglinide may be a clinically useful anti-diabetic drug.

A novel reaction for annulation onto alpha,beta-unsaturated ketones: W(CO)(5).L promoted exo- and endo-selective cyclizations of omega-acetylenic silyl enol ethers prepared by 1,4-addition of propargyl malonate to enones.

A highly useful method for five- and six-membered ring annulation onto alpha,beta-unsaturated ketones is described. 1,4-Addition of propargylmalonate to alpha,beta-unsaturated ketones in the presence of silyl triflate gives 7-siloxy-6-en-1-yne derivatives in good yield. W(CO)(5).L-catalyzed cyclization of these substrates can be induced to give preferentially either exo- or endo-cyclized products in good yield simply by changing the reaction solvent. [reaction: see text]

[Subacute cor pulmonale due to microscopic pulmonary tumor embolism].

We report a case of subacute pulmonary hypertension caused by microscopic pulmonary tumor embolism due to the dissemination of gastric cancer cells. The patient, a 61-year-old man with no history of malignant diseases, was admitted to our hospital on October 14 in 1998 because of cough and dyspnea on effort, that had developed since the previous month. On admission, chest radiography including CT scans showed slight cardiomegaly and disseminated reticulonodular shadows predominating in the lower lung fields of both lungs, and arterial blood gas analysis disclosed severe hypoxemia. Lung perfusion scintigraphy revealed multiple irregular defects in both lungs. Echocardiography indicated right ventricular overload, and the pulmonary artery systolic pressure was estimated to be higher than 80 mmHg. Disseminated intravascular coagulation (DIC) developed on the 6th day of hospitalization. Multiple pulmonary embolism with DIC of unknown cause was diagnosed, and the patient was given anticoagulant therapy with heparin. However, he died of respiratory failure on the 7th day of hospitalization. At autopsy, an invasive cancer was found in the stomach, resembling type IIc early gastric cancer. The lumens of the pulmonary arterioles were significantly narrowed by fibrocellular proliferation and thrombi accompanying tumor cell clusters, and some of the microvessels were completely occluded. Disseminated microscopic pulmonary metastasis of malignant tumors should be included in the differential diagnosis of subacute pulmonary hypertension due to multiple pulmonary embolism of unknown cause.

Studies on new platelet aggregation inhibitors 1. Synthesis of 7-nitro-3,4-dihydroquinoline-2(1H)-one derivatives.

A series of 6-cyclic aliphatic amino-7-nitro-3,4-dihydroquinoline-2(1H)-ones were prepared and tested for platelet aggregation inhibitory effect, cardiotonic activity and chronotropic activity. These compounds appeared to show selective inhibitory activity against platelet aggregation. Among them, 6-(4-ethoxycarbonylpiperidino)-7-nitro-3,4-dihydroquinoline-2(1H)-one (22f) showed the most potent inhibitory activity and high selectivity. A divergent synthetic route to 6-cyclic aliphatic amino-7-nitro-3,4-dihydroquinoline-2(1H)-one derivatives has also been investigated.

[Increased neuron-specific enolase levels in patients with long-standing pyothorax-associated lymphoma].

A 78-year-old man was admitted for the evaluation of chest pain and a subcutaneous giant mass in the left chest, which had been growing for 3 months. A computed tomogram of the chest revealed a giant tumor attached to the parietal pleura with calcification of long-standing pyothorax. Pathological findings of a specimen obtained from this tumor showed diffuse proliferation of large atypical lymphocytes with 1-2 nucleoli and abundant cytoplasm. In immunohistochemical studies, tumor cells stained positive for CD20 but not for CD45 RO. The diagnosis was long-standing pyothorax-associated lymphoma (diffuse large-cell lymphoma, B-cell type). The patient's serum neuron-specific enolase (NSE) level was 101 ng/ml on admission, and declined in tandem with a chemotherapy-induced decrease in tumor size. In addition, immunohistochemical studies showed staining of tumor cells by anti-NSE polyclonal antibody. Although rarely observed in patients with malignant lymphoma, increased serum NSE levels may serve as an index of chemotherapeutic effectiveness.

Extragonadal germ cell tumor of the prostate associated with Klinefelter's syndrome.

PURPOSE: We report on a case of extragonadal germ cell tumor of the prostate associated with Klinefelter's syndrome. METHODS/RESULTS: The patient was a 33-year-old man. A transrectal prostate biopsy suggested combined germ cell tumor (yolk sac tumor + teratoma). Because there was no tumor except from the prostate, we considered this case to be a primary extragonadal germ cell tumor of the prostate. The prostate tumor responded to systemic chemotherapy with cisplatin, vinblastine and bleomycin and elevated lactate dehydrogenase and alpha-fetoprotein levels normalized. In addition to chemotherapy, the patient also underwent radiation therapy. CONCLUSION: The patient has survived for approximately 4 years since the diagnosis.

Tranilast inhibits the proliferation of human coronary smooth muscle cell through the activation of p21waf1.

Restenosis after percutaneous transluminal coronary angioplasty (PTCA) occurs due to vascular smooth muscle cell proliferation and migration. Recently, tranilast, an anti-allergic drug, has been used for the prevention of restenosis after PTCA. To determine the molecular mechanism involved, the effect of tranilast on the proliferation of human coronary smooth muscle cells (SMCs) was investigated. Tranilast arrested the proliferation of human coronary SMCs at the G0/G1 phase of the cell cycle. In association with this inhibitory effect, tranilast increased p21waf1 and p53 tumor suppressor factor, and decreased cyclin-dependent kinase 2 (CDK2) activity. These results suggest that tranilast inhibits the proliferation of human coronary SMCs during restenosis after PTCA via an induction of p21waf1 and p53. Tranilast may thus allow us to prevent restenosis after PTCA by interfering with this mechanism.

Ki-1 (CD30)-positive anaplastic large cell lymphoma, sarcomatoid variant accompanied by spontaneously regressing lymphadenopathy.

Although it has been reported that primary Ki-1 (CD30)-positive anaplastic large cell lymphoma (ALCL) of the skin may undergo spontaneous regression, it is rare for ALCL without cutaneous involvement to have spontaneously regressing lymphadenopathy. We report a case of sarcomatoid variant of ALCL accompanied by spontaneously regressing lymphadenopathy. The patient had gastric and pulmonary involvement of ALCL in addition to systemic lymphadenopathy, but with no cutaneous involvement. The lymphadenopathy spontaneously improved gradually during a period of one month without any treatment. At the same time, multiple small nodules in both lung fields decreased on chest computed tomography and multiple elevated gastric tumors with dimples were endoscopically recognized to have improved. He has since been treated with combination chemotherapy because of recurrence of the lymphadenopathy.

[Chronic thromboembolic pulmonary hypertension associated with initial pulmonary involvement in Takayasu arteritis].

A 37-year-old non-smoking woman was admitted to our hospital because of nocturnal coughing and exertional dyspnea after using an ultrasonic humidifier. Chest roentgenograms and computed tomography showed many ground-glass opacities in the right upper lobe and left upper lung field. Her symptoms were alleviated and erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels returned to normal following the administration of prednisolone (40 mg/day). The same symptoms subsequently recurred, and ESR and CRP levels increased proportionately to a decreased dosage of prednisolone. In addition, chest computed tomography showed new opacities in the left lower lobe. Transbronchial lung biopsy specimens revealed multiple stenotic or obstructive changes in the small pulmonary arteries by organizing thromboemboli, with no vasculitis. The diagnosis of chronic thromboembolic pulmonary hypertension was made on the basis of multiple defects from lung perfusion scintigraphy, irregular or tapering of the pulmonary arteries detected by pulmonary arteriograms, and increased pulmonary pressure measured by echocardiography. We propose that the pulmonary thromboembolism observed in this case was related to the initial pulmonary involvement of Takayasu arteritis, since the patient's symptoms, ESR and CRP levels all improved markedly following the administration of prednisolone.

Pyoderma gangrenosum following cytosine arabinoside, aclarubicin and granulocyte colony-stimulating factor combination therapy in myelodysplastic syndrome.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis, which may be associated with systemic conditions such as hematologic disorders. We present a patient who had been diagnosed as having myelodysplastic syndrome associated with PG at onset, in whom a febrile ulcerative skin lesion developed following cytosine arabinoside, aclarubicin and granulocyte colony-stimulating factor (G-CSF) combination chemotherapy in the course of the disease. Skin biopsy revealed dense neutrophilic infiltrate in the dermis with central epidermal ulceration, consistent with the diagnosis of PG. Oral prednisolone was effective for the skin lesion. In this case, G-CSF application may participate in the recurrence of PG.

Synthesis of C-ring aromatic taxoids and evaluation of their multi-drug resistance reversing activity.

The C-aromatic taxoids were synthesized to develop effective inhibitors against drug efflux mediated by p-glycoproteins. Among those tested using multi-drug resistant tumor cells (2780AD), the benzoate 11 exhibited significant activity as potent as verapamil, a well-established MDR reversing agent.

Synthesis and evaluation of artificial taxoids with antitumor and multi-drug resistance reversing activities.

Artificial taxoids were synthesized and subjected to evaluation of their ability of multi-drug resistance reversing and antitumor activities. While the taxoid 4 could not increase cellular accumulation of vincristine in multi-drug resistant tumor cells, the C4-hydroxy analog 15 showed significant effect. However, these compounds showed weak activities on growth inhibition of cancer cells.

[Bilateral hilar and mediastinal lymphadenopathy accomporying pulmonary infiltration with eosinophilia].

A 46-year-old man had had an occasional dry cough in the early morning since about the age of 20, but had received no treatment. He had been taking an antirheumatic drug for 2 years for rheumatoid arthritis. The patient complained of fever and dry coughing that began in the middle of November 1995, and he was treated for acute bronchitis. His condition did not improve, and he was admitted to the hospital in early December. Wheezing and rhonchi were heard in both lung fields. His white blood cell count was 19,000/mm3, and the eosinophil percent age was 48%. A chest CT scan revealed macular lesions with an increased density in both lung fields, and markedly swollen mediastinal and hilar lymph nodes. Analysis of alveolar lavage fluid revealed an increased number of cells (total) and eosinophilia (37%), and examination of a transbronchial lung biopsy specimen indicated infiltration with eosinophils and lymphocytes. Our diagnosis was eosinophilic pneumonia. The patient's condition improved soon after the start of pulse therapy with steroids. Bilateral swelling of mediastinal and hilar lymph nodes is rare in patients who have pulmonary in filtration with eosinophilia (the PIE syndrome).

Malignant solitary fibrous tumor arising in the right buttock associated with metastatic parietal pleural and intrapulmonary tumors in addition to pleural effusion.

A malignant solitary fibrous tumor arising in the right buttock associated with metastatic parietal pleural and intrapulmonary tumors and pleural effusion was found in a 59-year-old man. A chest computed tomogram revealed three tumors attached to the parietal pleura with rib destruction, and a tumor in the left lower lung field. Histologically, the tumors of the buttock and parietal pleura were characterized by proliferation of bundles of spindle-shaped or oval cells separated by wavy hyalinized collagen tissue with no expression of cytokeratin, S-100 protein, muscle actin or epithelial membrane antigen, but these cells weakly expressed CD34 and strongly expressed vimentin.

[A case report of ileovesical fistula in radiation enteritis].

A 49-year-old female was admitted with chief complaint of fecaluria on March 4th 1993. A radiation therapy had been performed for uterocervical cancer 18 years ago. The small intestine and bladder was detected by DIP- and cystogram simultaneously. It was diagnosed as an ileovesical fistula. A segmental resection of the ileum with partial cystectomy was performed on March 23rd. Histopathologically, the ileum showed a radiation enteritis. Eventually, we diagnosed that this ileovesical fistula was caused by radiation. After operation, an incompletion of suture occurred. So we made an ileostomy secondarily and performed hyperbaric oxygen therapy. The patient was getting well temporarily but died of gastric hemorrhage on May 1st.

[Acute pulmonary disease in systemic lupus erythematosus successfully treated with prednisolone pulse therapy].

A 46-year-old man was admitted to the hospital because of chest pain and left pleural effusion. Fever and dyspnea developed on the third hospital day. Interstitial shadows and pleural effusions in both lower lung fields appeared on chest roentgenograms. Microscopic examination of transbronchial lung biopsy specimens taken on hospital day 5 showed thickening of the alveolar walls and desquamation of macrophages into the alveolar spaces. Analysis of bronchoalveolar lavage fluid revealed many cells and macrophages. Tests for anti-nuclear antibody and anti-DNA antibody were positive, which, in addition to serositis and proteinuria, established the diagnosis of systemic lupus erythematosus. The interstitial shadow on chest roentgenograms was believed to have reflected an acute pulmonary manifestation of systemic lupus erythematosus. The symptoms and the abnormality on chest roentgenograms were relieved within 1 month of the start of pulse therapy with prednisolone.