Pleiotropic effects of mitiglinide in type 2 diabetes mellitus.

This study investigated the effects of mitiglinide in 16 patients with type 2 diabetes mellitus treated with 30 mg/day mitiglinide, divided into three doses given just before each meal, for approximately 12 months. A 450 kcal meal tolerance test was performed at baseline and after 3, 6 and 12 months, and levels of plasma glucose and immunoreactive insulin were measured. Various parameters of glucose metabolism and lipid metabolism, urinary albumin and markers of atherosclerosis, coagulation and fibrinolysis were also determined. Mitiglinide showed a rapid stimulatory effect on insulin secretion and reduced the levels of plasma glucose. The free fatty acid level significantly decreased at 60 min after the meal tolerance test. Mitiglinide also significantly lowered glycosylated haemoglobin and raised 1,5-anhydroglucitol after 6 months, and significantly decreased urinary albumin after 12 months. These data indicate that mitiglinide may have beneficial effects not only on glycaemic control but also on lipid metabolism and urinary albumin excretion, and may have a role in the prevention of the vascular complications of diabetes.

Release of alpha-neoendorphin from the anterior pituitary gland of conscious rats.

alpha-Neoendorphin (alpha-NEO) is a proenkephalin B-derived opioid peptide and kappa type opioid receptor agonist. In the present study, we used a combination of microdialysis and a highly sensitive radioimmunoassay to measure the extracellular levels of immunoreactive (ir)-alpha-NEO from the anterior pituitary gland of conscious free-moving rats. When rats were given water ad libitum under a 12:12 h light-dark cycle with lighting from 06.00 to 18.00 h, ir-alpha-NEO showed circadian rhythmicity that peaked at 00.00-03.00 h and reached a minimum at 12.00-15.00 h. Furthermore, we investigated whether naloxone (10(-6) to 10(-8) M) affected ir-alpha-NEO level. The alpha-NEO release induced by naloxone was optimum at 10(-7) M, and 10(-6) M naloxone seemed to induce alpha-NEO release to a lesser degree. These results suggested that alpha-NEO release by naloxone might be mediated via anterior pituitary cell auto-receptor (kappa type) inhibition.

Modification of acetylcholine release by nociceptin in conscious rat striatum.

Nociceptin (NOC), an endogenous ligand for the orphan opioid receptor ORL1 (ORL1), has recently been recognized as a neuropeptide. We used brain microdialysis and on-line high performance liquid chromatography (HPLC) to examine the effect of NOC on the basal outflow of acetylcholine (ACh) in the freely moving rat striatum in vivo. ACh release was reduced by nociceptin at a concentration of 10(-5) M to 79% of control release. This effect of NOC was attenuated by [Phe1Psi(CH2-NH)Gly2]nociceptin-(1-13)-NH2 (PhePsi), suggesting that NOC activates the ORL1 receptor and (PhePsi) acts as an antagonist on ORL1 in rat striatum in vivo. These findings indicate that NOC may act as a neuropeptide which inhibits ACh release in the striatum via ORL1.

Modification of dopamine release by nociceptin in conscious rat striatum.

Nociceptin (NOC), an endogenous ligand for the orphan receptor ORL1, has recently been recognized as a neuropeptide. We used brain microdialysis and on-line high performance liquid chromatography to examine the effect of NOC on the basal outflow of dopamine (DA) and its metabolite in the freely moving rat striatum in vivo. The percent change of DA release induced by NOC at concentrations of 10-6 and 10-5 M were 383% and 398%, respectively. This effect of NOC was attenuated by naloxone, suggesting that NOC activates classic (micro, delta, kappa) receptors in a very little way. These data indicates that NOC may act as a neuropeptide which enhances DA release from the striatum of rat brain via an opioid receptor.

Endothelin-3 modification of dopamine release in anaesthetised rat striatum; an in vivo microdialysis study.

Endothelin-3 (ET-3), a member of the vasoconstrictive peptide family, has recently been recognized as a neuropeptide. We used brain microdialysis and on-line HPLC to examine the effect of ET-3 on the basal outflow of monoamines and their metabolites in the ketamine-anaesthetised rat striatum in vivo. Although intrastriatal infusion of ET-3 (40 pmol/rat) did not change basal dopamine (DA) release, after perfusion of DA releasing agent (5 x 10(-5) M ouabain or 120 mM KCl), ET-3 could increase the DA level. Further, these effects of ET-3 were attenuated by calcium-free Ringer. These data indicated that ET-3 may act by modifying the exocytosis from the striatum of rat brain to enhance DA release after depolarization induced by an agent such as KCl or ouabain.

[Clinical experience with sustained release cephalexin (S-6436) in urology (author's transl)].

Clinical studies of S-6436 were conducted in 30 urinary tract infection patients in urology with the following conclusion. The patients received the drug twice a day after breakfast and dinner. 1. Of the 30 patiens, excellent efficacy was observed in 9 patients, good efficacy in 14, fair in 5 and poor in 2. The effectiveness (excellent or good) was 76.7%. 2. Twenty-seven (27) strains were isolated from the 30 patients and 23 strains (85.2%) of the 27 disappeared with the administration of the drug. 3. Side effects were found in 3 patients (10%) of the 30. The incidence was almost similar to that of regular cephalexin. No remarkable changes in laboratory data were observed. 4. S-6436 which requires the administration of only twice a day is a preparation which is more convenient for patients than regular cephalexin which requires the administration of four times a day.

[Retroperitoneal plasmacytoma: a case report].

We have experienced a case of retroperitoneal plasmacytoma. A 47-year-old man was admitted to our hospital with the chief complaints of right lumbago and lower abdominal dull pain. Roentgenography revealed retroperitoneal tumors, and right nephrectomy and excision of left pararenal tumors were performed. The histological examination and urine immunoelectrophoresis showed retroperitoneal plasmacytoma. No signs or symptoms of multiple myeloma were recognized postoperatively. The literature is reviewed briefly concerning the diagnosis and treatment of retroperitoneal plasmacytoma.

[Management with antithrombin III concentrate in a pregnant woman with hereditary antithrombin III deficiency].

Pregnant women with hereditary antithrombin III (AT-III) deficiency are frequently associated with thromboembolic disorders. We have treated a pregnant woman with hereditary AT-III deficiency, who had suffered from thromboembolic disorders at her past three gestations, with AT-III concentrate. Dosage of AT-III concentrate to maintain plasma AT-III activity over 80% was 3,500 units per week during second and third trimesters, but more frequent administration was necessary around delivery. In recent reports, pregnant women with hereditary AT-III deficiency had been treated with heparin or warfarin except for during abortion and delivery, in which time AT-III concentrate was widely utilized. But the use of heparin or warfarin during gestation is occasionally harmful, AT-III concentrate should be chosen for management in pregnancy in women with hereditary AT-III deficiency.

[Coombs negative autoimmune hemolytic anemia in a patient with myelodysplastic syndrome].

A 29 year-old-man who had been diagnosed as having myelodysplastic syndrome (MDS) in August 1985 was re-admitted to our hospital because of fever and palpitation. His peripheral blood showed severe pancytopenia and bone marrow findings remained to be compatible with MDS (refractory anemia), but karyotype of bone marrow cells revealed 7 monosomy in 17 of 20 metaphases examined. Other laboratory findings revealed decreased serum haptoglobin, positive urine hemosiderin and the normal resistance of red cell membrane. In addition, both Ham test and sugar water test were negative. The titer of cold agglutinin was low, Donath-Landsteiner antibody was not detected. These findings suggested the association of autoimmune hemolytic anemia (AIHA), although both direct and indirect Coombs' test were negative. After administration of 50mg of prednisolone daily, the frequency of red cell transfusion was markedly decreased and transfused red cell life span was prolonged from 10.4 days to 27 days. Afterward, his hematological status rapidly transformed into that of acute nonlymphocytic leukemia about 13 months after admission and he died of gastrointestinal bleeding and cerebral bleeding. Cases of MDS with immunological disorder have been reported. This is, however, the first case of MDS associated with Coombs negative AIHA.

[L-asparaginase-induced hyperlipidemia in a case of acute lymphoblastic leukemia].

A 15-y-o girl who had relapsed acute lymphoblastic leukemia, followed by the two-years complete remission, was treated with a reinduction chemotherapy including methotrexate, vincristine, L-asparaginase and dexamethasone (MOAD). During the chemotherapy, a remarkable hyperlipidemia has developed. The plasma levels of triglyceride and total cholesterol reached 14,450 mg/dl and 1,750 mg/dl, respectively. The laboratory data strongly suggest that L-asparaginase could induce this hyperlipidemia of Friedrickson type V. We could successfully reduce the levels of triglyceride and total cholesterol to the normal range by LDL-apheresis, and treat the patient with the chemotherapy excluding L-asparaginase to attain the second CR.

Continuous stimulation of human glucagon-like peptide-1 (7-36) amide in a mouse model (NOD) delays onset of autoimmune type 1 diabetes.

AIMS/HYPOTHESIS: We examined the effect of glucagon-like peptide-1 (GLP-1) on the development of diabetes and islet morphology in NOD mice by administering GLP-1 to prediabetic mice. METHODS: Eight-week-old female NOD mice were infused subcutaneously with human GLP-1 via a mini-osmotic pump for 4 or 8 weeks. In mice treated with GLP-1 for 4 weeks, blood glucose levels and body weight were measured. An intraperitoneal glucose tolerance test (IPGTT) and evaluation of insulitis score were also performed. Beta cell area, proliferation, apoptosis, neogenesis from ducts and subcellular localisation of forkhead box O1 (FOXO1) were examined by histomorphometrical, BrdU-labelling, TUNEL, insulin/cytokeratin and FOXO1/insulin double-immunostaining methods, respectively. RESULTS: Mice treated with human GLP-1 for 4 weeks had lower blood glucose levels until 2 weeks after completion of treatment, showing improved IPGTT data and insulitis score. This effect continued even after cessation of the treatment. In addition to the increase of beta cell neogenesis, BrdU labelling index was elevated (0.24 vs 0.13%, p < 0.001), while apoptosis was suppressed by 54.2% (p < 0.001) in beta cells. Beta cell area was increased in parallel with the translocation of FOXO1 from the nucleus to the cytoplasm. The onset of diabetes was delayed in mice treated with GLP-1 for 4 weeks, while mice treated with GLP-1 for 8 weeks did not develop diabetes by age 21 weeks compared with a 60% diabetes incidence in control mice at this age. CONCLUSIONS/INTERPRETATION: Continuous infusion of human GLP-1 to prediabetic NOD mice not only induces beta cell proliferation and neogenesis, but also suppresses beta cell apoptosis and delays the onset of type 1 diabetes.

Clinical significance of circulating hepatocyte growth factor, a new risk marker of carotid atherosclerosis in patients with Type 2 diabetes.

AIMS: Recent studies have provided increasing evidence that hepatocyte growth factor (HGF) has a pathophysiological role in the development of diabetic complications. We set out to determine the relationship between serum HGF and risk factors for macroangiopathy including carotid atherosclerosis. Carotid atherosclerosis is an established and important risk factor for both cerebral and coronary artery diseases. METHODS: We studied 89 patients (48 males, 41 females, mean age 62.5 +/- 10.3 years) with Type 2 diabetes (DM). RESULTS: Serum levels of HGF correlated positively with both intimal-media thickness (IMT) (r = 0.24, P = 0.0248) and plaque score (r = 0.27, P = 0.0126). In multiple regression analysis, serum HGF was associated independently with IMT (standardized beta = 0.28, P = 0.0499). We also found that both IMT and plaque score were higher in patients with ischaemic heart disease (IHD) than in patients without IHD, and that plaque score in patients with lacunar infarcts was higher than in patients without lacunar infarcts. CONCLUSIONS: Serum HGF concentration may be a new marker of atherosclerotic complications in patients with Type 2 DM.