Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin compared with α-glucosidase inhibitor in Japanese patients with type 2 diabetes inadequately controlled on sulfonylurea alone (SUCCESS-2): a multicenter, randomized, open-label, non-inferiority trial.

We assessed the efficacy and safety of sitagliptin compared with α-glucosidase inhibitor (αGI) in 120 of Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled on stable ≤2 mg/day glimepiride alone [mean hemoglobin A1c (HbA1c) 7.7%] by the randomized, active-controlled, non-inferiority trial. Patients were randomly assigned to receive additional sitagliptin or αGI for 24 weeks. The primary endpoint was change in HbA1c from baseline to week 12. After 12 weeks, sitagliptin reduced HbA1c by -0.44% (p < 0.001) relative to αGI. At 24 weeks, the reduction was almost identical between the groups (-0.091%, p = 0.47). Gastrointestinal disorders were more common with αGI than with sitagliptin, but only minor hypoglycaemia occurred in both groups at similar frequency. These data suggested that sitagliptin was not inferior to αGI for reduction of HbA1c in Japanese T2DM patients receiving glimepiride alone, and well tolerated with minimum risk of gastrointestinal symptoms and hypoglycaemia.

Large-scale production and properties of human plasma-derived activated Factor VII concentrate.

BACKGROUND AND OBJECTIVES: An activated Factor VII (FVIIa) concentrate, prepared from human plasma on a large scale, has to date not been available for clinical use for haemophiliacs with antibodies against FVIII and FIX. In the present study, we attempted to establish a large-scale manufacturing process to obtain plasma-derived FVIIa concentrate with high recovery and safety, and to characterize its biochemical and biological properties. MATERIALS AND METHODS: FVII was purified from human cryoprecipitate-poor plasma, by a combination of anion exchange and immunoaffinity chromatography, using Ca2+-dependent anti-FVII monoclonal antibody. To activate FVII, a FVII preparation that was nanofiltered using a Bemberg Microporous Membrane-15 nm was partially converted to FVIIa by autoactivation on an anion-exchange resin. The residual FVII in the FVII and FVIIa mixture was completely activated by further incubating the mixture in the presence of Ca2+ for 18 h at 10 degrees C, without any additional activators. For preparation of the FVIIa concentrate, after dialysis of FVIIa against 20 mm citrate, pH 6.9, containing 13 mm glycine and 240 mm NaCl, the FVIIa preparation was supplemented with 2.5% human albumin (which was first pasteurized at 60 degrees C for 10 h) and lyophilized in vials. To inactivate viruses contaminating the FVIIa concentrate, the lyophilized product was further heated at 65 degrees C for 96 h in a water bath. RESULTS: Total recovery of FVII from 15 000 l of plasma was approximately 40%, and the FVII preparation was fully converted to FVIIa with trace amounts of degraded products (FVIIabeta and FVIIagamma). The specific activity of the FVIIa was approximately 40 U/ micro g. Furthermore, virus-spiking tests demonstrated that immunoaffinity chromatography, nanofiltration and dry-heating effectively removed and inactivated the spiked viruses in the FVIIa. These results indicated that the FVIIa concentrate had both high specific activity and safety. CONCLUSIONS: We established a large-scale manufacturing process of human plasma-derived FVIIa concentrate with a high yield, making it possible to provide sufficient FVIIa concentrate for use in haemophiliacs with inhibitory antibodies.

A case of POEMS syndrome with high concentrations of interleukin-6 in pericardial fluid.

The POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy of various forms, monoclonal gammopathy, skin changes) is a rare multisystem disorder of unknown pathogenesis. Overexpression of proinflammatory cytokines has been implicated in the pathogenesis of POEMS syndrome, however, it is not known whether there is an association between abnormalities in cytokines and pericardial fluid. We present a case of POEMS syndrome with high concentrations of interleukin-6 (IL-6) in pericardial fluid. In our patient, pericarditis developed into cardiac tamponade, and the concentration of IL-6 in pericardial fluid was remarkably elevated compared with that in serum (1760 vs. 6.57 pg mL(-1)). We suggest that IL-6 is associated with the progression or maintenance of pericarditis as a result of POEMS syndrome.

Diabetic ketoacidosis associated with recurrent pulmonary edema and rhabdomyolysis in a patient with Turner's syndrome.

Turner's syndrome is a condition involving total or partial absence of one X chromosome and has been associated with a number of diseases including non insulin dependent diabetes mellitus, abnormalities of glucose metabolism and hypothreosis. There have been many case reports in which Turner's syndrome is associated with type 2 diabetes, but the association with type 1 diabetes and/or life threatening complications is very rare. We present an unusual case of a patient with Turner's syndrome who has type 1 diabetes and is complicated with ketoacidosis, severe acute and recurrent pulmonary edema and rhabdomyolysis.

Fulminant Mycoplasma pneumoniae pneumonia.

A 64-year-old woman, who was previously in good health was admitted because of progressive respiratory distress. Her chest radiograph revealed bilateral widespread alveolar infiltrates. She was given a diagnosis of pneumonia caused by Mycoplasma pneumoniae serologically, acute respiratory distress syndrome, and disseminated intravascular coagulation. She died of multiple organ failure despite intensive therapy with mechanical ventilation, intravenous erythromycin and corticosteroids, continuous hemodiafiltration, and plasma exchange. Although Mycoplasma pneumoniae infection is usually a benign self-limited disease, this case emphasizes its potentially serious nature even in normal healthy individuals.

Growth hormone secreting adenoma with unusual extension: coexisting pituitary cyst and its clinical significance.

A 58 year old man showed acromegalic features. The serum growth hormone (GH) level was 7.3 ng/ml and SMC (somatomedin-C) 637 U/ml. Triple stimulation test showed abnormal response compatible with a GH secreting tumour. The conventional enhanced MRI revealed a less enhanced hemisphere-shaped lesion at the right corner of the sella turcica. In addition, dynamic MRI demonstrated an elongated lesion extending to the left beyond the midline. The patient underwent transsphenoidal surgery. Besides the soft and suckable tumour at the right corner, we entered into a small cavity loosely filled with the tumour, which was subsequently also removed. The operative finding corresponded to the lesion shown in dynamic MRI. Postoperative GH and SMC levels became 2.3 ng/ml and 326 U/ml respectively. Incidental pituitary cystic lesions in autopsied cases have been reported to be 6-33%. This case had a GH secreting adenoma with coexisting pituitary cyst. The coexisting pituitary cyst supposedly influenced the unusual shape and extension of the pituitary adenoma. Coexistence of such lesion should be kept in mind for microadenoma on neuroradiological evaluation and on intraoperative inspection surrounding the tumour.

A case of rheumatoid pericarditis with high concentrations of interleukin-6 in pericardial fluid.

A case of rheumatoid pericarditis that developed into cardiac tamponade without deterioration of rheumatoid arthritis is described. The concentration of interleukin-6 (IL-6) in pericardial fluid was notably increased compared with serum. IL-6 may be associated with progression or maintenance of rheumatoid pericarditis.

[A case of pseudo-Bartter's syndrome with marked nephrocarcinosis].

A 38-year-old woman was admitted to our hospital on October 21, 1996 for evaluation of thirst, bilateral backache and a feeling of abdominal fullness. She had hypokalemia, normotension, hyperreninemia, hyperaldostronism and hyperplasia of the juxtaglomerular apparatus on renal biopsy. Ultrasonography, intravenous pyelography and computed tomography showed marked bilateral renal calcification. Considering her history of persistent soft stool caused by chronic laxative abuse for 15 to 16 years and past diuretic abuse for several years since 1986, we diagnosed her as pseudo-Bartter's syndrome with nephrocarcinosis. The value of urinary Ca excretion was in the normal range, and acidification disturbance in NH4Cl loading test was revealed. In addition, she had taken analgesics for 2 to 3 years and interstitial nephritis on renal biopsy was seen. It is thus suggested that the cause of nephrocarcinosis in this case was the reduction of Ca solubility in the tubular cavity induced by incomplete renal tubular acidosis associated with analgesic nephropathy or interstitial nephritis caused by hypokalemia.

Bilateral pleuritis caused by Legionella micdadei.

A 58-year-old woman was hospitalized because of progressive respiratory distress. She had a history of myasthenia gravis and invasive thymoma. After thymectomy, she had been administered oral prednisolone and intrathoracic anti-cancer drugs postoperatively. Her chest radiograph revealed bilateral pleural effusions. Legionella micdadei (L. micdadei) was isolated from the pleural effusions, and she was diagnosed as pleuritis caused by L. micdadei. She died despite intensive therapy with mechanical ventilation, drainage tube in the chest and intravenous erythromycin. Although only two cases of Legionellosis caused by L. micdadei have been reported in Japan, clinicians should be aware of L. micdadei as one of the candidates for infection in immunosuppressed hosts.

Eicosapentaenoic acid and docosahexaenoic acid inhibit vascular smooth muscle cell proliferation by inhibiting phosphorylation of Cdk2-cyclinE complex.

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of triacylglycerol (TG) were dose dependently incorporated into phospholipid fraction of vascular smooth muscle cells (VSMC) and suppressed the proliferation of VSMC. Flow cytometric analysis demonstrated both EPA and DHA inhibited G1/S progression. EPA and DHA inhibited the phosphorylation of Cdk2 protein and Cdk2 kinase activity without altering the amount of cyclin E and p27(kip1) proteins and cyclin dependent kinase activating kinase activity by growth stimulation. This mechanisms remained to be clarified but this is the first report of a novel mechanisms of inhibition of DNA synthesis by EPA and DHA.

Geranylgeranylpyrophosphate plays a key role for the G1 to S transition in vascular smooth muscle cells.

Pravastatin, a HMG-CoA reductase inhibitor was found to inhibit DNA synthesis of vascular smooth muscle cells (VSMC) in a dose-dependent manner. Flow cytometric analysis demonstrated that pravastatin induced G1 arrest. Mevalonate restored the inhibitory effect of pravastatin on DNA synthesis and on cell cycle progression, suggesting the importance of mevalonate itself and/or its metabolites in VSMC proliferation. The major intermediate metabolites of mevalonate, geranylgeranyl-pyrophosphate (GGPP), farnesyl pyrophosphate (FPP) and IPP (isopentenyl pyrophosphate) were prepared in the form of liposomes, and the effects of GGPP, FPP and IPP on pravastatin induced inhibition of VSMC proliferation and G1 arrest were examined. Only GGPP restored the pravastatin-induced inhibition of DNA synthesis and G1 arrest. Pravastatin inhibited translocation of Rho small GTPase from cytosol to membrane. By the addition of GGPP, Rho small GTPase are geranylgeranylated and translocated to membranes during G1/S transition. These data suggest that GGPP, rather than FPP or IPP, is an essential metabolite among mevalonic acid metabolites for VSMC proliferation and the G1/S transition.

Complexes of apoA-1 with phosphatidylcholine suppress dysregulation of arterial tone by oxidized LDL.

The aim of this study was to determine whether apolipoprotein A-1 (apoA-1) may suppress the vasomotor dysregulation by oxidized low-density lipoprotein (ox-LDL), which is known to be an atherogenic lipoprotein. The isolated porcine coronary arterial rings and the cultured endothelial cells from the porcine coronary arteries were exposed to ox-LDL in the presence or absence of complexes of apoA-1 with dimyristoylphosphatidylcholine (DMPC/apoA-1), apoA-1 alone, or DMPC alone. DMPC/apoA-1 but not apoA-1 alone or DMPC alone was found to suppress both impairment of endothelium-dependent arterial relaxation and vasocontraction caused by ox-LDL in the isolated porcine coronary arterial rings suspended in organ chambers. DMPC/apoA-1 absorbed lysophosphatidylcholine (LPC) from ox-LDL and decreased the transfer of LPC from ox-LDL to the surface membrane of the cultured endothelial cells, but apoA-1 alone and DMPC alone had no effect. High-density lipoprotein exerted the protective actions mimicking those observed in DMPC/apoA-1. Thus DMPC/apoA-1 decreased the transfer of LPC from ox-LDL to surface membrane by absorbing LPC, leading to the suppression of ox-LDL-induced dysregulation of endothelium-dependent arterial tone. Therefore, apoA-1 appears to require formation of the complexes with phospholipids to prevent the endothelial dysfunction caused by ox-LDL.

Mechanisms of enhanced production of PGI2 in cultured rat vascular smooth muscle cells enriched with eicosapentaenoic acid.

The present investigation was performed to clarify the effect of EPA on PGI2 production in vitro using cultured rat vascular smooth muscle cells (VSMC). To simulate in vivo conditions, a triacylglycerol (TG) emulsified form of EPA was used. An increase in EPA content was achieved without alteration of arachidonic acid concentration. These experiments clearly demonstrated that co-incubation of EPA-TG increased PGI2 production by cultured VSMC in a dose dependent fashion. Among polyunsaturated fatty acid TG examined (docosahexaenoic acid, linoleic acid, oleic acid and EPA), only EPA-TG was effective. Cyclooxygenase (COX) was activated, but neither phospholipase A2 nor PGI2 synthase activity was changed. EPA treatment did not alter the amount of COX-1 and COX-2 protein in VSMC. Addition of antioxidants, such as butylated hydroxytoluene or vitamin E, decreased MDA levels in the medium and cells and reversed the enhanced PGI2 production in EPA rich-VSMC. Therefore, the high polyunsaturation of EPA could generate low levels of lipid peroxides and thereby lead to activation of COX and an increased PGI2 production. Although EPA increased PGI2 production, only a negligible amount of PGI3 was produced by rat aortic tissues. Enhanced production of PGI2 might contribute to the anti-atherogenic effect of EPA.