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.

[Anti-thrombotic and anti-atherogenic action of eicosapentaenoic acid].

Epidemiological studies performed in Greenland Eskimos and Japanese indicated that ingestion of fish meat rich in omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), reduces the incidence of cerebro- and cardiovascular thrombotic diseases. Therefore, the effect of administration of purified EPA, derived from sardine oil, on hemorrheological properties and serum lipids in patients with thrombotic disorders was studied. Dietary supplementation of EPA resulted in decrease in platelet aggregability with reduction of TXA2 production, prolongation of bleeding time, decrease of platelet adhesiveness, increase of red cell deformability, and improvement of serum lipid concentration. Decrease in platelet TXA2 production may be ascribed to the decrease in arachidonate (AA) content of platelet membrane, inhibition of AA release from platelet membrane and competitive inhibition of AA metabolism at the level of cyclo-oxygenase, by EPA. Administration of EPA increased PGI2 production in the rat thoracic aorta and co-culture of rat aorta smooth muscle cell with EPA also increased PGI2 production, but suppressed smooth muscle cell proliferation. This may be explained by a EPA-derived peroxide stimulation of cyclo-oxygenase activity. Administration of EPA decreased platelet-derived growth factor (PDGF) production in rat peritoneal macrophages. In EPA-rich peritoneal macrophages from rat given EPA, incorporation of acetyl LDL and accumulation of cholesterol in macrophages decreased. This may indicate that dietary supplementation of EPA suppress foam cell formation. An interesting finding is that EPA-rich LDL obtained from rabbits given EPA is less susceptible to Cu(2+)-catalyzed oxidative modification. This seems to indicate that EPA may also suppress lipid peroxidation of lipoprotein.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term administration of highly purified eicosapentaenoic acid provides improvement of psoriasis.

Nine patients with chronic stable psoriasis (4 males and 5 females) were entered in this trial. Eicosapentaenoic acid (EPA) ethylester (90% pure) without docosahexaenoic acid (DHA) in gelatin-coated capsules at a daily dose of 3.6 g was administered to 9 patients for 3 months, 7 patients for 6 months and 6 patients for 12 months. The clinical changes of skin lesions of the patients with 12 months of treatment were as follows: marked improvement 1, improvement 3, relative improvement 1, no change 1. A clinical improvement of skin lesions was first observed 2-3 months after EPA treatment. The supplementation of highly purified EPA caused a significant increase in the content of plasma EPA and docosapentaenoic acid without affecting that of arachidonic acid (AA) and DHA. EPA decreased the production of leukotriene B4 (LTB4) and increased the formation of leukotriene B5 (LTB5) and 5-hydroxyeicosapentaenoic acid significantly in A23187-stimulated neutrophils. The LTB5/LTB4 ratio positively correlated with the plasma EPA/AA ratio and was directionally related to the clinical score, although the directional data were not statistically significant. We could not observe any side effects of EPA over 1 year. Although its effects are modest, it is nontoxic and its favorable effect appears to continue for the duration of its usage, indicating that EPA could be beneficial for the long-term treatment of psoriasis.

Eicosapentaenoic acid and adult diseases in Japan: epidemiological and clinical aspects.

Residents of a coastal fishing village in Japan consume larger amounts of fresh fish rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) than those in inland farming villages. A higher content of EPA and DHA in the plasma and reduced platelet aggregability was observed in the residents of the fishing village than in farmers. Incidence of thrombotic cardiovascular disorders was lower in the fishing area than in the farming area. Oral ingestion of highly purified EPA or DHA reduced platelet aggregability and improved serum lipid profile in healthy subjects and in hyperlipidaemic patients, though DHA seems to be much less potent. In clinical studies with highly purified EPA, improvement of clinical features was noted in patients with thrombotic cardiovascular disorders. It is also shown that EPA and DHA have an anti-inflammatory effect in man although EPA is far more active than DHA.

The effects of dietary omega-3 fatty acids on the DU-145 transplantable human prostatic tumor.

Two omega-3 fatty acids present in fish oil are effective inhibitors of some models of mammary and colon tumorigenesis in rodents. The present studies were conducted to determine if eicosapentaenoic and docosahexaenoic acids can modify the growth of DU-145 human prostatic tumor cells in nude mice. Two experimental diets tested contained either 23.52% corn oil or 20.52% fish oil, plus 3% corn oil (w/w). In the fish oil-fed group of mice: (a) tumor growth was significantly inhibited; (b) tumor cells in histological sections were smaller but more connective tissue was present; (c) immunochemical staining for human prostatic acid phosphatase was less intense, and (d) tumor content of PGE2 was smaller than in the 23.52% corn oil-fed group. Fatty acid composition of phosphoglyceride and neutral lipid fractions of liver, prostate, and tumor tissue reflect the dietary intake of omega-3 and omega-6 fatty acids. These results are consistent with a role for omega-3 fatty acids in the inhibition of growth of human prostatic tumor cells in nude mice by dietary modification.

Eicosapentaenoic acid as a modulator of inflammation. Effect on prostaglandin and leukotriene synthesis.

Products derived from arachidonic acid (AA) via both the cyclo-oxygenase and lipoxygenase pathways play a role in inflammation: prostaglandins (PGs), particularly PGE2, contribute to the formation of oedema, erythema and hyperalgesia whereas leukotriene B4 (LTB4), a product of the 5' lipoxygenase, may modulate the recruitment of leukocytes. We have previously reported that supplementation of a standard rat diet with eicosapentaenoic acid (EPA) caused a significant increase in the formation of LTB5, which is less active biologically than LTB4, and a decrease in the synthesis of LTB4 by stimulated leukocytes. Now we have assessed the effects of administration of highly purified EPA ethyl ester (79% pure), in two models of acute inflammation. Supplementation of a standard rat diet with 240 mg/kg/day EPA for 4 weeks significantly decreased the concentration of PGE2 and TXB2 in inflammatory exudate derived from implantation of carrageenin impregnated sponges: neither the concentration of LTB4 nor the cell number were reduced significantly. Triene prostaglandins were not detected in the exudate, however, significant levels of LTB5 were present. In the second model, oedema induced by injection of carrageenin into rat paws was significantly reduced in animals fed an EPA-rich diet. Supplementation of the diet with EPA could, by mainly reducing the synthesis of prostaglandins, offer a novel and non-toxic approach to the modulation of an inflammatory response.

Effect of orally administered eicosapentaenoic acid (EPA) on the formation of leukotriene B4 and leukotriene B5 by rat leukocytes.

Eicosapentaenoic acid (EPA) is a poor substrate for the fatty acid cyclo-oxygenase but is a good substrate for lipoxygenase enzymes which catalyse the biosynthesis of hydroperoxy-acids, hydroxy-acids and leukotrienes. Recently, we reported that leukotriene B5 (LTB5) was at least 30 times less potent than LTB4 in causing aggregation, chemokinesis and degranulation of polymorphonuclear leukocytes in vitro. In this paper, the effect of oral administration of EPA on LTB4 and LTB5 production by rat leukocytes stimulated with the calcium ionophore, A23187, was assessed. The concentration of LTB was determined by radioimmunoassay and also by reverse-phase high pressure liquid chromatography using PGB3 as internal standard. Supplementation of a normal rat diet with EPA (240 mg/kg per day) for 4 weeks caused a significant increase in the formation of LTB5 and a decrease in the synthesis of LTB4 by stimulated leukocytes. The EPA-rich diet significantly increased the EPA content of leukocyte phospholipids without altering the content of arachidonic acid (AA) or linoleic acid. The ratio of EPA/AA in leukocytes correlated (r = 0.795, P less than 0.001) with the LTB5/LTB4 ratio produced after stimulation of leukocytes. If LTB4 has a chemotactic role during inflammation, the present data suggest that an EPA rich diet could decrease the accumulation of leukocytes at sites of inflammation.

Studies on the mechanism of antiaggregatory effect of Moutan Cortex.

The effects of Moutan Cortex and one of its major components, paeonol, on platelet aggregation and arachidonic acid (AA) metabolism in human platelets were studied. One week oral administration of water extract of Moutan Cortex [Moutan Cortex (w), 3 g/day] significantly reduced platelet aggregation and thromboxane B2 (TXB2) formation induced by collagen, epinephrine and ADP. Paeonol dose-dependently inhibited ADP and collagen induced platelet aggregation in vitro. Moutan Cortex (w) and paeonol dose-dependently inhibited the conversion of exogenous [14C]AA to [14C]heptadecatetraenoic acid [( 14C]HHT) and [14C]TXB2 by washed human platelets, while both of them increased its conversion to [14C]12-hydroxy eicosatetraenoic acid [( 14C]12-HETE). High dose of Moutan Cortex (w) inhibited the release of [14C]AA from prelabeled platelets in vitro, while paeonol did not. These results suggest that a reduction in platelet aggregation by the oral administration of Moutan Cortex might be ascribed to a decrease in thromboxane synthesis and that paeonol might play an important role in the antiaggregatory effect of Moutan Cortex because of its potent inhibitory effect on platelet aggregation and thromboxane formation.