Kenji Hoshina

Effect of a new anti-ulcer drug, (3-[p-(trans-4-aminomethylcyclohexylcarbonyl)-phenyl] propionic acid hydrochloride, TEI-5103) on prostaglandin (PG) levels in rat gastric mucosa.

1. Effect of TEI-5103 on the levels of various prostaglandins (PGs) in rat gastric mucosa was studied by HPLC and RIA methods. 2. When administrated in vivo, TEI-5103 significantly increased the level of prostaglandin E2 (PGE2) but only slightly increased that of prostaglandin I2 (PGI2) or thromboxane A2 (TXA2). 3. In the water-immersion stress model, the PGE2 level in control animals was increased immediately after stress and then decreased gradually to the initial level. Indomethacin (5 mg/kg, s.c.) sustained a lower PGE2 level during the experiment, as well as aggravated the lesions. 4. TEI-5103 (400 mg/kg, p.o.) increased the PGE2 level just before stress, and it resulted in the prevention of lesion formation. 5. TEI-5103 inhibited the activity of 15-OH-PG-dehydrogenase from guinea pig lungs, but did not affect the activity of phospholipase A2 from porcine pancreas.

Effects of a novel acylindole derivative on experimental thrombotic models, ulceration of the gastric mucosa and prostacyclin production in the aorta

Abstract 3-Benzoyl-N-β-ethoxyisopropyl-2-methylindole (TEI-4120) strongly inhibited arachidonic acid- and collagen-induced aggregation of platelets of several animal species (IC 50 : 3.3×10 −6 M − 3.1×10 −8 M). It also inhibited the second phase of ADP- or epinephrine-induced human platelet aggregation (IC 50 : 2.0×10 −6 M − 1.0×10 −5 M). TEI-4120 at oral doses of 1–30 mg/kg was effective on aggregation of platelets removed from animals. In several experimental thrombotic models, TEI-4120 at doses of 1–30 mg/kg (p.o.) inhibited thrombus formation. It was less ulcerogenic than typical nonsteroidal antiinflammatory drugs such as indomethacin and caused only slight gastric lesions at a dose of 400 mg/kg (p.o.). It was also only a weak inhibitor of prostacyclin biosynthesis in rat aorta in vivo, a dose of about 100 mg/kg being required to inhibit prostacyclin biosynthesis. These results show that TEI-4120 has strong anti-platelet activity and suggest that it should be a good anti-thrombotic drug with weak side effects.

Inhibition of prostaglandin synthesizing enzymes by haptoglobin and plasma of rat with inflammation

ラットの足蹠にcarrageenin, compound48/80あるいはadjvantを注射すると, 一定時間後の血漿にprostaglandin E2生合成の阻害作用およびhaptoglobin値の増加が認められた.一方, 部分精製したhaptoglobinはarachidonic acidを基質とするprostaglandin E2生合成を用量依存性に阻害した.ウシ精嚢microsomeの精製酵素を用いてその作用機作を検討したところ, haptoglobinが活性化因子のhemeと相互作用して阻害作用を示すことが明らかになった.しかし, prostaglandin E2生合成に対して阻害作用を示すhaptoglobin濃度 (ID50) は, 炎症ラット血漿では11μg/mlであるのに対して, 部分精製したhaptoglobinでは175μg/mlであり, 炎症ラット血漿の阻害作用をhaptoglobinのみで説明できないことが示唆された.