Subacute sarcoid myositis with ocular muscle involvement; a case report and review of the literature.

Sarcoidosis is a chronic granulomatous disease that can affect multiple organs. The lungs, eyes, and skin are known to be highly affected organs in sarcoidosis. There have been reports based on random muscle biopsy that 32-80% of systemic sarcoidosis comprises noncaseating granulomas; however, muscle involvement in sarcoidosis is generally asymptomatic and has an unknown frequency. We describe a case of acute to subacute sarcoid myositis of the skeletal and extraocular muscles. Typical ophthalmic involvement (manifested by infiltration of the ocular adnexa, intraocular inflammation, or infiltration of the retrobulbar visual pathways) and extraocular sarcoid myositis (as with the present case) is infrequently reported. It is important to keep in mind the rare yet perhaps underestimated entity of sarcoid myositis, and to utilize muscle biopsy and imaging tests for appropriate diagnosis and management of patients with sarcoidosis.

The effects of beraprost Na, a stable prostacyclin analog, on animal models of stroke.

We evaluated the effects of beraprost Na (Sodium (+-)-(1R*,2R*, 3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3- hyd roxy-4-methyl-1- octen-6-ynyl]-1H-cyclopenta[b]benzofuran-5-butylate, beraprost), a stable and orally active prostacyclin (PGI2) analog with potent antiplatelet and vasodilating properties, on two stroke models, namely sudden death induced by arachidonate (AA) in rabbits and spontaneous stroke in stroke-prone spontaneously hypertensive rats (SHRSP). In the AA-induced sudden death model, 30 min after beraprost administration (1 or 3 mg/kg, po), AA was injected into the rabbit internal carotid artery, and incidence of convulsion and sudden death were assessed. Beraprost decreased both incidence of convulsion and mortality of rabbits. In SHRSP, orally administered beraprost (100 micrograms/kg, twice a day from 56-385 d of age) improved survival rate and decreased incidence of stroke. Preventive effects of beraprost on the two stroke models may have been caused mainly by the improvement of cerebral circulation. These results indicate that beraprost may have potential in the treatment and/or prevention of the cerebral circulatory disorders.

Prostacyclin and beraprost sodium as suppressors of activated rat polymorphonuclear leukocytes.

Beraprost sodium (beraprost) is a stable analogue of prostaglandin I2 (PGI2), which can be administrated orally. In the present study, the effect of beraprost on the activation process of polymorphonuclear leukocytes (PMNs) was examined in vitro. Beraprost effectively inhibited chemotaxis of PMNs induced by formyl-methionyl-leucyl-phenylalanine (FMLP). Like prostaglandin E2 (PGE2), beraprost elevated intracellular cAMP level and inhibited the influx of extracellular Ca2+ in PMNs. The concentration-response curves showed that the inhibitory effect of beraprost on chemotaxis was correlated with the increment of intracellular cAMP level of the PMNs and inhibition of influx of extracellular Ca2+. Beraprost also inhibited inositol phospholipid metabolic turnover and superoxide anion production of PMNs induced by FMLP at relatively high concentration. These results suggest that the inhibitory effect of beraprost on the PMN function especially chemotaxis is mediated through the elevation of the intracellular cAMP level, which interferes with the signal transduction process probably through the inhibition of Ca2+ mobilization in PMNs. The above-mentioned effects of beraprost were also the case with PGI2. The potency of beraprost was comparable to PGI2 in the present study. Considering its stability, these results thus raise a possibility that beraprost might exert anti-inflammatory effect in vivo.

[Cardiovascular effects of beraprost sodium (TRK-100), a prostacyclin analogue in the dog].

Effect of prostacyclin analogue, beraprost sodium (Sodium (+/-)-(1R*, 2R*, 3aS*, 8bS*)-2, 3,3a,8b-tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen+ ++-6- ynyl]-1H-cyclopenta-[b]benzofuran-5-butyrate, TRK-100), on the cardiovascular system of the anesthetized dog was investigated. TRK-100 was injected intra-arterially and intravenously to study the vasodilating effect of the drug by a magnetic flow meter. Intra-arterial injection of TRK-100 augmented blood flow of vertebral, coronary, renal, supramesenteric, hepatic and femoral artery at a dose range of 0.0003 to 3,000 micrograms/bed. The threshold doses of TRK-100 and PGI2 in the mesenteric artery were 0.003 micrograms and 0.0003 micrograms, respectively, and the same values were obtained in the splenic artery. Those were slightly lower than those of other arteries. Intravenous injection of TRK-100 augmented mesenteric and renal arterial flow to 193 +/- 30% and 118 +/- 4%, respectively. In this system augmentation of mesenteric and renal arterial flow was 179 +/- 19% and 135 +/- 1%, respectively, while vertebral, carotid, and femoral arterial flow decreased, respectively, to 71.4 +/- 2.1%, 80.0 +/- 9.4% and 61.4 +/- 5.6% by TRK-100 and 70.6 +/- 5.6%, 79.5 +/- 6.9% and 67.1 +/- 4.7% by PGI2. Inhibitory effects on heart functions such as cardiac output, left ventricular pressure, LV dP/dt, oxygen consumption, and cardiac work were seen. The effect was similar to PGI2. Coronary vascular resistance, total peripheral resistance and systemic blood pressure were also decreased by TRK-100 and PGI2.

Effect of beraprost sodium on peripheral circulatory disturbances induced by various stimuli.

Effects of beraprost sodium (sodium(+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2-hydr oxy-1- [(E)-(3S*)-3-hydroxy-4-methyl-octen-6-ynyl]-1H-cyclopenta[b] benzofuran- 5-butyrate, TRK-100), a stable prostacyclin analogue, on the peripheral circulatory disturbances induced by various vasoconstrictive stimuli were studied. Orally administered beraprost sodium (10, 30 micrograms/kg) caused increase in skin blood flow in anesthetized rats and rise in skin temperature in conscious rats. Intravenously administered beraprost sodium (0.01-0.3 microgram/kg) reduced the recovery time of decreased pulse pressure by topical cooling of the leg in anesthetized rats. In conscious rabbits, intravenous infusion of beraprost sodium (10 micrograms/kg/min) inhibited the fluctuation of ear artery diameter, and dilated the ear artery and vein, resulting in a rise in the ear temperature. In anesthetized dogs, intravenously administered beraprost sodium (0.313-5 micrograms/kg) caused decrease in femoral blood flow and muscle blood flow in the hindlimb, however, it caused increase in skin blood flow at the hind leg instep. Furthermore, intra-arterially administered beraprost sodium (0.1-0.3 microgram/kg/min) under stimulation of lumbar sympathetic nerve caused increase in femoral artery blood flow and selective increase in the skin blood flow without affecting muscle blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of beraprost sodium on peripheral circulation insufficiency in rats and rabbits.

Beraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is a chemically and biologically stable epoprostenol analogue which possesses both potent antiplatelet and peripheral vasodilating actions. Its effect on obstruction of the peripheral artery was studied in three different models: 1. acute thrombosis induced by electrical-stimulation of the femoral artery in rabbits, 2. occlusion induced by intra-arterial injection of sodium laurate in rats and 3. tail gangrene induced by subcutaneous injections of both ergotamine and epinephrine in rats. Oral administration of beraprost sodium resulted in suppression of thrombus formation in the acute thrombosis model, marked improvement of macroscopic and histological observations in the laurate-occlusion model and inhibition of tail gangrene extension. In contrast, ticlopidine improved thrombus formation in the acute thrombosis model and slightly improved histological observation in the laurate-occlusion model, but not in the tail gangrene model. Cilostazol suppressed lesions in the acute thrombosis model, but not in the tail gangrene model. These findings suggest that beraprost sodium may be very useful clinically for the therapy of peripheral circulation insufficiency diseases such as Buerger's disease and Raynaud's disease.

General pharmacology of beraprost sodium. 1st communication: effect on the central nervous system.

Beraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is an orally active epoprostenol (prostaglandin I2, PGI2) analogue. Its effect on the central nervous system (CNS) was studied. 1. When orally administered in mice, beraprost sodium at 0.3 mg/kg caused a flush of skin, a suppression of spontaneous motility, and a fall of body temperature. At 1 mg/kg and more, it showed obvious sedation, prolongation of hexobarbital hypnosis, and analgesic action in acetic acid-induced writhing test. However, even at 3 mg/kg beraprost sodium neither induced ataxia nor had anticonvulsant activity. Hypothermia was also observed in rabbits at 1 mg/kg (p.o. and i.v.). 2. When intravenously administered, beraprost sodium exerted long-lasting action on the CNS, while its pharmacological effects resembled those of PGI2. 3. Oral administration of beraprost sodium did not inhibit aggregation toxicity induced by methamphetamine (20 mg/kg i.p.) in mice. Beraprost sodium at doses higher than 1 mg/kg enhanced aggregation toxicity induced by methamphetamine (5 mg/kg i.p.), while intracerebral ventricular administration of beraprost sodium failed to enhance it. 4. In rat spinal reflex, intravenous administration of beraprost sodium (0.1 mg/kg) slightly enhanced monosynaptic reflex and at a high dose (1 mg/kg) suppressed polysynaptic reflex. 5. In the rabbit EEG, intravenous administration of beraprost sodium at a high dose (1 mg/kg) showed some effects such as the continuous pattern of wakefulness and a fall in power of the EEG.(ABSTRACT TRUNCATED AT 250 WORDS)

General pharmacology of beraprost sodium. 2nd communication: effect on the autonomic, cardiovascular and gastrointestinal systems, and other effects.

Beraprost sodium (sodium (+/-)-(1R*,2R*,3as*,8bS*)-2,3,3a,8b-tetrahydro-2- hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6-ynyl]-1H- cyclopenta[b]benzofuran-5-butyrate, TRK-100) is an orally active epoprostenol (prostaglandin I2, PGI2) analogue. Its general pharmacological effects on peripheral organs were studied. 1. In isolated organs, beraprost sodium relaxed the trachea and increased atrial beating rate (2.4 x 10(-5) mol/l). It also dose-dependently contracted the stomach, aorta, ileum and uterus (2.4 x 10(-7)-2.4 x 10(-4) mol/l). These effects of beraprost sodium were similar, but inferior to those of PGI2 and PGE1. 2. Intravenous administration of beraprost sodium produced a dose-related decrease in blood pressure (BP), its potency being about 1/3 times that of PGI2 in anesthetized rats and dogs. Beraprost sodium and PGI2 had no effects on heart rate (HR), and enhanced respiration in conjugation with a decrease in BP. Oral administration of beraprost sodium in high doses (1-3 mg/kg in rats and 0.3 mg/kg in dogs) caused a decrease in BP. A compensatory tachycardia and an elevated plasma renin activity (PRA) occurred after low doses (0.1-0.3 mg/kg) in rats. In contrast, a change of HR and PRA in rabbits and dogs was mild. 3. Beraprost sodium produced suppression of digestive organs: markedly, gastric motility and secretion and intestinal transport; slightly, but significantly, biliary secretion. On the other hand, it enhanced ileal motility at a high dose (300 micrograms/kg i.v.). 4. Oral administration of beraprost sodium caused a decrease in urinary volume and electrolyte excretion in rats. 5. Oral administration of beraprost sodium prolonged bleeding time in mice, while it had no effect on the blood coagulation system in vitro. In addition, beraprost sodium had no hemolytic action. 6. The other effects of beraprost sodium were weak. Beraprost sodium had no local anesthetic activity and no effect on salivation, pupil size and neuromuscular transmission in the skeletal muscle. Beraprost sodium slightly contracted the uterus of non-pregnant rats in situ and dose-independently inhibited carrageenin-induced paw edema. In conclusion, beraprost sodium produced various effects on the autonomic, cardiovascular, and gastrointestinal systems. Probably, these effects may be based on its own action like PGI2.

Effect of beraprost sodium (TRK-100) on acetic acid-induced skin ulcer.

Effect of beraprost sodium (TRK-100), a stable PGI2 analog, on experimentally induced skin ulcer was studied in rats. An experimental skin ulcer was developed by intradermal injection of acetic acid. Injection of glacial acetic acid to the skin in the left hind leg instep of rats resulted in the necrosis of the skin, and a skin ulcer developed in 3 days. The ulcer area reached its peak on the 5th day, and recovered to its control level within 4 weeks. The effects of TRK-100 and indomethacin on the ulcer were tested. TRK-100 showed suppressive effects on the development of the ulcer. A dose of 30 micrograms/kg (p.o.) accelerated healing of the ulcer when scored macroscopically on the 9th or 15th day. At a dose of 100 micrograms/kg (p.o.), it reduced the development of the ulcer and accelerated healing with statistical significance from the 5th day and thereafter. Indomethacin also reduced the development of the ulcer and accelerated healing with statistical significance from the 7th day and thereafter. These results suggest TRK-100 may be effective on the inhibition of the development and accelerated the healing of the skin ulcer formed in various pathological states.

Studies on the antiplatelet effect of the stable epoprostenol analogue beraprost sodium and its mechanism of action in rats.

Baraprost sodium (sodium (+/-)-(1R*,2R*,3aS*,8bS*)-2,3,3a.8b- tetrahydro-2-hydroxy-1-[(E)-(3S*)-3-hydroxy-4-methyl-1-octen-6- 1H-cyclopenta[b]benzo-furan-5-butyrate, TRK-100) is a novel stable epoprostenol (prostaglandin I2, PGI2) analogue having antiplatelet and vasodilating actions. Its effect on platelet aggregation in whole blood ex vivo and platelet suspension in vitro, formation of cyclic AMP(cAMP), production of malondialdehyde(MDA), and 45Ca++-influx into platelets were studied in rats. Oral administration of TRK-100 (0.3-1 mg/kg) showed a dose-dependent inhibition of platelet aggregation induced by ADP and collagen in whole blood and also inhibited in vitro thrombin-induced aggregation of platelet suspension in the presence or absence of external Ca++. Oral TRK-100 (0.3-3 mg/kg) dose-dependently increased plasma cAMP levels and this action was confirmed in vitro with platelet rich plasma in the presence or absence of theophylline. 45Ca++-influx into platelets stimulated by thrombin was dose-dependently inhibited by TRK-100 (3-100 nmol/l). TRK-100 (3-100 nmol/l) also suppressed MDA production induced by thrombin in platelet suspension but not that induced by arachidonic acid. From these results, TRK-100 which is orally active was suggested to exert its antiplatelet action through the increase of cAMP in platelets by activation of adenylate cyclase, concomitantly followed by the inhibition of Ca++-influx and thromboxane A2 formation.

The in vitro and ex vivo antiplatelet effect of TRK-100, a stable prostacyclin analog, in several species.

Effect of TRK-100, a stable PGI2 analog, on platelet function was tested in vitro and ex vivo. TRK-100 at the dose range of 0.5-300 nM inhibited platelet aggregation induced by arachidonic acid, adenosine 5'-diphosphate and collagen in several species including human platelets. The potency of TRK-100 was 1/2 to 1/5 that of PGI2. The effect was strong in human and cat platelets. In conscious rabbits and rats, oral TRK-100 at the dose range of 0.1-1 mg/kg inhibited ex vivo platelet aggregation up to 80% in the rat and 70% in the rabbit, and the effect lasted over 5 hr. However, in both species, the effect on blood pressure was minimal. In anesthetized rabbits, inhibition of platelet aggregation was the same level as in the conscious animal, but blood pressure depression was observed. Cyclic AMP levels of human platelets, 2 min after incubation, was elevated up to 2.4 microM/10(9) platelets by 100 ng/ml of PGI2 and 1.5 microM by 100 ng/ml of TRK-100. It was shown that TRK-100 has a potent antiplatelet effect both in vitro and ex vivo in many species through elevation of platelet cAMP. These results suggest that TRK-100 may be a potential oral antithrombotic drug.

[Analysis of the signalling pathway of TNF in normal cells and tumor cells].

The internalization process and intracellular distribution of 125I-labeled TNF, in L-M (murine tumorigenic fibroblasts, highly sensitive to TNF cytotoxicity) cells and in HEL (human embryonic lung cells, non-sensitive to TNF cytotoxicity) cells bearing TNF receptor, were elucidated by pulse-chasing and by Percoll density gradient centrifugation. Effect of TNF treatment on the RNA and protein synthesis of target cells was also studied using 3H-UDR and 35S-methionine incorporation. In both L-M and HEL cells, receptor-bound 125I-TNF was rapidly internalized and delivered to lysosomes within 15-30 min, followed by degradation and release into the culture medium. RNA synthesis and protein synthesis were not affected by TNF treatment in HEL cells, but marked stimulation (3.5 times and 4.2 times, respectively) was observed in L-M cells.

Antithrombotic effect of TRK-100, a novel, stable PGI2 analogue.

TRK-100, a stable PGI2 analogue structurally different from carbacyclines, was compared with other antiplatelet drugs for its effect on platelet functions using animal models. TRK-100 (10-300 nM) inhibited rat platelet aggregation induced by ADP (3 microM), collagen (12.5 micrograms/ml) and A23187 (10 microM), and its potency was about 1/3-1/7 that of PGI2. TRK-100 (0.3-3 mg/kg, p.o.) dose-dependently inhibited rabbit platelet adhesion (ED50: 2.2 mg/kg), and its effect lasted over at least 5 hr. In contrast, aspirin and ticlopidine (both at 300 mg/kg, p.o.) showed only a slight inhibition (4-7%). In the thrombocytopenia induced by collagen injection in rats, TRK-100 (3-300 micrograms/kg, i.v.; 0.1-3 mg/kg, p.o.) dose-dependently inhibited a decrease in platelet number, and its ED50 was 0.48-0.62 mg/kg orally and 13.7-16.4 micrograms/kg intravenously, while the inhibition by aspirin and ticlopidine (both at 1000 mg/kg, p.o.) was 40 and 37%, respectively. In the experimental thread thrombosis in rats. TRK-100 (0.03-3 mg/kg, p.o.) dose-dependently inhibited thrombus formation, and its ED50 was 0.46 mg/kg, being 21 and 87 times as potent as aspirin and ticlopidine, respectively. These results reveal that TRK-100 has a potent antiplatelet activity and is orally and intravenously effective for a variety of thrombosis models, suggesting that it may have a therapeutic value as an antithrombotic drug.

[Analysis of the TNF receptor in KYM cells by affinity cross-linking].

We investigated the identity of the TNF receptor on the KYM cell membrane by cross-linking 125I-TNF and the presumed receptor site with DSS, and subjecting the TNF-receptor complex to electrophoresis. Four specific bands were observed at 145 K, 50 K, 35 K, and 17 K, and those at 50 K, 35 K and 17 K being consistent with trimers, dimers and monomers of TNF, respectively. The 145 K band disappeared after addition of excess unlabelled TNF or anti-human recombinant TNF monoclonal antibody (IV3-E), which quenched the cytotoxic activity of TNF and inhibited the TNF binding to the receptor. The molecular weight of native TNF as estimated by gel filtration was 45 K and this observation showed that native TNF existed only as the TNF trimer. These results confirmed that 95K, i.e., the difference between 145 K and 50 K, is the molecular size of the TNF receptor.

[Analysis of TNF receptor by binding assay].

The existence of a TNF receptor on TNF-sensitive tumor cells and on certain normal cells was elucidated by specific binding assay. A close correspondence (r = 0.855) was shown between the receptor number and the sensitivity of the tumor cells. However, for normal cells, despite the existence of TNF receptors, no cytotoxic effect was observed. Furthermore, certain normal diploid cells underwent proliferation as a result of TNF stimulation. It was therefore concluded that the existence of TNF receptor is essential but not sufficient in itself for TNF-induced cytotoxicity.

Antitumor effect of tumor necrosis factor against various primarily cultured human cancer cells.

The antitumor activity of tumor necrosis factor (TNF) against various primarily cultured human cancer cells (32 cases) was investigated by the 51Cr cytotoxic release assay and the tumor stem cell assay. Over 50% sensitivity (the ratio to the cytotoxicity in L929 cells) was noted in 4 of 14 cases of gastric cancer (28.6%), 7 of 9 cases of leukemic cells (77.8%), and 1 case each of pancreatic carcinoma and ovarian cancer. Scarcely any sensitivity, however, was observed in 1 case of acute promyelocytic leukemia or in some of the gastric cancer cases. No correlation was observed between the histological type of the cancer and TNF sensitivity. The above results seem to confirm that TNF has significant antitumor activity against human cancer cells.

[Antitumor effect of the tumor necrosis factor against various types of human cancer cells].

The antitumor activity of tumor necrosis factor (TNA) against various human cancer cells (32 cases) was investigated by 51Cr cytotoxic release assay and tumor stem cell assay. Over 50% sensitivity (the ratio of cytotoxicity for L929 cells) was shown by 4 of 14 cases of gastric cancer (28.6%), 7 of 9 cases of leukemic cells (77.8%), and 1 case each of pancreatic carcinoma and ovarian cancer. However, scarcely any sensitivity was shown by APL, a portion of the gastric cancer cells, normal lymphocytes or colony-forming cells tested. No correspondence was observed between the histological type of the cancer and TNF sensitivity. The above results seem to confirm the significant antitumor activity of TNF against human cancer cells.

Effect of a stable prostacyclin analogue on platelet function and experimentally-induced thrombosis in the microcirculation.

Sodium dl-4-[1R,2R,3aS,8bS)-1,2,3a,8b-tetrahydro- 2-hydroxy-1-[(3S,4RS)-3-hydroxy-4-methyl-oct-6- yne-(E)-1-enyl]-5-cyclopenta[b]benzofuranyl]butyrate (TRK-100) is a stable analogue of prostacyclin (epoprostenol, PGI2). The drug was shown to be a potent inhibitor of platelet aggregation in vitro, induced by adenosine diphosphate (ADP), using platelet-rich plasma (PRP) from human and several animal species. The inhibitory activity of TRK-100 using human platelets was half that of PGI2 and eight times that of PGE1. There was a marked tendency for platelet clumps to disaggregate following secondary aggregation in the presence of TRK-100 at final concentrations higher than 1 ng/ml. This activity was similar to PGI2 and more than 30 times that of PGE1. TRK-100 was shown to induce the disaggregation of a pre-existing thrombus in the microcirculation of the hamster cheek pouch. A dose-dependent response was obtained following oral administration of the drug at levels of 50-200 micrograms/kg. Optimal activity was observed 30-60 min after dosing and activity was sustained throughout the experimental period. TRK-100 was more active than PGE1 in the test system and appeared to be of a similar potency to PGI2. Since this drug is stable, orally active and without the hypotensive activity of PGI2, it is considered to be a potentially useful agent for antithrombotic therapy.

Effect of proglumide on glycoprotein synthesis in aspirin-induced gastric erosions in rats.

The effect of proglumide on the rate of incorporation of (3H)-N-acetylglucosamine into glycoproteins (GP synthesis) in the glandular stomach in normal, fasting and aspirin-treated rats was studied. GP synthesis was significantly reduced by fasting. In Donryu rats, administration of aspirin (100 mg/kg) significantly decreased GP synthesis and induced the concurrent development of gastric erosions in the corpus, but not in the antrum, where no erosion was detected. Meanwhile, in Wistar rats little or no decrease of GP synthesis was observed in the glandular stomach and only slight erosions were found in the corpus. A negative linear correlation was found between the area of erosions and GP synthesis in the corpus of Donryu rats. Pretreatment with proglumide accelerated GP synthesis in the normal glandular stomach and restored the GP decrease caused by fasting. Gastric erosions induced by aspirin were also inhibited by proglumide and the GP decrease in the corpus was prevented. These results suggest that decreased synthesis of glycoproteins may be associated with the development of erosions induced by aspirin and that proglumide may partly exert its anti-erosive activity by stimulating glycoprotein synthesis in the glandular stomach.