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The effects of tetragastrin on mucus glycoprotein (mucin) metabolism and mucosal protection in rat gastric mucosa were investigated. Rats were administered with various doses of tetragastrin (12, 120, or 400 micrograms/kg body weight; s.c.), followed by 50% ethanol-induced gastric injury. Tetragastrin caused a significant increase in mucin content in the corpus mucosa and prevented 50% ethanol-induced gastric mucosal damage in a dose-dependent manner. For assessment of the effects of tetragastrin on the metabolism of gastric mucin in detail, changes in mucin distribution in the three different layers of rat gastric mucosa were examined one hour after single administration of tetragastrin. A significant increase in the mucin content was noted in the mucus gel and surface mucosal layer. Mucin content in the deep mucosa corresponding mainly to the mucus neck cell mucin underwent virtually no change by this treatment. An increase in mucin in the mucus gel and surface mucosa would thus appear due to the administration of tetragastrin and may possibly be related to the protective action of the gastric mucosa against injury. The data demonstrate a possibility that gastrin may have potential for enhancing gastric mucosal protection associated with mucus secretion and/or mucus synthesis on the surface mucosa of rat gastric mucosa.

A method was devised for separating rat gastric mucosa into three layers each containing a different mucin species. The mucus gel (first layer) was removed by stirring the gastric mucosa in a solution of phosphate-buffered saline containing 2% N-acetylcysteine. The surface mucosa (second layer), rich in surface mucus cells, was then separated from the deep mucosa (third layer) containing mucus neck cells, by scraping with forceps. The effectiveness of this method was confirmed by light microscopical observation after GOCTS-PCS (dual staining by the galactose oxidase-cold thionin Schiff method and paradoxical concanavalin A method) and AB-PAS staining (dual staining with alcian blue and the periodic acid Schiff method). The fixed specimen of scraped mucus and cell debris was rich in AB-PAS and GOCTS positive mucus, but was hardly stained by PCS, indicating mucus derived from surface mucus cells to have been efficiently recovered from this preparation. The residual mucosa could be stained by PCS but hardly at all by AB-PAS or GOCTS. The lyophilized powder specimens obtained from the three different layers of rat gastric mucosa were used to extract and quantify mucus glycoprotein (mucin). This was done to examine changes in mucin content in the three layers of gastric mucosa one hour following the oral administration of 20% ethanol or 0.35 N hydrochloric acid, both mild irritants. Mucin content was noted to significantly increase in the first layer but hardly at all in the second layer. In the third layer, it decreased significantly by 0.35 N hydrochloric acid, but changed only slightly by 20% ethanol administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous infusion of endotoxin (0.25 mg/kg/hr for 4 hr) was shown to induce disseminated intravascular coagulation (DIC) in rats, which resulted in hypofibrinogenemia, prolongation of prothrombin (PT) and partial thromboplastin time (PTT), thrombocytopenia, and elevated levels of fibrinogen/fibrin degradation products (FDP). Oral administration (100 mg/kg) of the selective PAF antagonist, SM-10661 ((+/-)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl), counteracted the changes caused by the endotoxin. Intravenous infusion of SM-10661 (6mg/kg bolus 2 min before endotoxin infusion + 6 mg/kg/hr for 4 hr infusion) also counteracted DIC. When suboptimal doses of gabexate mesilate, a synthetic protease inhibitor (3 mg/kg i.p.), and SM-10661 (2 mg/kg bolus + 2 mg/kg/hr for 4 hr infusion) were administered concomitantly, hematological parameters improved. The results suggest that PAF may play a role in the pathogenesis of DIC, and that together with the results already reported for other PAF antagonists, SM-10661 may be useful in the treatment of DIC.

A method was established for recovering the mucus gel layer of rat gastric mucosa without damage to underlying surface epithelium. The mucus gel was solubilized by stirring the gastric mucosa in a solution of N-acetylcysteine (NAC), a mucolytic agent. Optimal mucus gel solubilization was possible by treatment with 2% NAC for 5 minutes at room temperature. Mucus glycoprotein was quantitatively extracted and measured from the mucus gel sample obtained by the NAC treatment. This treatment caused no damage to surface epithelial cells, as observed by a light microscope. Besides NAC, pronase solution was also adequate for solubilizing the mucus gel layer without any damage to the surface epithelium. However, extraction and measurement of mucus glycoprotein from the pronase-treated mucus gel sample was not possible due to contamination by high molecular hexose-containing substances which were eluted along with the mucus glycoprotein from the column of Bio-Gel A-1.5m. This NAC method was used to examine changes in mucus glycoprotein content in the mucus gel at one hour following the oral administration of 16,16-dimethyl prostaglandin E2. A significant increase in mucus glycoprotein of the gel was brought about by the prostaglandin treatment. Thus, the present method was suitable for estimating the amount of mucus secreted in to the mucus gel layer.

SM-10661 [(+/-)-(cis)-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl] displayed marked in vitro inhibition of rabbit platelet aggregation induced by 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (alkyl-PAF), 1-O-hexadecyl-2-acetyl-sn-glycero-3-phosphocholine (C16-PAF), and 1-O-octadecyl-2-acetyl-sn-glycero-3-phosphocholine, with IC50, values of 5.50, 5.94, and 3.68 microM, respectively. It also inhibited alkyl-PAF-induced aggregation of human platelets with an IC50 of 3.00 microM, but it did not inhibit platelet aggregation induced by ADP, collagen, arachidonic acid, the thromboxane A2 agonist U46619, or the Ca ionophore A23187, at concentrations up to 400 microM. Furthermore, SM-10661 antagonized [3H]-C16-PAF binding to rabbit platelets competitively, with an IC50 of 1.0 microM. SM-10661 protected against alkyl-PAF-induced lethality in mice with an ID50 of 6.0 mg/kg intravenously or 24 mg/kg orally. In guinea pig, SM-10661 inhibited the alkyl-PAF (0.1 micrograms/kg)-induced increase in bronchial pressure, with an ID50 of 0.7 mg/kg intravenously or 15 mg/kg orally. Bronchial hyperreactivity to bombesin after the infusion of alkyl-PAF was also inhibited dose-dependently by the infusion of SM-10661, with an ID50 of 25 mg/kg. In addition, SM-10661 inhibited alkyl-PAF (0.01 micrograms/kg)-induced hypotension in rats, with an ID50 of 0.36 mg/kg intravenously or 33 mg/kg orally. SM-10661, when given orally, showed rapid absorption and good duration of pharmacological activity in rats and rabbits.

In our previous reports, low dose acid secretagogues caused increase in corpus mucus glycoprotein content in rats. This increase was not due to the direct action of protons. The present study was conducted to determine whether this increase has a mucosal function or not Rats were given histamine (0.8 mg/kg) intraperitoneally or tetragastrin (12 micrograms/kg) subcutaneously. One hour following the acid secretagogues administration, the animals were given 1 ml of 30, 40 or 50% ethanol orally and then sacrificed after one hour. Gastric mucus glycoproteins were isolated from the corpus region of stomach. The following results were obtained: 1) Histamine prevented the gastric mucosal damage and the decrease of corpus mucus glycoprotein content induced by 40% ethanol ingestion. 2) Tetragastrin prevented the gastric mucosal damage induced by 30 approximately 50% ethanol ingestion and the decrease of corpus mucus glycoprotein content induced by 40 approximately 50% ethanol ingestion. Based on these results, the increase of corpus mucus glycoprotein content induced by acid secretagogues has a mucosal function. Moreover, tetragastrin strengthened the mucosal defence together with acid secretion.

Tetracycline has been used for the local treatment of malignant pleurisy ever since of Robinson (1972) reported its effectiveness. In this report, we try to elucidate possible mechanisms of action of this drug from the viewpoints of (1) pharmacokinetic analysis following intrapleural administration, and (2) pleural reaction. The results were as follows: (1) In 5 patients with malignant pleural effusion, 500 mg of doxycycline was injected into the pleural cavity and pharmacokinetic analysis was performed. The clearance curve of doxycycline in pleural fluid was described by either a one-compartment model or a two-compartment model. The mean half life of slow space was 33.3 hr, which suggested delayed excretion of this drug from pleural space. (2) The direct effect of doxycycline on pleura was studied in rabbits. At a dose of 10 mg per kg of body weight, the mesothelial cells became cuboid and contained vacuoles in their cytoplasma. With increasing dose up to 40 mg per kg, the changes in mesothelial cells were enhanced. In submesothelial tissue, edema and cellular infiltration were noticed. Three weeks later, normalization of mesothelium was observed, being followed by connective tissue proliferation. These findings may support the efficacy of tetracycline for local treatment of malignant pleurisy.

Fluorescein angiography was carried out in 150 glaucoma subjects. Among them 94 subjects were selected to evaluate the correlation between functional loss and the findings of fluorescein angiography in the optic disc. The intensity of fluorescence was assessed in the superficial reticular capillaries and radial epipapillary capillaries. Functional loss was estimated by the visual field defects and cup-disc ratio. A marked decrease in the capillaries was seen in accordance with the increase in the cup-disc ratio. Also, the intensity of fluorescence in the optic disc paralleled the change in the visual field: the greater the deterioration in the visual field, the fewer the capillaries in the optic nerve head and vice versa. The fluorograms of 94 subjects were placed in one out of six groups, i.e. (1) normal, (2) arcuate scotoma, (3) superior or inferior nasal defects, (4) superior or inferior defects, (5) central residue or (6) temporal residue. The common factors correlating the fluorescein angiography in the glaucomatous optic disc with visual field loss were explored in 94 subjects, and it was possible to predict the visual field change from the capillary distribution in the glaucomatous optic disc.

A 42-year-old woman presented with orthostatic hypertension. Increased plasma renin activity was noted and blood pressure rose gradually with standing. Selective renal arteriography indicated narrowing of the distal portion of the right renal artery and poststenotic dilatation and signs of arterial stenosis due to fibromuscular dysplasia. Greater arterial narrowing resulted from tortion due to nephroptosis brought about by excessive renin secretion. Thus, both renal arterial stenosis and nephroptosis were considered responsible for the present orthostatic hypertension. Percutaneous transluminal renal angioplasty was found very effective for normalizing standing blood pressure and renal blood flow.

Five patients with malignant pleural effusion were treated with intrapleural administration of ACNU. Three of 5 patients showed cytologically negative in the pleural fluid and the fluid was eliminated in two patients. In 5 patients, 200 mg of ACNU was injected into the pleural space and pharmacokinetic behavior was studied. The clearance curves of ACNU in pleural fluid were described by either one-compartment model or two-compartment model. The mean half life of slow phase was 0.75 hour. These results indicate that ACNU disappears rapidly from the pleural space after the intrapleural administration. The effect of ACNU on the pleura was studied histologically in rabbits. At a dose of 3mg per kg body weight, the mesothelial cells were swelling and small areas of cellular desquamation appeared over the pleural surface. With increase in dosage, these findings were more pronounced and in the submesothelial tissue there was edema as well as cellular infiltration. In rabbits given two injections with interval of one week, the pleura showed a stronger reaction than that produced by single injection.

The effects of NC-1300 on gastric acid and mucus glycoprotein secretion were investigated in pylorus-ligated (4 h) rats. NC-1300 (30 mg/kg, intraduodenally) significantly inhibited gastric acid concentration more than 90%. The agent did not affect the total mucus glycoprotein output in the gastric juice, but caused by about 1.5 times denser mucus glycoprotein secretion than that in the control group. The amount of mucus glycoprotein in the mucous gel layer increased by about 1.4 times with this agent. Thus, NC-1300 not only inhibits acid secretion but also promotes mucus secretion, and this may explain its ability to protect the stomach against necrotizing agents.

Solutions of phenylephrine hydrochloride at concentrations of 1, 2 and 5% were instilled in one eye of 5 normal volunteers. Both eyes were photographed concurrently with an infrared film, and the pupil diameter was determined by an image analyzer using the developed film. The mydriatic effects were expressed by the difference in the pupil diameter of the experimental and the fellow control eyes determined concurrently. The mydriatic effects with these 3 solutions reached a peak about one hour and 15 minutes after instillation; the peak effects and the logarithm of the drug concentrations showed a linear relationship. An extrapolation of the relationship gave a least effective concentration of 0.07%. From the time course of the mydriatic effects, the pharmacokinetic coefficients were calculated using a computer. The average values were 0.24 +/- 0.08 hour for the time lag of the mydriatic response to appear, 1.31 +/- 0.19 hour-1 for the apparent elimination rate constant and 1.47 +/- 0.28 hour-1 for the apparent absorption rate constant.

Fourty-four patients with advanced non-small cell cancer of the lung were treated with a combination chemotherapy of mitomycin C, endoxan, and cisplatin (MEP). The overall response rate was 20%, with 9 partial responses. The median duration of response was 7 months. The overall median survival was 10 months. No significant difference was noted in survival time between PR and NC. MEP therapy seems to provide a relatively easy therapeutic approach in the treatment of advanced lung cancer with no associated renal toxicity or loss of hair.