Biomedical subjects

L E Borella

Publications and source records attributed to L E Borella.

15 recordsLinked to original sources

PubMed1991

Inhibition of interleukin-1 (IL-1) induced neutral proteases from rabbit articular chondrocytes by WY-46,135 and WY-48,989.

The effects of potential anti-osteoarthritic compounds both on the direct inhibition of collagenase and neutral protease activities and on IL-1 induced release of neutral proteases from rabbit articular chondrocytes were investigated. WY-46,135 ((+)-N-[[[(5-chloro-2-benzothiazolyl)thio]phenyl]acetyl]-L- cysteine) directly inhibited collagenase activity (IC50 = 15.4 microM). This inhibition was reversible upon dialysis. WY-46,135 also directly inhibited neutral protease activity (IC50 = 16.8 microM) but did not significantly block bacterial collagenase activity at a concentration of 80 microM. In contrast, WY-48,989 (4-[[2-(7-chloro-2-phenyl-2H-pyrazolo[4,3-c]quinolin-4- yl)ethyl]amino]benzonitrile) did not directly inhibit either collagenase (10 microM) or neutral protease (100 microM) activity. Both WY-48,989 and WY-46,135 inhibited IL-1 stimulated release of neutral proteases (IC50 = 3 microM). The activities of these compounds represents two potential approaches for the treatment of osteoarthritis. WY-46,135 combines direct metalloprotease inhibitory activity with the inhibition of IL-1 stimulated neutral protease release from articular chondrocytes while WY-48,989 selectively inhibits the IL-1 induced release of metalloproteases.

Acetylcysteine↗

PubMed1990

N-phenyl-2-pyridinecarbothioamides as gastric mucosal protectants.

A series of substituted 2-pyridinecarbothioamides was synthesized and evaluated for gastric mucosal protectant activity in the rat. Out of this investigation N-(3,5-difluorophenyl)-2- pyridinecarbothioamide (23, AY-31,574) was identified. This compound was much more potent than sucralfate and ranitidine against ethanol-induced lesions. Compound 23 was equipotent with ranitidine against gastric injury caused by stress. Unlike ranitidine, 23 was found to be devoid of antisecretory activity in the pylorus-ligated rat model, making it a selective mucosal protectant. Such a potent selective mucosal protectant may provide a novel clinical approach in treating ulcers.

Amides↗

PubMed1990

Mucosal protective activity of activated aluminum complex.

The antacid ES Riopan was acidified ex vivo to pH 2.5 to completely eliminate its buffering capacity and was then tested as a mucosal protective agent. The pH 2.5 acidified antacid solution was named activated aluminum complex. Activated aluminum complex was 8.2 times more potent than its parent antacid in protecting against acidified aspirin-induced gastric lesions in the rat. Activated aluminum complex had a duration of action greater than 10 h in the ethanol-induced gastric lesion model, while ES Riopan was active for 6 h. Activated aluminum complex was able to inhibit both acid- and nonacid-mediated ulcers in the stomach and intestine. Its mucosal protective activity was not blocked by pretreatment with indomethacin. These results demonstrate that the nonbuffering antacid activated aluminum complex exerted a more potent and longer-lasting mucosal protective activity than its parent antacid. The activity was probably due to the presence of a hexaaquoaluminum cation and supports the argument that antacids possess mucosal protective effects independent of their acid-neutralizing capacity.

Aluminum Hydroxide↗

PubMed1989

Gastric antisecretory and antiulcer/cytoprotective effects of 2-cyano-3-(ethylthio-3-methylthio)-2-propenoic acid methyl ester.

AY-28,200 (2-cyano-3-(ethylthio-3-methylthio)-2-propenoic acid methyl ester), a new gastric antisecretory/antiulcer agent, inhibited basal and pentagastrin-stimulated gastric acid secretion in the conscious rat (ED50 = 7.6 and 1.9 mg/kg i.g., respectively). For inhibition of basal secretion, peak activity was attained in 5 to 6 h after dosing and was maintained for more than 10 h, with no gastric antisecretory activity occurring at 24 h. The K+ stimulated H+-K+ ATPase activity from rabbit gastric microsomes was inhibited by AY-28,200 (IC50 = 22 mumol/l). AY-28,200 inhibited ethanol-induced gastric lesions, at 3 mg/kg p.o. AY-28,200's cytoprotective effects against ethanol lasted for more than 4 h. AY-28,200 blocked acetylsalicylic acid and stress-induced gastric ulcers but was inactive against indomethacin-induced gastric ulcers. These results suggest that AY-28,200 is a parietal cell proton pump inhibitor with cytoprotective properties, and may produce its cytoprotective effect by stimulating the formation of endogenous prostaglandins.

Adenosine Triphosphatases↗

PubMed1989

Cytoprotective and antiulcer activities of the antacid magaldrate in the rat.

The cytoprotective and antiulcer activities of the antacid magaldrate (ES Riopan) as well as its effects on gastric mucosal blood flow and mucus secretions, were determined in the rat. Magaldrate afforded protection against gastric necrotic lesions induced by absolute ethanol (ED50, as magaldrate, 419 mg/kg); gastric ulcers induced by acidified acetylsalicylic acid (ED50 540 mg/kg), stress (cold restraint, ED50 388 mg/kg), indometacin (ED50 281 mg/kg), and pylorus ligation; and intestinal ulcers induced by cysteamine (ED50 243 mg/kg) and indometacin (ED50 184 mg/kg). At a dose of 8 ml/kg (1728 mg/kg magaldrate), the cytoprotective effect of magaldrate against ethanol was evident 1 min after oral administration and lasted more than 8 h. The cytoprotection induced by magaldrate was decreased by pretreatments with the depletor of endogenous thiols, n-ethylmaleimide, or with the cyclooxygenase inhibitor, indometacin. Magaldrate did not affect gastric mucosal blood flow, but it increased gastric mucus secretion. This later effect may be a factor responsible for the cytoprotective activity of the agent. The efficacy of magaldrate may be due not only to its antacid, bile sequestering, and antipeptic activities, but also to its cytoprotective activity. The present results suggest that magaldrate could be effective in preventing gastric damage caused by alcohol and antiinflammatory drugs.

Aluminum Hydroxide↗

PubMed1989

Activated aluminum complex derived from solubilized antacids exhibits enhanced cytoprotective activity in the rat.

Removing the buffering capacity of aluminum-containing antacids by acidification greatly increased their cytoprotective activity over the parent antacid. Commercially available antacids were acidified with 6 N HCl. Peak mucosal protective activity occurred at pH 2.5, and declined at lower pH. At pH 2.5, the antacid suspensions became solubilized and no acid-neutralizing capacity remained. This solution was named activated aluminum complex. Based on aluminum ion content, each aluminum-containing antacid suspension tested demonstrated a comparable increase in potency on acidification against ethanol-induced lesions. HCl (pH 2.5) was inactive against ethanol-induced lesions. At cytoprotective doses, activated aluminum complex did not cause gastric lesions when orally administered by itself, demonstrating that it is not acting as a local mucosal irritant. The data suggest that solubilization of aluminum-containing antacids in acidic medium enhances their mucosal protective activity, probably by releasing an activated species of aluminum ion reported to be a hexaaquoaluminum cation.

Aluminum↗

PubMed1980

A simple non-radioactive method for the simultaneous quantitative determination of stomach empyting and intestinal propulsion in the intact conscious rat.

A simple non-radioactive method for the simultaneous assessment of stomach emptying and intestinal propulsion in intact fasted conscious rats was developed employing Amberlite pellets. The Amberlite pellets were administered by gastric gavage and the rats were killed 20 or 120 min later. The number and percent of the pellets in the stomach and intestines and the distance travelled by each pellet in the small intestine were determined. The distance travelled by the leading pellet in the small intestine was employed as a parameter to determine effects on intestinal propulsion independent of the stomach emptying activity. Chlorisondamine (s.c.), atropine (s.c.), pentobarbital (i.p.) and sesame seed oil (p.o.) inhibited both stomach emptying and intestinal propulsion in a dose-related manner. All these agents also caused a dose-related displacement of the pellets in the small intestine which resulted in a more cephalad-oriented distribution of the pellets. Propantheline (s.c.) exerted a dose-related inhibition on the stomach emptying but not on intestinal propulsion. Carbachol (s.c.) increased both the rate of stomach emptying and that of propulsion in the small intestine.

Animals↗

PubMed1979

Sucralfate: antipeptic, antiulcer activities and antagonism of gastric emptying.

The antiulcerogenic and antipeptic activities of sucralfate (Ulcerlmin), a basic aluminum sucrose sulfate complex, were investigated. In rats, sucralfate inhibited the formation of ulcers induced by pyloric ligation, indometacin and cysteamine. In doses antagonizing forestomach ulcer formation, sucralfate increased the pH of the gastric juice in a dose-related manner. In vitro, at pH 1.9, sucralfate inhibited rat, dog and hog pepsin in a concentration-related manner and also the peptic activity in human gastric juice. Sucralfate may act as an inhibitor of pepsin by precipitating the enzyme or by binding with it reversibly. The antipeptic activity appears to be directly related to the amount of sucralfate in suspension rather than that in solution. In the gastrointestinal tract, the basic nature of sucralfate may enhance the antipeptic activity of the sucralfate molecule. In rats, sucralfate decreases the rate of gastric emptying.

Aluminum↗

PubMed1978

A relatively specific and quantitative assay for histamine H2-receptor blocking activity by determination of inhibition of histamine-induced gastric acid secretion in the rat.

A relatively specific method for the quantitative assay of histamine H2-receptor antagonists has been developed. The method is based on the antagonism of the histamine-induced, and the spontaneous, gastric acid secretion in the stomach-perfused, urethane-anesthetized acute rat. For the induced gastric acid secretion, the animal received two consecutive equal injections of histamine (2 mg/kg, intrajugularly), the second 1.7 h after the termination of the first histamine-induced acid hypersecretion. Atropine (5 mg/kg), chlorisondamine (2 mg/kg), imipramine (10 mg/kg) and tripelennamine (5 mg/kg), administered i.p., failed to inhibit the histamine-induced, or the spontaneous, gastric acid secretion. Metiamide inhibited the histamine-induced acid secretion (ED50 1.85 mg/kg, i.p.) and the spontaneous acid secretion (10 mg/kg, i.p.). These results suggest that in the rat model employed in this study, histamine and H2-receptors play a very important role in the regulation of the gastric acid secretion. Other mechanisms involving cholinergic tone, biogenic amine uptake and histamine H1-receptors do not seem to intervene.

Animals↗

PubMed1978

Alrestatin: gastric acid antisecretory-antiulcer activity in the rat.

Alrestatin sodium (AY-22,284-A) inhibited gastric acid secretion and decreased the volume of gastric juice produced in the pylorus-ligated rat when administered intraperitoneally or perorally. Pentagastrin-induced gastric acid output in the unanesthetized rat was antagonized. The pyloric ligation-induced ulcer formation in the rat was inhibited. Alrestatin sodium did not exhibit an anticholinergic profile. The drug did not block the norepinephrine neuronal uptake mechanism in rat brain or heart; it did not alter the endogenous norepinephrine concentration in the heart and decreased endogeneous brain norepinephrine concentration. Alrestatin sodium is an effective inhibitor of gastric acid secretion and ulcer formation in the rat.

Aldehyde Reductase↗

PubMed1976