Administration Of Cinchophen Research Articles

Healing process from cinchophen-induced acute gastric mucosal lesion in the rat: a scanning microscopic study.

The healing process in the microvasculature of cinchophen-induced acute gastric mucosal lesion was studied by the vascular corrosion casting method and conventional scanning electron microscopy. Thirty-six hours after cinchophen injection, prominent degeneration and exfoliation of surface mucous cells, along with exposure of the underlying connective tissue, were seen. The vascular casts showed leakage of resin and the occlusion of capillaries, which indicates breakage of the capillary network. One week after cinchophen injection, the denuded gastric mucosa was almost covered with surface mucous cells of irregular shape. The vascular casts showed signs of healing of the capillary network, including capillary neogenesis. The lesion was nearly healed by 2 to 3 weeks after cinchophen administration. Cinchophen induces the formation of acute gastric mucosal lesions that affect the surface mucous cells as well as the underlying vasculature. The subsequent healing process involves the regeneration of epithelial cells over the denuded areas and reconstruction of the underlying vascular network.

Are epinephrine and gastrin accelerative factors of acute cinchophen ulcer?: Studies on gastric mucosal microcirculation and gastric secretion.

Measurements of serum epinephrine and gastrin, simultaneously, gastric mucosal blood flow and gastric secretion were carried out in cinchophen treated dogs. No significant changes in either serum concentrations of epinephrine and gastrin or fundic mucosal microcirculation after a single 100 mg/kg cinchophen administration were found while gastric secretion increased markedly after the medication. On the other hand, a significant increase in serum epinephrine and gastrin levels was observed while gastric secretion decreased significantly after large doses of cinchophen (300 mg/kg) were injected intravenously. Here gastric mucosal microcirculation is decreased. Repeated administration of 100 mg/kg cinchophen for 3 to 7 days brought about an increase in epinephrine and gastrin levels and caused an occurrence of fundic mucosal hemorrhage. Sympathetic discharge and gastrin release were not seen after a 3-week period of cinchophen administration. Cinchophen ulcers were produced, even when contact between the bile and the stomach mucosa was avoided. Vagotomy had no connection with ulceration and gastric secretion.

Induction of UDP glucuronyltransferase in the liver and extrahepatic organs of the rat

UDP glucuronyltransferase (4-methylumbelliferone) activity was enhanced in the liver of the rat after administering phenobarbital, cinchophen or 3-methylcholanthrene, in the lung after administration of cinchophen or 3-methylcholanthrene, and in the kidney after cinchophen. The UDP glucuronyltransferase of the spleen could not be induced with the dosage of the drugs used. Chlorpromazine was not able to induce either hepatic or extrahepatic UDP glucuronyltransferase. Chlorpromazine competitively inhibited hepatic UDP glucuronyltransferase in vitro .

Gastric lesions produced by cinchophen in the ferret

The gastric ulcerogenicity of cinchophen was evaluated in the ferret, which has a stomach anatomically and physiologically similar to man. Cinchophen was administered by gastric intubation to a total of 36 ferrets in single, daily doses of 220 mg/kg, 5 times a week, and animals were sacrificed from 3 hr to 35 days. Acute exudative inflammation was noted at 3 hr after administration of cinchophen, was more severe at 3–4 days, and was especially prominent in the antrum. Deep linear, multiple, hemorrhagic ulcerations were also observed and acute antral ulcers were found in 25% of treated animals. These manifestations subsided at 7 days despite continued administration and began to reappear at 14–35 days. An antral ulcer was found in one of 5 ferrets at 35 days. Secretory studies on chronic fistula ferrets injected ip with a single 220 mg/kg dose of cinchophen indicated that the acid concentration and output and the pepsin activity were not altered by cinchophen during a 3-hr period following cinchophen administration. Histopathologic study of 6 antral pouch ferrets demonstrated only slight, acute inflammatory changes following cinchophen administration directly into the pouch and no antral changes following po administration. Thus, the present investigation suggests that topical irritation of the gastric mucosa by cinchophen is not a significant factor, but that the presence of gastric acid (but not hypersecretion) plays an important role in cinchophen-induced ulcerogenesis.

Role of the hypothalamus in the pathogenesis of cinchophen-induced gastric ulcers in dogs.

The effects of hypothalamic lesions on cinchophen-induced gastric ulcers were studied in 38 male mongrel dogs. Chronic gastric ulcers were produced in 100% of the cinchophen-administered dogs without hypothalamic lesion. When cinchophen was administered to animals with anterior, posterior and lateral hypothalamic lesions, this incidence of gastric ulcers was not prevented. In dogs with lesions of the middle portion of the hypothalamus, the incidence of chronic ulcers was decreased two-thirds; in dogs with lesions of the ventromedial nuclei of the hypothalamus, goldthioglucose did not protect against the development of cinchophen ulcers. Chronic gastric ulcers were not produced in all of the dogs with lesions of the median eminence. These data suggest that daily administration of cinchophen produced gastric ulcers in the pyloric region through the mechanism of the median eminence.

EFFECTS OF CINCHOPHEN ON THE GASTRIC ELECTRICAL ACTIVITIES

Electromyographic effects of intravenous administration and hypothalamic implantation of cinchophen on the gastric motor activities were studied in the mongrel dogs. Intravenous administration of cinchophen sodium in both doses of 100 mg and 300 mg per kg of body weight induced the prolongation of the intervals of spike potentials in the first 5 minutes. In the next 5 minutes, only by 300 mg/kg administration, the intervals were prolongated. Then in the third 5 minutes, action of cinchophen on the gastric motor activities ceased in both cases. The degree of prolongation aftcr administration in a dose of 300 mg/kg was greater than that ot 100 mg/kg.A consistent prolongation in the intervals of spike potentials was observed following only middle hypothalamic implantation of 1 mg cinchophen sodium. Median eminence implants, however, failed the prolongation of the intervals of spike potentials.These findings suggest that cinchophen reduced the gastric motor activities through the direct action upon the middle hypothalamus.

Enhanced glucuronide formation in different tissues following drug administration

A study was made of the o-aminophenol glucuronide synthesis in the slices of the liver, kidney and gastrointestinal tract after the administration of 3,4-benzpyrene, cinchophen, 3-methylcholanthrene, phenobarbital and salicylic acid to elucidate whether the responses of the different tissues are similar to these drugs known to enhance drug metabolism. A 1.6-fold increase of o-aminophenol glucuronide synthesis was found in liver slices 5 days after a single intraperitoneal injection of 3-methylcholanthrene whereas there was no increase in the slices from the kidney or from the various parts of the gastrointestinal tract. The i.p. administration of 3,4-benzpyrene had a similar effect. The intragastric administration of cinchophen for 3 days resulted in a two-fold increase of the synthesis in the slices from the liver, glandular stomach, caecum and colon, and a 3-fold increase was found in the kidney. In the duodenum only a slight increase of activity was observed when the analysis was carried out 24 hr after the last dose, but a 1.6-fold increase was found after 48 hr. The i.p. administration of phenobarbital for 3 days resulted in a 1.4-fold increase of the synthesis in the liver, but no change of activity was found in the kidney or in the various parts of the gastrointestinal tract. The intragastric administration of salicylic acid for 3 days resulted in a 1.9-fold increase in the kidney but only insignificant changes were found in the various parts of the gastrointestinal tract or in the liver when analysed 24 hr after the last dose. The enhancement of the glucuronide biosynthesis caused by the administration of the various drugs thus reveals marked organ specificity.

PLASMA CORTICOSTERONE CONCENTRATION AUGMENTED AFTER CINCHOPHEN ADMINISTRATION AND ITS MECHANISM

Cinchophen sodium administered intravenously to Holtzman rats caused a significant increase in plasma corticosterone concentration, reaching a peak at 30 minutes after injection : a linear log-dose-response curve was obtained between 10 to 40 mg per 100 g body weight of cinchophen and plasma corticosterone level This effect of cinchophen was inhibited by hypophysectomy as well as lesions placed in the median eminence.Intraperitoneal administration of 0. 5mg of dexamethasone and 5 mg of nembutal per 100 g body weight failed to suppress the effect of 40mg per 100g body weight of cinchophen, in sharp contrast with those of histamine and adrenalin.It appears reasonable to suggest that the median eminence is involved in a rise in the plasma corticosterone concentration following cinchophen administration.

Levels of uridine diphosphate glucose dehydrogenase and UDPG in the gastrointestinal mucous membrane.

The mucosal activity of uridine diphosphate glucose dehydrogenase was found to decrease very rapidly with increasing distance from the pylorus in the oral third of the rat small intestine and to remain almost constant in the rest. In the caecum and the oral half of the large intestine, however, the activity was as high as at the oral end of the small intestine. The activity observed in the aboral half of the large intestine and the glandular stomach was of the same order of magnitude as that observed in the middle of the small intestine. The enzyme activity in the liver and kidney was lower than at the oral end of the small intestine. Here and in the caecal mucous membrane the activity increased after intragastric administration of cin-chophen. The enzyme activity as a function of gut wall depth was also studied and found to be high in the mucous membrane and in the deep glands of the duodenum in the dog. Muscle layers were inactive, which explains why the duodenum displayed a two-phase distribution of enzyme activity.The mucosal content of uridine diphosphate glucose in the trichloracetic-acid-perfused small intestine of the rat did not show any great differences in the main part of the organ, with the exception of the last 10 cm segment, in which a somewhat higher content was observed.

THE INFLUENCE OF HYPOPHYSECTOMY ON GASTRIC SECRETION IN RESPONSE TO CINCHOPHEN

The gastric secretion after administration of cinchophen was studied in dogs with Heidenhain gastric pouch. An intravenous injection of cinchophen 150mg/kg to normal dogs produced a marked increase especially in the gastric pepsin concentration after 3 hours, attaining a maximal level at 6 hours, but a slight increase in the volume and the acid concentration of gastric juice which reached a peak within 3 hours. This gastric secretory response to cinchophen was completely inhibited by hypophysectomy. Even though the gastric secretory response to ACTH was closely similar to that of cinchophen, this response occurred in the normal as well as hypophysectomized dog.The results of experiments support the hypothesis that the gastric secretion in response to cinchophen is activated through a neurohumoral mechanism via the hypothalamic-pituitary-adrenocortical system.

EXPERIMENTAL INVESTIGATION ON CHINCHOPHEN GASTRIC ULCER

Cinchophen was administered to dogs either orally or intravenously in a dose of 0.15 g/kg for about 3 weeks, and the development of typical gastric ulcer was observed in all the cases. At the same time, activation was demonstrated in neural secretion of the hypothalamus and in function of the adrenal cortex. In total pouch dogs, the secretion of gastric juice began about 3 hours after the oral administration of cinchophen, and lasted about 3 hours. In this case, the secretion of hydrochloric acid, especially pepsin, was remarkably accelerated, and different secretion curve from those of insulin and histamine was obtained.When the pituitary stalk was completely cut, the flow of neural secretion after cinchophen administration was checked at the section of the nerve bundles, and neither adrenocortical function, nor gastric juice secretion was activated, and the development of gastric ulcer was completely inhibited. In dogs whose vagus and sympathetic nerve were blocked, adrenocortical hyperfunction took place after cinchophen administration samely as in normal dogs. Also characteristic enhanced secretion of gastric juice and development of typical gastric ulcer were observed.In bilateral adrenalectomized dogs, gastric juice was not eahanced by cinchophen administration, but typical gastric ulcer developed. This latter was also observed either in bilateral testectomy or bilateral thyroidectomy, both combined with adrenalectomy.

CYTOLOGICAL STUDIES ON THE ADEN OHYPOPHYS IS IN RESPONSE TO CINCHOPHEN

The author has consecutively investigated cytological changes in the adenohypophysis of the dog following oral administration of cinchophen.For the cytological manifestation, GOMORI's aldehyde-fuchsin-azan and periodic acid SCHIFF reaction were employed and differential cell count was made.Thirty minutes after administration, α-cells were somewhat enlarged and vacuolated β-cells and PAS positive cells already increased. Af ter one hour, degranulation in α-cells was found especially in apical part of the cell and granules in the β-cell were decreased with extensive vacuolation in cytoplasm. After 3 and 5 hours, α-cell degranulated progressively and diminished in its size and number. Granules in β-cells decreased and were hardly stained by fuchsin. Size of β-cells was strikingly variable. On the other hand, chromophobes, particularly granulated chromophobes, were increased. Changes in δ-cells were not distinct. After 7, 12 and 24 hours, restoration progressed, although not accomplished even after 24 hours.ACTH release after administration of cinchophen has been revealed in both previous and this, investigations, but additional hormone release seemed also not deniable from these findings.

Action of Banthine Upon Cinchophenic Ulcer in Dogs

Summary Taking into account the great number of animals in which cinchophenic peptic ulcers have been studied in their different evolution periods, the author investigated the action of Banthine upon this type of ulcer. For this investigation 48 dogs were employed, 32 males and 16 females. The following problems were analyzed: action of Banthine by the oral, intramuscular and intravenous routes upon cinchophenic peptic ulcer in the dog. The action of Banthine orally in the prophylaxis of this type of ulcer was also studied. The results were as follows 1. On a total of 12 dogs, the administration of Banthine in doses of 50 to 100, mg. daily for 11 to 18 days inhibits the development of cinchophenic ulcer in 100 per cent of cases. Most of the animals' stomachs showed healed or healing gastric ulcerations. In other cases corrosive gastritis was found, particularly on the lesser curvature. 2. Banthine, administered to dogs intravenously in doses of 10 to 20 mg. simultaneously with the ingestion of cinchophen, impedes the development of ulcer in 100 per cent of the cases. 3. In dogs the daily administration of cinchophen was accompanied by the intramuscular injection of 10 to 20 mg. of Banthine. In no case was the typical cinchophenic ulcer observed. In most cases congestive and corrosive gastritis was found; in one case a marked cicatrization of a recent ulcerative lesion was observed. 4. Banthine administered orally in doses of 50 to 150 mg. daily for 5 to 15 days before beginning cinchophen had no significant prophylactic effect.

CLINICAL AND BIOCHEMICAL STUDY OF REMISSIONS IN NONSPECIFIC ARTHRITIS

IT IS WELL known that nonspecific arthritis is a disease which is characterized by relapses and remissions. 1 It is also generally accepted that whereas there is no specific curative agent for this disease, there are many measures which hasten remissions in both rheumatoid arthritis and osteoarthritis. 2 As Hench 3 recently stated in discussing the use of gold therapy in rheumatoid arthritis, a remission may be obtained by this method in six months in a case in which it otherwise might require six years. Using measures other than chrysotherapy, a smaller percentage of remissions has been reported after the use of such diverse treatments as hyperthermia with typhoid vaccine, 4 hypervitaminosis with massive doses of activated ergosterol (viosterol), 5 bismuth therapy, 6 low carbohydrate diets, 7 administration of cinchophen, 8 starvation, 9 administration of streptococcus vaccine, 10 administration of foreign protein, 11 bee venom therapy 12 and even anesthesia. 13 Of striking significance is the fact that the highest percentage of remissions

Acute Yellow Atrophy Following Cinchophen Administration

ABOUT twenty years ago Cabot1 first reported a case of acute yellow atrophy allegedly due to cinchophen. Although similar cases have been recognized since that time, clinicians who use cinchophen with no observed untoward effects have minimized it as a hepatotoxic agent. One series has been reported, for example, in which cinchophen was given to 2500 patients without a fatal case.2 The toxic manifestations of cinchophen against which the physician is usually cautioned are chiefly those of the skin. Among them, urticaria and the erythematous morbilliform rashes are said to be most frequently encountered. But perhaps more important are signs . . .

EFFECT OF CINCHOPHEN ON SECRETION OF CHOLIC ACID

Those investigators who have observed damage to the liver after administration of cinchophen to laboratory animals used doses at least ten times the equivalent dose for human beings estimated on the basis of body weight. 1 Those who have used the same or smaller doses failed to find any striking evidence of hepatic damage 2 or of depression of hepatic function. 3 Stalker, Bollman and Mann 4 gave twice the average human dose to a relatively large number of dogs for periods up to thirty-nine weeks. Though they observed gastrointestinal intolerance, which usually subsided, they did not observe jaundice or microscopic evidence of pathologic changes in the liver and other tissues, other than peptic ulcer. It was believed that if cinchophen has a direct toxic effect on the liver it should be manifested by a disturbance of secretion of cholic acid, since the output of that substance is readily affected by an

Effect of Rammstedt Operation on Incidence of Ginchophen Ulcer

ConclusionThe Rammstedt operation decreases the incidence of gastritis, hemorrhagic erosions and ulceration that follows cinchophen administration in dogs. This indicates that pylorospasm plays a significant but not an all inclusive role in the genesis of cinchophen ulcers.

EXPERIMENTAL PEPTIC ULCER PRODUCED BY CINCHOPHEN

The administration of cinchophen is an effective method for producing chronic peptic ulcer in dogs. It may be said that the method is uniformly successful, depending on three conditions; they are: (1) sufficient cinchophen administered over (2) a sufficient period to dogs which (3) take food every day. Surgical alteration of the gastrointestinal tract is not necessary for the production of this type of ulcer. The chronic ulcer is usually single and appears in the same region of the stomach in which it is noted in man, namely, on the posterior wall near the lesser curvature and between the incisura and the pylorus. Infrequently an ulcer is seen on the anterior wall, and none has been noted on the greater curvature. Duodenal ulcer occurs rarely and has been noted only in association with a larger gastric ulcer. The ulcer begins to heal with the discontinuation of administration of cinchophen and

EXPERIMENTAL PEPTIC ULCER PRODUCED BY CINCHOPHEN

Cinchophen has been used since 1911 in the treatment of gout. Toxic cirrhosis of the liver has developed in a few cases after its use. In attempting to produce hepatic damage experimentally in dogs, Churchill and Van Wagoner1in 1931 noted peptic ulcer in many of their animals. This and subsequent work by these investigators suggested to us that we attempt to produce peptic ulcer by the administration of cinchophen. Ulceration developed readily in dogs after the administration of this drug. This led to a consideration experimentally of (1) the genesis and healing process of this type of ulcer, (2) the effect of a mechanical irritant and (3) the possibility of producing ulcer by the administration of cinchophen other than by the oral route. REVIEW OF THE LITERATURE Experimentally, the methods for the production of acute peptic ulcer have been many and relatively simple, while, on the other hand,

EFFECT OF CINCHOPHEN ON THE GASTRIC SECRETION

The administration of cinchophen is an effective method for the production of chronic peptic ulcer in dogs. The ulcer thus produced is similar in most respects to the lesion seen in human beings. The ulcer begins as a diffuse gastritis with destruction of the mucosal cells and the formation of multiple erosions throughout the gastric mucosa. These erosions become acute ulcers, which tend to heal. The majority do heal, but one persists as a chronic ulcer, and the gastritis subsides. This chronic lesion is usually situated from 2 to 3 cm. from the pyloric ring on the lesser curvature or on the posterior wall of the stomach. Occasionally, two or more gastric ulcers are present, and there may be an associated duodenal ulcer in a small percentage of the animals. The ulcer readily heals when the administration of cinchophen is stopped. Many controversial articles have been written on gastric secretion.