Arpad Somogyi

Jejunal ulcers produced by indomethacin

While studying the anti-inflammatory effect of indomethacin in rats we frequently observed acute perforating jejunal ulcers leading to generalized peritonitis. The following experiments were made to verify this accidental observation. Female Sprague-Dawley rats (Holtzman Farms, Madison, Wisconsin, U.S.A.) weighing about 1OOg and kept on Purina Laboratory Chow and tap water ad libitum received single doses of indomethacin (1, 2, 4 and 8 mg) into the jugular vein. Depending on the dose, 20-90% of the rats died within two to four days. The survivors were killed at different intervals after indomethacin treatment. After macroscopic inspection specimens of jejuna were fixed in ethanol-formol and embedded in paraffin for staining with haematoxylin-phloxine and with the PAS technique. On opening the abdominal cavity, generalized peritonitis was observed. A serofibrinous exudate filled the abdomen and many adhesions developed between the intestinal loops. Twenty-four h after treatment numerous circular or elongated ulcers 2 to 4 mm in size became evident in the jejunum. Some of these ulcers were superficial, affecting only the mucosa, others penetrated into the muscularis and destroyed the entire intestinal wall. The most severe lesions were observed between the second and the fourth days. Doses as low as 1 mg indomethacin caused ulceration while the administration of 8 mg led to extensive lesions and accelerated death. No ulcers were found in the stomach, ileum or colon.

Prevention by Spironolactone of 7,12-Dimethylbenz(a)anthracene-induced Adrenal Necrosis

Summary Administration of spironolactone protects the rat against 7,12-dimethylbenz (a) anthracene-induced adrenal necrosis.

Suppression by spironolactone of 7,12-dimethylbenz(a)anthracene-induced mammary tumors

Abstract Pretreatment with spironolactone, an antimineralocorticoid steroid lactone, delays the development and decreases the incidence and yield of 7,12 -dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in rats. The mechanism of this suppressive action is not fully understood but on the basis of some recent findings it seems reasonable to suppose that spironolactone is capable of influencing the intermediary metabolism of DMBA by inducing or stimulating microsomal enzymes in the hepatocytes which convert the carcinogen into inactive derivatives. Direct evidence is still lacking but the problem warrants further study primarily because spironolactone, in contrast to the other microsomal enzyme inducers, is a non-toxic compound which can be administered for a considerable length of time without serious consequences.

Calcergy inhibited by calciphylactic challengers.

The subcutaneous calcification effected in the rat at sites directly treated with calcergens, such as lead acetate, CeCl3, CaCl2, and KMnO4, is inhibited by simultaneous local application of various calciphylactic challengers, but not by many other compounds.

Inflammation, topical stress and the concept of pluricausal diseases☆

Abstract Eleven experimental models of acute connective-tissue reactions were designed for comparative investigations in the rat: anaphylactoid edema, ischemic necrosis, formalin-induced pedal inflammation, various forms of calciphylaxis and calcergy, thrombohemorrhagic phenomena (THP), acute conditioned necrosis (ACN), and delayed tissue-clearance of dyes. Several of these reactions can only be produced by the conjoint application of two drugs (a “conditioner” and a “challenger”), both of which are inactive in themselves. Furthermore, the same lesion (calcification, necrosis, thrombosis) can be produced by several pairs of agents, as long as their members belong to appropriate categories. Even temporary ischemia, produced by the short-term application of a clip to a skin fold, though well tolerated in itself, can act as a challenger and elicit qualitatively different topical lesions (dye accumulation, thrombosis with hemorrhage, calcification, or necrosis) whose nature depends upon the conjoint application of conditioning factors. All these findings suggest that, despite chemical and pharmacologic differences, the members of any one group of conditioners and challengers have some latent pathogenic potencies in common and that they can be conveniently classified on this basis. The following drugs were found to block the manifestations of some of the above mentioned acute connective-tissue reactions: chlorpromazine, compound 48/80, cyproheptadine, dibenzylchloroethylamine, heparin, histamine, 5-hydroxytryptamine (5-HT), phenoxybenzamine, phentolamine, and polymyxin. The ischemic necrosis produced by long-term application of the skin clip is prevented by various systemic stressors (spinal-cord transection, restraint, starvation, forced muscular exercise); apparently, systemic stress can induce “cross-resistance” against the damaging effect of topical stress. 5-HT and mast-cell dischargers possess a pro-inflammatory effect upon the poditis elicited by the intrapedal injection of various irritants. These same compounds delay the tissue clearance of intracutaneously administered dyes; they also act as conditioners for the production of ACN by the subcutaneous administration of normally rapidly absorbed and well-tolerated irritants. Hence, the influence of mast-cell products upon inflammation, dye absorption, and necrosis is presumably due to a single mechanism: the retardation of tissue clearance. The implications of these findings for the pharmacologic analysis of acute connective-tissue reactions are briefly discussed.

Acceleration and inhibition of wound healing by topical treatment with different types of inflammatory irritants

Abstract Experiments on rats indicate that the healing of wounds can be accelerated or inhibited at will by topical treatment with appropriate irritants. Croton oil enhances wound contraction, presumably because it stimulates fibroblast proliferation and collagen formation. Carrageenin has an opposite effect, perhaps because it is phagocytosed by fibroblasts and blocks their ability to form collagen fibers and to promote contraction. These opposing effects of the irritants are manifest both in open skin wounds and in the connective tissue surrounding closed subcutaneous air pouches. The bearing of these observations is discussed in connection with the accelerated healing of secondary wounds and the identification of endogenous hormone-like substances that are believed to regulate granuloma formation.

Der Einfluß einiger Hormone auf die heteroplastische Knorpel- und Knochenbildung im Herzmuskel der Ratte

SummaryA chronologic study was made of the histopathologic changes which occur in the cardiac apex of the rat following the application of Selyes „ventricular ligature“. Organisation in the necrotic cardiac muscle begins soon after ligature. Later, the granulationtissue is gradually replaced by scar tissue which is poor in cells but rich in fibers. In the subendocardial fibrous tissue, cartilage and bone develop. It is emphasized that cartilage formation is not initiated by calcification. Instead, the fibroblasts are converted to cartilage cells and, later, calcium salts are deposited in the matrix. This is followed by endochondral bone formation. Finally, bone marrow appears in the intertrabecular spaces.Triamcinolone mildly hindered connective-tissue proliferation, thyroxine increased cartilage and bone formation, while estradiol did not influence these processes.ZusammenfassungEs wird über histopathologische Untersuchungen des chronologischen Verlaufs an der durchSelyes „Ventrikel-Ligatur“ hervorgerufenen Herzspitzennekrose bei Ratten berichtet. In dem der Nekrose verfallenen Myokard setzt alsbald Organisation ein; dann wandelt sich allmählich das Granulationsgewebe in eine zellarme und faserreiche Narbe um. In den subendokardialen Schichten des Narbengewebes entstehen erst Knorpel-, später Knochenherde. Der Prozeß der Knorpelbildung wird nicht von Verkalkung eingeleitet; vielmehr werden zuerst die Fibroblasten zu Knorpelzellen, um die sich dann sekundär Kalziumsalze ablagern; danach spielt sich eine typische endochondrale Ossifikation ab. Schließlich erscheint Knochenmarkgewebe zwischen den Knochenbalken.Triamcinolon hemmt geringgradig die Bindegewebsproliferation, Thyroxin steigert die Knorpel- und Knochenbildung, während Östradiol diese Vorgänge nicht beeinflußt.

Sensitization by corn oil for the production of cardiac necroses by various steroids and sodium salts

Abstract In the rat, the production of extensive and usually fatal myocardial necroses by fluorocortisol or desoxycorticosterone in combination with Na2HPO4 is greatly accelerated and aggravated by the oral administration of corn oil. Cortisol, progesterone and methyltestosterone do not produce myocardial necroses under these conditions even if, in addition to Na2HPO4, corn oil is given. Not all sodium salts are equally potent in producing myocardial necroses when administered in combination with fluorocortisol and fat supplements. In this respect, NaH2PO4, Na2HPO4, NaClO4 and NaHSO4 are most effective, NaHCO3 is somewhat less active, whereas NaCl is inactive under otherwise comparable conditions.

A mechanism of protection against intoxication with various metals

Abstract Calcergens are compounds that cause topical calcification upon subcutaneous injection in unpretreated rats, whereas calciphylactic challengers do so only after systemic pretreatment with a conditioning factor (e.g., vitamin D compounds, parathyroid hormone). Both the mortality and the splenic calcification, commonly elicited by the intravenous injection of various calcergens (rare earth metal chlorides), are prevented, or at least greatly diminished, by pretreatment with calciphylactic challengers (ferric dextran, chromium dextran and, to a lesser extent, aluminum dextran). This prophylactic effect is due to the challenging metal moiety of the chelates, since dextran alone does not protect. These findings are reminiscent of earlier observations that had shown that the topical calcifying effect of calcergens is likewise inhibited by the admixture of calciphylactic challengers. It is possible that the antagonism depends upon changes in calcium or phosphorus metabolism since the eliciting agents are limited to metals having specific calcinotic effects.