[Clinical study of the intra-articular administration of a new corticosteroid derivative (paramethasone acetate)].
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Pseudo-allergic reactions to corticosteroids: diagnosis and alternatives.
Two patients treated with parenteral paramethasone (Triniol) and dexamethasone (Sedionbel) are described. A few minutes after administration of the drugs, they presented urticaria (patients 1 and 2) and conjunctivitis (patient 1). The purpose of our study was to determine the cause of the patients' reactions, the immunological mechanisms involved and whether these patients would be able to tolerate any kind of corticoid. Clinical examinations and skin, oral and parenteral challenges with different corticosteroids and ELISA tests were performed. In the two patients, skin and ELISA tests with paramethasone were negative, as was the prick test with each of its excipients. A single-blind parenteral challenge with Triniol was positive in both patients after the administration of 1 ml of the drug, and negative with its excipients. We also carried out oral and parenteral challenges with other corticosteroids and found intolerance to some of them. These results suggest that paramethasone caused pseudoallergic reactions in our patients. Corticosteroids different from paramethasone also produced hypersensitivity reactions in these patients; however, a few of them were tolerated. The basic mechanisms of those reactions are not yet fully understood. To our knowledge, this is the first report of a pseudo-allergy caused by paramethasone.
Adult↗
Naproxen: corticosteroid-sparing effect in rheumatoid arthritis.
Ambulatory patients with a diagnosis of "classical" or "definite" active adult rheumatoid arthritis were selected. They had been stabilized for at least six months previously with oral administration of paramethasone acetate plus various analgesics and/or nonsteroidal anti-inflammatory agents. During an initial period of two to five weeks, the paramethasone dosage was adjusted and other medications replaced by placebo to find the minimum required to keep the patient at a level similar to the one at the beginning of the study. Subsequently, with the double-blind method, the effect of 400 mg naproxen daily was compared with placebo, making periodic and progressive reductions in the corticosteroid dosage, unknown to the patient, until a tolerable minimum was found. The average total observation time was 14 weeks. Results obtained in the first 28 patients showed an average reduction of 57 per cent in paramethasone dose for the group treated with naproxen, versus 21 per cent for the control group. One patient experienced euphoria which could possibly have been related to the test drug. It is concluded that naproxen possesses a significant corticosteroid-sparing effect with negligible toxicity.
Adult↗
Effects of corticosteroid treatment and inflammation on the cellular content of blood and exudate in mice.
Inflammatory exudates have been produced in mice by intraperitoneal injection of thioglycollate broth 24 hr and again 3 hr before collecting of the exudate. The first injection of broth exerts a "priming" effect leading to an enhanced response to the second injection. By this procedure more than 30 x 106 leucocytes of which 78 per cent. were polymorphs were obtained from each mouse. Administration of paramethasone reduced the number of cells in the exudate when given at the same time as broth but not when given 3 hr before collection of the exudate. In contrast paramethasone was equally effective when given either 24 hr or 3 hr before harvest in suppressing the appearance of intravenously injected pontamine sky blue in the exudate. It was striking that treatment with paramethasone which had reduced the number of polymorphs in the exudate had actually increased the number in blood.
Animals↗
Two cases of specific adverse reactions to systemic corticosteroids.
Although true allergic reactions due to systemic corticosteroid therapy are not frequent, they should be kept in mind since allergic reactions to this kind of therapy are possible. We report two cases of specific adverse reactions resulting from systemic corticosteroid therapy which were diagnosed by provocation tests. The corticosteroids involved in each case were paramethasone and betamethasone, and methyl-prednisolone in both of them. Additives and other corticosteroids were studied by skin tests and challenges, with negative results. The structures of paramethasone and betamethasone are similar, with a 16 carbon methyl group in both, and with a fluoride in the alpha position of the 6 carbon in paramethasone, and a fluoride in the beta position of the 9 carbon and a 6 carbon methyl group in betamethasone. Methyl-prednisolone differs from that of other corticosteroids in its 6 carbon methyl group. We report two cases of specific adverse reactions caused by corticosteroids. Positive challenge tests showed a possible immunologic hypersensitivity mechanism in both cases. The patients' reactions demonstrated cross-reactivity between methyl-prednisolone and the corticosteroids having a 16 carbon methyl group, and fluoride or methyl radicals on the 6 carbon.
Adrenal Cortex Hormones↗
Anaphylactic shock following povidone.
OBJECTIVE: To report a patient with an anaphylactic reaction related to povidone administration. CASE SUMMARY: A 37-year-old man with a history of allergic rhinitis presented with urticaria, dyspnea, wheezing, rhinorrhea, and dysphonia 20 minutes after the intraarticular administration of mepivacaine hydrochloride and paramethasone acetate in his right knee. Two months after this episode, he was admitted for controlled provocation tests. Tests on mepivacaine were negative. The preparation of paramethasone contained the excipients benzalkonium chloride, polysorbate 80, and povidone. In vitro tests and provocation were negative with polysorbate 80 and benzalkonium chloride, but positive with povidone. DISCUSSION: Povidone, a mixture of synthetic polymers, is commonly used as an excipient in pharmaceutical products, an additive in food products, and a dispersant and stabilizer in hairsprays. Although it is well tolerated when used topically or parenterally, local and systemic effects have been reported. Furthermore, multiorgan involvement resulting from accumulation of the drug in the reticuloendothelial system has been described. The immunologic properties of povidone have not been explored in humans, but have been in animals. In fact, the capacity of povidone to release histamine and its immunogenicity are proportional to its molecular weight. An immunoglobulin (Ig) E-mediated hypersensitivity reaction in asthma has been reported. In our case, povidone was responsible for the syndrome. However, we cannot determine the exact mechanism. An unspecific histamine release and/or an IgE-mediated hypersensitivity could be involved. CONCLUSIONS: Povidone was responsible for a severe anaphylactic reaction in our patient. The possibility of an iatrogenic adverse effect caused by the excipient but not by the active ingredient should be considered in patients exhibiting similar symptoms. We believe that the excipients used in the preparation of all medicines should be disclosed.
Adult↗
Inverted skin changes induced by estrogen and estrogen/glucocorticoid on aging dermis.
To evaluate hormone replacement therapy effects at the peripheral level, the present trial explored the oral effects of mestranol (80 micrograms/day for 10 days) and mestranol plus paramethasone (80 micrograms + 6 mg/day for 10 days) on the skin of postmenopausal women. This double-blind study included 13 patients. Skin biopsies were obtained from the thigh area by a single punch, 5 mm in diameter, before and after treatment, and the sections, six per sample, were micrometrically evaluated. Various features of the epidermis and dermis layers were stained using the hematoxylin and eosin, Masson, Verhoeff's and Gomori techniques. Statistically significant changes were found in the papillar dermis thickness; mestranol reduced it and mestranol plus paramethasone increased it. The current results encourage widening these observations of the possible advantage of this estrogen/glucocorticoid combination, in order to alleviate the cellular degenerative process.
Administration, Oral↗
Rat pleurisy induced by kaolin or croton oil: time course of fluid accumulation and white cell migration.
Rat pleurisy was induced by intrapleural injection of 0.1 ml of 1% kaolin or 1% croton oil, and the time courses of pleural fluid accumulation and white cell migration were examined. Peak pleural fluid accumulation was observed at respectively 5 and 16 h after the inciter injection. Migration of white cells into the pleural cavity showed a peak at respectively 7 or 24 h after each inciter. Polymorphonuclear leukocytes were predominant in pleural cells of kaolin pleurisy at 3 h, while in croton-oil pleurisy the major white cells were mononuclear cells and lymphocytes at 3 h, and polymorphonuclear leukocytes appeared later around 16 h. Pretreatment with several agents modified both types of induced pleurisy. Kaolin pleurisy at 3 h was suppressed by indomethacin, mefenamic acid, paramethasone, bromelain and soy-bean trypsin inhibitor, while croton oil pleurisy at 3 h was suppressed significantly by indomethacin and paramethasone.
Animals↗
NONSPECIFIC ANTI-INFLAMMATORY AGENTS. SOME NOTES ON THEIR PRACTICAL APPLICATION, ESPECIALLY IN RHEUMATIC DISORDERS.
A number of acute and chronic inflammatory disorders are amenable to varying degrees of therapeutic control with the administration of nonspecific anti-inflammatory drugs. An evaluation of these suppressive agents in the field of rheumatic diseases and practical suggestions regarding their administration are presented. Eight synthetically modified corticosteroid compounds are available commercially. Each of them exhibits qualitative differences in one or several physiologic actions, each has certain advantages and disadvantages in therapy, and each shares the major deterrent features of corticosteroids. Prednisone, prednisolone, methylprednisolone, fluprednisolone and paramethasone have similar therapeutic indices, and there is little choice between them for the usual rheumatoid patient requiring steroid therapy. Conversely, the therapeutic indices of dexamethasone, betamethasone and triamcinolone are lower than that of prednisolone; they are less desirable for routine use and should be reserved for specially selected cases. Salicylates are preferred to adrenocortical steroids in the treatment of the ordinary patient with acute rheumatic fever. Steroid therapy should be reserved for resistant cases and for those with significant carditis. Salicylates are mainstays for pain relief in rheumatoid arthritis, but with the analgesic doses usually employed their anti-inflammatory action is slight.Phenylbutazone is a highly useful anti-inflammatory agent, especially in management of acute gouty arthritis and ankylosing (rheumatoid) spondylitis; its metabolite, oxyphenylbutazone, does not exhibit clear-cut advantages. Colchicine specifically suppresses acute gouty arthritis. Its analogues, desacetylcolchicine and desacetylthiocolchicine, produce fewer unpleasant gastrointestinal symptoms, but may promote agranulocytosis and alopecia.A number of indole preparations with anti-inflammatory activity have been tested clinically. One of them, indomethacin, has received extensive therapeutic trial; with dosages that can be tolerated the drug is fairly effective in the symptomatic control of ankylosing (rheumatoid) spondylitis but it is of questionable value in peripheral rheumatoid arthritis.
Adrenal Cortex Hormones↗
A new model of osteoarthritis in rabbits. II. Evaluation of anti-osteoarthritic effects of selected antirheumatic drugs administered systemically.
A battery of drugs with antirheumatic properties was tested for effects on the progress of osteoarthritis induced by a lateral meniscectomy procedure in knee joint cartilage of rabbits. Oral administration of the potent glucocorticoids, paramethasone acetate or triamcinolone, resulted in dramatic inhibition of cartilage degeneration. Significant protection against development of osteoarthritic lesions was also observed in rabbits treated with pirprofen or CGS 5391B but not with 9 other nonsteroidal antiinflammatory drugs. A marked reduction in joint pathology was also observed in rabbits treated with tribenoside (a glucofuranoside derivative) and with tamoxifen (an anti-estrogen). Slightly protective effects of borderline significance were observed with orgotein (a superoxide dismutase), gold sodium thiomalate, and D-penicillamine. Chloroquine and calcitonin were without effect. Therapeutic effectiveness of drugs in this model of osteoarthritis cannot be explained on the basis of their antiinflammatory properties.
Animals↗
Effect of corticosteroids on indomethacin-induced intestinal ulceration in the rat.
A single dose of indomethacin induces a severe gastrointestinal syndrome in the rat, characterized by intestinal ulceration, perforation, and death. The mechanism by which indomethacin induces this syndrome is unclear, although it has been suggested that a loss of mucosal integrity leads to inflammation and necrosis of the intestinal wall. The purpose of the present investigation was to study the effect of corticosteroids on indomethacin-induced ulceration. Prednisolone administered orally, even as a single dose (10 mg/rat), significantly reduced the severity of ulceration following indomethacin. This protective effect was most pronounced when prednisolone was administered 1 hr postindomethacin and decreased as the period between indomethacin and prednisolone administration increased. Of the steroids studied, the rank order of efficacy in reducing the severity of indomethacin-induced ulceration was paramethasone acetate > betamethasone > prednisolone. Hydrocrotisone was not significantly effective at the doses ultilized. Our results suggest that corticosteroids exert a cytoprotective effect on intestinal mucosa similar to that produced by prostaglandins.
Administration, Oral↗
CHEMOTHERAPY OF ARTHRITIS INDUCED IN RATS BY MYCOBACTERIAL ADJUVANT.
Arthritis induced in rats by mycobacterial adjuvant has been used for the study of compounds of known value in the treatment of rheumatoid arthritis in man. The development of the arthritic syndrome in treated and control rats was followed by measuring the changes in foot thickness of both hind-feet with a micrometer. This method allowed the effect of anti-inflammatory compounds to be expressed quantitatively. Anti-inflammatory activity was readily observed in certain steroids, pyrazolidines, salicylates and sodium aurothiomalate. Chloroquine and hydroxychloroquine were inactive. The inhibition obtained by daily treatment with the steroid paramethasone disappeared when treatment was withdrawn.
Adjuvants, Immunologic↗
Metabolism of systematically given corticosteroids.
In the metabolism of a systemically administered corticosteroid, one of three possible main pathways is determined by the position in the molecule of the substituents which are added in the drugs to the naturally occurring ones. (I) Chiefly, hydrogenation in ring A and/or the 20-position: cortisol, cortisoine, prednisolone, prednisone, and 6alpha-methylprednisolone (II) In the presence of a substituent in the 16-position mainly 6beta-hydroxylation: dexamethasone, betamethasone, and triamcinolone. (III) In the presence of a substituent in the 16-position, and fluorine in the 6alpha-position principally defluorination in the 6alpha-position and 6beta-hydroxylation: fluocortolone and paramethasone. Complete metabolism, in long-term use, can be expected in the case of the substances mentioned under II and III, but not of those under I. Enzyme induction, both actively and passively, is negligible in group I and marked in groups II and III.
Adrenal Cortex Hormones↗
Inflammatory linear verrucose epidermal nevus.
A typical case of inflammatory linear verrucose epidermal nevus (ILVEN), with quite a psoriasiform histologic pattern, is reported. Intralesionally administered paramethasone acetate caused a temporary suppression of the clinical and histopathologic inflammatory features. The concept of ILVEN is briefly discussed.
Adult↗
Histological changes induced by tibolone and estrogen/glucocorticoid on aging skin.
OBJECTIVE: The aim of this study was to investigate the oral effects of tibolone and mestranol plus paramethasone on the skin of postmenopausal women. A second purpose was to determine endometrial thickness with transvaginal ultrasound. MATERIALS AND METHODS: This randomized study was carried out in 39 healthy postmenopausal women. Skin biopsies were obtained from the thigh area by a single punch, before and after treatment, and the sections were evaluated. Current characteristics of both groups were measured at follow-up. RESULTS: No gross differences were observed in size, distribution or imaging of collagen, elastic or reticular fibers. Statistically significant changes were found in the papillar dermis thickness. There were no statistically significant differences in the sonographic measurements. CONCLUSION: The estrogen/glucocorticoid combination provides a way to evaluate in parallel the cellular metabolism effects on the irreversible aging process. The current results encourage widening these observations of the possible advantage of this combination, in order to alleviate the cellular degenerative process.
Aged↗
Lysosomal enzyme secretion from human neutrophils mediated by cyclic CMP: inhibition of cyclic GMP accumulation and neutrophil function by glucocorticosteroids.
The effects of several glucocorticosteroids on cyclic GMP accumulation, guanylate cyclase activity, calcium influx, lysosomal enzyme secretion, and phagocytosis were studied in human neutrophils. Contact between neutrophils and serum-treated zymosan particles, in the presence of calcium at pH 7.4, triggered these cellular events within five minutes. Each of these neutrophil functions was markedly inhibited by methylprednisolone sodium succinate, triamcinolone acetonide hemisuccinate and paramethasone acetate but was unaffected by two mineralo-corticosteroids. Human neutrophil soluble guanylate cyclase activity was not changed by the glucocorticoids. Inhibition of phagocytosis by, and lysosomal enzyme secretion from, neutrophils by glucocorticosteroids may be the result of a reduction in cyclic GMP accumulation within these cells. The data suggest that glucocorticosteroids inhibit cyclic GMP accumulation in neutrophils by reducing the influx of extracellular calcium into the cells, thereby limiting the availability of intracellular calcium for metabolic processes associated with the accumulation of cyclic GMP.
Aldosterone↗
Release of chondrocyte-stimulating factor by rabbit peritoneal macrophages.
Cultured rabbit peritoneal macrophages, after stimulation with lipopolysaccharides (LPS), produce a factor that induces normal rabbit articular cartilage cells (chondrocytes) to release collagenase and other neutral proteases in their culture medium. The release of the factor as well as the activation of chondrocytes can be significantly inhibited by paramethasone (10(-6) M). Rabbit peripheral blood monocytes produce this factor in smaller quantities. Activation with LPS does not enhance the release of factor any further by these cells. Lymphocytes have no direct effect on the chondrocytic protease synthesis. Furthermore, conditioned medium of activated lymphocytes failed to stimulate monocytes or macrophages in the absence of LPS. The macrophage medium exhibits mitogenic and phytohaemagglutinin-enhancing activity towards thymocytes of C3H/HeJ mice, but not against species-specific rabbit lymphocytes. The lymphocyte-activating factor, derived from a mouse macrophage cell line, P388D1 cells, or from other sources, was unable to stimulate chondrocytic protease secretion. Such specific induction of chondrocytic proteases by a macrophage-derived factor may have an important role in cartilage destruction in arthritic conditions, where synovium is only marginally involved.
Animals↗
The Arthus reaction in rats, a possible test for anti-inflammatory and antiheumatic drugs.
The Arthus reaction is an immunologically induced inflammatory response characterized by immune complex deposition, complement fixation, polymorphonuclear leukocyte infiltration and tissue damage. Many of these same pathological tissue alterations are found in the lesions of rheumatoid arthritis (RA). The similarities between the reversed passive Arthus reaction (RPAR) and RA led us to investigate the usefulness of the RPAR in the search for new antirheumatic agents. The RPAR was elicited in the skin of rats using chicken ovalbumin and the IgG fraction of rabbit anti-ovalbumin. Paramethasone, hydrocortisone, indomethacin, pirprofen, sulfinpyrazone, thalidomide and theophylline all gave significant inhibition of the RPAR. Ibuprofen, naproxen, cyprohepatadine and cromolyn sodium were inactive, while phenylbutazone and ASA exhibited a dose-dependent effect. The data show that the Arthus reaction, which is the result of the complex interaction of many factors, can be affected either generally or selectively at different time intervals by various therapeutic agents. The RPAR in rats may prove useful in detecting new therapeutic agents for the treatment of RA.
Animals↗