ARTHRITIS & RHEUMATISM Vol. 38, No. 11, November 1995, pp 1687-1693 0 1995, American College of Rheumatology 1687 SOMATOSTATIN-INDUCED MODULATION OF INFLAMMATION IN EXPERIMENTAL ARTHRITIS MARC0 MATUCCI-CERINIC, FRANCESCO BORRELLI, SERGIO GENERINI, ALFRED0 CANTELMO, ISABELLA MARCUCCI, FABRIZIO MARTELLI, PAOLO ROMAGNOLI, STEFAN0 BACCI, ANGEL0 CONZ, PAOLO MARINELLI, and SIMONE MARABINI Objective. To study the antiinflammatory effect of different doses of intraarticular somatostatin in experimental arthritis in rabbits. Methods. Chronic arthritis was induced by a single injection of fibrin into the knee joint of rabbits previously sensitized to this antigen. The effects of sequential intraarticular injections of somatostatin into the rabbit knee, at doses of 500,750,and 1,000 pg, were monitored by measuring knee joint circumferences and hematologic parameters. The measurements were compared with those obtained following use of triamcinolone acetonide and placebo. At the end of the experiments, the knee joints were examined histologically. Results. Somatostatin treatment induced a statistically significant and dose-related reduction of knee joint swelling. This effect was shorter than that produced by triamcinolone acetonide; however, the antiinflammatory activity elicited by successive doses of triamcinolone acetonide declined both in extent and duration, while the effects of somatostatin remained unchanged at each successive treatment. Histopathologic observations showed that both somatostatin and triamcinolone acetonide reduced the inflammatory signs in the joint structures, although triamcinolone acetonide appeared to be more effective. Conclusion. These findings suggest that somatostatin exerts an antiinflammatory effect in this model of experimental arthritis and may represent a valid and Marco Matucci-Cerinic, MD: University of Cagliari, Cagliari, Italy; Francesco Borrelli, BS, Alfred0 Cantelmo, Isabella Marcucci, Fabrizio Martelli: Research Institute “C. Serono SpA,” Ardea, Rome, Italy; Sergio Generini, MD, Paolo Romagnoli, MD, Stefan0 Bacci, BS, S h o n e Marabini, MD: University of Florence, Florence, Italy; Angelo Conz, DVM, Paolo Marinelli, DVM: Biomedical Research Institute “A. Marxer” (RBM), Ivrea, Turin, Italy. Address reprint requests to Marco Matucci-Cerinic, MD, Istituto di Clinica Medica IV, viale Pieraccini 18, 50139-Florence, Italy. Submitted for publication December 27, 1994; accepted in revised form June 13, 1995. safer alternative to corticosteroids for intraarticular therapy of arthritis. Somatostatin is a ubiquitous undecatetrapeptide that is widely distributed throughout the central nervous system (1). It was first isolated in the hypothalamus (2) and is known to inhibit the hypophysial release of growth hormone, thyrotropin-releasing hormone, and prolactin (3). In the peripheral nervous system, somatostatin is present in catecholaminecontaining fibers and in sensory terminals, together with substance P (SP) and calcitonin gene-related peptide. Evidence suggests that somatostatin is involved in the modulation of neurogenic inflammation through the inhibition of SP release and SP-provoked neurotransmission (4-6) and through the inhibition of SP-induced neutrophil chemotaxis and GTPase activity (7). In addition, somatostatin can mediate nociception via a unique pathway different from that used by SP (8). Somatostatin has a wide range of biologic effects, mediated by receptors on a variety of target cells ( e l l ) . The major physiologic areas of somatostatin action are 1) as a neurotransmitter, 2) on glandular secretion, 3) smooth muscle contractility, and 4) cell proliferation. Somatostatin induces a marked vasoconstriction, particularly in the splanchnic system, which has led to its use in the treatment of esophageal bleeding and hemorragic states. In vitro, somatostatin has shown a unique capacity to inhibit the growth of neoplastic cells. For this reason it has been used, particularly in its analog form, in the treatment of cancer (12). Somatostatin also affects the immune system, by inhibiting the Proliferation of human T lymphocytes (13), inhibiting the production of immunoglobulin by B lymphocytes (14), and reducing interferon-y production by monocytes (15). It is able to inhibit the release of histamine and leukotriene D4 1688 MATUCCI-CERINIC ET AL from immunologically stimulated human basophils (16), but not from mast cells (17). The possibility of using somatostatin to treat arthritis has been raised by reports of its analgesic properties in animals (Borrelli F, Cantelmo A, MarteHi F: unpublished observations) and humans (18,19). It has been studied in rheumatoid arthritis (20), psoriatic arthritis (21,22), and osteoarthritis (23). In experimental animal models, somatostatin has shown antiinflammatory activity in acute arthritis induced by urate crystals in rats (24). Apparently there are no other published studies that have evaluated the effect of somatostatin on a chronic experimental arthritis, although previous reports in rats have demonstrated the ability of some analogs to delay the onset of adjuvant arthritis, thus limiting the seventy of inflammation (25). The aim of this study was to test the efficacy of intraarticular administration of somatostatin in experimental arthritis. Somatostatin was compared with a drug currently used for the local treatment of arthritis (triamcinolone acetonide) in an animal model of arthritis, i.e., antigen-induced arthritis in rabbits. In the model, the arthritis develops following a single injection of fibrin into the knee joint of rabbits previously sensitized to the same substance, and produces a chronic self-perpetuating disease that closely resembles human rheumatoid arthritis (26). MATERIALS AND METHODS Animals. Male New Zealand white rabbits (initial body weight 1.8-2.2 kg) from Charles River Italia (Calco, Como, Italy), maintained under controlled environmental conditions and fed ad libitum with a standard pellet diet and water, were used for the experiments. Substances tested. The commercial preparation of somatostatin (Stilamin 3 mg/vial; Serono SPA, Rome, Italy) was used for this study. Triamcinolone acetonide as its commercial preparation, Kenacort-A Retard (Bristol-Myers Squibb, Rome, Italy) was used as the reference drug. Induction of arthritis. Arthritis was induced using the method proposed by Lewis (27), with minor modifications. Ninety-eight rabbits were initially sensitized with 1 ml of an emulsion consisting of 10 mg bovine fibrin (Sigma, St. Louis, MO) in equal volumes of sterile physiologic saline and Freund’s complete adjuvant (FCA; Difco, Detroit, MI) containing 2 mg Mycobacterium tuberculosis H37RA (Difco). This emulsion was injected intracutaneously into 5 separate sites on the back of each animal. After 2 weeks, the animals received a booster sensitization consisting of an emulsion of 5 mg bovine fibrin in 0.25 ml sterile saline and 0.25 ml FCA injected intracutaneously into a single site on the back. Seven days later, a sterile solution of 10 mg bovine fibrin in 1 ml saline was injected into the left knee joint of each rabbit under intravenous penthobarbitone sodium an- esthesia (20 mglkg). The right knee joint received an equal volume of sterile saline as a control. The day of the challenging injection of fibrin was considered to be day 0. Drug administration. Eighteen days after the intraarticular injection of fibrin, when a stable monarticular arthritis was obtained, 60 rabbits showing clear signs of the disease (defined as joint swelling of more than 8 mm, measured by joint circumference) were selected. The rabbits were randomly assigned, by computer-generated numbers, to 6 intraarticular treatment groups of 10 each, as follows: 1) saline, 0.25 muknee joint (controls); 2) mannitol, 0.25 ml/ knee joint of a solution at 26.62 mg/ml (placebo), corresponding to the amount of mannitol contained in the highest dose of Stilamin; 3) triamcinolone acetonide, 5 mg/knee joint (in 0.25 ml); 4) somatostatin, 500 &knee joint (in 0.25 ml); 5) somatostatin, 750 &knee joint (in 0.25 ml); 6) somatostatin, 1,000 &knee joint (in 0.25 ml). The first intraarticular injection was performed on day 18. Additional injections were administered when the effect of the drug was tapering and the circumference of the joint reached the baseline value determined prior to treatment. The animals in groups 1 , 2 , 4 , 5, and 6 were treated on days 18,25, 32, 39,50,60,74, and 81 following the challenge injection. Rabbits in the third group received an intraarticular injection of triamcinolone acetonide on days 18, 39, 50, 60,74, and 81. On the same days, the contralateral (right) knee joints of all animals were injected with an equal volume of saline. Data on animals that died prior to the end of the study were not included in the analysis. At the end of the study, there were 7 animals remaining in the control and placebo groups and 8 in each of the test drug groups. Clinical assessment. The extent of the inflammatory reaction was evaluated by tape-measuring the knee joint circumferences in all animals, to the nearest millimeter. These measurements were performed just before the intraarticular challenge injection of fibrin (baseline) and repeatedly thereafter, under local anesthesia with Ethyl Chlorure (Synthelabo SPA, Milan, Italy). Starting at the time of pharmacologic treatment (day 18 post-challenge), measurements of left and right knee joint circumferences were performed daily except Sunday. On the days of drug administration, they were always performed prior to injection. The differences between the drug-injected (left) and the saline-injected (right) joints were recorded on all observation days for every animal, and the circumference variations of the drug-treated and control animals were calculated. Hematologic and hematochemical assessment. A series of hematologic parameters, including red blood cell (RBC) count, total and differential white blood cell (WBC) count, and erythrocyte sedimentation rate (ESR), and hematochemical parameters (serum protein electrophoresis) were also determined, using standard laboratory methods, on the animals prior to the experiment (baseline values), before the first pharmacologic treatment, and 26, 54, and 82 days later (days 13, 28, 55, and 88 post-challenge, respectively). Histopathologic assessment. Following the last blood sampling, and from 1 to 4 days after the last treatment, i.e., at the time of the maximal expected reduction of edema, the rabbits were killed and their left knee joints were removed SOMATOSTATIN IN EXPERIMENTAL ARTHRITIS for histologic examination. Animals in the placebo and control groups were killed on the fifth day after treatment. The untreated right knee joints were also excised from 2 randomly selected animals in each experimental group. The specimens, fixed in 10% buffered neutral formalin, were decalcified, embedded, cut with a microtome, and stained with hematoxylin and eosin. They were examined by light microscopy by 2 of the authors (PR and SB), who were blinded to the treatment information. In order to evaluate the degree of inflammation, an overall histologic score was created using 8 different parameters: 1) synovial lining (0 = simple, pavement epithelium; 1 = cuboidal cells and/or bilayered epithelium one-third or less of visible surface; 2 = bilayered epithelium on more than one-third, and/or multilayered epithelium on one-third or less, of visible surface; 3 = multilayered epithelium on one-third or more of visible surface); 2) subsynovial cells (0 = rare cells; 1 = quite numerous cells along one-third or less of visible surface; 2 = quite numerous cells along more than one-third, and/or very numerous cells along one-third or less, of visible surface; 3 = very numerous cells along more than one-third of visible surface); 3) leukocytic infiltrate (0 = no infiltration; 1 = modest infiltration along one-half or less of visible surface; 2 = modest infiltration along more than one-half, and/or marked infiltration along one-half or less, of visible surface; 3 = marked infiltration along more than one-half of visible surface); 4) lymphoid follicles (1 point for each follicle); 5) vasculitis (1 point for every vessel with infiltration in the wall thickness); 6) necrosis (1 point for each necrotic area); 7) fibrin deposits (1 point for each deposit); and 8) polynuclear giant cells (1 point for each cell). Statistical analysis. The differences between the druginjected and the saline-injected knee joints on each observation day were used to calculate the variations of the joint circumferences. Their peak values, i.e., the maximal reduction of edema as compared with baseline (the value immediately before drug injection), were subjected to one-way analysis of variance. Scheffe's test was used to compare effects in the drug- and placebo-treated groups. Student's Days from atthntls mducbon Figure 1. Effects of repeated intraarticularadministration of somatostatin (1,000 pg) and triamcinolone acetonide (5 mg) on the course of antigen-induced experimental arthritis in rabbits. I 0 1689 2 4 6 8 No. of adnunistration Figure 2. Second-order polynomial regression of the peak variations of knee joint circumference induced by repeated injection of somatostatin and triamcinolone acetonide in antigen-induced experimental arthritis, in rabbits. t-test was used to compare control and placebo groups. Histopathologic data were analyzed by Wilcoxon rank sum test; significance levels were computed for each treated group versus controls. P values less than 0.05 were considered significant. RESULTS Joint swelling. The intraarticular injection of fibrin in fibrin-sensitized rabbits produced a marked swelling of the knee joint, as measured by its circumference. Swelling peaked within 6 days and then reached a plateau. In both the control and placebo groups, the joint swelling persisted to the end of the experiment, i.e., 86 days after the challenge injection. No statistically significant differences were found between the placebo and control groups (Student's t-test) at any time during the experiment. Treatment with the study drugs started on day 18 post-challenge, when the knee joint swelling was stable. Animals that received an intraarticular injection of 5 mg triamcinolone acetonide showed a significant reduction of the circumference of the swollen joint in comparison with placebo-treated animals, with maximal effect noted at the fifth day post-injection (Figure 1). Successive administrations of triamcinolone acetonide produced slighter and shorter-lived effects than the first injection (Figure 1). The differences in mean joint circumference in triamcinolone acetonidetreated animals compared with placebotreated animals were, however, statistically significant at all but 2 time points. Intraarticular administration of somatostatin (at 1690 MATUCCI-CERINIC ET AL WBC 16000 Controls 14000 Placebo 12000 10000 Triamcinolone SOM 500 mcglkg n SOM 750 mcglkg SOM 1000 mcglkg -22 13 PMN 28 55 88 55 88 MN so1 sol 40 60 30 40 20 20 10 0 0 -22 13 , 82 55 88 -22 13 ESR 28 l2BC 5 : 7 ) i -22 13 2a 55 88 -22 13 28 55 88 Figure 3. Effects of triamcinolone acetonide and somatostatin (SOM) on hematologic parameters in rabbits with experimental knee joint arthritis. WBC = white blood cell count; PMN = polymorphonuclear cells; MN = monocytes; ESR = erythrocyte sedimentation rate; RBC = red blood cell count. 500, 750, and 1,000 pg) on day 18 post-challenge induced dose-related reductions of knee joint circumference. These were particularly significant with so- matostatin at 1,000 pg (Figure 1). At first injection, somatostatin reduced knee swelling regardless of dose; however, this effect was of shorter duration than SOMATOSTATIN IN EXPERIMENTAL ARTHRITIS 16 12 10 a* a 2 x=537 0 a a 0 Som 750 s m loo0 TA Figure 4. Total score assigned to the histologic sections of rabbit knee joints removed at the end of the treatment period. Each point represents the average score for each animal, from 2 independent observers. The continuous lines with numbers above or below indicate the mean total scores for each treatment group (see text for details). Som = somatostatin (500, 750, or 1,000 pg); TA = triamcinolone acetonide). that seen with triamcinolone acetonide. When compared with triamcinolone acetonide, all 3 doses of somatostatin produced, on successive administrations, a reduction of joint circumference similar to the effect of the first injection; this reduction was always statistically significant for both the 750 and 1,000 pg doses and, in several cases, even for the lowest dose (data not shown). This is shown in Figure 2, where the peak variations of knee joint circumference induced by somatostatin and triamcinolone acetonide are plotted as second-order polynomial regression lines. No side effects were observed in any of the treatment groups. Blood values. The hematologic and hematochemical values of the animals were measured several times during the experiment (Figure 3). An increased WBC count was observed in all of the experimental groups following the induction of arthritis; these counts subsequently decreased toward normal values only in animals treated with triamcinolone acetonide. Increased ESR and slightly decreased albumin: globulin ratios were also recorded, but there was no evident effect of treatment on these parameters. No variations in the RBC counts were observed. Histologic findings. Histologic examination performed on arthritic knee joints removed from the animals at the end of the experiment (more than 80 days following induction of arthritis and 65-70 days after the initiation of pharmacologic treatment) revealed that none of the treatments affected the thick- 1691 ness of synovial lining, compared with that in controls. All treatment groups, including the placebo group, showed significant decreases in subsynovial cellularity. Only somatostatin at 750 pg and triamcinolone acetonide significantly reduced the leukocytic infiltrate, The number of lymphoid follicles was influenced only by triamcinolone acetonide, while both triamcinolone acetonide and 500 pg somatostatin appeared to limit vasculitis. Total scores from the global evaluation of histopathologic parameters are shown in Figure 4. As expected, triamcinolone acetonide was effective in reducing the signs of arthritis. Somatostatin at 500 pg and 750 pg also demonstrated significant results when compared with controls, whereas somatostatin at 1,000 pg and placebo did not. Necrosis, fibrin deposits, and polynuclear giant cells were not observed in any group. DISCUSSION The animal model of arthritis selected for our experiments leads to a severe and long-lasting disease in -60% of the animals and has joint manifestations similar to those in patients with rheumatoid arthritis. This study shows that triamcinolone acetonide treatment of the inflamed knee joint results in a significant and sustained reduction of swelling. The local injection of somatostatin similarly displayed a potent, but shorter, antiinflammatory effect, the intensity of which was dose related. For the highest dose tested (1,000 pg), the effect was comparable with that seen with corticosteroid therapy. Interestingly, while the antiinflammatory activity elicited by successive doses of triamcinolone acetonide declined both in extent and duration, the effects of somatostatin remained unchanged at each successive treatment. This may be one advantage of somatostatin over corticosteroid in treatment of chronic disease. The mechanism of action of somatostatin is still a matter of debate, The effect of somatostatin on various lymphocyte populations and on leukocyte migration and activation has been widely studied. Despite numerous reports documenting the inhibitory effect of somatostatin on the proliferation of human T lymphocytes (13) and on neutrophil chemotaxis and activation induced by SP (7), growth hormone, and prolactin (28), the role of somatostatin in immunomodulation is still unclear. Somatostatin has been shown to stimulate polymorphonuclear cell migration in vitro in a dose-dependent manner (29). Other reports have shown variable in vitro effects with comparable doses of somatostatin ( to lo-* moles/liter), including 1692 inhibition of concanavalin A-induced lymphocyte proliferation (13,30), lack of effect on lymph node cells stimulated with mitogens (31), and enhancement of untreated (32,33) or mitogen-stimulated lymphocyte proliferation (34). In our study, somatostatin did not reduce the number of white blood cells, but it did limit leukocyte infiltration (mainly lymphocytes) at the dose of 750 pg and reduced vasculitis (evaluated on the basis of infiltration in the wall thickness) at the dose of 500 pg. The role of somatostatin on synoviocyte proliferation is unclear. The possible presence, in vivo and in vitro, of somatostatin receptors on rheumatoid arthritis synoviocytes suggests that this peptide may directly influence the metabolism of these cells (35). In the present study, histologic evidence suggests that neither somatostatin nor triamcinolone acetonide affected synoviocyte proliferation. The mechanisms by which somatostatin affects inflammation are complex and yet to be determined, although neuroendocrine and/or immune effector central mechanisms combined with local actions are probably involved. The antiinflammatory effect of somatostatin may be partly due to its central suppression of growth hormone release, which has been demonstrated to enhance adjuvant arthritis (36). Somatostatin also inhibits neurogenic inflammation due to negative feedback of terminal afferents with inhibition of SP release (4) and modulation of cell-mediated immunity (32). Interestingly, somatostatin enhances the activity of gold salts in psoriatic arthritis (22). Because gold salts are thought to act through the induction of a peripheral neuropathy ,the common pathway of somatostatin and gold salts could be the inhibition of SP release from sensory terminals (37), thus preventing neurogenic inflammation and reducing nociception. Endothelial cells might be another target for somatostatin. The synovial microvascular endothelium may play a central role in the pathogenesis of rheumatoid arthritis, and a modulation of inflammation by endothelial cells, through the control of leukocyte chemotaxis, adhesion, and infiltration, has been suggested (38). In addition, the synovial endothelium has been directly implicated in the rheumatoid erosive process because of its ability to generate proinflammatory reactive oxygen species (39,40). Somatostatin interaction with endothelial cells might induce vasoconstriction and reduce the expression of adhesion molecules, thus modifying the development of the immune response by attenuating endothelial cell adhesiveness for mononuclear cells (41). MATUCCI-CERINIC ET AL In conclusion, in this experimental model, somatostatin had an antiinflammatory effect that was almost comparable with that of triamcinolone acetonide in extent, but not in duration. The shorter duration of the effects of somatostatin compared with the corticosteroid may be due to the different formulation of the 2 drugs. Triamcinolone acetonide is a microcrystalline suspension that persists at the site longer than a soluble preparation such as somatostatin. Because of its rapid in vivo degradation (42), somatostatin has always been thought to have limited practical application for clinical use. Although its antiinflammatory effect when administered by the intraarticular route is shorter than that of triamcinolone acetonide, it lasts for several days, far longer than its half-life. This may be related to the protected environment of the articular cavity, the presence of active metabolites of somatostatin, or a reduction of degrading enzymes at the site of inflammation. Based on these results, and considering the well-known side effects of corticosteroid therapy relative to the proven safety of somatostatin, it seems that somatostatin may be a valid alternative for intraarticular treatment of chronic arthritis. ACKNOWLEDGMENTS The authors express their gratitude to Prof. Andrzej Stanisz and Dr. Albert Agro, McMaster University, Hamilton, Canada, for their helpful advice and text revision; to Ms. A. Fatale for technical assistance, and to Mr. C. Cafiero for skillful statistical analysis. REFERENCES 1. McGuigan JE: Hormones of the gastrointestinal tract. In, En- 2. 3. 4. 5. 6. 7. docrinology. Edited by LJ De Groot, GM Besser, GF Cahill. Philadelphia, WB Saunders, 1989 Brazeau P, Vale A, Burgus R, Ling N , Butcher M, Rivier J , Guillemin R: Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 179:77-79, 1972 Polak J , Bloom SR: Somatostatin localization in tissues. Scand J Gastroenterol 119:ll-19, 1986 Gazelius B, Brodin E, Olgart L, Panopoulos P Evidence that substance P is a mediator of antidromic vasodilatation using somatostatin as a release inhibitor. Acta Physiol Scand I13:155159, 1981 Green PG, Basbaum AL, Levine JD: Sensory neuropeptide interactions in the production of plasma extravasation in the rat. Neuroscience 50:745-749, 1992 Payan D, Levine J, Goetzl E: Modulation of immunity and hypersensitivity by sensory neuropeptides. J Immunol 132: 1601-1064, 1984 Kolasinski LS, Haines KA, Siege1 EL, Cronstein BN, Abramson SB: Neuropeptides and inflammation: a somatostatin analog SOMATOSTATIN IN EXPERIMENTAL ARTHRITIS 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. as a selective antagonist of neutrophil activation by substance P. Arthritis Rheum 35:369-375, 1992 Kurashishi Y, Hirota N, Sato Y, Hino Y, Satoh M, Takagi M: Evidence that substance P and somatostatin transmit separate information related to pain in the spinal dorsal horn. Brain Res 325:294-298, 1985 Patel YC, Murthy KK, Escher E, Bouville T, Spiess I, Srikant CB: Mechanism of action of somatostatin: an overview of receptor function and studies of the molecular characterization and purification of somatostatin receptor protein. Metabolism 9:6349, 1990 Bhathena S, Louie J, Schechter G, Redman R, Wahl L, Recant L: Identification of human mononuclear leukocytes bearing receptor for somatostatin and glucagon. Diabetes 30: 127-131, 1981 Sreedharan S, Kodama K, Peterson K, Goetzl E: Distinct subsets of somatostatin receptors on cultured human lymphocytes. J Biol Chem 264:949-952, 1989 Schally AV: Oncological applications of somatostatin analogues. Cancer Res 48:69774985, 1988 Payan DG, Hess CA, Goetzl EJ: Inhibition by somatostatin of the proliferation of T lymphocytes and Molt 4 lymphocytes. Cell Immunol 84:433-438, 1984 Stanisz AM, Befus D, Bienenstock J: Differential effects of vasoactive intestinal peptide, substance P, and somatostatin on immunoglobulin synthesis and proliferation by lymphocytes from Peyer’s patches, mesenteric lymph nodes, and spleen. J Immunol 136:152-156, 1986 Muscettola M, Grasso G: Somatostatin and VIP reduce interferon y production by human peripheral blood mononuclear cells. Immunobiology 180:419430, 1990 Goetzl EJ, Payan DG: Inhibition by somatostatin of the release of mediators from human basophils and rat leukocemic basophils. J Immunol 133:3255-3259, 1984 Theoharides TC, Douglas WW: Mast cell histamine secretion in response to somatostatin analogues: structural considerations. Eur J Pharmacol 73:131-136, 1981 Chrubasik J, Meynadier .I, Blond S, Scherpereel P, Ackerman E, Weinstock M, Bonath K, Cramer H, Wunsch E: Somatostatin, a potent analgesic. Lancet 2:1208-1209, 1984 Sicuteri F, Geppetti PA, Marabini S, Lembeck F: Pain relief by somatostatin in attacks of cluster headache. Pain 18:35%365, 1984 Matucci-Cerinic M, Marabini S: Somatostatin treatment for pain in rheumatoid arthritis: a double blind versus placebo study in knee involvement. Med Sci Res 16:233-234, 1988 Matucci-Cerinic M, Lotti T, Cappugi P, Boddi V, Fattorini L, Panconesi E: Somatostatin treatment of psoriatic arthritis. Int J Dermatol 2756-58, 1988 Matucci-Cerinic M, Livi R, Pignone A, Lotti T, Partsch G, Cagnoni M: Gold salts and somatostatin: a new combined analgesic treatment for psoriatic arthritis. Drugs Exp CIin Res 1 8 5 3 4 1 , 1992 Silveri F, Morosini P, Brecciaroli D, Cervini C: Intraarticular injection of somatostatin in knee osteoarthritis: clinical results and EGF-1 serum levels. Int J Clin Pharmacol Res 14:79-85, 1994 Denko DW, Gabriel P: Effects of peptide hormones in urate crystal inflammation. J Rheumatol 12:971-975, 1985 1693 25. Rees RG, Eckland DJA, Lightman SL, Brewerton DA: The effects of somatostatin analogue, BM23014, on adjuvant arthritis in rats (abstract). Br J Rheumatol 28 (suppl 2):40, 1989 26. Dumonde DC, Glynn LE: The production of arthritis in rabbits by an immunological reaction to fibrin. Br J Exp Pathol43:373382, 1962 27. Lewis AJ: The local anti-inflammatory activity of rimexolone (Org 6216) in fibrin-induced monoarticular arthritis and adjuvantinduced arthritis. Agents Actions 10:25&265, 1980 28. Wiedermann CJ, Reinisch N, Niedermuhlbichler M, Braunsteiner H: Inhibition of recombinant human growth hormoneinduced and prolactin-induced activation of neutrophils by octreotide. Naunyn Schmiedebergs Arch Pharmacol 347:336 341, 1993 29. Partsch G, Matucci-Cerinic M: Effect of substance P and somatostatin on migration of polymorphonuclear cells in vitro. Inflammation 16539-547, 1992 30. Scicchitano R, Dazin P, Bienenstock J, Payan DG, Stanisz AM: Distribution of somatostatin receptors on murine spleen and Peyer’s patch and B lymphocytes. Brain Behav lmmun 1: 173184, 1987 31. Krco CJ, Gores A, Go VL: Gastrointestinal regulatory peptides modulate in vitro immune reactions of mouse lymphoid cells. Clin Immunol Immunopathol 39:30&318, 1986 32. Pawlikowski M, Stepien H, Kunert Radeck J , Schally AV: Immunomodulatory action of somatostatin. Ann N Y Acad Sci 496:233-239, 1987 33. Pawlikowski M, Stepien H, Kunert Radek J, Schally AV: Effect of somatostatin on the proliferation of mouse spleen lymphocytes in vitro. Biochem Biophys Res Commun 12952-55, 1985 34. Johansson 0, Sandberg G: Effect of the neuropeptides betaMSH, neurotensin, NPY, PHI, somatostatin and Substance P on proliferation of lymphocytes in vitro. Acta Physiol Scand 137: 107-111, 1989 35. Vanhagen PM, Markusse HM, Lamberts SWJ, Kwekkeboom DJ, Reubi JC, Krenning EP: Somatostatin receptor imaging: the presence of somatostatin receptors in rheumatoid arthritis. Arthritis Rheum 37: 1521-1527, 1994 36. Berczi I, Nagy E, Asa SL, Kovacs K: The influence of pituitary hormones on adjuvant arthritis. Arthritis Rheum 27:682-688, 1984 37. Levine JD, Moskowitz MA, Basbaum AL: The effect of gold, an antirheumatic therapy, on substance P levels in rat peripheral nerve. Neurosci Lett 87:200-202, 1988 38. Pearson CM, Paulus HE, Machleder HI: The role of the lymphocyte and its products in the propagation of joint disease. Ann N Y Acad Sci 256:15&157, 1975 39. McCord JM: Oxygen-derived radicals: a link between reperfusion injury and inflammation. Fed Proc 462402-2406, 1987 40. Blake DR, Merry P, Unsworth J, Kidd BL, Outhwaite JM, Ballard R, Moms CJ, Gray L, Lunec J: Hypoxic reperfusion injury in the inflamed human joint. Lancet 1:289-292, 1989 41. Leszczynski D, Josephs MD, Fournier RS, Foegh ML: Angiopeptin, the octapeptide analogue of somatostatin, decreases rat heart endothelial cell adhesiveness for mononuclear cells. Regulatory Peptides 43: 131-140, 1993 42. Bethge N, Dielt T, Kosick M, Holz J: Somatostatin half-life: a case report in one healthy volunteer and a three month followup. Hormone Metab Res 13:709-710, 1981
1/--страниц