Adhesion formation is a topical problem of clinical medicine. Since adhesion especially often inhibits normal movement of tissues, including organs, it is considered as a serious complication after surgery. The incidence of intraperitoneal adhesions ranges from 67 to 93% after general surgical abdominal operations and up to 97% after open gynecological pelvic procedures.
It has been estimated that in the United States, there are 117 hospitalisations for adhesion-related problems per 100,000 people, and the total cost for hospital and surgical expenditure is about $1.3 billion [Abdominal adhesiolysis: inpatient care and expenditures in the United States in 1994/N. F. Ray, W. G. Denton, M. Thamer et al.//J. Am. Coll. Surg.—1998.—Vol. 186.—P. 1-9].
The main approaches in preventing adhesions include adjusting surgical techniques, limiting trauma to intra-abdominal structures, and applying adjuvants to decrease adhesion formation [Risberg B. O. Adhesions: Preventive strategies/B. O. Risberg//Eur. J. Surg. Suppl.—1997.—Vol. 577.—P. 32-39].
However, the use of some medicinal preparations for the prevention of adhesions is limited by the following factors:
Ischemic zones are at risk of adhesion formation, but they are distant from blood flow and thus from pharmacological effects of medications administered by common routes (per os, intravenously, intramuscularly, etc.);                1) An extremely rapid absorption mechanism which is typical for the peritoneal membrane affects the elimination half-life and efficacy of many medicinal agents administered intraperitoneally;        2) Any anti-adhesion agent should show its specific activity against the adhesion formation but not the normal wound repair which is necessary for adequate surgical treatment.        
Intra-peritoneal thrombokinase, fibrinolysin, streptokinase, urokinase, hyaluronidase, chymotrypsin, trypsin, papain, and pepsin act directly by breakdown of the fibrinous mass and indirectly by stimulating plasminogen activator activity. The use of these agents is still awaiting appropriate human clinical trials [Alpay Z. Postoperative adhesions: from formation to prevention/Z. Alpay, G. M. Saed, M. P. Diamond//Semin. Reprod. Med.—2008.—Vol. 26, N 4.—P. 313-321].
The use of non-steroidal anti-inflammatory agents, glucocorticosteroids and antihistamines, progesterone/estrogen, anticoagulants, fibrinolytics, and antibiotics has not been found very effective in reducing adhesions and has been associated with an inadequate safety profile and a high incidence of various side effects [Pathogenesis, consequences, and control of peritoneal adhesions in gynaecologic surgery/Practice committee of the American society for reproductive medicine, The society of reproductive surgeons//Fertil. Steril.—2008.—Vol. 90, Suppl. 5.—S. 144-149].
A pathologically justified approach to the prevention of adhesions is the use of methods and agents preventing approximation and adhesion of injured abdominal surfaces [Davey A. K. Surgical adhesions: A timely update, a great challenge for the future/A. K. Davey, P. J. Maher//J. of Minimally Invasive Gynecology.—2007.—Vol. 14.—P. 15-22].
An ideal barrier showing a high safety and efficacy profile should be noninflammatory, nonimmunogenic, and persist during the critical remesothelisation phase, staying in place without sutures or staples, and furthermore remain active in the presence of blood and be completely degradable. In addition, it should neither interfere with healing, promote infection and oncological process, nor itself cause adhesions [Yeo Y. Polymers in the prevention of peritoneal adhesions/Y. Yeo, D. S. Kohane//European. J. of Pharmaceutics and Biopharmaceutics.—2008.—Vol. 68.—P. 57-66].
Nowadays, polymer solutions [Falabella C. A. Cross-linked hyaluronic acid films to reduce intra-abdominal postsurgical adhesions in an experimental model/C. A. Falabella, W. Chen//Dig. Surg.—2009.—Vol. 26, N 6.—P. 476-481], solid membranes [Hyaluronan derivatives in postsurgical adhesion prevention/D. Pressato, E. Bigon, M. Dona et al.//in: Hyaluronan: Proceedings of an International Meeting, September 2000, North East Wales Institute, UK, Woodhead Publishing, Cambridge, England, 2002.—P. 491-499], precasted [A novel hyaluronan-based gel in laparoscopic adhesion prevention: preclinical evaluation in an animal model/P. A. D. Laco, M. Stefanetti, D. Pressato et al.//Fertil. Steril.—1998.—Vol. 69.—P. 318-323] or in situ hydrogels [Next-generation hydrogel films as tissue sealants and adhesion barriers/S. L. Bennett, D. A. Melanson, D. F. Torchiana et al.//J. Card. Surg.—2003.—Vol. 18.—P. 494-499] are used as these barriers preventing adhesion formation.
The use of crystalloid solutions for long-term separation of abdominal layers has been found inappropriate due to the rapid absorption of water and electrolytes from peritoneal cavity, with up to 500 ml of iso-osmolar sodium chloride absorbed in less than 24 hours in humans [Kinetics of peritoneal fluid absorption in adult man/L. Shear, C. Swartz, J. Shinaberger et al.//N. Engl. J. Med.—1965.—Vol. 272.—P. 123-127]. Because it takes 5 to 8 days for peritoneal surfaces to remesothelialise, a crystalloid solution should be absorbed well before the process of fibrin deposition and adhesion formation are complete. Clinical studies showed an adhesion re-formation rate of approximately 80% in patients who received crystalloid solutions [De Cherney A. H. Clinical problem of intraperitoneal postsurgical adhesion formation following general surgery and the use of adhesion prevention barriers/A. H. De Chemey, G. S di Zerega//Surg. Clin. North. Am.—1997.—Vol. 77.—P. 671-688].
Attempts have been made to use different polymer materials, in particular polymers of glucose (Dextran 70, isodextrin), carboxymethyl cellulose, and hyaluronic acid.
Dextran 70 (32% dextran 70 (Hyskon, Pharmacia, Sweden)) is a frequently used solution for adhesion prevention. Its main characteristics are as follows: dextran is slowly absorbed and draws fluid into the abdominal cavity. It also decreases clot formation [Gutmann J. N. Principles of laparoscopic microsurgery and adhesion prevention/J. N. Gutmann, M. P. Diamond//in: Practical Manual of Operative Laparoscopy and Hysteroscopy: Ed. Azziz R., Murphy A. A.—New York: Springer, 1992.—P. 55-64]. Follow-up studies of the initial observation did not show a reduction in adhesions. Moreover, significant side effects, such as ascites, weight gain, pleural effusion, labial edema, liver function abnormalities, and, albeit rare, disseminated intravascular coagulation and anaphylaxis, were noted, and dextran solution is used very rarely now. [di Zerega G. S. Contemporary adhesion prevention/G. S. di Zerega//Fertil. Steril.—1994.—Vol. 61.—P. 219-235]. The results have been inconsistent [Tulandi T. Intraperitoneal instillates/T. Tulandi//Infertil. Reprod. Med. Clin. North. Am.—1994.—Vol. 5.—P. 479-483].
Difficulties have been found in using porous polytetrafluoroethylene membranes as local barriers due to the formation of pseudocapsules [The Surgical Membrane Study Group: Prophylaxis of pelvic sidewall adhesions with Gore-Tex surgical membrane: A multicentre clinical investigation//Fertil. Steril.—1992.—Vol. 57.—P. 921-923]. Moreover, it has been technically difficult to use this material in laparoscopic surgery [Tulandi T. Adhesion prevention in laparoscopic surgery/T. Tulandi//Int. J. Fertil. Menopausal. Stud.—1996.—Vol. 41.—P. 452-457]. It requires a physical fixation and is not degradable. Therefore, it should be left or surgically removed later. Removal procedures may cause surgical traumas and lead to adhesion formation. These technical difficulties and usability problems have made the medication unpopular, and it is used very rarely now.
Oxidized regenerated cellulose (Interceed) is the only adjuvant approved for the specific purposes of postsurgical adhesion prevention. ORC appears to decrease adhesion formation-reformation beyond that achieved with meticulous surgical technique. ORC reduces both raw surface area and the occurrence of adhesion formation-reformation by a margin of 20% [Interceed (TC7) Adhesions Barrier Study Group: Prevention of postsurgical adhesions by Interceed (TC7), an absorbable adhesion barrier: A prospective, randomized multicenter clinical study//Fertil. Steril.—1989.—Vol. 51.—P. 933-938]. When applied to a raw peritoneal surface, it becomes gel within 8 hours [Synergistic effects of Interceed (TC7) and heparin in reducing adhesion formation in the rabbit uterine horn model/M. P. Diamond, C. B. Linsky, T. Cunningham et al.//Fertil. Steril.—1991.—Vol. 55.—P. 389-394]. ORC can be applied easily by laparoscopy, and does not need suturing. However, clinical observation indicates that small amounts of bleeding at the time that ORC is applied results in blood permeating the weave of the material. Fibroblasts grow along the strands of clotted blood with subsequent collagen deposition and vascular proliferation [Frankfurter D. Pelvic adhesive disease/D. Frankfurter, A. H. De Cherney//Postgrade Obstet. Gynecol.—1996.—Vol. 16.—P. 1-5]. This means that the presence of intraperitoneal blood negates any beneficial effect [Effect of blood on the efficacy of barrier adhesion reduction in the rabbit uterine horn model/C. B. Linsky, M. P Diamond, G. S. di Zerega et al.//Infertility.—1988.—Vol. 11.—P. 273-280].
Summing up the current approaches to the prevention of postoperative adhesions in the peritoneal cavity, Burlev V. A. et al. (2009) [Burlev V. A. Peritoneal adhesions: pathogenesis and prophylaxis. V. A. Burlev, E. D. Dubinskaya, A. S. Gasparov//Reproductive disorders.—2009.—No. 3.—P. 36-44] regret to state that all current methods for adhesion prevention are insufficiently effective (and quite expensive as well) and further studies are required to improve the efficacy of anti-adhesion measures.
The most similar to the present invention in technical terms is a method for the prevention of adhesions consisting in the injection of a combination of sterile Lintex-Mesogel gel and derinate into the serous sac [Method for the prevention of postoperative adhesions: Patent 2363476 of the Russian Federation: MKn51: A61K31/711, A61K31/717, A61P41/00/Gomon M. S., Lipatov V. A., Konoplya A. I., Bezhin A. I., Loktionov A. L., Kasyanova M. A., Sukovatykh B. S., Godova A. Yu.; patent applicant/holder Gomon M. S., Lipatov V. A.—No. 2007147670/14; submitted on Dec. 20, 2007; published on Aug. 10, 2009, Newsletter No. 22.—6 pages].
This method for the prevention of adhesions consists in the following. During abdominal operation, for example, laparotomy or laparoscopy, and/or before the covering of the serous sac at the final stage of the surgical intervention, the areas with high probability of primary or recurrent adhesion development (for example, deseronised areas, anastomotic areas, areas with acute or possible inflammation, trauma zones after adhesion dissection, areas of abdominal drying, etc.) are treated with sterile Lintex-Mesogel gel and depot derinate. The volume of derinate is 1% to 25% of total mixture volume. The combination of the derinate and polymer gel is achieved when a mixture is prepared extemporaneously immediately before use, with the correct proportions of components. The ratio of gel-to-derinate solution volumes (based on 1.5 mg of derinate in 1 kg) should be such as the injected solution does not exceed 25% of the total volume, because more fluid may reduce the viscosity of the gel and its anti-adhesion activity. For adhesion prevention purposes, a portion of gel is applied to the serous surface using a syringe or squeezed into the palm of the surgeon's hand from the container where the mixture has been prepared, and applied by smooth movements on the raw abdominal surface, deseronised areas and areas where adhesions may occur (areas with signs of inflammation or ischemia: edema, hyperemia, dilated vessels, discoloration, peristalsis, decreased pulsation of abdominal vessels, etc.). When diffusion processes occur (for example, after abdominal sanation in patients with generalised peritonitis), the combination of gel and derinate is applied at a dose calculated according to the table mentioned by G. DiZerega (1999 r.), that is 2.4 ml/kg for humans, and 10.7 ml/kg for animals (rats). When laparoscopic procedures are performed, specific injectors are used to apply gel with depot derinate.
Disadvantages of this method include the necessity to prepare the sterile solution during the operation, which can make the surgical process more complicated. Other disadvantages include difficulties in achieving homogeneity, difficulties in derinate dosing (need to be weighed), the need to use specific injectors/manipulators in laparoscopic procedures, and an absence of components inhibiting the activity of fibroblasts—cells which synthetic activity stimulates adhesion formation.
The p38 MAP-kinase inhibitor SB203580 is known to be an inhibitor of pro-inflammatory cytokine production [Badger A. M., Bradbeer J. N., Votta B. et al. Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function//J. Pharmacol. Exp. Ther.—1996.—Vol. 279.—P. 1453-1461].
However, no data were obtained by the inventors and no literature references were found concerning the use of p38 MAP-kinase inhibitor as an agent exhibiting anti-adhesion activity.
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USPTO Backgrounds