RU2297227C2 - Method for preventing transplants's detachment after through keratoplasty in children in the group of risk - Google Patents

Abstract

FIELD: medicine, ophthalmology.

SUBSTANCE: since the first post-surgical day it is necessary to introduce perorally cyclosporin at a single dosage of 2 mg/kg body weight and methipred - 0.5 mg/kg once daily for about 6-12 mo. Combination of such a mode of introduction and dosages of preparations enables to decrease the frequency of transplant's detachment and its cataract after keratoplasty in children of high-risk group and, also, decrease toxicity of cyclosporin and methipred.

EFFECT: higher efficiency of prophylaxis.

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Description

The present invention relates to ophthalmology and is intended to reduce the frequency of transplant rejection after end-to-end keratoplasty in children at high risk.

Cross-keratoplasty has been and remains the only effective way of treating numerous and diverse corneal opacities in childhood, which account for a significant proportion of cases of childhood blindness and low vision.

The functional result of corneal transplantation, as you know, is directly determined by the nature of the biological reaction to donor tissue. In the total mass of observations, from 60 to 75% of transplants are transparently surviving during the first year after the operation, and every third case of insolvency is due to the rejection reaction. In the high-risk group (repeated keratoplasty, limbkeratoplasty, or transplantation into a vascular bed), the incidence of failed grafts ranges from 75% to 90%, and the rejection reaction already accounts for 2/3 of all failures [Hill J.C. Systemic cyclosporine in high-risk keratoplasty: long-term results. // Eye. - 1995 .-- Vol. 9. - p. 422-428].

The level of technology. Rejection is easier to prevent than to cure. The legitimacy of such a formulation of the question has long been no doubt. All discussions are devoted mainly to the choice of a more effective and / or less toxic method. In the modern arsenal of ophthalmic surgery, there are the following means of prevention of transplant rejection.

A known method for the prevention of transplant rejection based on tissue typing. It is based on the selection of a pair of donor-recipient for antigens of the HLA system. In this operation, immunohistochemical studies precede the results of which a cornea with a similar antigenic set is selected from a donor bank to a recipient. In the very first full-scale clinical trial of this method [D'Amaro J., Volker-Dieben H.M., Kruit P.J. et all. HLA matching and other factors in corneal transplantation; a single center experience with more than 1800 consecutive transplants in 15 years. In: Proceedings of the X1 international histocompatabilty workshop conference. Ed. by Tsuji K., Aizawa M., Sasazuki T. - Vol. II. - Oxford University Press, Oxford. - 1992. - p.478-479] the authors achieved in 80% of the recipients in the high-risk group transparent engraftment of the donor cornea for 15 years.

Further studies, however, have yielded conflicting results, and the feasibility of this procedure is currently being called into question [Vail A. Gore S.M., Bradley B.A. et all. Influence of donor and histocompatibility factors on corneal graft outcome. // Transplantation. - 1994 .-- Vol. 58. p.1210-1216; Waldock A. Corneal transplantation: how successful are we? // Br. J. Ophthalmol. - 2000 - Vol. 84. - p.813-815]. In addition to the highly controversial effectiveness, the widespread use of tissue typing is constrained by high time and financial costs. As a rule, it takes several days to select a donor / recipient pair for HLA determinants. The viability of the donor endothelium in anticipation of the results of the study suffers so much that its subsequent transplantation is often doomed to failure for other purely biological reasons.

A known method of preventing transplant rejection using topical glucocorticoids. Corticosteroids are considered the gold standard for the prevention of transplant rejection at risk. All doubts about the appropriateness of typing in a high-risk group, for example, are caused by the fact that similar results can be achieved faster and cheaper - using corticosteroids alone.

In accordance with the scheme developed in the framework of Collaborative Cotneal Transplantation Studies [Vail A., Gore S.M., Bradley B.A., at all. On behalf of Corneal Transplant Follow-up Study Collaborators. Corneal graft survival and visual outcome: a multicenter study. // Ophthalmol. - 1993. - Vol.101 - p.120-127], the 1st week after surgery, a 1% prednisone solution is instilled into the eye every 2 hours, the 2nd week - every 4 hours, from the 3rd to the 10th week - every 6 hours; then the dose is gradually reduced and brought to the end of the year to 1 drop per day. Such therapy allows maintaining transplant transparency according to various data in 35-60% of patients at risk.

At the same time, long-term local use of glucocorticoids leads to suppression of transplant epithelization, contributes to the appearance of corneal erosion, their soon ulceration and infection. Another typical complication of this therapy is the gradually developing steroid glaucoma, which inevitably leads to transplant failure and in the absence of a rejection reaction.

A known method of preventing transplant rejection using the systemic use of glucocorticoids [Hill J.C. Immunosuppression in corneal transplantation.// Eye. - 1995 .-- Vol. 9. - p. 247-253]. The administration of glucocorticoids is usually resorted to when the transplant engraftment is threatened by a concomitant systemic disease: infectious allergic scleritis and uveitis, atopic sclerokeratitis, rheumatoid arthritis or lupus with eye manifestations. Local use of glucocorticoids in these cases is considered to be obviously ineffective.

Metipred is prescribed in tablets at a dose of 0.5-1 mg / kg body weight for a single dose in the morning for 6-12 months. Further, the daily dose of metipred is reduced by 1 mg every 2-3 weeks, until it is completely canceled by 12-18 months after surgery (unless glucocorticoid therapy is chronic).

With the systemic administration of glucocorticoids, you always have to choose between the desire to keep the transplant transparent and the risk of causing serious complications with such therapy. The latter include diabetes mellitus, osteoporosis, gastric ulcer, superinfection, dysplasia, myasthenia gravis, and more. Due to the severity of all these complications, systemic administration of glucocorticoids in children is limited.

There is also known a method for the prevention of transplant rejection, comprising the systemic use of cyclosporine in adults. At one time, cyclosporin A, a powerful immunosuppressant from the macrolide antibiotic group, revolutionized the practice of organ transplantology, significantly reducing the frequency of rejection of the kidneys, heart, and liver. Similar results were expected from its use in keratoplasty. Such expectations, for the most part, did not materialize.

The systemic administration of cyclosporine (4-4.5 mg / kg / day) for 1 year after corneal transplantation to patients with a high risk of rejection radically reduces the frequency of transplant failure - up to 5-7% [Maychuk D.Yu., Moroz Z.I. Cyclosporin in keratoplasty. // Ophthalmic surgery. - 1996. - No. 4. - p. 56-63]. In the keratoconus group, in which traditionally no prophylaxis of rejection (as unnecessary) is carried out, the survival of the grafts is not much higher than this level.

The systemic use of cyclosporine, however, is accompanied by frequent and severe toxic reactions, which in 10-45% of cases take the form of malignant arterial hypertension, nephropathy or hepatitis [Poon A.S., Forbes J.E., Dart J.K. Systemic cyclosporin A in high risk penetrating keratoplasties: a case-control study. // Br. J. Ophthalmol. - 2001 .-- Vol.85, N12. - p.1464-1469]. Long-term use of cyclosporine is possible only in initially healthy patients and with careful monitoring of their somatic state. In addition, due to the very variable pharmacokinetics of the drug, it is constantly necessary to monitor the level of cyclosporin in the blood, choosing each patient its optimal dose. Such laboratory monitoring is very laborious and expensive [Reinhard T., Sundmacher R., Heering P. Systemic cyclosporin A in high risk keratoplasties. // Graefes Arch. Clin. Exp. Ophthalmol. - 1996 .-- Vol.234. - p. 115-121]. The high toxicity of the drug and the need to constantly monitor its level in the patient’s blood significantly limit the possibility of using this highly effective immunosuppressant in children.

Attempts to reduce the toxicity of the drug due to its local purpose were unsuccessful. The problem is the low lipophilicity of cyclosporine and, accordingly, its low permeability through the epithelial barrier of the cornea. The bioavailability of cyclosporine increases dramatically when it is dissolved in olive oil, but then it penetrates into the systemic circulation, moreover, in a concentration approaching therapeutic. Accordingly, the threat of nephro- and hepatotoxic complications increases.

SUMMARY OF THE INVENTION

The objective of the invention is to develop such a method for the prevention of transplant rejection, which would allow the use of known immunosuppressive drugs in children.

In clinical practice, a widespread method of combining drugs of the same orientation, but with a different mechanism of action. This combination gives a potentiation effect when the dose of drugs is reduced, and their therapeutic effect is summed up. Side effect, in this case, decreases (due to its well-defined dose dependence). This principle is based on modern intravenous anesthesia, antibiotic therapy for severe infections, chemotherapy for malignant neoplasms, and treatment regimens for hypertension.

To prevent transplant rejection in children at high risk, we proposed combining 2 known immunosuppressive drugs with different mechanisms of action. In this combination, the therapeutic effect of the drugs is potentiated, and the frequency and severity of adverse, toxic reactions - due to a decrease in the dose of the drugs - is reduced.

The technical result of the invention is a significant reduction in the frequency of transplant rejection after end-to-end keratoplasty in children at high risk.

The technical result is achieved through a combination of 2 different immunosuppressants and their introduction in certain modes and doses. Cyclosporin and metipred are known to act on different parts of the immune system. Metipred suppresses mainly the proliferation of immunocompetent cells and vascular permeability, cutting off immune responses at the very beginning. Cyclosporin, on the other hand, acts primarily on T-helpers, inhibiting their release of interleukins and other chemotaxis factors in the stage of an already launched immune conflict. With a combination of these drugs, their therapeutic effect is potentiated, so that it becomes possible to use subtherapeutic doses without causing damage to the main effect. Dosage reduction, in turn, eliminates the side effects of drugs.

Thus, there is the possibility of the safe use of these drugs in children as a result of a decrease in their general toxicity and the preservation of the immunosuppressive effect.

DETAILED DESCRIPTION OF THE INVENTION

The method is as follows: patients assigned to the high-risk group are prescribed cyclosporin A (Sandimmun preparation manufactured by Sandoz, Switzerland) from the first day after surgery in capsules or in the form of a solution orally at the rate of 2 mg / kg of weight and metipred in tablets orally from calculating 0.5 mg / kg of body weight per dose per day. Against this background, a biochemical blood test and urinalysis are performed once every 2 weeks in search of signs of nephropathy, diabetes or hepatopathy. In the absence of clinical and laboratory signs of intoxication (persistent increase in blood pressure, at least 2-fold excess of normal levels of creatinine, urea, bilirubin and / or transaminases in the blood, stable hyperglycemia, proteinuria more than 0.5 g / l, severe leukopenia) therapy in the above dosages continue for 6-12 months. When signs of clinical or laboratory intoxication appear, therapy is immediately discontinued and local use of glucocorticoids according to the CCTS regimen is started.

The use of immunosuppressive agents for the prevention of transplant rejection at risk has a long history and rich clinical practice. This practice proceeds from the classical idea that the transplant rejection reaction is based on immune mechanisms: recognition of a foreign cornea by recipient monocytes, transmission of antigenic information to T lymphocytes, their sensitization and proliferation, then migration to donor tissue and its active destruction.

In our practice, when prescribing small, subtherapeutic doses of cyclosporine in combination with metipred in a group of children with a high risk of rejection within 6 to 12 months after surgery, 5 out of 8 grafts remained transparent and another 2 were translucent. None of the patients during the entire observation period had clinical manifestations of intoxication or any significant deviations of the biochemical and hematological composition of the blood. In the control group, in which the prevention of transplant rejection consisted in the local use of dexamethasone according to the CCTS regimen, out of 7 transplants, 4 became cloudy.

Example. Patient G., 11 years old, IS No. 302, diagnosis: OD Alkaline burn of the cornea (03.1998), total clouding of the cornea, neovascularization of the cornea, IV st. by Mohan. Visual acuity is the correct light projection. OS - without pathology. Body weight 52 kg. Somatically almost healthy.

On 06/20/1999, under the general anesthesia, through subtotal keratoplasty was performed on the right eye due to burn clouding of the cornea. The diameter of the graft is 7.5 mm, reinforced in the recipient’s bed with a continuous twisting seam in combination with 5 interrupted sutures. As a donor material used fresh cadaveric cornea, de-epithelialized immediately before surgery.

From the 1st day after the operation, cyclosporin 100 mg and metipred 25 mg were prescribed once a day orally. For the prevention of infectious complications, tobrex is prescribed 1 drop in the eye 4 times a day during the first 10 days after surgery. To stimulate epithelialization of the transplant, Vitasik and Actovegin were used 1 drop in the eye 3 times a day for the first 2 months after surgery.

A clinical examination of the eye was performed weekly, a biochemical and general blood test and a general urinalysis were performed monthly.

Sutures were removed 6 months after surgery. From the same period, the dose of cyclosporine and metipred began to be reduced as planned, by the 8th month after the operation, the therapy was stopped due to the outlined increase in the level of creatinine and blood urea. Azotemia resolved spontaneously to the next study, after 1 month.

The last inspection was in March 2005. The graft is transparent, visual acuity with a correction of 0.6.

Thus, the proposed method allows to achieve a pronounced decrease in the frequency of transplant rejection in children at high risk.

Claims (1)

A method for the prevention of transplant rejection after end-to-end keratoplasty in children at high risk, including the administration of cyclosporine in a single dose of 2 mg / kg weight and metipred - 0.5 μ / kg weight orally once a day from the first postoperative day for 6-12 months .