Data on the use of urokinase and prourokinase in ophthalmology began to appear in the domestic literature after 1993. They were used for hemorrhages inside the eye and fibrinoid syndrome that occurs after lensvitrectomy.
Later, for these purposes, it was proposed to use recombinant prourokinase, the drug of which was developed at the Technogen Research and Production Enterprise in collaboration with the Cardiology Research and Production Enterprise of the Ministry of Health of the Russian Federation. The use of the drug was not limited only to hemophthalmos; it was also prescribed for other hemorrhages inside the eye - hyphema, intraretinal, preretinal and subretinal hemorrhages. Officially, in 1999, the new drug was named “Gemaza”.
The developers of Gemaza created a drug for the treatment of cardiovascular pathologies, in particular, for dissolving blood clots. True, the research of domestic scientists helped to discover other points of application of the new drug, for example, in ophthalmology. At the moment, Gemaza is widely used in cases of acute circulatory disorders in the vessels of the retina, with hemorrhages inside the eye (including traumatic ones), for the treatment of postoperative fibrinoid syndrome, hemophthalmia in diabetic retinopathy. It is also used in the case of surgical treatment of submacular hemorrhages and proliferative diabetic retinopathy.
Detailed description of the study
Cytokines are proteins that are produced in cells of the immune system (lymphocytes, macrophages), in fibroblasts, endothelial and other cells. They act on target cells in order to change (modulate) their functions. Changes in functions can have a positive effect (increase growth, cell survival) or a negative effect (stop growth, trigger programmed cell death).
Cytokines are divided into three main types:
- Pro-inflammatory (increasing inflammation in the body);
- Anti-inflammatory (limiting inflammation in the body);
- Colony-stimulating (increasing the production of white blood cells during an immune or inflammatory response).
Cytokines that affect white blood cells are called interleukins. This study determines the level of interleukin-6. Interleukin-6 (IL-6, IL-6) is a protein belonging to the group of pro-inflammatory cytokines. IL-6 is a mediator of acute inflammation - it helps activate acute phase proteins (C-reactive protein, haptoglobin, etc.) in the liver and lymphocytes in the blood. Thanks to these functions, the human immune defense system can normally counteract microbes, tumor cells and other foreign agents.
Interleukin-6 occupies an important place in the life of CD4+ T-lymphocytes (T-helpers) circulating in the bloodstream. These cells actively participate in all types of immune defense of the body. For example, during the humoral immune response, activated T helper cells produce IL-6, which stimulates plasma cells (activated B lymphocytes), thereby promoting the production of currently needed antibodies (immunoglobulins).
IL-6, together with C-reactive protein (acute phase protein), is used as a marker of inflammation, especially in infectious and autoimmune diseases.
IL-6 is increased in patients with sepsis (severe systemic infection) and may reflect its severity. In addition, the concentration of interleukin-6 may increase with local infectious pathologies, such as infections of a prosthetic joint. It has been established that the level of IL-6 in this infection has a higher diagnostic accuracy compared to the indicators of CRP, ESR and leukocyte count.
The main autoimmune pathologies characterized by increased IL-6 include rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Crohn's disease and ulcerative colitis. Due to the fact that interleukin-6 increases inflammation and the immune response in the body, special drugs have been developed - IL-6 blockers, which disrupt the interaction of interleukin with its receptor.
There is also interest in interleukin-6 in oncology practice. It is based on the fact that tumor cells are able to synthesize this interleukin on their own, which can contribute to the growth of the tumor. The study of IL-6 in malignant neoplasms is carried out in conjunction with traditional tests as an additional biomarker in the diagnosis of malignant ovarian tumors.
In the Hemotest laboratory you can find out the level of interleukin-6 in the blood in quantitative equivalent with maximum accuracy to the hundredth.
Properties of Gemaza
The active component of the drug, the recombinant fibrinolytic proenzyme prourokinase, is formed during the genetic transformation of the bacterium Escherichia coli. It works as follows. When combined with small doses of plasmin, prourokinase takes the form of plasminogen activator - urokinase, which can catalyze the transition of plasminogen to plasmin. It is worth pointing out that urokinase is the main plasminogen activator even without fibrin.
Gemaza is practically non-allergenic and has a high specificity of action. The direction of modification of the N-terminal receptor-binding domain of RPU suppresses its interaction with the urokinase receptor, so its systemic administration eliminates any potential side effects due to stimulation of regulatory processes that control cell migration and tissue remodeling. The drug is characterized by increased affinity for fibrin, and is completely resistant to plasminogen activator inhibitors.
References
- Titov, V.N. The role of macrophages in the development of inflammation, the action of interleukin-1, interleukin-6 and the activity of the hypothalamic-pituitary system (literature review). Clinical laboratory diagnostics, 2003. - No. 12. — P. 3-12.
- Histology (introduction to pathology) / ed. E.G. Ulumbekova, Yu.A. Chelysheva, 1997. - pp. 527-545.
- Kumar, V., Abbas, A., Aster, J. Robbins and Cotran Pathologic Basis of Disease, 2014. - 1408 p.
- Viedma, J., Pérez-Mateo, M., Domínguez, J. et al. Role of interleukin-6 in acute pancreatitis. Comparison with C-reactive protein and phospholipase A, 1992. - Vol. 33. - P. 1264-1267.
Use of the drug
In clinical practice, Gemaza is now widely used for the purpose of more effective treatment of various types of hemophthalmos and hyphemas, complications of cataract extraction and lensvitrectomy surgery - fibrin effusion, thrombosis and prethrombotic conditions of the retinal veins, as well as to improve local blood circulation in diabetic retinopathy, for the treatment of hemorrhagic complications . Gemaz is prescribed after antiglaucomatous interventions to prevent the occurrence of adhesions, as well as in the event of a block of the filtration opening. Clinical experience has proven the high effectiveness and safety of the drug with no side effects.
The methods of administration of Gemaza are very different: under the conjunctiva, into the anterior chamber of the eye, parabulbar or intravitreal at 5000 IU, or by implantation of a sub-Tenon infusion system. It is noted that the highest concentration of the active substance in CT is detected in the case of its intravitreal delivery.
Studying the pharmacokinetics of Hemaza in animals in 2003, researchers administered the labeled drug using all of the above methods. During the experiments, it was revealed that the maximum concentration of the active substance in the ocular cavity was shown by intravitreal administration - 92% of the initial dose, an hour after injection into the ST, by 12 o'clock, this figure was less than 1%. Thus, it is the intravitreal administration of Gemaza that creates the therapeutic concentration of the active substance in the CT, and the accumulation of a substance that can cause undesirable side effects does not occur.
Intravitreal injections
When prescribing intraocular injections of the drug Gemaza, they are performed by a specialist with the necessary experience in such procedures, or a practicing surgeon, in a specially equipped office or in a sterile operating room. Before intraocular administration of the drug, local drip anesthesia is performed. After performing an intravitreal injection, an antimicrobial drug is instilled into the eye.
To perform parabulbar and subconjunctival injections, an ampoule of Gemza lyophilisate is diluted with 0.5 ml of 0.9% sodium chloride to obtain a dose corresponding to 5000 IU.
To perform intravitreal injections, Gemaz lyophilisate is diluted in 1 ml of 0.9% sodium chloride and administered in a dose of 0.2-0.3 mg of the resulting solution.
As a rule, parabulbar and subconjunctival injections of the drug include from 1 to 10 injections per course. Intravitreal administration is carried out once.
Side effects and contraindications
Intraocular injections of the drug Gemaza are the most effective way to deliver the drug to the affected area. However, they are often accompanied by allergic reactions with swelling and redness of the face, symptoms of chemosis and decreased eye mobility.
One of the complications of administering high doses of the drug is the occurrence of hemorrhage in the eye. In order to prevent it, if necessary, the doctor may prescribe intramuscular injections of ethamsylate.
Gemaza injections are not prescribed in the following cases:
- Individual intolerance to the components of the solution;
- High risk of gastrointestinal bleeding;
- Hemorrhagic diathesis;
- Bacterial endocarditis;
- Tuberculosis in the active phase;
- High-grade proliferative diabetic retinopathy with gliosis;
- An increase in diastolic blood pressure above 105 mm Hg. Art. with arterial hypertension;
- Hypertensive crisis;
- Chronic renal failure;
- Severe liver diseases.
In addition, Gemaza injections are contraindicated in patients under 18 years of age, as well as in women during pregnancy and breastfeeding.
Newspaper "News of Medicine and Pharmacy" Ophthalmology (417) 2012 (thematic issue)
One of the reasons for the sharp loss of visual acuity in patients with diabetes mellitus (DM) is intraocular hemorrhages, which are often recurrent, have a toxic effect on the retina and, in many cases, are difficult to treat. With hemophthalmia, a restructuring of the colloidal structure of the vitreous occurs, its liquefaction and formation, combined with toxic damage to the retina by lipid peroxidation products (radical retinal damage syndrome). This pathogenetic chain is quite arbitrary and is described in the literature as the most unfavorable variant of the development and prognosis of the disease [1].
Based on this, the use of drugs aimed at stopping bleeding and subsequent resorption of shed blood with restoration of the transparency of the vitreous body is essential in the treatment of hemophthalmia. The hemostatic, fibrinolytic, proteolytic and hyperosmotic agents used for this purpose today do not always achieve a positive result, and the use of some of them causes severe allergic reactions. Therefore, the search for new effective drugs that promote faster resorption of intraocular hemorrhages is an urgent task [1, 2].
The purpose of this study was to study the effectiveness of the drug Gemaza in the treatment of hemophthalmos in patients with diabetes.
Material and methods
The subjects of the study were 75 patients (78 eyes) with varying degrees and localization of hemophthalmos and suffering from diabetes.
Among the examined men there were 38, women - 37. Research methods included visometry, perimetry, tonometry with a 10-gram load according to Maklakov, A/B eye scanning. Patients, according to the generally accepted classification, were divided into 3 groups depending on the degree of hemophthalmos: group 1 - partial hemophthalmos (up to 1/3 of the vitreous), group 2 - subtotal (from 1/3 to 2/3), Group 3 - total hemophthalmos (up to 2/3 of the vitreous).
One of the modern, highly effective drugs for the treatment of hemophthalmia is Gemaza, which is a lyophilized enzyme preparation containing a mixture of recombinant prourokinase (RPU) with dextran and sodium chloride. The active substance of the drug is RPU, dextran and sodium chloride, which create an inert enzyme matrix. Hemase catalyzes the conversion of plasminogen into plasmin-serine protease, capable of lysing fibrin clots, and has a high specificity of action, since it activates plasminogen mainly in the area of the blood clot, which reduces the risk of possible bleeding and hemorrhage. The specific activity of hemase is 80,000–100,000 IU per 1 mg of protein. Hemase is highly soluble in water and saline, has low toxicity and good tolerability. Pharmacological studies of the drug showed its high thrombolytic and fibrinolytic activity [3, 4].
Treatment included parabulbar administration of Gemaza at a dose of 5000 IU after preliminary dilution in 0.5 ml of 0.9% sodium chloride solution into the affected eye daily, 10 injections per course of treatment. Treatment was carried out against the background of basic glucose-lowering therapy on the basis of the Republican Scientific and Medical Center for Endocrinology of the Ministry of Health of the Republic of Uzbekistan. The control group consisted of 20 patients (20 eyes) with hemophthalmos who received traditional symptomatic drug therapy (emoxipine, dicynon, ascorutin, actovegin).
Eye examinations were carried out before the start of treatment, after 5 and 10 days during treatment and 1 month after its completion.
Results and its discussion
Our study proved that the effectiveness of treatment of hemophthalmos directly depends on the location, volume and duration of hemorrhage into the vitreous body. During the study, patients tolerated the drug Gemaza satisfactorily, painlessly, and we did not observe any local or general allergic reactions. The high therapeutic effectiveness of Gemaza was noted in the treatment of relatively small hemorrhages, especially those located in the anterior parts of the vitreous. Corrected visual acuity in these cases increased on average from 0.10 ± 0.03 to 0.60 ± 0.02 (p < 0.001) already one month after the start of treatment (Table 1). A/B scanning of the eyes revealed a decrease in the darkening characteristic of hemophthalmos up to complete acoustic transparency of the vitreous body. In the control group, resorption of hemophthalmos was practically not observed during the first month. In subtotal hemophthalmos, resorption with an increase in visual acuity was observed in 43.3% of patients. In patients with recurrent hemorrhages in the vitreous body and retina, resorption of hemophthalmos with further restoration of visual acuity was observed only in 21.5% of cases. At the same time, the resorption of hemorrhages in the vitreous body was more active compared to that in retinal hemorrhages. In our opinion, low visual acuity was partly explained by exudative and proliferative changes in the retina in diabetes.
The therapeutic effect of Gemaza depended to an even greater extent on the duration of the hemorrhage and the presence of proliferative processes in the vitreous body. Hemorrhages over a period of several days resolved completely or partially with an increase in visual acuity in 51.3% of patients, while the process of resorption and an increase in visual acuity were noted from the fifth day until the end of the course of treatment. Among patients with recurrent hemorrhages against the background of proliferative diabetic retinopathy (DR) with the presence of mooring and tractional retinal detachment, resorption of hemorrhages was observed only in 12.7% of cases, and lysis or thinning of the moorings was not observed in any case. The antioxidant properties of the drug contributed to the improvement of visual functions, especially in patients with non-proliferative DR, who had an increase in visual acuity of 0.5–0.9 (Table 1).
However, in patients with extensive, often recurrent retinal hemorrhages and hemophthalmos, especially with proliferative DR, the use of Gemaza due to its pronounced fibrinolytic and disaggregating effect and the risk of developing repeated hemorrhages was more limited. In these cases, treatment began with hemostatic therapy and prescribed dicinone 2.0 ml intramuscularly once a day for 10–15 days and aminocaproic acid, which was administered parabulbarly at 0.5 ml daily for 3–5 days. After which Gemaza was used in the form of parabulbar injections in the above dosage.
Thus, Gemaza is an effective remedy for the resorption of hemophthalmos, especially in the early stages after hemorrhage, in the presence of proliferative processes in the vitreous body and retina. Gemaza can be used as an adjuvant in combination with other drugs and methods.
Conclusion
1. It has been established that the treatment of hemophthalmos in patients with diabetes is highly effective with the drug Gemaza, which has hemoresorption and fibrinolytic properties and does not produce side effects.
2. Parabulbar administration of Gemaza is recommended in a dose of 5000 IU per 0.5 ml of 0.9% sodium chloride solution in ophthalmology clinics and clinics for hemophthalmia of various etiologies and DR.
First published in the journal “Diabetes Mellitus”, 2010, No. 2
Commentary by the endocrinologist of the Federal State Institution "Endocrinological Research Center", Professor O.M. Smirnova to the article by N.M. Normatova “Results of using the drug Gemaza in the treatment of hemophthalmos in patients with diabetic retinopathy”
Diabetic retinopathy (DR) poses a huge problem for both the endocrinologist and the ophthalmologist. The hemophthalmos that occurs with DR poses a serious threat of irreversible vision loss and, on the other hand, complicates the possibility of carrying out pathogenetic treatment - retinal photocoagulation. In the article, the author cites his own experience, comparing the effectiveness of treating hemophthalmia by parabulbar administration of the drug Gemaza with “traditional drug therapy (emoxipine, dicynon, ascorutin, actovegin).” First of all, I would like to object to the author that the main task is still to achieve the target values of glycemia, blood pressure and lipid spectrum. This is exactly what the doctor needs to pay attention to, since with high glycemia, frequent hypoglycemia, and increased blood pressure, hemophthalmos will recur endlessly. I consider hemostatic therapy in the form of administering dicinone 2.0 ml intramuscularly for 10 days, and even more so Actovegin, incorrect and contrary to modern international recommendations. Indeed, Gemaza is used by ophthalmologists to accelerate the resorption of hemophthalmos to ensure the restoration of transparency of the eye media for subsequent photocoagulation of the retina. In this case, the drug is administered not parabulbarly, but intravitreally, which can be considered quite justified. Unfortunately, at present there are no reliable and pathogenetically justified means for the conservative treatment of DR. But Gemaza and a number of other drugs can be used not as the main one, but only as a symptomatic treatment, including for the elimination of hemophthalmos.
