Method for therapeutic treatment of primary open-angle glaucoma
FIELD: medicine, ophthalmology.
SUBSTANCE: one should apply an autohemocomponent preparation being supernatant liquid of patient's autoblood at increased serotonin content obtained due to irreversible thrombocytic aggregation due to the impact of 0.5 mg ATP per 1.0 ml plasma followed by a 30-min-long centrifuging at the rate of 1000, 2000 and 3000 rot./min for 20, 7 and 3 min, correspondingly. In case of no exudative phenomena on patient's eye bottom the obtained preparation should introduced at the quantity of 7-10 ml once in 48 h for 1 mo (totally, 15 injections). In case of exudative-hemorrhagic phenomena it should be introduced parabulbarly at the volume of 0.5 ml and parenterally - 7.0-10.0 ml once in 48 h for 1 mo per 15 injections, correspondingly. The preparation enables to improve visual functions due to decreased tissue hypoxia and normalization of microcirculation in visual analyzer.
EFFECT: higher efficiency of therapy.
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The present invention relates to ophthalmology and is intended for therapeutic treatment of primary open angle glaucoma (POAG).
Currently recognized multifactorially development of POAG. Given the complexity of the pathogenesis of POAG, the deployment of surgical and therapeutic efforts exclusively on the reduction of intraocular pressure (IOP) cannot be considered adequate. Today in the treatment of patients with POAG one of the main problems is the stabilization of visual functions after IOP normalized. It is known that normal levels of IOP in POAG often do not provide stabilization of visual functions as the main reasons for the progression of the disease are unresolved chronic hypoxia and ischemia of the tissues of the eye and brain (4). In the fight against hypoxia and ischemia in patients with POAG currently uses a comprehensive approach that includes various types of electrical stimulation of the optic nerve, antioxidants, agents that improve trophism (1). The disadvantages of these methods are the low efficiency and the inability widespread implementation of this type of treatment because of technical neoshamanistic, as well as the possibility of allergic reactions to xenobiotics.
Our attention to the problem of the pathogenesis and treatment of glaucoma attracted serotonin is one of the evolutionary the NGOs oldest Central neurotransmitters, governing as a behavioral system, and participating in the regulation of tone and rhythmic fluctuations in blood microvessels, providing normal tissue metabolism and homeostasis (5). For more than 50 years studying the role serotina in humans and mammals have 14 types of serotonin receptors. The involvement and role of the many serotonin receptors in ocular physiology is not fully explained and are the subject of ongoing research.
It is known that serotonin and its receptors are present in almost all the structures of the eye and the visual analyzer. For example, in the iris and ciliary body of humans and animals (11), moisture chamber (14), the retina, in the suprachiasmatic nuclei (12), reticular formation (8), in the primary visual cortex (field 17) - (10).
In numerous animal studies it was found that the IOP reduction and regulation of the dynamics of a chamber of the moisture associated with the stimulation of the serotonin receptors of the iris and ciliary processes (13).
In recent years, accumulated evidence of the protective role of serotonin in the development of cerebral ischemia (9) and its antiapilepticescoy (neuroprotective) action (6). Thus, to date, we know that serotonin is directly related to the normal blood supply to the eye, the regulation of intraocular pressure, d is the Namik chamber moisture and perception, processing and storage of visual images, as well as the trophic neurons.
In domestic and foreign literature we did not find publications on the effects of blockers of serotonin receptors and products containing serotonin, on the state of the field of view (FOV) and visual acuity (VA) in healthy and patients with POAG.
Given the above, the task was to show the role of blockade of serotonin receptors 5-HT3on the state of intraocular pressure, visual field, visual acuity and develop a method of therapeutic treatment of POAG autokeratometry preparation containing an increased concentration of serotonin as serotonin, as a drug, domestic and foreign industry is not available.
The technical result of the invention is the improvement of visual functions by reducing tissue hypoxia and normalization of microcirculation in the visual analyzer. The technical result is achieved due to the use autohematopoietic drug with a high content serotina (serotoninergisen autoplasma). As you know, serotnin not ordinarily penetrate the blood-brain barrier, but when its damage and increase the concentration of serotonin in the blood plasma of he (serotonin) enters the Central nervous system is mu releases, for example, from paraproteins serotonin receptors in neurons, astroglia and blood vessels of the microvasculature of the visual analyzer. This provides an increase in the release of neurotrophic protein and elimination of perfusion deficit in the visual cortex and optic nerve.
The premise of the proposed invention was experimental and clinical studies on five healthy volunteers (10 eyes)taking a selective blocker of serotonin receptors 5-HT3- Latran widely used in medical practice for the prevention of postoperative nausea and vomiting. The drug was administered in a conventional dosage of 0.008 g every 8 hours for 5 days. IOP before the appointment of latrine there were 13.3±0,79 mm Hg, after taking a course of IOP significantly increased (p<0.05) and was 16.1±0.71 mm Hg. Of the 10 eyes, two (two patients) IOP has not changed; the maximum increase in IOP was 6.0 mm Hg in 1 eye; 4.0 mm Hg increased in two eyes and 3.0 mm Hg increased in five eyes. To the original IOP returned in the eyes of all within 5-6 weeks. In the study of peripheral borders of the FOV for the entire period of observation was reported deviations from the norm, and the sum of the degrees averaged 520°±3,3°. Before the appointment of latrine five eyes were fixed single scotomas in the bundle is e from 1 to 3 (average 0.8±0,11), after receiving this drug scotomas were determined in all the eyes in number from 4 to 14 (average of 7.6±1,05; p<0.01), and to the initial level, the number of cattle returned after 12 weeks.
Thus, for the first time it was shown that blockade of one of the 14 types of receptors induces defects in visual fields and increased IOP. Studies have shown that blockade of serotonin receptors or decreased concentration of serotonin in the visual analyzer can lead to the symptoms observed in POAG, namely, increased IOP, and defects in visual fields. Hence, for the treatment of POAG makes sense to use products that contain serotonin. Given the fact that domestic and foreign pharmaceutical industry has no such preparations, there is a need to develop technology for autohematopoietic drug with a high content of serotonin (serotoninergisen autoplasma).
Taking into account information about the morphological and physiological characteristics of the platelet (7) to obtain serotoninergisen autoplasma you must do the following:
1) in platelet-rich plasma to start the mechanism of irreversible platelet aggregation by adding thereto 0.5 mg/ml 1% solution of ATP (3).
2) to Change the mode centrifugation from 1000,2000, 3000 rpm for 30 minutes - 20, 7 and 3 minutes, respectively, formed platelet aggregates are deposited on the bottom of the tube. The supernatant represents autokeratometry the drug with increased fibrinolytic, resorptive activity that contains high on 60-250% concentration of serotonin. The level of serotonin in plasma and autoprepare was determined by fluorometric method (2) on the spectrophotometer SPF-125, 'AMICO(USA).
The resulting autoprepare depending on the presence of exudative-hemorrhagic phenomena in the fundus or the absence thereof is administered as follows:
1) in the presence of exudative-hemorrhagic phenomena in the fundus of the drug is administered parabulbarno 0.5 ml after 48 hours, eye, in which detected these changes on the course of treatment 15 injection; at the same time the drug is administered parenterally 7,0-10,0 ml after 48 hours of treatment 15 injection;
2) in the absence of exudative phenomena in the fundus drug is administered parenterally 7,0-10,0 ml after 48 hours of treatment 15 injection within one month.
Patient HWY, 62. Diagnosis: right eye-IIIa(severe) FNH. Exudative maculopathy. Left eye-IIa(advanced) POAG.
IOP on the right and left eye and 16,4 14,9 mm Hg, respectively. The boundaries of the field of view (FOV) 8 meridians at right eye-206&x000B0; on the left-499°. Visual acuity (VA) of the right eye = 0,1 with correction of 0.15. The optic disc (optic nerve disc) with clear contours, slate-grey, the vascular bundle is shifted to the nose, with pregibon vessels on 1100,230and 500.THE Central area of the fundus ophthalmoscopically retinal edema and 3 rounded hemorrhage. The acuity of the left eye = 0.5 s correction of 0.6. The optic nerve disc with clear contours, monotonously gray, the vascular bundle is shifted to the nose without kinks. Exudative-hemorrhagic effects were detected.
Treatment. The patient received parabulbarno right eye at 0.5 ml autohematopoietic drug with a high content of serotonin 180% after 48 hours, a total of 15 injections. In addition, the same drug was administered intramuscularly in a dose of 10.0 ml after 48 hours at 15 injection.
After treatment, the IOP in the right eye 16,1 mm Hg, PZ=373°OZ=0,3 correction of 0.4. In the Central area of the fundus is complete resorption of retinal edema and hemorrhages. Left eye IOP=15,9 mm Od, PZ=499°OZ=0,8 correction of 1.0.
Thus, therapeutic effect of the treatment of POAG in this case resulted in considerable expansion of the peripheral field of vision and increase visual acuity in the treated and the contralateral eye. The results of treatment are presented in figure 1 and 2, where the line “a” indicates the state of the field of view before treatment line “b” - after the treatment. The result was encouraged by 180% serotonin and increased fibrinolytic and resorptive effect autohematopoietic drug.
Patient TPI 52 years. Diagnosis: OU IIa(advanced) POAG. OD-exudative maculopathy.
Right eye - IOP=19,2 mm Hg, OZ=0.6 n/K, the optic nerve disc with clear contours, decolorizer, the vascular bundle is shifted to the nose, kinks vessels no. In the macular region of the flat retinal edema. Left eye IOP=21,0 mm Hg, OZ=0,8 n/a, optic nerve disc with clear contours, pale pink, the vascular bundle is slightly shifted to the nose, kinks vessels not identified. The Central field of view (CPS) in both eyes studied the analyzer HUMPHREY. defects in CPS of varying severity (absolute scotomas - black color, relative gray). In quantitative terms in CPS of the right eye revealed 369 cattle, in the left - 149.
The treatment was carried out gamecomponents drug with a high content of 95% of serotonin. In the right eye parabulbarno was administered 0.5 ml, intramuscularly in a dose of 8.0 ml as previously described. The whole treatment took 15 parabulbar and 15 intramuscular injection.
After the treatment the IOP in both eyes was on the same level. OZ on his right eye - 0,8 n/K. the LAKE on the left eye to 1.0. In CPS right eye decreased the number is in the defects from 369 to 205. In the contralateral eye, the number of cattle decreased from 149 to 48.
A follow up survey conducted after 6 and 12 months showed the following: IOP and the LAKE remained on their laurels after treatment. In CPS increased the number of cattle, but their number was significantly lower than before treatment. The results of treatment are presented in figure 3, 4, 5, 6, 7. Thus, this example also illustrates the positive therapeutic effect in the treatment of POAG, as evidenced by the resorption of retinal edema and visual acuity improvement and a significant improvement CPS both in the treated and contralateral eyes. This is due to the local (resorptive) and the system (via the Central nervous system) action autohematopoietic drug with increased serotonin levels.
All proposed method were treated 24 patients with advanced and severe stages of POAG. All POAG patients continued to be treated by more than one local anti-hypertensive drug. IOP does not exceed 17-24 mm Hg, OZ with correction were in the range of 0.07 to 0.8. In 15 patients for 3-6 months on one eye in the Central area of the fundus ophthalmoscopically was determined retinal edema and(or) single point of hemorrhage. This group of patients serotoninergisen plasma was introduced parabulbarno and parenteral above method. 9 Bo is lnyh POAG in the fundus was not revealed exudative-hemorrhagic changes. This group of patients gamecomponents drug was administered intramuscularly in a dose of 7.0-10.0 ml after 48 hours, at the rate of 15 injection.
In the group of 15 patients with POAG obtained the following results: the LAKE has increased in 14 of the 15 eyes 0.42±0.05 to 0.65±0.07 respectively (p<0,05). Improving OZ 0.02 in does not count (1 eye), the maximum VA improvement from 0.5 to 1.0 was observed in one patient, the remaining patients the VA improvement was in the range of 0.1-0.3. VA improvement was accompanied by resorption of hemorrhages and retinal edema. In the contralateral eyes of OZ has increased from 0.63±0.03 to 0,81±0,04 (p<0.05) and was 0.18. In addition, there was an enlargement of peripheral fields of vision in the treated and contralateral eyes. In patients it ranged from 309°±31,2° up to 415°±20,7° (p<0.01), and these changes were related 14 out of 15 eyes. In the contralateral eyes widening PZ occurred in 13 out of 15 eyes with an average of 370°±24,5° (before treatment) to 460°±19,5° (p<0,05) after treatment.
In the group of 9 patients (18 eyes) with POAG receiving serotoninergisen plasma only in the form of intramuscular injection, visual acuity increased on average by 0.15 to: from 0.57±0.05 to 0,72±0,03. Significantly expanded the boundaries of peripheral PZ 350°±27,5° 437°±24,4° (p<0,05). In addition, significantly improved the status of the Central visual field (decreased absolute number with the Otomi). Therapeutic effect concerning the expansion PZ continued for 9-12 months, then PZ returned to his former borders. OZ remained at that level for the entire observation period (12 months).
Follow-up period (12 months), during which therapeutic effect, shows the high efficiency of the proposed method of treatment of patients with POAG. In addition, a positive outcome in contralateral eyes indicates a violation (pathological permeability) of the blood-brain barrier for a number of metabolites, blocking serotonin receptors in the area of primary visual cortex (field 17). This fact indicates the need for specific metabolites that damage the blood-brain barrier and ways to neutralize them, which will probably eliminate one of the reasons for the development of POAG.
Sources of information
1) Anisimov HE, Tour A.N., Anisimov S.I. Comprehensive treatment of glaucomatous neuropathy. Glaucoma, 2001, No. 1, P.21-24.
2) Cohen BM, Nechaev, NV Sensitive and rapid method for the simultaneous determination of l-DOPA, noradrenaline, serotonin and 5-OICK in one sample. Laboratory work, 1979, No. 5, S-303.
3) Fly A.I. method for the treatment of hemorrhages in the internal environment and shell eyes. Patent RU No. 2119316 - C1-1998.
4) Nesterov A.P. Primary glaucoma), 199. 265 S.
5) Simonenkov A.P., Fedorov V.D. whether chronic serotonin deficiency basis of diabetic and age-angiopathy. - Bull. Exp. Biol. The honey. 1997; 123(1) S-110.
6) Ahlemeyer Century, Bcier H., I. Semkova, et al. S-100 beta protects cultured neurons against glutamate - and staurosporine-induced damage and is involved in the antiapoptotic action of the 5-HT(1A)-receptor agonist, BayX3702. Brain Res, 2000; 858(1):121-8.
7) Bertram G. Katzung Basic & Clinical Pharmacology (sixth edition), San Francisco, 1995; 2:26-43.
8) Bidmon, H. J., Schfeicker A., Wicke, K., et al. Localisation of mRNA for h5-HT1B and h5-HT1D recptors in human dorsal raphe. Naunyn Schmiedebergs Arch Pharmacal, 2001; 263(3):364-8.
9) Caicoya A. G., Beneytez M. E., Delgado M, et al. Biochemical, electrophysiological and neurohormonal studies with B-20991, a selective 5-HT1A receptor agonist. Pharmacology, 2001; 64(4):234-42.
10) Hall, H., Farde C., Halldin, S., et al. Autoradiographic localisation of 5 - HT(2A) receptors in the human brain using [(3)H] Ml 00907 and [(11)] M100907. Synapse, 2000; 38(4); 421-31.
11) Harries L. S., Awe, S. 0., Opere S. A., et al. 3H-serotonin release from bovine iris-ciliary body: pharmacology of prejunction serotonin 5-HT7 autoreceptors. Exp Eye Res 2001; 73(1):59-67.
12) Jiang L. G., K. Teshima, Y. Yang, et al. Pre - and postsynaptic actions of serotonin on rat suprachiamatic nucleus neurons. Brain Res, 2000; 866(1-2): 247-56.
13) Osborne, N. N., J. P. Wood, Melena J., et al. 5-Hydroxytryptamine 1A agonists: potential use in glaucoma. Evidence from animal studies. Eye 2000; 14(pt3b): 454-63.
14) F. Veglio, De-Sanctis U., D. Schiavone, et al. Evaluation of serotonin levels in human aqueous humor. Ophthalmologica, 1998; 212(3):160-3.
1. The method of therapeutic treatment of primary open-angle glaucoma, characterized in that it uses autokeratometry the drug, which is a supernatant autologous blood of a patient with elevated is the first serotonin, resulting from irreversible aggregation of platelets by exposure to 0.5 mg of ATP in 1.0 ml of plasma and the subsequent thirty-minute centrifugation at a speed of 1000, 2000 and 3000 rpm for 20, 7 and 3 min, respectively, and the drug is administered parenterally.
2. The method according to claim 1, characterized in that in the absence of exudative phenomena in the fundus of the drug is administered in the amount of 7-10 ml, once every 48 hours for one month (a total of 15 injections).
3. The method according to claim 1, characterized in that in the presence of exudative-hemorrhagic phenomena in the fundus of the drug is administered parabulbarno 0.5 ml and parenteral 7,0-10,0 ml of 1 every 48 hours within 1 month of 15 injections, respectively.
SUBSTANCE: method involves intravenously administering 0.1-1% aqueous solution of khlorin, selected from group containing photolon, radachlorine or photoditazine at a dose of 0.2-0.5 mg/kg or 0.2-1% aqueous solution of porphyrin like photogem at a dose of 0.2-1 mg/kg. Laser irradiation of blood is carried out 5-15 min later after beginning photosensitizer injection into cubital vein of one arm via laser light guide set in advance in the cubital vein of the other arm during 10-40 min at wavelength of 661-666 nm and power of 20-50 mW one session per day during 3-10 days with the aqueous solution of khlorin used as the photosensitizer, or laser irradiation of blood with wavelength equal to 630-633 nm during 10-45 min with power of 20-50 mW one session per day with the aqueous solution of porphyrin used as the photosensitizer. Repeated intravenous administration of photosensitizer is carried out 1-3 months later combined with repeated laser irradiation of blood.
EFFECT: reduced risk of tumor cells dissemination and metastasis development.