Method for applying anecortavi acetas for protecting patient vision acuity having age-specific yellow spot degeneration

FIELD: medicine.

SUBSTANCE: method involves introducing anecortavi acetas at a dose of 3-15 mg in posterior juxtascleral injection or injection into vitreous body or as implant.

EFFECT: enhanced effectiveness of treatment.

18 cl, 5 dwg, 4 tbl

 

In relation to this application claims the priority of the filing date of U.S. 60/401220 filed 05.08.2002.

The present invention relates to the use of acetate anecortave to maintain vision and protect visual acuity in patients with age-related macular degeneration (AMD).

The level of technology

AMD is currently the main cause of functional blindness in patients erased 50 in developed countries. Although the exudative form is only present in 15-20% of patients suffering from AMD, but exudative AMD is the main cause of most of the vision loss (1). To date, the only approved treatment for choroidal subfoveolyarnoy neovascularization (CNV)associated with exudative AMD was laser photocoagulation. In 2000, for the treatment of certain subfoveal lesions in this group of patients was approved photodynamic therapy drug vicodin Visudyne®. However, it was shown that the treatment retards, but does not stop vision loss in most reported patients (2).

Because irreversible retinal damage in exudative AMD is the direct result of abnormal growth of choroidal blood vessels under the retina and/or retinal pigment epithelial (PES), was about the Eden clinical evaluation of the effectiveness of a number of angiostatic agents in the treatment of this eye disorder. Angiogenesis is a complex of interrelated processes, in this connection, there are a number of potential opportunities for therapeutic intervention. In contrast to other experimental methods of therapeutic treatment of AMD, which were intended only for the specific inhibition of angiogenesis stimulated vascular endothelial growth factor (VEGF) (3, 4), acetate anecortave inhibits the growth of blood vessels by inhibiting proteases required for the migration of endothelial cells of blood vessels (5, 6). The uniqueness acetate anecortave is that he is able to inhibit angiogenesis after receipt of the enabling signal and, thus, independently of him. Thus, this drug has the ability to nonspecific inhibition of angiogenesis caused by a wide range of well-known stimulators of angiogenesis in the eye structures (7). The ability acetate anecortave to inhibition of angiogenesis, regardless of the initiating pathogen is confirmed by a large number of evidence obtained preclinical studies, including a large number of animal models of neovascularization (6, 8-10).

Disclosure of inventions

The present invention is directed to preparations and techniques to prevent the loss of visual acuity SV is related to AMD, as well as for preservation of visual acuity in patients with AMD, and slow the spread of lesions associated with AMD. These methods include 3-30 mg acetate anecortave or its corresponding alcohol by juxtacrine injection, providing transcleral intake of medicines.

Brief description of drawings

Figure 1. While the average change in visual acuity in logMAR scale at 6 months relative to baseline is comparable to the studied groups, there is a statistically significant difference (p=0,0032) between treatment acetate anecortave 15 mg and intravenous placebo. After one injection of acetate anecortave at a dose of 15 mg acuity logMAR scale changes for 6 months on average less than 1 line on the logMAR scale (4 letters on the logMAR scale) to measure + of 0.08 logMAR. In contrast, after one treatment placebo acuity logMAR scale has deteriorated over the same period by more than 2 rows (12 letters on the logMAR scale) to measure + of 0.24 logMAR. The difference in the values of indicators logMAR at 6 months was statistically significant (p=0,0032).

Figure 2. Comparison of visual acuity 6 months after the start of the study all 128 patients in the four target groups, defined as a decrease of less than 3 lines on the logMAR scale, or 15 letters on the logMAR scale relative to the preliminary baseline. Although this analysis is not reached statistical significance, however, there is a clear tendency that treatment with a single injection of acetate anecortave at a dose of 15 mg has the advantage compared with the introduction of a placebo.

Figure 3. A subgroup analysis to compare the preservation of vision in the four target groups 6 months after the start of the study patients, the original had predominantly classic lesions. For large data subgroups of patients was reached statistically significance (p=0,0209) in the comparison group, subjected to the action of acetate anecortave at a dose of 5 mg, and the group, which was given a placebo.

Figure 4. The percentage of patients with improved vision, defined as an increase of at least 2 lines on the logMAR scale, or 15 letters on the scale of logMAR visual acuity at 6 months compared with baseline. This summary analysis for all 128 patients involved in the study revealed a statistically significant difference of positive influence acetate anecortave at a dose of 15 mg to improve vision at 6 months (p=0,025) compared with the introduction of a placebo.

Figure 5. Total analysis of the percentage changes in the area of lesions at 6 months compared with baseline. Statistically significant positive effect of acetate anecortave dose of 1 mg compared with placebo, in terms of the slowdown in the growth of lesions (p=0.0005), the inhibition of a shared component of CNV (p=0.0001) and a classic CNV component (p=0,0008).

The implementation of the invention

Acetate anecortave (4, 9(11)-pregnadien-17α, 21-diol-3,20 dione 21 acetate) clinically tested as monotherapy for the treatment of subfoveal exudative AMD in the ongoing multicenter study. The results of the interim analyses of clinical data on safety and efficacy obtained during the first 6 months after a single treatment, presented in the description.

This ongoing study was undertaken to compare the clinical effectiveness of treatment with acetate anecortave and the introduction of a placebo for preservation (maintenance) of view, and slowing the growth of lesions associated with CNV. The study involved patients with visual acuity on a scale from 0.3 logMAR (equivalent to 20/40 table Snellen) to 1.2 (equivalent to 20/320 in the table Snellen) and primary or recurrent subfoveal choroidal revascularization (CNV) due to AMD, with the size of lesions up to 30,48 mm2(12 squares disk). Criteria for inclusion of patients in this study, and the exceptions are listed below. At initial and subsequent visits to the best correspondent of the Ktsia visual acuity in logMAR scale was obtained from all patients, following the recommendations previously approved the study Early treatment of diabetic retinopathy". Prior to registration and treatment have assessed the suitability of the area affected patients for participation in this study through the analysis of standardized fluorescent angiograms in the Center for the study of digital angiograms (DARC) using certified "readers" (specially trained professionals mesh layer of the eyeball). Using DARC also masked were evaluated changes angiographic characteristics of the lesions lesions on the benchmarks. Each of the received values is the average of at least two independent estimates, data readers DARC. Since all angiographic data of this study, obtained using the same fundus cameras and digital cameras and stored as uncompressed digital images, the total area of foci of damage can be more accurately represented in "mm2"that is more preferable than the angiographic view the data in a more "visual" performance of disk space.

Between April 1999 and may 2001 18 participating research centers in the US and the EU were recorded and subjected to 128 patients participating in this dual m is Kirovenergo research revealing the dependence of the dose-effect. Before treatment, patients were equally randomized depending on injectable dose sterile suspension anecortave: 30 mg (N=33), 15 mg (N=33), 3 mg (N=33) or placebo (filler, N=30). Masking in clinical centers in relation to the target groups was carried out in two ways. Used drug was masked by placing it in sets for injection containing the investigational drug and device for insertion through the rear juxtacrine injection of opaque hermetically Packed boxes, marked only by the number of the patient. The boxes were numbered sequentially in each clinical center, and patients were assigned sequential serial numbers in accordance with their registration. Randomization was based on the sequential numbering of the sets of reference and was separate in each center to maintain equal distribution of prescribed treatment. Masking the studied groups were also maintained in each center by the fact that injections were conducted routed to the researcher, and the subsequent evaluation of the results was carried out by a masked examiner. After registration each patient acetate anecortave or placebo is administered through a special Cana is Liu in the back part of the eye through the rear juxtacrine injection volume of 0.5 ml in the external surface of the sclera near the fovea. A suitable cannula described in U.S. patent No. 6413245 B1, available for use.

Data on clinical efficacy obtained by measurements best corrected visual acuity in logMAR scale and analysis of standardized fluorescent angiograms. An independent safety Committee overseeing the study, continues to conduct periodic assessment of data on clinical safety derived from basic physiological research laboratory blood and urine tests and a complete ophthalmologic investigations, including angiography with indocyanin green. Here's clinical data on safety and efficacy obtained in 1-2 day, 2 weeks, 6 weeks, 3 months and 6 months after randomization patients and specified treatment.

Initial results on the efficiency obtained in this ongoing study include the mean change in best corrected visual acuity in logMAR scale relative to the baseline. Secondary results on efficiency are: the percentage of patients with persistent or supported by vision (defined as a decrease in visual acuity of less than three lines on the logMAR scale [less than 15 letters on the logMAR scale]); the percentage of patients with clinics and significant vision impairment (defined as a decrease in visual acuity, at least three lines on the logMAR scale [at least 15 letters on the logMAR scale]); percentage of patients with severe vision loss (defined as loss of at least six rows on the logMAR scale [at least 30 letters on the logMAR scale]); and the changing characteristics of damage in CNV (defined as the total area of damage, total CNV and General classic CNV).

All analyses for efficacy were based on the principle of assigned treatment (intent-to-treat). All patients received their assigned drug, were examined respectively. Recent observation was used to add the missing parameters. Compared with baseline was carried out using analysis of variance (for results that continue to do) and Chi-square Pearson (for paired results). Changes in visual acuity and settings damages relative to baseline were studied on the model of variance analysis of repeated changes with appropriate comparative data for 6 months. The paired comparison of the results obtained within 6 months, were carried out using Chi-square Pearson. All results of ophthalmologic tests based on changes in the study (i.e. treatment) eyes.

In this PR is an ongoing study, the re-introduction of the investigational drug was carried out by injection, implemented unmasked investigator, if the score given masked expert, testified about the possible favorable impact on the patient. In this ongoing study was installed in a 6-month interval between doses, and the basis for the establishment of this period was based on the results of preclinical studies showing that acetate anecortave entered as depo-drug delayed release in the rear surface of the sclera, provide therapeutic levels of the drug in the adjacent choroid and the retina for more than 6 months (data not shown). Sixty-two (62) of the 128 patients who participated in this study received at least three rear juxtacrine injection of acetate anecortave or placebo at intervals of 6 months, while 16 patients were subjected to at least five such introductions. As of August 2002, 50 patients continued treatment with 6-monthly intervals as part of this masked study medication. However, the results are presented for the effectiveness is based on a single initial introduction of the investigational drug.

While there were no statistically significant differences in the target groups of the original pokazatel is m age sex, race, visual acuity in logMAR scale or characteristics of the lesion (table 2). Originally planned to conduct the treatment of predominantly classic subfoveal lesions, but later, the Protocol was developed that made it possible inclusion in the study and treatment of patients with minimal classic lesions. Of the 128 patients participating in this study, 80% (102 of 128) in the beginning it was mainly classical damage, while 20% (26 of 128) had a classical minimum damage. Mainly classical damage was defined as classic CNV occupies at least 50% of the total area damage foci (defined in this study when obtaining angiographic evidence of neovascularization, serous detachment of the pigment epithelium of the retina, increased "blocked" fluorescence staining of blood and/or late staining). Baseline characteristics of patients in this study were generally similar to those described for visudyne (Visudyne®) TAR study (2), except that the majority (80% vs. 40%) of the patients described in this study initially had predominantly classic lesions.

Intermediate examination of all 128 patients was conducted by the La to determine the average change in visual acuity in logMAR scale (figure 1) within 6 months relative to baseline. The effect achieved with the introduction of acetate anecortave at a dose of 15 mg, statistically superior to the effect of the introduction of the placebo (p=0,0032) 6 months after the start of the study. Also showed a positive trend in the treatment as acetate anecortave at a dose of 30 mg, and a dose of 3 mg, compared with the introduction of the placebo, although statistical significance was not achieved. Acetate anecortave at a dose of 15 mg has the best efficiency in stabilization of vision in the four groups studied.

Upon receipt of the results of the second study has been analyzed, the percentage of patients with good vision in 6 months after the start of the study. Preservation (maintenance) of view, defined as a decrease in visual acuity of less than three lines on the logMAR scale relative to the original values was taken as the relevant clinical performance indicator, which was used as the primary measure for evaluating therapy subfoveolyarnoy AMD changing in previous reports (2). The results of this analysis after 6 months is presented in figure 2. Demonstrated much better results preservation of visual acuity after 6 months in patients exposed acetate anecortave at a dose of 15 mg than the introduction of a placebo, although the results did not reach statistical value is determined at the level of p=0.05. While 88% of patients exposed acetate anecortave at a dose of 15 mg maintained their vision after 6 months, only 70% of patients subjected to introduction of a placebo, showed similar positive results. However, as shown in figure 3, the analysis of these data in large subgroup of patients with predominantly classic lesions with CNV revealed a significant beneficial effect of acetate anecortave at a dose of 15 mg on preservation of visual acuity in 92% of patients subjected to its action, after 6 months, compared to 65% of patients in the placebo group (p=0,0209). The efficiency of introducing acetate anecortave at a dose of 15 mg for conservation of view is further confirmed by the results of comparison of clinically significant vision loss in the examined groups (table 3). There is a statistically significant advantage acetate anecortave at a dose of 15 mg compared with placebo, identified during the assessment 6 months after the start of the study (p=0,0224)in preventing severe visual loss (table 4).

The figure 4 presents the results of the analysis of the percentage of patients with improved visual acuity at six months, at least 2 lines on the logMAR scale relative to the baseline. In 18% of patients exposed acetate anecortave at a dose of 15 mg, vision improved, at least on page 2 the key on the logMAR scale compared to 3% of patients in the group received 30 mg, 6% in the group receiving 3 mg, and 0% in the group that received placebo. The difference between acetate anecortave at a dose of 15 mg and placebo was statistically significant (p=0,025).

Because preclinical data show angiostatin efficiency acetate anecortave were analyzed changes in surface area of foci damage CNV relative to the original values. Was measured and compared the total area of damage, the total area of CNV and the total area of classic CNV for the studied groups. Although the average size of the lesions was similar at the initial examination in all surveyed groups, however, differences within these groups decreased the sensitivity to inter-group differences when the analysis of mean change in comparison with baseline. Changes to the data characteristics of the lesions were analyzed as the percentage changes compared with baseline, which was a more sensitive indicator for the analysis of group damage, the total area of which is varied with the initial survey in the range from 0.28 to 33,25 mm2. As shown in figure 5, the effect in the treatment of acetate anecortave at a dose of 15 mg statistically superior effect with the introduction of the placebo in reducing the total area of the surface of the affected (p=0.0005), the total surface area with CNV (p=0.001) and the total surface area of classic CNV (p=0,0008) 6 months after the start of the study. In addition, there is a tendency to the fact that treatment with acetate anecortave in doses of 30 mg and 3 mg is superior to placebo for inhibiting the growth of foci of damage.

After the final inspection of all patients after 6 months all information received relating to the safety of the treatment was analyzed by an Independent safety Committee overseeing the study. The results of this assessment were not found to be clinically relevant data associated with analyzed by the tool or by the introduction, which would be cause for concern about the safety of this treatment for patients. The most common ophthalmologic changes were changes in lens clarity, analyzed using classification systems cataract II (LOCS), and included data on the color of the nucleus of the lens, the opalescence of the nucleus, cortical and posterior subcapsular changes. Cataracts are a common concomitant disease in this group of patients, and the observed changes were registered for all the studied groups and in relation to the contralateral (not treated) eyes. Described changes due to cataract, were characterized as mild and usually not related to treatment. The second most spread is tradendae ophthalmological change - reduction of vision (defined as a decrease in ≥4 lines on the logMAR scale compared to the previous visit), is also a common problem in this group of patients. This reduction occurred in all examined groups in the contralateral eye. Other ophthalmologic changes (occurring with a frequency greater than 5%) represented ptosis, eye pain, subconjunctival hemorrhage, ocular itching, ocular burning/sharp pain, pupillary disorder, foreign body sensation, hyperemia of the eyeball and abnormal vision. These changes are identified in all four target groups, both in the eye exposed to, and in the contralateral eye, were originally classified as mild disorders that are not associated with treatment and transitory by nature. One report about the increase of intraocular pressure (IOP) (≥10 mm Hg) relative to baseline values in patients treated with acetate anecortave at a dose of 30 mg has been attributed to concomitant disease. From among the identified ophthalmological changes most often pertained to treatment of the following disorders: ptosis, eye pain, subconjunctival hemorrhage, eye itching and eye pain/acute pain. Reactions due to treatment were in the majority of cases the AEB soft, transient was observed in all four examined groups.

The most frequently encountered in this research ophthalmologic changes in comparison with the original figures represented in this study, hypertension, peripheral oedema, depression, and arthritis, and none of them was associated with therapy. Were not documented the changes caused by the impact, blood chemistry, Hematology, or urinalysis.

The information presented here are the result of interim analysis of clinical data obtained 6 months after the beginning of long-term research aimed at identifying the effectiveness of acetate anecortave as monotherapy for the treatment of exudative AMD. This analysis shows that a single back juxtacrine introduction acetate anecortave at a dose of 15 mg is a safe and effective treatment to preserve or improve vision or to prevent severe loss of vision. These data also show that acetate anecortave inhibits the growth area of lesions in patients with subfoveolyarnoy CNV resulting from AMD. Although there is a tendency that a single introduction of each of the three concentrations of acetate anecortave has the advantage compared with the introduction of a placebo, however, a single weeniehead anecortave at a dose of 15 mg statistically superior to placebo as functional, and anatomical indicators of clinical effectiveness.

Acetate anecortave is angiostatic agent designed to inhibit the formation of new blood vessels of the eye. Acetate anecortave is the result of specific chemical modification of the basic structure of cortisol. These modifications led to the creation of angiostatin "eye", which inhibits the growth of blood vessels, but does not cause receptore-mediated side effects of glucocorticoid steroids. Data preclinical studies show that acetate anecortave does not show the recorded corticosteroid activity (8, 9) and in this study, no clinical signs of corticosteroid side effects in relation to the eye (such as increased intraocular pressure or acceleration of the progression of cataracts). In the subsequent analysis of safety data in patients who have been exposed to acetate anecortave at least within 6 months, an Independent safety Committee showed no clinically significant events associated with the drug or procedure used, which could compromise the security of the proposed treatment.

Acetate anecortave is unique angiostatic agent, to the which stimulates the inhibitor of plasminogen activator 1 and inhibits both urokinasetype plasminogen activator, and metalloproteinase-3 matrix, representing the two enzymes required for cell migration of vascular endothelium during angiogenesis (5, 6). Data preclinical studies in models of corneal, retinal and choroidal neovascularization, confirm the effectiveness of this tool in the inhibition of the growth of blood vessels (5, 6, 8-10).

Presented here is an interim analysis of clinical data based on masked assessment standardized fluorescein angiograms in DARC (analytical centre, which was used in this study), demonstrates angiostatin effectiveness of the studied tools in the analysis 6 months after single rear juxtaglomerular introduction. This analysis showed that acetate anecortave has a statistically significant advantage over placebo for the slow growth of the area of damage analysis after 6 months. This revealed not only the slowdown in the growth of total lesions, but also inhibition of the shared component and classic CNV CNV component.

Summary the analysis of data obtained after 6 months, showed a tendency acetate anecortave at a dose of 15 mg has the advantage in relation to the conservation of view compared with placebo treatment, as well as obladaettakim advantage of persistence of vision in a large subgroup of patients with predominantly classic lesions. Acetate anecortave 15 at a dose of 15 mg is also statistically superior to placebo for improvement of vision, defined as improvement in visual acuity of 2 or more lines on the logMAR scale. On the other hand, a single impact acetate anecortave at a dose of 15 mg inhibits both clinically significant loss of vision and severe vision loss after 6 months compared to treatment with placebo.

The superiority of the effect of introducing acetate anecortave at a dose of 15 mg compared with placebo for stabilization of view is demonstrated through an analysis of the average change over 6 months relative to baseline of view on the logMAR scale. Although baseline visual acuity in logMAR scale were very similar for the groups treated with acetate anecortave at a dose of 15 mg and placebo (0,73 against 0,76 respectively or equivalent to 20/100 in table Snellen), the effect of the change in visual acuity after 6 months in the two surveyed groups were clearly distinguishable. After a single injection of 15 mg acetate anecortave visual acuity changed on average only 4 letters on the logMAR scale after 6 months, giving a final average value on the logMAR scale 0,81 (equivalent to 20/125 table Snellen). When the group receiving placebo for the same period there has been a deterioration of more than 12 letters on the logMAR scale, which gives the average end the current value on the logMAR scale 1,01 (equivalent to 20/200 in table Snellen). This difference in visual acuity in 2 rows on the logMAR scale between the study groups, likely plays a significant role in the daily activities of a patient suffering subfoveolyarnoy AMD.

All three doses of the acetate anecortave, as was shown in the description, safe and in the study 6 months after a single injection tend to slow the growth area of foci damage and prevent severe vision loss. Clinical data presented here suggest that the dose of 15 mg is at the top or near the top of the curve dose-effect built for this drug, thus, higher concentrations are unlikely to cause increase of efficiency in vivo. Alternatively, there may be differences in the formation and physical structure depo-preparations with a slow release on the rear surface of the sclera, which is a consequence of the introduction of various concentrations of suspensions of drugs evaluated in this study, which could in some way affect the absorption of acetate anecortave in overlying choroid and the retina.

Clinical efficacy acetate anecortave at a dose of 15 mg compared with placebo in the prevention of clinically significant vision loss (defined as p is losing 15 or more letters on the logMAR scale), and severe vision loss (defined as a loss of 30 or more letters on the logMAR scale) after 6 months, at least, comparable with similar data obtained after 6 months in the treatment visudyne (Visudyne®) TAR study (2). Based on the advantages of a single injection of 15 mg acetate anecortave compared with placebo treatment to preserve vision and growth inhibition of foci damage was initiated basic research to compare the effectiveness of acetate anecortave at a dose of 15 mg and photodynamic therapy visudyne (Visudyne®). Currently registers patients for this study in 40-50 clinical centers in North America, Australia and the European Union.

Should be taken into account that the acetate anecortave or its corresponding alcohol (4, 9 (11)-pregnadien-17α, 21-diol-3,20-dione) can also be entered through juxtacrine implantation, as described, for example, in the following patents available for public use, and international publications: U.S. patent No. 6413540B1; U.S. patent No. 6416777B1; WO 03/009784 and WO 03/009774. Juxtacrine introduction in the form of a depot of the drug, or any other method provides transscleral delivery of drugs. It can also be introduced by injection into the vitreous body or implantation, as described in the parallel systems is considered the application of the U.S. registration number 10/385791.

The following criteria for the selection of patients for participation in this study.

Inclusion criteria of patients and criteria for their exclusion from the study group

Inclusion criteria

- The patient must give in and sign the informed consent, to be able to carry out required for the study visit and to be able to follow the instructions.

- The patient must be at least 50 years.

- The patient may be of any race as well as gender. Female patients capable of pregnancy (those who are not postmenopausal or has not lost the ability to bear children due to surgery), may participate only if they are not lactating and have a negative test for pregnancy while visiting for the selection and before each of the three subsequent injections, and if they agree to use adequate methods of controlling pregnancy (hormonal - oral, implantable or injectable chemical contraceptives; mechanical - spermicidal means in combination with a barrier such as a condom or diaphragm; intrauterine devices; or sterilization of surgical partner by) to prevent pregnancy within 24 months of the study. Pregnancy tests using urine will be conducted before each is doing, when visits every 3 months after treatment and at the last visit for all female patients, with the potential to become pregnant. Male patients whose partners also may become pregnant should use a reliable means to avoid fatherhood while participating in this study, because the injected drug can affect sex cells, it is also possible unknown effects on the development of the embryo.

- Clinical diagnosis of age-related macular degeneration and primary or recurrent subfoveolyarnoy neovascular membranes, which are not treated the image enhancement laser for MPS and have the following characteristics listed below:

the total area of the lesion 12 disk space or less,

and

50% or more of the total area of damage (determined by angiographic evidence of neovascularization associated adjacent area of serous retinal pigment epithelium of the retina, increased "blocked" fluorescence, and/or after staining) represent the choroidal neovascularization (CNV),

and either

classical component of the total CNV is >50% of the total choroidal neovascularization,

or

classical component of the total CNV is >0,75 square drive (1.6 mm2)

- Clinical diagnosis of exudative age-related macular degeneration and primary or recurrent subfoveolyarnoy neovascular membrane (with the physical characteristics described above), which is an indication for treatment with laser photocoagulation is the most common technique MPS, if patients formally rejected this treatment by written waiver.

- Best adjusted in accordance with the recommendations for the Early treatment of diabetic retinopathy" (ETDRS) visual acuity of 0.3 (20/40 table Snellen) to 1.2 (equivalent to 20/320 in the table Snellen) in the study eye during the registration visit. Contralateral ("not investigated") eyes must have best corrected according to ETDRS visual acuity of 1.6 (equivalent to 20/800 in table Snellen) or even better, as well as clinical evidence of macular degeneration (i.e. Druze, changes in the pigment epithelium of the retina or signs of exudative disease or discoid scarring).

Exclusion criteria

- The patient has the disease or disorder that could interfere with scheduled visits for research or completion of this study (i.e., unstable cardiovascular disease, unstable pulmonary disease, or AIDS).

p> - The patient has a history of any disorders or diseases that would hinder regular visits to research or completion of this study (i.e. unstable cardiovascular disease, unstable pulmonary disease or HIV).

- The patient has a history of eye disease in the study eye (other than AMD), which (or its consequences) could affect the visual acuity of the studied eyes (i.e. amblyopia, uncontrolled glaucoma with IOP > 30 mm Hg, ischemic neuropathy of the optic nerve, clinically significant diabetic macular edema, a significant nonproliferative or proliferative diabetic retinopathy, significant active uveitis).

Screening fluorescent angiographic images and/or angiographic images with indocyanin green cannot be adequately rendered by the researcher and the Center for the study of digital angiograms.

- The patient revealed clinical signs of myopic retinopathy or diagnosed refraction >-8 diopters at the time of the study.

The patient had a history of previous intraocular surgery on the examined eye less than two (2) months prior to registration in the study.

- The patient has a history of experimental procedure aimed at the treatment of AMD and the subjugated eyes (excluding daily vitamin and/or mineral therapy), which is different from photocoagulation treatment of exudative AMD in the study eye.

The patient was entered implant for the correction of depressions sclera.

- Use of any investigational medicinal product or treatment, associated or not associated with AMD, during the 30 days preceding the introduction of the investigational medicinal product, excluding daily vitamin and/or mineral therapy.

- The patient has allergic anamnesis or sensitivity to drugs of the family of steroids or dyes of the fluorescein and/or Indianola green, which is clinically important in this study for the compilation of expert opinions.

- The patient was exposed to radiation (other than exposure to the proton beam) or him systematically conducted antiangiogenic therapy for the treatment of exudative WCPO in both eyes. Only patients who received treatment other eye by exposure to a beam of protons can be to participate in the study.

- The patient is under the effect of anticoagulant therapy, with the exception of aspirin and antiaggregants therapy. The patient has a history of disorders of hemostasis.

- The patient has a confirmed clinical thinning of the sclera.

Table 1 presents baseline characteristics of patients prinipals the x part in this study. None of the parameters was not identified significant differences between study groups.

tr>
Table 1
Baseline patient characteristics
ACET Anek

30 mg (n=33)
ACET Anek

15 mg (n=33)
ACET Anek

3 mg (n=32)
Placebo

(n=30)
P - value :
N%N%N%N%
Age (years)
<65412,1515,213,100,00,3349
65-747of 21.27of 21.2928,1826,7
75-841957,61751,51546,9 1963,3
85-9339,1412,17of 21.9310,0
Woman1854,51854,51546,91860,00,7781
White33100,033100,032100,030100,0-
Classic component* of the total area of lesions
<50% classic7of 21.2824,27of 21.9413,30,7333
≥50% classic2678,82575,82578,12686,7
Age - Average(CO)75,7 (7,5)75,8 (8,3)78,1 (7,5)78,3 (5,8)0,3193
logMAR VA-mean (SD)0,72 (0,26)0,73 (0,26)0,83 (0,24)0,76 (0,26)0,2859
The total area of the lesion, mm2the mean (SD)8,6 (6,9)7,4 (6,6)9,0 (7,5)6,9 (5,7)0,5796
CNV, mm2the mean (SD)7,4 (6,0)6,4 (5,5)7,9 (7,0)6,0 (5,2)0,5721
Classic, mm2the mean (SD)5,7 (5,3)5,0 (5,0)5,3 (4,7)4,2 (4,2)0,6847
* Determined from the ratio of the sizes of the classical component to the total size of the lesion.

Table 2 shows the change (deterioration or improvement) of visual acuity at 6 months relative to baseline, expressed in lines on the LogMAR scale. There is a clear tendency that the treatment of a single introduction of the acetate anecortave at a dose of 15 mg, compared with the introduction of the placebo prevents clinically significant vision loss, defined as the deterioration of vision on the 3 lines on the logMAR scale, or 15 letters on the logMAR scale (12% vs. 30%) relative to the baseline.

Table 2
Clinically significant change of view on the logMAR scale for 6 months
The change in logMAR scale
≥2 line improvement1 line improvementNo changes1 line deterioration2 line deterioration≥3 line deterioration
N%N%N%N%N%N%
ACET Anek 30 mg13,0412,11030,3515,2515,2824,2
ACET Anek 15 mg618,213,08 24,2412,11030,3412,1
ACET Anek 3 mg26,3001237,5412,5618,8825,0
Placebo0026,71136,7413,3413,3930,0

Table 3 shows the analysis of cases, significant loss of vision at 6 months compared with baseline in the target groups. Treatment with acetate anecortave at a dose of 15 mg significantly more productive administration of placebo (p=0,0224) to prevent significant vision loss, defined as the deterioration of the 6 strings on a scale logMAR or 30 letters on the logMAR scale.

Table 3
Severe loss of vision (≥6 lines on the logMAR scale) for 6 months
Total<6 lines worse≥6 lines worse
ImpactNN%N%
ACET Anek 30 mg332575,76824,24
ACET Anek 15 mg333296,9713,03
ACET Anek 3 mg322578,13721,88
Placebo302376,67723,33
Total12810582,032317,97

P=0,0224, Acetate Anecortave at a dose of 15 mg compared with placebo, Fisher's exact test

All the above mentioned patents and other cited sources included in the description by reference.

This invention has been described with reference to specific preferred embodiments; however, it should be clear that it can be implemented in other specific forms or variations without departure from its specific or essential characteristics. The embodiment described above, therefore, be considered as illustrative in all aspects and do not limit the scope of the invention which is defined in the attached claims, to a greater extent than in the above description.

Literature

1. Seddon JM. Epidemiology og age-related mascular dgeneration. Retina, Ryan SJ (ED.). St. Louis: Mosby, 2001; 1039-50.

2. Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin - TAP Report 1. Arch. Ophthalmol. 1999; 117: 1329-45.

3. The EyeTech Study Group. Preclinical and phase 1A clinical evaluation of an anti-VEGF pegylated aptamer (EYE001) for the treatment of exudative age-related macular degeneration. Retina 2002; 22: 143-52.

4. Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. Arch. Ophthalmol. 2002; 120: 338-46.

5. DeFaller JM and Clark AF. A new pharmacological treatment for angiogenesis. In Pterygium, Taylor HR (ED.) The Haegue: Kugler Publications, 2000; 159-181.

6. Penn JS, Rajaratnam VS, Collier RJ and Clark AF. The effect of an angiostatic steroid on neovascularization in a rat model of retinopathy of prematurity. Invest. Ophthalmol. Vis. Sci. 2001; 42: 283-90.

7. Casey R, Li WW. Factors Controlling Ocular Angiogenesis. Amer. J. Ophthalmol. 1997; 124: 521-529.

8. Clark AF. AL-3789: a novel ophthalmic angiostatic steroid. Exp. Opin. Invest. Drugs 1997; 6: 1867-77.

9. McNatt LG, Weimer L, Yanni J and Clark AF. Angiostatic activity of steroids in the chick embryo CAM and rabbit cornea models of neovascularization. J. Ocular Pharm. Therap.1999; 15(5): 413-23.

10. BenEzra D, Griffin BW, Naftzir G, Sharif NA and Clark AF. Topical formulations of novel angiostatic steroids inhibit rabbit corneal neovascularization. Invest. Ophthalmol. Vis. Sci. 1997; 38: 1954-62.

1. The method of preventing loss of visual acuity due to age-related macular degeneration (AMD), including the introduction of the patient from 3 to 15 mg compounds, representing acetate anecortave or its corresponding alcohol by the rear juxtacrine injections or through juxtacrine introduction in the de of the implant, or by injection into the vitreous body, or the introduction of the implant into the vitreous body.

2. The method according to claim 1 in which the compound is injected through the rear juxtacrine injection.

3. The method according to claim 2, in which the compound is administered at a dose of 15 mg.

4. The way to maintain visual acuity in humans suffering from age-related macular degeneration, involving the introduction of this patient from 3 to 15 mg compounds, representing acetate anecortave or its corresponding alcohol by the rear juxtacrine injections or through juxtacrine the administration in the form of the implant, or injection into the vitreous body, or the introduction of the implant into the vitreous body.

5. The method according to claim 4, in which the specified connection enter through the rear juxtacrine injection.

6. The method according to claim 4, in which the compound is administered at a dose of 15 mg.

7. Method of inhibiting the growth of lesions, due to age-related macular degeneration, involving the introduction of a patient from 3 to 15 mg compounds, representing acetate anecortave or its corresponding alcohol by the rear juxtacrine injections or through juxtacrine the administration in the form of the implant, or injection into the vitreous body, or the introduction of the implant into the vitreous body.

8. The method according to claim 7, in which is specified Obedinenie enter through the rear juxtacrine injection.

9. The method according to claim 7, in which the compound is administered at a dose of 15 mg.

10. The method according to claim 7, where the lesion is predominantly classical subfoveal defeat.

11. The method according to claim 7, where the defeat is minimal classic defeat.

12. The method according to any one of claims 1, 4 or 7 in which the compound is administered wxtaskbaricon in the form of an implant.

13. The use of acetate anecortave or its corresponding alcohol, in an amount of from 3 to 15 mg for receiving medicines to prevent the loss of visual acuity due to age-related macular degeneration.

14. The use of acetate anecortave or its corresponding alcohol, in an amount of from 3 to 15 mg, to obtain drugs for maintenance of visual acuity in a person suffering from age-related macular degeneration.

15. The use of acetate anecortave or its corresponding alcohol, in an amount of from 3 to 15 mg, to obtain a medicine for inhibiting the growth of lesions, due to age-related macular degeneration.

16. The use according to any one of p-15, where the compound is injected at a dose of 15 mg.

17. Method of inhibiting the growth of blood vessels due to age-related macular degeneration, involving the introduction of a patient from 3 to 15 mg compounds, representing acetate, aneko the tava or its corresponding alcohol, through the rear juxtacrine injections or through juxtacrine the administration in the form of the implant, or injection into the vitreous body, or the introduction of the implant into the vitreous body.

18. The method according to 17, in which the number of input connections is 15 mg



 

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FIELD: organic chemistry, medicine, biochemistry pharmacy.

SUBSTANCE: invention relates to using the known 2-phenyl-substituted imidazotriazinone of the formula (I): (vardenafil) possessing improved properties as compared with other known inhibitors of phosphodiesterase-5 (PDE-5), such as sildenafil and tadalafil. Proposed compound is used for preparing drugs used in treatment of cardiac insufficiency.

EFFECT: valuable medicinal and biochemical properties of compound.

1 tbl

FIELD: medicine, ophthalmology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to design of ophthalmological agents of broad spectrum based on vegetable components, vitamins and trace elements. Agent for treatment of eye diseases comprises bilberry berries of sublimation drying, dihydroquercetin, beta-carotene, selexen, lutein, vitamins B1, B2, B6, B12 and zinc. Agent shows the effect of broad spectrum and possesses regenerating, tonic and regenerative effect being without irritating, allergizing, inflammatory and other undesirable effects, and excluding mechanical contact with eye surface.

EFFECT: valuable medicinal properties of agent.

5 cl

FIELD: medicine.

SUBSTANCE: method involves carrying out tonometry, patient examination in slit lamp light, determining filtration cushion size and relief, carrying out test with sterile air introduced under conjunctiva in operation zone in combination with glycocorticosteroid preparation. Filtration cushion height increasing and air entering the anterior chamber, diuretic drugs are prescribed and preparations inhibiting intraocular fluid secretion. Filtration cushion becoming flat, glycocorticosteroid preparations, enzyme preparations are introduced and antimetabolite is introduced under conjunctiva outside of operation field. Filtration cushion relief being variable and air passes into the anterior chamber, anti-inflammatory therapy, anti-proliferative treatment course, glycocorticosteroid and enzyme preparations are prescribed. Filtration cushion becoming flat, and air does not enter the anterior chamber, gonioscopy is carried out and surgical intervention zones are revised in the cases of open internal fistula and antibiotic of cytostatic activity is to be prescribed. Internal fistula being blocked, laser surgical intervention is carried out. Hypertension being persistent, anti-glaucoma intervention is carried out in another eyeball segment with antibiotic of cytostatic activity being applied.

EFFECT: enhanced effectiveness of treatment selection.

FIELD: organic chemistry, medicine, ophthalmology, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzo[g]quinoline of the formula (I): as a free base or acid-additive salt used in treatment of glaucoma and myopia, and to a method for their synthesis and a pharmaceutical composition. In compound of the formula (I) each A and B means hydrogen atom (H); X means -CH2; Y means sulfur atom (S); R1 means H or (C1-C4)-alkyl wherein this compound can be in form of a free base or acid-additive salt. Method for synthesis of compound of the formula (I) by claim 1 or its salt involves the conversion step of alkoxy-group in compound of the formula (II): wherein A, B, X, Y and R1 have values given in claim 1; R3 means (C1-C4)-alkyl to hydroxy-group, and conversion of synthesized compounds of the formula (I) to free base or its acid-additive salt.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

7 cl, 1 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: method involves administration of chitosan sponge with square up to 2 cm2 into sub-Tenon's space wherein chitosan sponge shows the deacetylation degree 98%, its molecular mass is 1000 kDa and it comprises 2.8 x 10-9 g of hyaluronic acid, 27.8 x 10-8 g of chondroitinsulfuric acid, 3.06 x 10-11 g of cattle serum growth factor and 7 x 10-9 g of heparin per 1 mm2 of chitosan sponge. Method provides stabilizing visual function, to improving vision and expanding vision field based on enhancing sensitivity of optic nerve as result of blood stream enhancing. Invention can be used in treatment of progressing glaucoma with non-stabilizing functions.

EFFECT: improved method of treatment.

1 tbl, 1 ex

FIELD: medicine, ophthalmology, medicinal biochemistry.

SUBSTANCE: invention relates to manufacturing ophthalmic composition used for reducing intraocular pressure. Invention proposes using inhibitors of glycogen synthase kinase-3. Proposed composition provides reducing intraocular pressure by increasing intraocular liquid efflux and to prevent loss of retina ganglion cells.

EFFECT: valuable medicinal properties of inhibitors.

19 cl, 6 ex

FIELD: medicine.

SUBSTANCE: method involves introducing Mytomycin C metabolite into eyes where compensated and subcompensated intraocular pressure being achieved as a result of maximum hypotensive therapy application. The preparation is introduced 4 weeks in advance before operation in initial and advanced glaucoma stages and 2-3 weeks in advance in cases gone too far. The dose to be introduced is equal to 0.1 ml with concentration equal to 0.15 mg/ml. Additional Mytomycin C injection of the same volume and concentration of 0.2 mg/ml is introduced after having finished the reparative operation.

EFFECT: enhanced effectiveness of treatment; prolonged intraocular pressure stabilization.

1 tbl

FIELD: medicine, ophthalmology.

SUBSTANCE: method involves administration of the preparation "Ginkor-Fort" in the dose 1 tablet, 2 times per a day for 2 weeks and after one month break the preparation "Diovenor" is administrated in the dose 1 tablet, once per a day for 2 weeks at the constant instillation of the preparation "Ksalatan" in the dose 1 drop, once time before night. Such schedule of the method provides the stable normalization of intraocular pressure based on improvement of venous orbital and cerebral circulation. Invention is designated for medicinal treatment of glaucoma discirculatory variant.

EFFECT: improved method of treatment.

2 tbl, 1 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: the present innovation deals with medicinal treatment of ischemic variant of primary glaucoma in case of stable normalization of intraocular pressure (IOP) in patients with myopic refraction. For this purpose, it is necessary to carry out electromagnetic impact successively onto cerebral orbital, temporal and occipital areas, carotid sinuses of cervical autonomic plexus, and, also, one should additionally inject gliatilin per 1.0 in combination with instillations of 0.5%-betaxolol solution per 2 drops twice daily into ocular conjunctival cavity. Therapy should last for 10 d at repeating the course once or twice annually. The method provides stable normalization of IOP, improves cerebral and orbital hemodynamics and stabilization of visual functions.

EFFECT: higher efficiency of therapy.

1 ex, 5 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: veterinary science.

SUBSTANCE: method involves a single parenteral administration of gonadotropic preparation mare in foal serum gonadotropin (MFGS). The preparation MFGS is administrated in period immediately preceding or coinciding with endogenous gonadotropic hormones wave incretion, namely for one of the following days after delivery: 51-53, 59-61, 66-68, 72-74, 80-82, 87-89, 93-95, 101-103, 108-110, 114-116, 122-124, 129-131, 135-137, 143-145, 150-152, 156-158, 164-166, 171-173. Method allows decreasing losses in productivity and capacity for fertilization of cows.

EFFECT: valuable property of preparation.

5 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I) or its pharmaceutically acceptable salt, or an enantiomer wherein n = 0 or 1; a - b means -CF=CH or -CHFCH2; R1 represents (C1-C3)-alkyl wherein alkyl is unsubstituted; R2 represents hydrogen atom; R3 is chosen from (C1-C4)-alkyl, (CH2)n-cycloheteroalkyl and (CH2)n-aryl; or R2 and R3 form in common 6-membered saturated ring condensed with 5-membered aromatic ring system comprising 2 heteroatoms chosen from nitrogen atom (N), and pharmaceutical compositions. Compounds of the formula (I) represent modulators of androgen receptors (AR) possessing tissue-selective effect. Proposed compounds are useful as androgen receptors agonists in osseous and/or muscle tissue in antagonizing AR in male patient prostate or in female patient uterus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

36 cl, 2 tbl, 72 ex

FIELD: medicine, oncology.

SUBSTANCE: invention describes four groups of dialkyltriazenyl-carrying estrogens and anti-estrogens that can be used for using as chemotherapeutic drugs in treatment of human and animal gonad carcinomas.

EFFECT: valuable medicinal properties of drugs.

8 cl, 11 dwg, 38 ex

FIELD: medicine, pharmaceutical technology, hormones.

SUBSTANCE: invention describes a method for preparing isotonic oily emulsions containing estradiol and progesterone in the ratio from 2:1 to 200:1 and wherein the emulsion comprises 0.005-0.5 wt.-% of estradiol and 0.05-5 wt.-% of progesterone, and this emulsion is designated for intravenous administration. Method for preparing such emulsions involves the following steps: (A) dissolving at least one hormone, i. e. estradiol or progesterone in oily phase, and (B) emulsifying oily phase in aqueous phase in the presence of an emulsifying agent. Emulsions prepared by this method under condition of minimal supply of oil and volume (liquid) result to the higher concentrations of hormones in premature baby blood.

EFFECT: improved and valuable pharmaceutical properties of emulsion.

6 cl, 2 tbl, 1 dwg, 2 ex

FIELD: medicine.

SUBSTANCE: system has at least one steroid hormone and propylene glycol monocaprylate as penetration accelerator. The steroid hormone is enclosed into polymer matrix. Transdermal system is to be used as hormone-substituting therapy and contraception means.

EFFECT: increased steroid hormone penetration through skin; reduced transdermal system application area.

8 cl

FIELD: medicine.

SUBSTANCE: system has at least one steroid hormone and propylene glycol monocaprylate as penetration accelerator. The steroid hormone is enclosed into polymer matrix. Transdermal system is to be used as hormone-substituting therapy and contraception means.

EFFECT: increased steroid hormone penetration through skin; reduced transdermal system application area.

8 cl

FIELD: medicine, urology, pharmaceutical industry, pharmacy.

SUBSTANCE: method for correction of PADAM involves oral administration of testosterone or its pharmacologically acceptable derivatives for 22-24 h as a preparative formulation providing onset of release of abovementioned medicinal substance in 4-7 h after its administration, and prolonged effect for 24 h. The testosterone preparative formulation comprises a core and envelope that is insoluble in stomach. A core comprises components in the following ratio, mas. p.: testosterone undecanoate, 1; magnesium basic carbonate, 82-100; sugar, 21.6-26.4; Eudragit E, 2.16-2.64, and calcium stearate, 1.08-1.32. A core is covered by envelope that is difficultly soluble in intestine and providing onset in a medicinal agent releasing in 4-7 h after its administration. Invention provides the testosterone level in a patient that repeats its physiological daily modulation completely. Invention can be used in treatment of patients suffering from partial age androgen deficiency (PADAM) and in production of testosterone preparations or its pharmacologically acceptable derivatives.

EFFECT: improved method of correction of deficiency.

6 cl, 2 tbl, 2 dwg

FIELD: pharmaceutical technology, pharmacy, steroids.

SUBSTANCE: invention describes a method for preparing steroid crystals showing the mean coarseness in desired limits from 1 to 25 mcm and without exceeding the required value. Method for preparing involves wetted grinding a steroid supersaturated solution in the crystallization process by using a device for carrying out this process resulting to preparing suspension of primary grains followed by its heating. Also, the claim describes crystals prepared by the proposed method and pharmaceutical composition containing these crystals based on steroid crystals.

EFFECT: improved preparing method.

12 cl, 7 tbl, 2 dwg, 11 ex

Casr antagonist // 2315036

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel compound represented by the following formula (1) , its pharmaceutically acceptable salts or optically active isomers wherein each symbol is given in the invention description. Proposed compound possesses antagonistic effect with respect to calcium-sensitive receptor (CASR). Also, invention relates to a therapeutically medicinal agent used in treatment of osteoporosis based on this compound, to a method for treatment of osteoporosis, calcium receptor antagonist and to agent promoting secretion of parathyroid hormone (PTH).

EFFECT: valuable medicinal properties of antagonist.

33 cl, 66 tbl, 5 ex

FIELD: steroids, pharmacy.

SUBSTANCE: invention describes a method for preparing crystals showing the mean coarseness index in the required limits from 3 to 25 mcm and maximal size 100 mcm, not above. Method involves the crystallization process of supersaturated solution of compound representing 11β-benzaldoximestra-4,9-diene wherein it is subjected for wetted grinding by using the correspondence device designated for such wetted grinding to obtain suspension of primary grains. Also, invention crystals prepared by the proposed method and a pharmaceutical agent containing these crystals.

EFFECT: improved preparing method.

14 cl, 8 tbl, 4 dwg, 4 ex

FIELD: medicine, immunology.

SUBSTANCE: invention proposes an agent enhancing the immunogenic properties of tetanus anatoxin (adjuvant). Invention proposes the vegetable triterpenic compound miliacin as an agent enhancing immunogenic properties of tetanus anatoxin. Agent enhances the immune response value in its applying as a vaccine preparation of tetanus anatoxin. The agent miliacin elicits its stimulating effect for both the first and repeated administration of vaccine that allows suggesting its possible applying for prophylactic vaccinations with tetanus anatoxin. Taking into account the high tolerance of miliacin in the broad range of its doses it is suggested its practical applying as an agent promoting to the enhanced formation of vaccinal immunity in prophylactic vaccinations with tetanus anatoxin.

EFFECT: valuable medicinal properties of agent.

6 tbl

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