Combined Drug with Antibacterial Effect Supports the Normal Intestinal Microflora.

Widespread use of antibiotics leads to an imbalance of normal intestinal microflora and to the development of multidrug resistance. The problem can be solved by administration of the antibiotics in combination with the drugs that have an immunotropic effect. We studied the effect of the drug containing technologically processed affinity purified antibodies to IFNγ, CD4 receptor, ß2-microglobulin of MHC class I, and ß2-domain of MHC II combined with antibiotics on the composition of intestinal microflora of pigs and the total number of microbiome resistance genes. Using the methods of NGS sequencing and quantitative PCR, we found that the drug contributes to the maintenance of normal microflora and, consequently, to the symbiotic relationship of the host with microflora, and prevents the reproduction of pathogenic bacterial species. Analysis for the presence of the resistance genes of gastrointestinal microorganisms showed that the drug does not affect the qualitative and quantitative composition of these genes of the intestinal microbiome.

Nootropic Activity of Prospekta in a Blind Placebo-Controlled Study in a Model of Focal Cerebral Ischemia in Rats.

Analysis of the pharmacological activity of the original drug Prospekta in a rat model of focal cerebral ischemia revealed its nootropic effect: course treatment in the post-ischemic period led to recovery of the neurological status of animals at the peak of neurological deficit. Evaluation of the therapeutic potential of the drug in morphological and functional CNS disorders allowed us to conclude that it is advisable to carry out further studies of its biological activity at the preclinical stage (the results obtained in animals were successfully confirmed in a clinical trial of drug efficacy in the treatment of moderate cognitive disorders in the early recovery period after ischemic stroke). Studies of the nootropic activity in other pathologies of the nervous system are also promising.

[The experience of using drug Afalaza for treatment of lower urinary symptoms in treatment-nave patients with benign prostatic hyperplasia].

INTRODUCTION: Benign prostatic hyperplasia (BPH) is one of the most common diseases in men over 50 years. The prevalence of the BPH increases with age, and pathologic features of BPH are found in about 90% of men over 80 years. AIM: The aim of the study was to study the efficacy and safety of Afalaza for the treatment of lower urinary tract symptoms (LUTS) in treatment-nave patients with BPH. MATERIALS AND METHODS: A multicenter study of using Afalaza for the treatment of LUTS in treatment-nave patients with BPH was carried out in 9 urological centers in Moscow. A total of 80 treatment-nave patients with BPH were enrolled. The improvement in the total score of IPSS, IIEF-5 and QoL after 30 weeks of therapy was evaluated as well as changes in prostate volume and maximum urinary flow rate (Qmax). RESULTS: After 30 weeks of therapy, there was a significant decrease in the total IPSS score. A decrease in the total IPSS score by 5.5 points (+37.9%) from 14.5+/-4.0 at the baseline to 9.0+/-4.1 at the visit 9 was seen. The QoL decreased by 1.8 (-38.3%) points from 4.7+/-1.0 at the baseline. The Qmax also changed from 12.7+/-4.6 to 16.4+/-5.7 (+28.3%) after 30 weeks of therapy. At the visit 9, the total IIEF5 score increased by 3.4+/-4.4 (+19.9%) from 17.1+/-4.3 at the baseline. In addition, prostate volume decreased from 42.7+/-11.1 at baseline to 41.0+/-9.8 cc post-treatment (-5.15%). A reduction of post-void residual urine volume from 26.0+/-25.3 at baseline to 17.7+/-24.2 (-31.9%) post-treatment was also shown. CONCLUSION: The results of a multicenter study demonstrate the efficacy of Afalaza for treatment of treatment-nave patients with LUTS/BPH. Afalaza reduces prostate volume and improves an erectile function.

[Antiamnesic effects divaza and its component model ß-amyloid amnesia]. / Antiamnesticheskoe deistvie divazy i ee komponentov na modeli ß-amiloidnoi amnezii u krys.

AIM: On amnesia models induced by (icv) injection of ß-amyloid fragment 25-35 peptide were evaluated antiamnestic actitity. MATERIAL AND METHODS: It was used of active antibody preparations (RA AT) to protein S100 (tenoten), to eNOS (impaza) and combinations (divaza) antiamnestic activity behavioral tests novel object conditioned response passive avoidance. RESULTS: Under the influence of RA AT S100 observed recovery of violation of the ß-amyloid short-term memory (1 hour after the initial presentation of objects), and RA AT eNOS were more effective when tested 24 hours later. Combined medication completely compensate for the simulated deflection behavior of rats did not differ from the intact control. The CRPA RA AT S100 had the greatest impact on the LP entry into the dark compartment, and RA AT eNOS influenced primarily on the emotional component of the reaction. When using the integrated product tends to increase the LP entry into the dark compartment was observed in the absence of changes in the number of boluses. Thus, tenoten had the greatest impact on cognitive impairment, impaza greater effect on the symptoms associated with surgery. CONCLUSION: Combined preparation divaza rendered more effective action, leveling and amnesia neophobia, which confirms the need for further research and prospect release of active drugs in models of neurodegenerative disorders.

The Use of Release-Active Antibody-Based Preparations for Vertigo Prevention in Adults.

The effectiveness of antibody-based release-active preparations Impaza (antibodies to eNOS), Tenoten (antibodies to brain-specific protein S-100), Dietressa (antibodies to type 1 cannabinoid receptor), Brizantin (combined preparation, antibodies to brain-specific protein S-100 and type 1 cannabinoid receptor), and Divaza (combined preparation, antibodies to brain-specific protein S-100 and eNOS) in the prevention of vertigo was studied on the model of intermittent accumulation of Coriolis accelerations (ICCA). Modification of activity of vestibular receptors and signal systems by release-active preparations contributed to an increase in ICCA tolerance time. Combined preparation Impaza possessed the most significant antinaupathic properties. Brizantin was less potent in this respect.

Effects of Impaza on the Generative Function of Female Rats.

The effects of impaza on ovulatory cycles, sexual behavior, and conception processes were studied in female rats. A two-week course of impaza in doses of 3 and 15 ml/kg did not affect alternation of estrous cycle phases, the incidence of estrus reducing. Sexual behavior of these females was characterized by activation of the receptive sexual motivations; conception was characterized by a higher fertility index and a lower fetal mortality.

[Release-active antibodies to S100 protein are able to improve the experimental allergic encephalomyelitis].

AIM: To reveal the effects of release-active antibodies to S100 protein in an animal model of multiple sclerosis. MATERIAL AND METHODS: Sixty female Wistar rats, aged 12 weeks, were included in the study. The pathology was induced by subcutaneous injection of the spinal cord homogenate. Afterwards the rats received a water solution of release-active antibodies to S100 protein (2,5 ml/kg/day, tenoten) or distilled water intragastrically during 30 days. Intramuscular injections of glatiramer acetate (4 mg/kg/day, copaxone) were used as a positive control. RESULTS AND CONCLUSION: Release-active antibodies to S100 protein enhanced the latency period of the disease, reduced its peak intensity and compensated the loss of body weight of the animals. The experimental drug effect was similar to the results of copaxone injections.

Subetta increases phosphorylation of insulin receptor ß-subunit alone and in the presence of insulin.

It has been previously shown that Subetta (a drug containing released-active forms of antibodies to the insulin receptor ß-subunit and antibodies to endothelial nitric oxide synthase) stimulated insulin-induced adiponectin production by mature human adipocytes in the absence of insulin. Therefore, it was assumed that Subetta could activate the insulin receptor. To confirm this hypothesis, the capacity of Subetta to activate the insulin receptor in mature human adipocytes in the absence or presence of the insulin was investigated. Cells were incubated either with Subetta or with vehicle, or with basal medium for 3 days. Then, adipocytes were treated with water or insulin (100 nm) for 15 min. Following treatment, lysates were prepared and phosphorylation of insulin receptor ß-subunits was analyzed by western blot analysis. It was shown that Subetta significantly increased (P<0.001) the 'phosphorylated-insulin receptor ß-subunit/total insulin receptor ß-subunit' ratios in both the presence and the absence of insulin. These results support previously published data and indicate that Subetta could activate the insulin receptor through the effect on its ß-subunits, whose conformational state is essential for insulin receptor activation. This action might serve as one of the primary mechanisms of the drug's antidiabetic effect.

Possible role and application of fMRI in the screening of release-active drugs.

Functional magnetic resonance imaging (fMRI) of the brain was applied for preclinical evaluation of the efficiency of Divaza preparation intended for the treatment of cerebrovascular disorders. Psychological testing (Stroop task) in the magnetic field of fMRI was performed before and after 12-week treatment course using a double blind placebo-controlled protocol. It was shown that standard psychological and neuropsychological protocols do not allow fully estimate the results of treatment, whereas fMRI targeted the pool of cerebral structures activated during task solution. In the treatment group (in contrast to placebo), active zones in these structures were found only during task solution. Thus, resolution capability of fMRI significantly extends the range of rational screening by identifying active zones and can radically change the procedure of selection and clinical trials.

Effects of chronic treatment with the eNOS stimulator Impaza on penis length and sexual behaviors in rats with a high baseline of sexual activity.

Endothelial nitric oxide synthase (eNOS) has an important role in erection, and it also affects aspects of sexual behavior. In this experiment, we determined whether a compound enhancing the activity of eNOS, Impaza, could stimulate any aspect of sexual behavior and increase penis length in rats with a high baseline of sexual activity. For comparison, the PDE5 inhibitor sildenafil was included. Male rats were orally treated with Impaza or sildenafil for 28 days. Impaza (3 ml kg(-1)) was given daily while sildenafil (3 mg kg(-1)) was given twice weekly. Tests for sexual incentive motivation and copulatory behavior were performed just before drug treatment and at days 7, 14 and 28 of treatment. In addition, the length of the protruding penis at mount, intromission and ejaculation was measured. Impaza but not sildenafil increased penis length at mount after 14 and 28 days of treatment. The compounds failed to modify sexual incentive motivation or copulatory behavior. It is suggested that Impaza enhanced intracavernous pressure, as such a pressure increase is the most likely explanation for enhanced penis length at mount. This effect, together with an absence of motivational actions, suggests that Impaza may be the most valuable treatment for erectile dysfunction.

Study of antitumor activity of antibodies to TNF-α on Walker carcinosarcoma model.

The effect of release-active antibodies to TNF-α (Artrofoon) on the development of Walker carcinosarcoma 256 was studied in Wistar rats. Intragastric dose of this drug significantly inhibited the growth of tumor node (55% inhibition of tumor growth), but less effectively than the reference drug cyclophosphamide (80%). The studied drug significantly prolonged animal' lifespan (+97%) and its efficiency in this respect was comparable to that of cyclophosphamide (+96%).

Induction of S100B gene expression in long-term potentiation in the hippocampal CA1 field depends on activity of NMDA receptors.

The effects of NMDA receptor blocker MK-801 on the increase in S100B protein mRNA content induced by long-term posttetanic potentiation in the hippocampal sections were studied. The level of S100B mRNA after 30-min tetanization in the presence of 10 µM MK-801 constituted 132% of the basal level, which was significantly (226%) lower than the control level. Hence, gene expression, induced by long-term posttetanic potentiation, in the glial cells (similarly as in the neurons) depended significantly on NMDA receptors.

Experimental study on the efficacy of the drug Brizantin in the model of nicotine dependence.

We estimated the efficacy of Brizantin preparation in suppressing nicotine dependence in rats. It was shown that nicotine-dependent rats in the situation of choice between the chamber with smoke or the chamber with food more frequently entered the chamber with tobacco smoke and stayed there longer. The rats that received Brizantin demonstrated significantly fewer visits to the chamber with smoke and spent there less time. Reduced locomotor activity and orientation and exploratory behavior in rats against the background of Brizantin administration also suggest reduced motivation for smoke inhalation. Thus, Brizantin effectively diminished nicotine dependence in rats in the model of nicotine addiction.

[The phenomenon of release activity and the hypothesis of "spatial" homeostasis].

When analyzing the technology of multiple sequential reductions in concentration of parent substance we have discovered a novel physical phenomenon. It was shown that dilutions of parent substance prepared using this technology have one common peculiarity - they are capable to exert direct modifying effect on parent substance altering spatial structure of parent substance and consequently its physical, chemical and biological properties. Technologically processed dilutions also exert activity when they do not contain molecules of parent substance. We have defined a newly revealed modifying activity manifested in the process of multiple sequential reductions in concentrations and associated with vehicle as release-activity while the drugs exerting modifying activity we have called release-active drugs. Having analyzed the ceffects of a drug in the whole range of doses - toxic, therapeutic, low doses as well as release-active form of a drug we came to a conclusion that there were supramolecular spatial matrices with the structure, which was identical to the one of a certain substance, and combines body molecules into semantic molecular assemblies. All biological systems unlike nonliving nature have dual structure - both individual and specific ones. Enhancement in any body spatial complexity is its key feature from the point of view of evolution development; that is why all processes - both normal physiologic and pathologic ones - shall comply with superiority of preservation of a body spatial structure hierarchy (hypothesis of spatial homeostasis).

Study of hypoglycemic activity of Subetta and rosiglitazone on the model of streptozotocin-induced diabetes mellitus in rats.

Antidiabetic activity of Subetta was revealed on the model of streptozotocin-induced diabetes mellitus in rats. Intragastric administration of this preparation in a dose of 5 ml/kg for 50 days reduced blood glucose levels, urine levels of glucose and ketone bodies, restored glucose tolerance in the oral glucose test, improved general condition and increased the survival rate of animals. The effectiveness of the drug was not inferior to that of rosiglitazone (8 mg/kg).

Experimental study of the effects of Dietressa, a new weight-reducing drug.

The capacity of a new drug containing ultra-low doses of antibodies to cannabinoid receptor type 1 (Dietressa) to reduce body weight gain in mice on a high-calorie diet was evaluated, possible mechanisms of drug action were analyzed, and its safety (abuse potential in the reaction of self-stimulation) was evaluated. Dietressa was not inferior to sibutramine in reducing body weight gain in mice and exhibited no abuse potential.

Release-activity: a long way from phenomenon to new drugs.

Multiple dilutions of the original substance release its peculiar activity referred to as "release-activity". Although this activity originates from the initial substance, it does not depend on its negligible concentration in extreme dilutions. Thus, the terms "dose", "ultralow dose", and "homeopathic dose", do not correctly describe the release-active solutions, since the concept of dose implies the presence of some part of the original substance in a dilution with its intrinsic therapeutic potency. The data are reported on the molecular and cellular mechanisms of the mode of action of the release-active agents, some of which being introduced into clinical practice.

Experimental study of the efficiency of impaza on the model of chronic aseptic prostatic inflammation.

We compared the efficacy of Impaza (antibodies against endothelial NO-synthase in ultra-low doses) and Serenoa repens on the rat model of chronic aseptic prostatic inflammation. Administration of Serenoa repens in a dose of 50 mg/kg for 1.5 months prevented the development of prostate sclerosis and increased luminal area, but did delay the development of atrophic processes. In animals treated with Impaza (3 ml/kg for 1.5 months), atrophic changes in the prostate gland were practically absent. These findings indicate that Impaza can be used in complex therapy of abacterial prostatitis.

Effects of Impaza on sexual behavior in different experimental models.

Experiments on different models for sexual behavior (seasonal and age-related inhibition of sexual function, animals with initially reduced sexual function) showed that ultra-low doses of anti-NO-synthase antibodies (Impaza) stimulate sexual motivation and copulative behavior in rats. The effects of the drug on different aspects of sexual behavior depend on the chosen model.