Farmatsiya i Farmakologiya

Taking into account the current Product specification file, the aim of the work was to develop the composition and technology for obtaining effervescent tablets based on solid dispersions of furazolidone in the form of an aqueous solution for external use. Materials and methods. The used substances were: furazolidone, anhydrous sodium carbonate (chemically pure), polyvinylpyrrolidone-24000±2000 (chemically pure), malic acid (analytically pure), tartaric acid (chemically pure), citric acid (chemically pure), sodium benzoate (chemically pure), ethyl alcohol 96% (chemically pure), purified water. Preparation of granulates is separate wet granulation in a fluidized bed (Mycrolab, BOSCH, Germany). Obtaining tablets is the process of pressing on a manual hydraulic test press (“PRG”, VNIR, Russia). The dependence of disintegration, abrasion capacity and crushing resistance on compacting pressure was investigated. Technological parameters of granulates, еру obtained effervescent tablets, shelf life and storage conditions were investigated according to the State Pharmacopoeia of the Russian Federation XIV th ed. Results. Two compositions of effervescent tablets containing solid dispersions of furazolidone as an active substance were obtained, which, when dissolved in 100 ml of water at room temperature (20°C), form a solution of furazolidone with a concentration of 0.004% in less than 5 minutes. The method of quantitative determination of the furazolidone content in the effervescent tablets was validated. A complex of physicochemical methods for the analysis of tablets was carried out. Quality standards have been developed. The developed compositions stability of instant tablets during storage during accelerated and long-term tests has been experimentally confirmed. The preliminary shelf life and storage conditions have been determined. Conclusion. The result of technological and chemical-pharmaceutical research is the creation and evaluation of the quality of a new instant furazolidone dosage form as effervescent tablet formulations.

A. O. Elagina

A. V. Belyatskaya

I. I. Krasnyuk (Jr.)

I. I. Krasnyuk

O. I. Stepanova

T. V. Fateeva

E. A. Smolyarchuk

S. V. Kozin

O. N. Plakhotnaya

O. V. Rаstopchina

J. V. Rau

Pharmacy & Pharmacology

DEVELOPMENT OF NITROFURAN DERIVATIVE: COMPOSITION AND TECHNOLOGY OF EFFERVESCENT TABLETS WITH SOLID DISPERSIONS

硝基呋喃衍生物的开发：含固体分散体的泡腾片组成与技术

Advanced glycation end-products play an important role in the development of diabetic complications, so slowing down of glycated proteins’ cross-links formation have been suggested as a potential therapeutic option for the treatment of vascular diabetic complications and preventing their progression. The aim of the work was to assess the influence of novel anticrosslinking agent DF-5 on the renal advanced glycation end-products and collagen contents, body weight, blood glucose and glycated hemoglobin levels and the development of early renal disease in streptozotocin-induced diabetic rats. Materials and methods. 40 male Sprague-Dawley rats were used in the study. Two months after inducing diabetes, the study substance was administered intragastrically once a day for 28 days (12.5 mg/kg). Measurements included the assessment of blood glucose and HbA1c levels, the evaluation of the renal function, and the results of histology and immunohistochemical staining of kidneys. Results. A repeated intragastric administration of DF-5 for 30 days significantly reduced the level of HbA1c in the blood, but did not affect the level of fasting blood glucose. DF-5 compound significantly reduced proteinuria and prevented kidney damage in experimental animals by limiting damage of the glomeruli and tubules. It was found that DF-5 inhibits the progression of an early renal dysfunction in rats with streptozotocin-induced diabetic nephropathy. This was associated with a decreased accumulation of advanced glycation end-products in the kidney, accompanied by the improvement of both renal morphology and function. Conclusion. The results obtained provide investigators with additional therapeutic options for the treatment of diabetic nephropathy and possibly other complications of diabetes.

A. A. Spasov

O. N. Zhukovskaya

A. I. Rashchenko

A. A. Brigadirova

R. A. Litvinov

N. A. Gurova

A. V. Smirnov

N. G. Pan’shin

H. S.A. Abbas

A. S. Morkovnik

DF-5 COMPOUND DELAYS DEVELOPMENT OF DIABETIC NEPHROPATHY IN RATS

DF-5化合物延缓大鼠糖尿病肾病的发展

Molnupiravir is one of the drugs for the etiotropic therapy of a new coronavirus infection COVID-19. It has confirmed its clinical efficacy in the treatment of patients with mild and moderate COVID-19, including those who are at high risk of progressing to severe disease. The aim of the study was to evaluate bioequivalence of the generic drug molnupiravir ALARIO-TL and the original drug Lagevrio with a single oral administration in healthy volunteers. Materials and methods. This bioequivalence study was an open, randomized, two-period crossover study. In each of the two periods, volunteers received a single dose of the test drug, or reference drug molnupiravir, in the form of capsules at the dose of 200 mg. The washout period between the doses was 3 days. To determine pharmacokinetic (PK) parameters and bioequivalence, the concentration the concentration of N-hydrozycytidine (NHC), the main molnupiravir metabolit in the blood plasma of volunteers was evaluated. The blood plasma sampling was carried out in the range from 0 to 16 hours in each of the study periods. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC (0–16) and C max of the test drug and reference drugs with the established equivalence limits of 80.00 – 125.00%. Results. A total of 28 healthy male volunteers were included in the study. According to the results of the statistical analysis, after the administration of the test and reference drugs, the 90% CIs for the ratio of the geometric means of AUC (0–16) and C max were 96.31% – 113.64% and 91.37% – 114.8%, respectively. These intervals fit within the established limits of 80.00–125.00%, which confirms the bioequivalence of the drugs. When comparing the frequency of the individual adverse events registration, no significant differences were found out after the administration of the test and reference drugs. Conclusion. Based on the results of this study, it can be concluded that the test and reference drugs of molnupiravir are bioequivalent. In addition, the data obtained indicate that the drugs have similar safety profiles.

V. B. Vasilyuk

A. Yu. Boroduleva

P. D. Sobolev

A. G. Nikiforova

V. G. Mozgovaya

O. V. Filon

A. V. Zinkovskaya

V. G. Ignatiev

M. Yu. Samsonov

I. S. Kozlova

E. K. Khanonina

BIOEQUIVALENCE STUDY OF GENERIC MOLNUPIRAVIR IN HEALTHY VOLUNTEERS

健康志愿者中仿制莫努匹韦的生物等效性研究

Currently, there are data that that make it possible to speak about a high clinical efficacy of the use of succinic salt of tyrosyl-D-alanyl-glycyl-phenylalanyl-leucyl-arginine (hexapeptide succinate) for the COVID-19 treatment. This article is devoted to the results of clinical trials of the original Russian drug based on it. The aim of the study was to evaluate a clinical efficacy, safety and tolerability of intramuscular and inhalation use of hexapeptide succinate in complex therapy in comparison with standard therapy in patients with moderate COVID-19. Materials and methods. The research was conducted from February 28, 2022 to November 22, 2022 based on 10 research centers in the Russian Federation. The study included hospitalized patients (n=312) over 18 years of age with moderate COVID-19 who had undergone a screening procedure and were randomized into 3 groups: group 1 received standard therapy in accordance with the Interim Guidelines in force at the time of the study, within 10 days; group 2 received hexapeptide succinate (Ambervin® Pulmo) intramuscularly at the dose of 1 mg once a day for 10 days; group 3 received hexapeptide succinate (Ambervin® Pulmo) 10 mg once a day by inhalation for 10 days. Results. According to the results of the study, therapy with the drug hexapeptide succinate, both intramuscular and inhaled, provided an acceleration of recovery up to the complete absence of the disease signs in more than 80% of hospitalized COVID-19 patients. By the end of the therapy course with the drug, more than 60% of patients had met the criteria for discharge from hospital and could continue the treatment on an outpatient basis. About 70% of patients in the inhalation group and 80% in the intramuscular hexapeptide succinate injection group had concomitant diseases (hypertension – 28%, obesity – 14%), which indicates the effectiveness of this drug use in comorbid patients. The use of the drug contributed to the restoration of damaged lung tissues, normalization of oxygenation, the disappearance of shortness of breath and a decrease in the duration of the disease symptoms compared with standard therapy. As a result of a comparative analysis of adverse events in terms of their presence, severity, causal relationship with the therapy and outcome, there were no statistically significant differences between the treatment groups. Conclusion. Thus, the results of the clinical study of the succinate hexapeptide efficacy and safety showed the feasibility of using the drug in pathogenetic therapy COVID-19 regimens.

L. A. Balykova

O. A. Radaeva

K. Ya. Zaslavskaya

P. A. Bely

V. F. Pavelkina

N. A. Pyataev

A. Yu. Ivanova

G. V. Rodoman

N. E. Kostina

V. B. Filimonov

E. N. Simakina

D. A. Bystritsky

A. S. Agafyina

K. N. Koryanova

D. Yu. Pushkar

EFFICACY AND SAFETY OF ORIGINAL DRUG BASED ON HEXAPEPTIDE SUCCINATE IN COMPLEX COVID-19 THERAPY IN ADULTS HOSPITALIZED PATIENTS

基于六肽琥珀酸原药在住院成人复杂新冠肺炎治疗中的疗效与安全性

Nirmatrelvir is an antiviral drug that, in combination with ritonavir, is an effective agent for the etiotropic therapy of patients with mild to moderate COVID-19. The aim of the study was to evaluate bioequivalence of the generic drug nirmatrelvir Аrpaxel in combination with ritonavir and the original drug Paxlovid, which is a combination of nirmatrelvir/ritonavir, in a single dose administration to healthy volunteers. Materials and methods. This research was an open-label, randomized, two-period crossover bioequivalence study. It included 2 periods, in each of which the volunteers received either a test drug (nirmatrelvir at the dose of 300 mg) in combination with ritonavir (100 mg), or a reference drug (a combination of nirmatrelvir 300 mg and ritonavir 100 mg), given as a single dose. A wash-out period between each of the administrations was 7 days. The blood sampling to determine the concentration of nirmatrelvir was carried out in the range from 0 to 36 h in each of the study periods. A nirmatrelvir concentration was determined by a validated HPLC-MS/MS method with a lower quantitation limit of 10 ng/mL. Bioequivalence was assessed by comparing 90% confidence intervals (CIs) for the ratio of geometric means of AUC (0–16) and C max of the test drug and reference drugs with the established equivalence limits of 80.00–125.00%. Results. In the study were included 68 healthy volunteers, 67 participants of which were included in the bioequivalence population. The pharmacokinetic parameters of the drugs were comparable to each other. The 90% confidence interval for the ratio of the geometric mean of the maximum drug concentration in the blood plasma and the area under the pharmacokinetic curve «concentration-time» from zero to the last blood draw within 36 hours of nirmatrelvir was 87.26–100.83 and 93.27–103.74%, which meets the criteria for assessing bioequivalence. The test drugs were well tolerated by the volunteers. The incidence of adverse events was similar for the test and reference drugs. No serious adverse events were recorded during the entire study. Conclusion. As a result of this study, bioequivalence of the test and reference drugs has been established.

R. A. Oseshnyuk

S. A. Lesnichuk

B. B. Garyaev

A. A. Abramova

A. N. Dolgorukova

Bioequivalence study of generic nirmatrelvir in healthy volunteers

健康志愿者中尼马瑞韦仿制药的生物等效性研究

The aim of the study was to analyze the literature sources for pharmacodynamic and pharmacokinetic features of gabapentin, providing its use in patients with neuropathic pain, as well as a comparative evaluation of its efficacy and safety when used in different doses. Materials and methods. PubMed, Google Scholar, EMBASE, ResearchGate scientific information network and elibrary.ru databases were used as search resources. The keywords used for the search were “gabapentin”, “mechanism of action”, “gabapentin targets”, “gabapentin pharmacodynamics”, “pharmacokinetics”, “pharmacokinetic parameters”, “neuropathic pain”, and “randomized clinical trials”. The depth of the search was 26 years (from 1998 to 2024). This review resulted in 87 literature sources. Results. Neuropathic pain (NeP) is one of the most common types of chronic pain, characterized by a high prevalence among people of the working age. Effective pharmacotherapy aimed at eliminating the pain syndrome is a key tool for improving the quality of life and preserving the work capacity of patients. Heterogeneity of etiologic factors involved in the genesis of NeP indicates the need to use drugs the analgesic effect of which is based on weakening the transmission of pain impulses in the CNS. In clinical trials, gabapentin has demonstrated efficacy in reducing the severity of pain in patients with postherpetic NeP, painful diabetic neuropathy and many other conditions accompanied by NeP. The dose of gabapentin 300 mg/day is the initial dose in the therapy of NeP and requires a further slow titration depending on the patient’s response to therapy and tolerability of the drug, especially in elderly and senile patients, as well as in patients with an impaired renal function. According to the published data, the most pronounced analgesic effect is achieved in the patients against the background of the gabapentin administration at a dose of 3600 mg/day. Conclusion. Gabapentin is the drug of choice in the management of patients with NeP of different etiology and intensity. A satisfactory safety profile and pharmacodynamic effects make gabapentin possible, despite the long history of its use, to remain a relevant drug used by a wide range of physicians, specialties, for pharmacotherapy of NeP patients.

O. I. Butranova

S. K. Zyryanov

Use of gabapentin for neuropathic pain therapy: A view from perspective of evidence-based medicine

加巴喷丁用于神经病理性疼痛治疗的循证医学视角

Tamsulosin is a first-line drug in the treatment of lower urinary tract symptoms (LUTS) in benign prostatic hyperplasia (BPH). Despite high estimates of its efficacy and safety, it rates may vary due to genetic polymorphisms of genes for the enzymes involved in the drugs metabolism. The aim of the work was to evaluate the carriage influence of genes polymorphisms of the CYP3A enzymes group of tamsulosin metabolizers on the efficacy and safety of therapy in patients with LUTS in BPH. Materials and methods. A total of 142 patients with LUTS, with an established BPH diagnosis (N40 according to ICD-10) were included in the study and underwent all stages. All patients received monotherapy with tamsulosin 0.4 mg/day for at least 8 weeks. An IPSS questionnaire with the definition of quality of life, a prostate ultrasound with the determination of the prostate volume and residual urine, as well as uroflowmetry, were used to evaluate the results of the treatment. Controls were performed at 2, 4 and 8 weeks from the start of the therapy. The carriage of polymorphic markers CYP3A4 (*1B, *22) and CYP3A5*3 was determined in patients; HPLC was used to determine drug concentrations in blood plasma and levels of cortisol and its metabolite 6-beta-hydroxycortisol in urine to assess the phenotypic activity of CYP3A. Results. No statistically significant associations between CYP3A phenotype (defined by CYP3A4 and CYP3A5 genotypes) and clinical parameters of the tamsulosin therapy efficacy and the safety assessment in the studied sample of patients were found ( p &gt;0.05). Similar data were obtained for individual variants of CYP3A4*1B, CYP3A4*22, CYP3A5*3 ( p &gt;0.05). The comparison of the tamsulosin residual equilibrium concentration values in patients in the study sample with respect to the carriers of CYP3A4 and CYP3A5 gene variants did not reveal the presence of significant differences in either CYP3A phenotypes and carriers and non-carriers of individual CYP3A4*1B ( p =0.57), CYP3A4*22 ( p =0.37) and CYP3A5*3 ( p =0.76) variants. No association was found between the metabolic ratio of 6-beta-hydroxycortisol / cortisol in urine and the CYP3A phenotype encoded by a combination of genotypes of CYP3A4 and CYP3A5 gene variants ( p &gt;0.05). Conclusion. A possible association between the carriage of CYP3A4*1B, CYP3A4*22, CYP3A5*3 variants, a CYP3A activity assessed by the content of an endogenous substrate of this isoenzyme and its metabolite in urine, the level of plasma concentration of the drug, and the efficacy and safety of tamsulosin, has not been confirmed. The contribution of CYP3A4 and CYP3A5 genetic polymorphisms to clinical parameters of the tamsulosin therapy requires a further study.

Sh. P. Abdullaev

M. N. Shatokhin

O. L. Sigailo

P. O. Bochkov

S. N. Tuchkova

O. V. Teodorovich

O. B. Loran

D. A. Sychev

Association of CYP3A4*1B, CYP3A4*22 and CYP3A5*3 polymorphisms carriage with efficacy and safety of tamsulosin in patients with benign prostatic hyperplasia

CYP3A4*1B、CYP3A4*22 和 CYP3A5*3 多态性与良性前列腺增生患者坦索罗辛疗效和安全性的关联

The aim of the work was to study the influence of the researcher on the muscle strength assessment in animals in the experiment by comparing the results of the automated “inverted grid” test and its classical variant. Materials and methods. Male lines (Bla/J, n =20; FUS(1-359), n =20; Tau P301S +/+ , n =20) and their background controls (C57BL/6J, n =20; CD1, n =20) were selected for the study. The dynamics of changes in the muscle deficit of the animals was evaluated in the automated and classical variant of the “inverted grid” test. Results. According to the results of the muscle strength assessment of mice with an edited genome of lines FUS(1-359) +/- , Tau P301S +/+ , B6.ADysf prmd /GeneJ, using the “inverted grid” test in the classical variant and the automated one, it was found that statistically significant differences were not obtained in comparison with the results obtained by the classical variant of the test. The standard error of the mean increases by 23–39% in the classical test compared to the automated one. It was shown that the standard error of the mean in the classical variant of the test in Tau P301S +/+ mice was 6.24; 5.94; 5.88; 7.38 at 4 age points; in FUS(1-359) +/- mice, 4.49; 6.8; 6.98 and 4.1; B6.ADysf prmd /GeneJ mice, 7.66; 7.58; 8.3 and 7.92, respectively. Conclusion. Thus, the value of the standard error of the results study mean of the changes dynamics in the muscle strength when using the automated variant of the “inverted grid” test was reduced in comparison with the results of the classical variant of the test. The results of the study show that the automation of generally recognized behavioral tests is able to increase the accuracy of the obtained data reducing the influence of a human factor on the manipulation.

P. R. Lebedev

E. V. Kuzubova

V. M. Pokrovsky

A. I. Radchenko

S. I. Osipyan

Yu. V. Stepenko

A. A. Apostol

L. M. Danilenko

A. A. Dolzhikov

T. G. Pokrovskaya

O. S. Gudyrev

Ya. S. Kochergina

O. V. Dudnikova

Investigator’s influence on the muscle strength assessment in animals in experiment: Comparison of automated “inverted grid” test and its classical variant

研究者在动物实验中对肌肉力量评估的影响：自动“倒网格”测试与其经典变体的比较

A quantitative assessment of nitric oxide (NO) production in body tissues is an urgent problem in pharmacology and biochemistry. The study of physiological processes occurring with the participation of NO, as well as the metabolism and pharmacodynamics of pharmacological agents from the group of NO donors, requires the introduction of accurate and reproducible methods for the quantitative determination of this metabolite in biological media. The aim of the study was to develop the HPLC-MS/MS methods for the quantitative determination of NO in various tissues of rats. Materials and methods. The indirect NO quantification was based on estimation of the level of more stable metabolites: nitrites and nitrates extracted from rat tissues by homogenization with water. The reduction of nitrates to nitrites was carried out using nitrate reductase. The derivatization of nitrites was based on a reaction with Griess reagent. The resulting azo dye was determined by HPLC-MS/MS using an Agilent InfinityLab Poroshell 120 EC-C18 4.6×100 mm, 2.7 μm analytical column. The total chromatographic analysis time was 12 minutes, and the analyte retention time was 6.1 minutes. The analytical range of the method was 0.1–100.0 nmol (in terms of nitrite) per 1 ml of plasma or tissue homogenate. Results. The developed a bioanalytical method was validated according to the following parameters: a selectivity, a matrix effect, a recovery degree, a sample transfer, an analytical range linearity, a lower limit of quantification (LLOQ), an intra- and inter-assay accuracy and precision, and a stability at all the stages of the analysis. To test the method, the NO content in the plasma, brain, heart, aorta and lungs of rats was determined. Conclusion. The developed bioanalytical HPLC-MS/MS methods fully meets the validation requirements. The metrological characteristics of the technique make it possible to highly accurately estimate the NO production in various tissues of rats, which is undoubtedly relevant and in demand in the study of pathological processes as well as the mechanism of action of pharmacological agents from the group of NO donors.

N. S. Popov

D. A. Gavrilenko

M. S. Baranov

V. Yu. Balabanyan

Development of a method for quantitative determination of nitric oxide (NO) in rat tissues based on high-performance liquid chromatography and mass spectrometry

基于高效液相色谱-质谱法的大鼠组织中一氧化氮(NO)定量测定方法的开发

The aim of the work was to compare the effects of ademethionine, acetylcysteine and taurine on the zoosocial behavior of rats in a post-intoxicated state after an acute ethanol poisoning. Materials and methods. The study was conducted on male rats of the Wistar line. The post-intoxication state was modeled by a single injection of ethanol (3 g/kg, intraperitoneally). 30 min after awakening, the animals were injected with a physiological solution, acetylcysteine (1 g/kg), ademetionine (100 mg/kg) or taurine (40 mg/kg). A zoosocial interaction test was performed 30 min after the administration. Results. Among the behavioral indicators investigated, the following were validated: the number of acts of freezing, their duration, the number of acts of sniffing in front, the number of acts of avoidance and the number of vertical stances without support ( p &lt; 0.05 between the values of the negative and positive control groups in all cases). The administration of acetylcysteine, ademetionine and taurine reduced the number of freezing acts by 53.64, 7.27 and 24.51%, respectively ( p &lt; 0.05 when compared with the indicator index in the animals from the positive control group in all cases). The administration of acetylcysteine and taurine reduced the number of avoidance acts by 50 and 10%, respectively ( p &lt; 0.05 when compared to that of the animals from the positive control group in both cases). All amino acids normalized the communicative performance, although it did not differ from that of the animals from the positive control group ( p &gt;0.05). Alcoholization reduced the number of vertical stances by 65% ( p &lt;0.001 when compared with that in the animals from the negative control group), and when followed by the administration of ademetionine and taurine, the reduction was 38 and 36%, respectively ( p &lt; 0.05 when compared to that in the animals from the negative control group). Conclusion. According to the data obtained, sulfur-containing amino acids, primarily those that had central effects, normalized neuronal functions, positively influencing a complex behavior of rats. Taking into account the results of the previous studies, it was possible to conclude that the therapeutic effect of ademetionine and taurine in the context of a post-intoxication state is mediated by their central effects, which are not so pronounced in comparison with acetylcysteine.

V. I. Petrov

N. A. Osadchenko

A. S. Tarasov

A. M. Dotsenko

E. I. Morkovin

Effectiveness assessment of sulfur-containing amino acids in rats with experimental “alcohol withdrawal syndrome” with modified zoosocial interaction methods

硫代氨基酸对实验性“酒精戒断综合征”大鼠的疗效评估及改良动物社交互动方法

Abbreviation	Farm. farmakol. (Pâtigorsk)
Journal Impact	0.44
Quartiles(Global)	PHARMACOLOGY & PHARMACY(Q4)

Publication Information	Publisher: Volgograd State Medical University, Pyatigorsk Medical and Pharmaceutical Institute，Publishing cycle: ，Journal Type: journal，Open Access Journals: Yes
Basic data	Year of publication: 2019，Proportion of original research papers: 89.13%，Self Citation Rate:20.00%， Gold OA Rate: 98.35%
Average review cycle	网友分享经验：8 Weeks

Farmatsiya i Farmakologiya

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