Pub Date : 2024-03-15DOI: 10.33380/2305-2066-2024-13-2-1505
A. Luferov, N. V. Bobkova, D. Bokov, M. Rodin, E. V. Sergunova, T. Y. Kovaleva, T. Rendyuk, A. V. Strelyaeva, A. M. Antsyshkina, T. V. Prostodusheva, S. G. Zaichikova, V. M. Baeva, I. B. Perova, K. Eller, V. Bessonov
Introduction. Yellow wood anemone (Anemone ranunculoides L.) is a herbaceous perennial. This plant grows in the European parts of Russia, Ciscaucasia, Siberia, Central Europe and other regions. It has many different pharmacological activities: immunomodulatory, sedative, anti-inflammatory, antitoxic, diuretic, antibacterial, antioxidant, antitumor and antirheumatic activity. These various effects are due to their biologically active compounds, which include ephemeroids, protoanemonin, saponins, tannins, resins, ascorbic acid, ranunculin, oils lipids and triterpene glycosides. As to phenolic compounds, currently there is no sufficient information on flavonoids and hydroxycinnamic acids (HCAs) profiles in different species of genus Anemone. Because these groups of compounds are quite specific for yellow wood anemone, their detailed study seems to be relevant.Aim. The objective of this research is to identify and quantify flavonoids, HCAs, and their conjugates in Yellow wood anemone leaves, flowers and rhizomes with roots.Materials and methods. The identification was carried out by using ultra-high-performance liquid chromatography with diode array and electrospray ionization-mass spectrometric detection (UHPLC–DAD–ESI-MS) with quantification of individual compounds by external calibration method.Results and discussion. Among the 47 compounds, 30 flavonoids and 17 derivatives of HCAs were detected. Quercetin glycosides were found to be the major flavonoids in aerial parts whereas chalcone glycosides – in underground parts. The major HCA in rhizomes with roots was feruloyltartaric acid (1.18 mg/g) whereas chlorogenic acid was predominant in leaves and flowers (8.68 mg/g and 2.62 mg/g accordingly). The total content of phenolic compounds was estimated at 60 mg/g on a dry weight basis.Conclusion. As a result of the research a detailed profile of flavonoids and HCAs acids of anemon was described. The data obtained can serve to identify this species in the standardization of medicinal plant materials and taxonomic studies.
{"title":"Identification and Quantification of Flavonoids and Hydroxycinnamic Acids in Yellow Wood Anemone (Anemone ranunculoides L.) by UHPLC-DAD-HESI/MS Analysis","authors":"A. Luferov, N. V. Bobkova, D. Bokov, M. Rodin, E. V. Sergunova, T. Y. Kovaleva, T. Rendyuk, A. V. Strelyaeva, A. M. Antsyshkina, T. V. Prostodusheva, S. G. Zaichikova, V. M. Baeva, I. B. Perova, K. Eller, V. Bessonov","doi":"10.33380/2305-2066-2024-13-2-1505","DOIUrl":"https://doi.org/10.33380/2305-2066-2024-13-2-1505","url":null,"abstract":"Introduction. Yellow wood anemone (Anemone ranunculoides L.) is a herbaceous perennial. This plant grows in the European parts of Russia, Ciscaucasia, Siberia, Central Europe and other regions. It has many different pharmacological activities: immunomodulatory, sedative, anti-inflammatory, antitoxic, diuretic, antibacterial, antioxidant, antitumor and antirheumatic activity. These various effects are due to their biologically active compounds, which include ephemeroids, protoanemonin, saponins, tannins, resins, ascorbic acid, ranunculin, oils lipids and triterpene glycosides. As to phenolic compounds, currently there is no sufficient information on flavonoids and hydroxycinnamic acids (HCAs) profiles in different species of genus Anemone. Because these groups of compounds are quite specific for yellow wood anemone, their detailed study seems to be relevant.Aim. The objective of this research is to identify and quantify flavonoids, HCAs, and their conjugates in Yellow wood anemone leaves, flowers and rhizomes with roots.Materials and methods. The identification was carried out by using ultra-high-performance liquid chromatography with diode array and electrospray ionization-mass spectrometric detection (UHPLC–DAD–ESI-MS) with quantification of individual compounds by external calibration method.Results and discussion. Among the 47 compounds, 30 flavonoids and 17 derivatives of HCAs were detected. Quercetin glycosides were found to be the major flavonoids in aerial parts whereas chalcone glycosides – in underground parts. The major HCA in rhizomes with roots was feruloyltartaric acid (1.18 mg/g) whereas chlorogenic acid was predominant in leaves and flowers (8.68 mg/g and 2.62 mg/g accordingly). The total content of phenolic compounds was estimated at 60 mg/g on a dry weight basis.Conclusion. As a result of the research a detailed profile of flavonoids and HCAs acids of anemon was described. The data obtained can serve to identify this species in the standardization of medicinal plant materials and taxonomic studies.","PeriodicalId":11259,"journal":{"name":"Drug development & registration","volume":"64 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140237397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-27DOI: 10.33380/2305-2066-2024-13-1-1761
T. N. Komarov, K. K. Karnakova, N. Bagaeva, O. Archakova, M. Popova, V. Shcherbakova, K. Zaslavskaya, P. A. Bely, I. Shohin
Introduction. COVID-19 (Coronavirus disease 2019) almost 4 years after he start of the pandemic is still a significant public health problem. SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) that causes COVID-19 continues to mutate and spread throughout the world. Molnupiravir and favipiravir have been shown to be efficacious against variety of RNA viruses including the SARS-CoV-2. The Ministry of Health of the Russian Federation approved the use of these drugs as a treatment of COVID-19. The developed drug contains the combination of two antiviral agents with different mechanisms of suppressing viral RNA replication, which suggests efficacy against the vast majority of ARVI pathogens found in the human population including SARS-CoV-2 and influenza.Aim. The aim of the pharmacokinetics study is comparison between JTBC00301 (INN: molnupiravir + favipiravir), film-coated tablets (LLC "PROMOMED RUS", Russia), Esperavir® (INN: molnupiravir), capsules (LLC "PROMOMED RUS", Russia) and Areplivir® (INN: favipiravir), film-coated tablets (LLC "PROMOMED RUS", Russia) to evaluate the impact of monocomponents on each other's pharmacokinetics.Materials and methods. The clinical and analytical phases as well as pharmacokinetic analyses have been performed as a part of a phase I, randomized, open-label, 3-period crossover study of drug JTBC00301 (INN: molnupiravir + favipiravir), film-coated tablets, 400 + 400 mg (LLC "PROMOMED RUS", Russia). The plasma concentration of β-D-N4-hydroxycytidine (NHC), the active metabolite of molnupiravir and favipiravir were determined in 42 healthy volunteers after taking the test drug JTBC00301 (1 tablet of 400 + 400 mg), the reference drug Esperavir® (2 capsules of 200 mg) and the reference drug Areplivir® (2 tablets of 200 mg). The descriptive statistics were calculated using Microsoft Excel (Microsoft Corporation, USA). The pharmacokinetic parameters, analysis of variance (ANOVA), the intra-subject coefficient of variation (CVintra) and 90 % confidence intervals (90 % CI) were calculated by R Project 3.5.1 software (package «bear», version 2.8.3-2), originally created by Hsin-ya Lee and Yung-jin Lee, Taiwan.Results and discussion. Pharmacokinetic parameters of NHC and favipiravir were determined, averaged pharmacokinetic profiles in linear and log-linear scales were plotted, analysis of variance was carried out. The 90% CIs for geometric mean ratios of Сmax and AUC(0–t) for NHC and favipiravir were all within the acceptance range of 80–125 % which means there is no effect of monocomponents on each other’s pharmacokinetics.Conclusion. The development of the fixed-dose drug combination of molnupiravir and favipiravir has great potential as it may allow to increase the safety profile and improve the tolerability of therapy as well as increase the effectiveness of antiviral therapy. The results justified the study of the subsequent phases of clinical trials of JTBC00301 (INN: molnupiravir + favipiravir), film-coated
{"title":"Reciprocal Impact of Molnupiravir and Favipiravir Monocomponents of the Combination Drug on Each Other's Pharmacokinetics in a Phase I Clinical Trial","authors":"T. N. Komarov, K. K. Karnakova, N. Bagaeva, O. Archakova, M. Popova, V. Shcherbakova, K. Zaslavskaya, P. A. Bely, I. Shohin","doi":"10.33380/2305-2066-2024-13-1-1761","DOIUrl":"https://doi.org/10.33380/2305-2066-2024-13-1-1761","url":null,"abstract":"Introduction. COVID-19 (Coronavirus disease 2019) almost 4 years after he start of the pandemic is still a significant public health problem. SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) that causes COVID-19 continues to mutate and spread throughout the world. Molnupiravir and favipiravir have been shown to be efficacious against variety of RNA viruses including the SARS-CoV-2. The Ministry of Health of the Russian Federation approved the use of these drugs as a treatment of COVID-19. The developed drug contains the combination of two antiviral agents with different mechanisms of suppressing viral RNA replication, which suggests efficacy against the vast majority of ARVI pathogens found in the human population including SARS-CoV-2 and influenza.Aim. The aim of the pharmacokinetics study is comparison between JTBC00301 (INN: molnupiravir + favipiravir), film-coated tablets (LLC \"PROMOMED RUS\", Russia), Esperavir® (INN: molnupiravir), capsules (LLC \"PROMOMED RUS\", Russia) and Areplivir® (INN: favipiravir), film-coated tablets (LLC \"PROMOMED RUS\", Russia) to evaluate the impact of monocomponents on each other's pharmacokinetics.Materials and methods. The clinical and analytical phases as well as pharmacokinetic analyses have been performed as a part of a phase I, randomized, open-label, 3-period crossover study of drug JTBC00301 (INN: molnupiravir + favipiravir), film-coated tablets, 400 + 400 mg (LLC \"PROMOMED RUS\", Russia). The plasma concentration of β-D-N4-hydroxycytidine (NHC), the active metabolite of molnupiravir and favipiravir were determined in 42 healthy volunteers after taking the test drug JTBC00301 (1 tablet of 400 + 400 mg), the reference drug Esperavir® (2 capsules of 200 mg) and the reference drug Areplivir® (2 tablets of 200 mg). The descriptive statistics were calculated using Microsoft Excel (Microsoft Corporation, USA). The pharmacokinetic parameters, analysis of variance (ANOVA), the intra-subject coefficient of variation (CVintra) and 90 % confidence intervals (90 % CI) were calculated by R Project 3.5.1 software (package «bear», version 2.8.3-2), originally created by Hsin-ya Lee and Yung-jin Lee, Taiwan.Results and discussion. Pharmacokinetic parameters of NHC and favipiravir were determined, averaged pharmacokinetic profiles in linear and log-linear scales were plotted, analysis of variance was carried out. The 90% CIs for geometric mean ratios of Сmax and AUC(0–t) for NHC and favipiravir were all within the acceptance range of 80–125 % which means there is no effect of monocomponents on each other’s pharmacokinetics.Conclusion. The development of the fixed-dose drug combination of molnupiravir and favipiravir has great potential as it may allow to increase the safety profile and improve the tolerability of therapy as well as increase the effectiveness of antiviral therapy. The results justified the study of the subsequent phases of clinical trials of JTBC00301 (INN: molnupiravir + favipiravir), film-coated ","PeriodicalId":11259,"journal":{"name":"Drug development & registration","volume":"286 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140427645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-27DOI: 10.33380/2305-2066-2024-13-1-1752
P. Karnakova, T. N. Komarov, O. Archakova, D. Ivkin, E. S. Vetrova, I. I. Terninko, I. Shohin, I. Narkevich
Introduction. Etmaben is a promising drug for the treatment of cardiovascular diseases, widely studied in preclinical studies. In order to conduct phase I clinical trials, it is necessary to develop a bioanalytical method for the quantitative determination of etmaben in human blood plasma.Aim. The aim of the study is to develop and validate a method for the quantitative determination of etmaben in human blood plasma using high-performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS) for the pharmacokinetic study.Materials and methods. The determination of etmaben in human blood plasma was carried out on a Nexera XR chromatograph with a mass-selective detector LCMS-8040 (Shimadzu Corporation, Japan). Sample preparation: precipitation with acetonitrile. Internal standard: promethazine. Column: Luna C18, 100 Å, 50 × 2.00 mm, 5 µm. Elution in gradient mode at a flow rate of 1.00 mL/min. Mobile phase: 0.1 % formic acid solution in water (eluent A), 0.1 % formic acid solution in acetonitrile (eluent B). Retention time for etmaben and promethazine is approximately 1.18 min and 1.15 min, respectively. Total chromatogram registration time: 4.00 min. Ionization method and mode: electrospray; negative mode for etmaben, positive mode for promethazine. Detection was carried out in the mode of multiple reaction monitoring (MRM): 249.90 → 92.15 m/z; 249.90 → 160.20 m/z (etmaben); 284.95 → 197.95 m/z (promethazine).Results and discussion. We have developed, for the first time, a method for determining etmaben and performed its full and partial validation according to current regulatory requirements.Conclusion. The method for determining etmaben in human blood plasma with a confirmed analytical range of 0.250–30.000 µg/mL has been developed and validated. The confirmed analytical range of the method based on the results of the partial validation was 0.040–35.000 µg/mL. The method was successfully applied in phase I clinical trials and can be used for other pharmacokinetic studies of etmaben.
{"title":"Development and Validation of an HPLC-MS/MS Method for the Quantitative Determination of Etmaben in Human Blood Plasma","authors":"P. Karnakova, T. N. Komarov, O. Archakova, D. Ivkin, E. S. Vetrova, I. I. Terninko, I. Shohin, I. Narkevich","doi":"10.33380/2305-2066-2024-13-1-1752","DOIUrl":"https://doi.org/10.33380/2305-2066-2024-13-1-1752","url":null,"abstract":"Introduction. Etmaben is a promising drug for the treatment of cardiovascular diseases, widely studied in preclinical studies. In order to conduct phase I clinical trials, it is necessary to develop a bioanalytical method for the quantitative determination of etmaben in human blood plasma.Aim. The aim of the study is to develop and validate a method for the quantitative determination of etmaben in human blood plasma using high-performance liquid chromatography with tandem mass spectrometric detection (HPLC-MS/MS) for the pharmacokinetic study.Materials and methods. The determination of etmaben in human blood plasma was carried out on a Nexera XR chromatograph with a mass-selective detector LCMS-8040 (Shimadzu Corporation, Japan). Sample preparation: precipitation with acetonitrile. Internal standard: promethazine. Column: Luna C18, 100 Å, 50 × 2.00 mm, 5 µm. Elution in gradient mode at a flow rate of 1.00 mL/min. Mobile phase: 0.1 % formic acid solution in water (eluent A), 0.1 % formic acid solution in acetonitrile (eluent B). Retention time for etmaben and promethazine is approximately 1.18 min and 1.15 min, respectively. Total chromatogram registration time: 4.00 min. Ionization method and mode: electrospray; negative mode for etmaben, positive mode for promethazine. Detection was carried out in the mode of multiple reaction monitoring (MRM): 249.90 → 92.15 m/z; 249.90 → 160.20 m/z (etmaben); 284.95 → 197.95 m/z (promethazine).Results and discussion. We have developed, for the first time, a method for determining etmaben and performed its full and partial validation according to current regulatory requirements.Conclusion. The method for determining etmaben in human blood plasma with a confirmed analytical range of 0.250–30.000 µg/mL has been developed and validated. The confirmed analytical range of the method based on the results of the partial validation was 0.040–35.000 µg/mL. The method was successfully applied in phase I clinical trials and can be used for other pharmacokinetic studies of etmaben.","PeriodicalId":11259,"journal":{"name":"Drug development & registration","volume":"83 7","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140426711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-27DOI: 10.33380/2305-2066-2024-13-1-1764
T. N. Komarov, N. Bagaeva, K. K. Karnakova, O. Archakova, D. Shchelgacheva, V. Shcherbakova, K. Zaslavskaya, P. A. Bely, A. V. Taganov, I. Shohin
Introduction. Favipiravir is an antiviral compound that inhibits the RNA-dependent polymerase and possesses antiviral properties against RNA viruses, including SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2). The new drug Areplivir® Zinc as a combination of favipiravir (200 mg) and zinc gluconate (70 mg) in the form of film-coated tablets has been developed by LLC "PROMOMED RUS", Russia. This combination of favipiravir and zinc gluconate could provide more effective treatment of COVID-19.Aim. The aim of the pharmacokinetics study is comparison between Areplivir® Zinc (INN: favipiravir + zinc gluconate), film-coated tablets (the manufacturer is JSC "Biokhimic", LLC "PROMOMED RUS" as registration certificate holder) and Areplivir® (INN: favipiravir), film-coated tablets (the manufacturer is JSC "Biokhimic", LLC "PROMOMED RUS" as registration certificate holder) to evaluate the effect of zinc on the favipiravir pharmacokinetics.Materials and methods. The clinical and analytical phases as well as pharmacokinetic analyses have been performed as a part of a phase I clinical trial. Chromatographic separation and detection of favipiravir were performed by high-performance liquid chromatography – tandem mass spectrometry (HPLC-MS/MS) method using Nexera XR high-performance liquid chromatograph with triple quadrupole tandem mass spectrometer LCMS-8040 (Shimadzu Corporation, Japan). The validated analytical range of the method was 50.00–15 000.00 ng/mL in human plasma. The plasma zinc concentrations were measured by a biochemical method with the use of the kit «Zinc-Novo (50)» (JSC "Vector-Best", Russia). The descriptive statistics were calculated using Microsoft Excel (Microsoft Corporation, USA). The pharmacokinetic parameters, analysis of variance (ANOVA), 90 % confidence intervals (90 % CIs) and the intra-subject variability (CVintra) were calculated by R Project 3.5.1 software (package «bear», version 2.8.3-2), originally created by Hsin-ya Lee and Yung-jin Lee, Taiwan.Results and discussion. The 90 % confidence intervals of the ratios for Сmax and AUC(0–t) were 86.48–100.38 % and 103.77–119.47 %, respectively. The 90 % confidence intervals were all within the acceptance range of 80.00–125.00 % which means there is no effect of zinc on the favipiravir pharmacokinetics. The intra-subject variability (CVintra) of favipiravir for the pharmacokinetic parameters Cmax and AUC(0–t) were 15.06 % and 14.23 %.Conclusion. The results justified the subsequent phases of clinical trials of Areplivir® Zinc (INN: favipiravir + zinc gluconate), film-coated tablets (LLC "PROMOMED RUS", Russia). This combination of favipiravir and zinc could expand the existing armamentarium of antiviral drugs for the treatment of COVID-19.
{"title":"Phase I Pharmacokinetics Study of Drug Areplivir® Zinc (INN: Favipiravir + Zinc Gluconate) (LLC \"PROMOMED RUS\", Russia)","authors":"T. N. Komarov, N. Bagaeva, K. K. Karnakova, O. Archakova, D. Shchelgacheva, V. Shcherbakova, K. Zaslavskaya, P. A. Bely, A. V. Taganov, I. Shohin","doi":"10.33380/2305-2066-2024-13-1-1764","DOIUrl":"https://doi.org/10.33380/2305-2066-2024-13-1-1764","url":null,"abstract":"Introduction. Favipiravir is an antiviral compound that inhibits the RNA-dependent polymerase and possesses antiviral properties against RNA viruses, including SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2). The new drug Areplivir® Zinc as a combination of favipiravir (200 mg) and zinc gluconate (70 mg) in the form of film-coated tablets has been developed by LLC \"PROMOMED RUS\", Russia. This combination of favipiravir and zinc gluconate could provide more effective treatment of COVID-19.Aim. The aim of the pharmacokinetics study is comparison between Areplivir® Zinc (INN: favipiravir + zinc gluconate), film-coated tablets (the manufacturer is JSC \"Biokhimic\", LLC \"PROMOMED RUS\" as registration certificate holder) and Areplivir® (INN: favipiravir), film-coated tablets (the manufacturer is JSC \"Biokhimic\", LLC \"PROMOMED RUS\" as registration certificate holder) to evaluate the effect of zinc on the favipiravir pharmacokinetics.Materials and methods. The clinical and analytical phases as well as pharmacokinetic analyses have been performed as a part of a phase I clinical trial. Chromatographic separation and detection of favipiravir were performed by high-performance liquid chromatography – tandem mass spectrometry (HPLC-MS/MS) method using Nexera XR high-performance liquid chromatograph with triple quadrupole tandem mass spectrometer LCMS-8040 (Shimadzu Corporation, Japan). The validated analytical range of the method was 50.00–15 000.00 ng/mL in human plasma. The plasma zinc concentrations were measured by a biochemical method with the use of the kit «Zinc-Novo (50)» (JSC \"Vector-Best\", Russia). The descriptive statistics were calculated using Microsoft Excel (Microsoft Corporation, USA). The pharmacokinetic parameters, analysis of variance (ANOVA), 90 % confidence intervals (90 % CIs) and the intra-subject variability (CVintra) were calculated by R Project 3.5.1 software (package «bear», version 2.8.3-2), originally created by Hsin-ya Lee and Yung-jin Lee, Taiwan.Results and discussion. The 90 % confidence intervals of the ratios for Сmax and AUC(0–t) were 86.48–100.38 % and 103.77–119.47 %, respectively. The 90 % confidence intervals were all within the acceptance range of 80.00–125.00 % which means there is no effect of zinc on the favipiravir pharmacokinetics. The intra-subject variability (CVintra) of favipiravir for the pharmacokinetic parameters Cmax and AUC(0–t) were 15.06 % and 14.23 %.Conclusion. The results justified the subsequent phases of clinical trials of Areplivir® Zinc (INN: favipiravir + zinc gluconate), film-coated tablets (LLC \"PROMOMED RUS\", Russia). This combination of favipiravir and zinc could expand the existing armamentarium of antiviral drugs for the treatment of COVID-19.","PeriodicalId":11259,"journal":{"name":"Drug development & registration","volume":"109 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140426399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-26DOI: 10.33380/2305-2066-2024-13-1-1593
F. S. Ivanov, K. V. Nasonova
Introduction. A launch of larger number of pharmaceutical preparations based on recombinant products and biotechnologies leads to determine a strategy for protection of exclusive rights for subjects implemented into manufacturing process, including strains of microorganism-producers.Aim. To define a possibility and a protection scope of microorganism strain as intellectual property subjects at a step of research, development and launch of pharmaceutical preparations, including biotechnological products.Materials and methods. The materials of the study were available publications in peer-reviewed journals on thematic queries based on keywords of the selected topic, official websites, regulatory legal acts, regulating the procedure for patenting subjects in the Russian Federation and foreign countries.Results and discussion. A brief review of regulatory acts on registration of a strain as an intellectual property subject is presented. It was defined features of a microorganism strain for patenting and for establishing an infringement of patent rights in the territory of Russian and foreign countries. A possible scope of patent rights for strains is indicated.Conclusion. The problems raised upon protecting strains as intellectual property subjects as well as possibilities of strain registration as exclusive right subjects are defined.
{"title":"Affect of Features of a Microorganism Strain on a Scope of Exclusive Rights","authors":"F. S. Ivanov, K. V. Nasonova","doi":"10.33380/2305-2066-2024-13-1-1593","DOIUrl":"https://doi.org/10.33380/2305-2066-2024-13-1-1593","url":null,"abstract":"Introduction. A launch of larger number of pharmaceutical preparations based on recombinant products and biotechnologies leads to determine a strategy for protection of exclusive rights for subjects implemented into manufacturing process, including strains of microorganism-producers.Aim. To define a possibility and a protection scope of microorganism strain as intellectual property subjects at a step of research, development and launch of pharmaceutical preparations, including biotechnological products.Materials and methods. The materials of the study were available publications in peer-reviewed journals on thematic queries based on keywords of the selected topic, official websites, regulatory legal acts, regulating the procedure for patenting subjects in the Russian Federation and foreign countries.Results and discussion. A brief review of regulatory acts on registration of a strain as an intellectual property subject is presented. It was defined features of a microorganism strain for patenting and for establishing an infringement of patent rights in the territory of Russian and foreign countries. A possible scope of patent rights for strains is indicated.Conclusion. The problems raised upon protecting strains as intellectual property subjects as well as possibilities of strain registration as exclusive right subjects are defined.","PeriodicalId":11259,"journal":{"name":"Drug development & registration","volume":"58 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140431019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-22DOI: 10.33380/2305-2066-2024-13-1-1433
A. E. Sukhanov, I. A. Krylov, V. V. Sepp, K. S. Bakulin
Introduction. Results of original research carried out by means of high performance thin layer chromatography (HPTLC) of various plant samples (air-dry raw material) of Dioscoreaceae, Ranunculaceae, Fabaceae, Melanthiaceae, Scrophulariaceae families are presented in this article.Aim. To carry out preliminary qualitative analysis by HPTLC method of steroidal sapogenins composition in hydrolyzed extracts, obtained from vegetative samples of above-ground and underground organs of some Dioscoreaceae, Ranunculaceae, Fabaceae, Melanthiaceae, Scrophulariaceae families.Materials and methods. Extraction from pre-dehydrated raw materials was carried out with 50 % aqueous isopropanol (c.p.) in an ultrasonic bath, followed by acidic hydrolysis of O-glycoside bonds, evaporation and redissolution of dry residue in 99 % methanol (c.p.); purification from suspended solids by filtering through filters with 20 µm perforation diameter. HPTLC was performed on apparatus complex CAMAG (Switzerland) using HPTLC Aluminium sheets Silica gel 60 F254 plates 20 × 20 cm, which were cut to the size 20 × 10 cm.Results and discussion. After scanning densitometry at 254 nm, we found that the separation of isopropanol extracts, followed by redissolution in strong methanol in this solvent system allows a fairly acceptable separation and identification of the compounds studied. Comparison of the tracks of plant extracts was performed with standard samples of steroid sapogenins, whose methanol solutions were applied to one stain-strobe of track 1, provided that they had different Rf indices and coloration after derivatization.Conclusion. Diosgenin was identified in plant extracts of rhizomes and roots of Dioscorea nipponica and Dioscorea caucasica and in seeds of Trigonella foenum-graecum preliminarily. Sarsasapogenin was verified in extracts of fruits of Sophora japonica, tigogenin in extracts of seeds of Trigonella foenum-graecum, herb of Pulsatilla patens and herb of Veronica officinalis. Yamogenin was detected in extracts of seeds of Trigonella foenum-graecum and herb of Veronica officinalis. This work is exploratory in nature, assessing the presence of certain saponins by their sapogenins in selected extracts. We will optimize the HPLC separation procedure and choose other detection methods to unambiguously assess the co-presence of the studied sapogenins with approximately the same staining shades after derivatization and matching retention indices: there are pairs of steroidal sapogenins that have the same retention, we decided to group them in mixtures so that there would be separation within the group and subsequent comparison with the original extracts would make it possible to identify those or other sapogenins in such extracts.
{"title":"Preliminary Qualitative Analysis of Plant Samples by High-performance Thin-layer Chromatography for the Presence of Steroid Sapogenins of Some Representatives of the Dioscoreacae, Fabaceae, Ranunculaceae, Melanthiaceae, Scrophulariaceae","authors":"A. E. Sukhanov, I. A. Krylov, V. V. Sepp, K. S. Bakulin","doi":"10.33380/2305-2066-2024-13-1-1433","DOIUrl":"https://doi.org/10.33380/2305-2066-2024-13-1-1433","url":null,"abstract":"Introduction. Results of original research carried out by means of high performance thin layer chromatography (HPTLC) of various plant samples (air-dry raw material) of Dioscoreaceae, Ranunculaceae, Fabaceae, Melanthiaceae, Scrophulariaceae families are presented in this article.Aim. To carry out preliminary qualitative analysis by HPTLC method of steroidal sapogenins composition in hydrolyzed extracts, obtained from vegetative samples of above-ground and underground organs of some Dioscoreaceae, Ranunculaceae, Fabaceae, Melanthiaceae, Scrophulariaceae families.Materials and methods. Extraction from pre-dehydrated raw materials was carried out with 50 % aqueous isopropanol (c.p.) in an ultrasonic bath, followed by acidic hydrolysis of O-glycoside bonds, evaporation and redissolution of dry residue in 99 % methanol (c.p.); purification from suspended solids by filtering through filters with 20 µm perforation diameter. HPTLC was performed on apparatus complex CAMAG (Switzerland) using HPTLC Aluminium sheets Silica gel 60 F254 plates 20 × 20 cm, which were cut to the size 20 × 10 cm.Results and discussion. After scanning densitometry at 254 nm, we found that the separation of isopropanol extracts, followed by redissolution in strong methanol in this solvent system allows a fairly acceptable separation and identification of the compounds studied. Comparison of the tracks of plant extracts was performed with standard samples of steroid sapogenins, whose methanol solutions were applied to one stain-strobe of track 1, provided that they had different Rf indices and coloration after derivatization.Conclusion. Diosgenin was identified in plant extracts of rhizomes and roots of Dioscorea nipponica and Dioscorea caucasica and in seeds of Trigonella foenum-graecum preliminarily. Sarsasapogenin was verified in extracts of fruits of Sophora japonica, tigogenin in extracts of seeds of Trigonella foenum-graecum, herb of Pulsatilla patens and herb of Veronica officinalis. Yamogenin was detected in extracts of seeds of Trigonella foenum-graecum and herb of Veronica officinalis. This work is exploratory in nature, assessing the presence of certain saponins by their sapogenins in selected extracts. We will optimize the HPLC separation procedure and choose other detection methods to unambiguously assess the co-presence of the studied sapogenins with approximately the same staining shades after derivatization and matching retention indices: there are pairs of steroidal sapogenins that have the same retention, we decided to group them in mixtures so that there would be separation within the group and subsequent comparison with the original extracts would make it possible to identify those or other sapogenins in such extracts.","PeriodicalId":11259,"journal":{"name":"Drug development & registration","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140439505","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-20DOI: 10.33380/2305-2066-2024-13-1-1632
M. Nikiforova, I. A. Valouev, A. V. Petrov, E. Beketov, I. E. Shokhin
Introduction. Adalimumab, a fully humanized monoclonal antibody, is a tumor necrosis factor (TNFα) inactivator that is used against a number of autoimmune diseases such as rheumatoid arthritis and other most common inflammatory arthropathies (ankylosing spondylitis, psoriatic arthritis). Despite the proven efficacy of adalimumab treatment, there is a risk of adverse events, tied up with the formation of anti-drug antibodies, including neutralizing antibodies. Currently, the evaluation and characterization of neutralizing antibodies has become an important part of clinical trials in the development of new drugs and biosimilars.Aim. The aim of this study is to develop and validate the cell-based functional method for neutralizing anti-adalimumab antibodies determination in human serum.Materials and methods. For determination of neutralizing anti-adalimumab antibodies, the cell line L-929 has been employed. L-929 is a cell line sensitive to the TNFα-mediated apoptosis; the neutralizing antibodies interact with adalimumab that leads to TNFα-mediated cytotoxicity. Cytotoxicity was measured using resazurin, an aromatic compound that is a redox indicator.Results and discussion. The developed method was validated for cut point, selectivity, sensitivity, precision, specificity and stability (short- and long-term). An important part of a method development for determining neutralizing antibodies is the selection of concentrations of TNFα (4 ng/ml) and adalimumab (250 ng/ml), as well as determining the minimum required dilution – this parameter is established as 1 : 20. Cut point was chosen as a «floating» cut point, and a correction factor (normalization factor) was determined equal to 0,86. The sensitivity of the developed method was estimated at 108,9 ng/ml of neutralizing anti-adalimumab antibodies.Conclusion. The obtained results can be applied for determining anti-adalimumab neutralizing antibodies in the assessment of the adalimumab immunogenicity, including clinical trials.
{"title":"Development and Validation of the Cell-based Functional Method for Neutralizing Anti-adalimumab Antibodies Detection in Human Serum","authors":"M. Nikiforova, I. A. Valouev, A. V. Petrov, E. Beketov, I. E. Shokhin","doi":"10.33380/2305-2066-2024-13-1-1632","DOIUrl":"https://doi.org/10.33380/2305-2066-2024-13-1-1632","url":null,"abstract":"Introduction. Adalimumab, a fully humanized monoclonal antibody, is a tumor necrosis factor (TNFα) inactivator that is used against a number of autoimmune diseases such as rheumatoid arthritis and other most common inflammatory arthropathies (ankylosing spondylitis, psoriatic arthritis). Despite the proven efficacy of adalimumab treatment, there is a risk of adverse events, tied up with the formation of anti-drug antibodies, including neutralizing antibodies. Currently, the evaluation and characterization of neutralizing antibodies has become an important part of clinical trials in the development of new drugs and biosimilars.Aim. The aim of this study is to develop and validate the cell-based functional method for neutralizing anti-adalimumab antibodies determination in human serum.Materials and methods. For determination of neutralizing anti-adalimumab antibodies, the cell line L-929 has been employed. L-929 is a cell line sensitive to the TNFα-mediated apoptosis; the neutralizing antibodies interact with adalimumab that leads to TNFα-mediated cytotoxicity. Cytotoxicity was measured using resazurin, an aromatic compound that is a redox indicator.Results and discussion. The developed method was validated for cut point, selectivity, sensitivity, precision, specificity and stability (short- and long-term). An important part of a method development for determining neutralizing antibodies is the selection of concentrations of TNFα (4 ng/ml) and adalimumab (250 ng/ml), as well as determining the minimum required dilution – this parameter is established as 1 : 20. Cut point was chosen as a «floating» cut point, and a correction factor (normalization factor) was determined equal to 0,86. The sensitivity of the developed method was estimated at 108,9 ng/ml of neutralizing anti-adalimumab antibodies.Conclusion. The obtained results can be applied for determining anti-adalimumab neutralizing antibodies in the assessment of the adalimumab immunogenicity, including clinical trials.","PeriodicalId":11259,"journal":{"name":"Drug development & registration","volume":"51 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140445812","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-20DOI: 10.33380/2305-2066-2024-13-1-1531
A. N. Afanaseva, V. Saparova, I. Makarenko, T. A. Selmenskikh, D. V. Kurkin, A. L. Hohlov, R. I. Drai
Introduction. Romiplostim is an analogue of the fusion protein peptide of thrombopoietin (TPO), which increases platelet count by binding and activating the human thrombopoietin receptor (TPO-R). It is used to treat thrombocytopenia associated with chronic immune thrombocytopenia. For romiplostim, one of the possible adverse reactions from the immune system is immunogenicity: the production of anti-drug antibodies to the medicinal product, including neutralising antibodies, which may affect the efficacy and safety profile of the medicinal product.Aim. Validate the procedure for determining neutralising antibodies to romiplostim in human plasma for further clinical studies of immunogenicity.Materials and methods. The study used rabbit polyclonal antibodies to romiplostim, Nplate® produced by Amgen Europe as a standard sample; a placebo produced by LLC "GEROPHARM", a cell line 32D-hTPOR clone 63 with stable expression of human TPO receptor and a chemiluminescence assay kit CellTiter-Glo® Luminescent Cell Viability Assay produced by Promega to assess specificity. The experiment was carried out on cell line 32D-hTPOR clone 63, which was seeded on the first day and the neutralizing antibody concentrations were titrated with a constant concentration of romiplostim, then the chemiluminescence was detected on the second day. Statistical processing of the results was carried out using Prism 9 software.Result and discussion. The specificity of the procedure was demonstrated; at maximum concentration, the medicinal product differs from placebo by 309 times in the residual level of cell viability. The linearity of the procedure in terms of the coefficient determination is 0.9969. The precision of the procedure was determined: the repeatability was 1–9 %, the intermediate precision was 3–18 %. The coefficient of variation in selectivity of the procedure was 22 %. For the accuracy parameter, the values for recovery/spike were determined as 90–101 %. It was proven that there was no matrix effect.Conclusion. It can be stated that the procedure is linear, specific, highly precise, correct, selective and with a proven absence of matrix effect, which allows it to be used to determine the immunogenicity of romiplostim medicinal products in clinical studies.
{"title":"Experimental Validation a Method for Assessing Neutralizing Antibodies of Romiplostim in Human Plasma","authors":"A. N. Afanaseva, V. Saparova, I. Makarenko, T. A. Selmenskikh, D. V. Kurkin, A. L. Hohlov, R. I. Drai","doi":"10.33380/2305-2066-2024-13-1-1531","DOIUrl":"https://doi.org/10.33380/2305-2066-2024-13-1-1531","url":null,"abstract":"Introduction. Romiplostim is an analogue of the fusion protein peptide of thrombopoietin (TPO), which increases platelet count by binding and activating the human thrombopoietin receptor (TPO-R). It is used to treat thrombocytopenia associated with chronic immune thrombocytopenia. For romiplostim, one of the possible adverse reactions from the immune system is immunogenicity: the production of anti-drug antibodies to the medicinal product, including neutralising antibodies, which may affect the efficacy and safety profile of the medicinal product.Aim. Validate the procedure for determining neutralising antibodies to romiplostim in human plasma for further clinical studies of immunogenicity.Materials and methods. The study used rabbit polyclonal antibodies to romiplostim, Nplate® produced by Amgen Europe as a standard sample; a placebo produced by LLC \"GEROPHARM\", a cell line 32D-hTPOR clone 63 with stable expression of human TPO receptor and a chemiluminescence assay kit CellTiter-Glo® Luminescent Cell Viability Assay produced by Promega to assess specificity. The experiment was carried out on cell line 32D-hTPOR clone 63, which was seeded on the first day and the neutralizing antibody concentrations were titrated with a constant concentration of romiplostim, then the chemiluminescence was detected on the second day. Statistical processing of the results was carried out using Prism 9 software.Result and discussion. The specificity of the procedure was demonstrated; at maximum concentration, the medicinal product differs from placebo by 309 times in the residual level of cell viability. The linearity of the procedure in terms of the coefficient determination is 0.9969. The precision of the procedure was determined: the repeatability was 1–9 %, the intermediate precision was 3–18 %. The coefficient of variation in selectivity of the procedure was 22 %. For the accuracy parameter, the values for recovery/spike were determined as 90–101 %. It was proven that there was no matrix effect.Conclusion. It can be stated that the procedure is linear, specific, highly precise, correct, selective and with a proven absence of matrix effect, which allows it to be used to determine the immunogenicity of romiplostim medicinal products in clinical studies.","PeriodicalId":11259,"journal":{"name":"Drug development & registration","volume":"248 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140448655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-20DOI: 10.33380/2305-2066-2024-13-1-1684
U. D. Filonova, P. Karnakova, K. K. Karnakova, M. Popova, A. A. Popova, O. Archakova, T. Komarov, I. Shohin
Introduction. Apixaban is an anticoagulant used in a number of thromboembolic diseases with an improved benefit-to-risk ratio, according to multiple clinical studies. Due to the prescription of apixaban as antithrombotic therapy in patients with COVID-19, an increase in its use has been observed. Thus, due to the widespread use of apixaban and the need to conduct pharmacokinetic and bioequivalence studies of the drug, it is important to develop and validate a simple and sensitive method for the quantitative determination of apixaban in human blood plasma.Aim. The aim of the study is to develop and validate a method for the determination of apixaban in human blood plasma using high-performance liquid chromatography with tandem mass selective detection (HPLC-MS/MS) for the subsequent bioanalytical study.Materials and methods. The determination of apixaban in human plasma was carried out by HPLC-MS/MS with rivaroxaban as an internal standard. The method of protein precipitation with acetonitrile was used as sample preparation. Mobile phase: 0.1 % solution of formic acid in water (eluent A); 0.1 % solution of formic acid in acetonitrile (eluent B). The total run time was 3.00 min. Column: Shim-pack Velox Biphenyl; 2.7 µm; 50 × 2.1 mm. Ionization source: electrospray with positive ionization mode. MRM transitions: 460.15 → 443.10 m/z (apixaban); 436.05 → 144.95 m/z (rivaroxaban).Results and discussion. The developed method was validated in accordance with the EAEU requirements for the following parameters: selectivity, calibration curve, accuracy and precision, lower limit of quantitation, suitability of standard samples, matrix effect, recovery, stability, carry-over, dilution effects. The parameters met the acceptance criteria.Conclusion. The confirmed analytical range of the developed and validated method was 1.00–300.00 ng/mL in blood plasma. The method for determining apixaban in blood plasma is simple and sensitive. This method was tested during the analytical part of the bioanalytical study and can be used to conduct other pharmacokinetic studies of apixaban drugs.
{"title":"Development and Validation of an HPLC-MS/MS Method for Quantification of Apixaban in Human Plasma","authors":"U. D. Filonova, P. Karnakova, K. K. Karnakova, M. Popova, A. A. Popova, O. Archakova, T. Komarov, I. Shohin","doi":"10.33380/2305-2066-2024-13-1-1684","DOIUrl":"https://doi.org/10.33380/2305-2066-2024-13-1-1684","url":null,"abstract":"Introduction. Apixaban is an anticoagulant used in a number of thromboembolic diseases with an improved benefit-to-risk ratio, according to multiple clinical studies. Due to the prescription of apixaban as antithrombotic therapy in patients with COVID-19, an increase in its use has been observed. Thus, due to the widespread use of apixaban and the need to conduct pharmacokinetic and bioequivalence studies of the drug, it is important to develop and validate a simple and sensitive method for the quantitative determination of apixaban in human blood plasma.Aim. The aim of the study is to develop and validate a method for the determination of apixaban in human blood plasma using high-performance liquid chromatography with tandem mass selective detection (HPLC-MS/MS) for the subsequent bioanalytical study.Materials and methods. The determination of apixaban in human plasma was carried out by HPLC-MS/MS with rivaroxaban as an internal standard. The method of protein precipitation with acetonitrile was used as sample preparation. Mobile phase: 0.1 % solution of formic acid in water (eluent A); 0.1 % solution of formic acid in acetonitrile (eluent B). The total run time was 3.00 min. Column: Shim-pack Velox Biphenyl; 2.7 µm; 50 × 2.1 mm. Ionization source: electrospray with positive ionization mode. MRM transitions: 460.15 → 443.10 m/z (apixaban); 436.05 → 144.95 m/z (rivaroxaban).Results and discussion. The developed method was validated in accordance with the EAEU requirements for the following parameters: selectivity, calibration curve, accuracy and precision, lower limit of quantitation, suitability of standard samples, matrix effect, recovery, stability, carry-over, dilution effects. The parameters met the acceptance criteria.Conclusion. The confirmed analytical range of the developed and validated method was 1.00–300.00 ng/mL in blood plasma. The method for determining apixaban in blood plasma is simple and sensitive. This method was tested during the analytical part of the bioanalytical study and can be used to conduct other pharmacokinetic studies of apixaban drugs.","PeriodicalId":11259,"journal":{"name":"Drug development & registration","volume":"2 11","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139957962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-02-19DOI: 10.33380/2305-2066-2024-13-1-1653
Y. Wang, N. R. Bulatova, E. E. Klen, G. A. Rozit, I. L. Nikitina, E. Smolyarchuk, K. A. Zavadich, I. D. Krylova, A. Samorodov
Introduction. A characteristic manifestation of vascular brain damage is depressive disorders that accompany both acute and chronic disorders of cerebral circulation. Depression not only reduces the patient's quality of life, but also complicates the treatment of basic vascular disease, increases the risk of stroke and death. Therefore, complex therapy of vascular depression includes not only antidepressants, but also basic means to correct the consequences of disorders of cerebral blood flow, including with antiplatelet activity. In this regard, the development of a new molecule based on thietane-containing heterocycles, combining the properties of an antidepressant and an antiplatelet agent.Aim. To conduct a preclinical evaluation of 4-(2-(4-nitrophenyl)-2-oxoethyl)-1-(thietane-3-yl)-1H-1,2,4-triazol-4 bromide when administered to rats.Materials and methods. A study was conducted of the effect of 4-(2-(4-nitrophenyl)-2-oxoethyl)-1-(thietan-3-yl)-1H-1,2,4-triazol-4-bromide on the hemostasis system during intravenous and intragastric administration to healthy white non-linear sexually mature male rats (n = 160). Thromboelastography was performed on a TEG 5000 device, activated with a 0.2 M solution of calcium chloride, Born aggregometry and standard clotting tests to assess the coagulation component of hemostasis.Result and discussion. The findings show that 4-(2-(4-nitrophenyl)-2-oxoethyl)-1-(thietane-3-yl)-1H-1,2,4-triazole-4-th bromide with peroral administration exceeded acetylsalicylic acid by 2.8 times in terms of ED50, and by 1.8 times with intravenous way of administration accordingly. A similar effect of pentoxifylline in the intravenous route of administration was recorded at a concentration of 27.8 mg/kg versus 12.4 mg/kg of compound I. The results of a complex method to assess the state of the hemostasis system indicate a more pronounced antiaggregational effect of compound I compared with pentoxifylline and acetylsalicylic acid.Conclusion. Preclinical studies of 4-(2-(4-nitrophenyl)-2-oxoethyl)-1-(thietane-3-yl)-1H-1,2,4-triazole-4 bromide, was demonstrated that a combination of antidepressant and antiplatelet activity, which can serve as a basis for further drug development.
{"title":"Results of Preclinical Studies of 4-(2-(4-nitrophenyl)-2-oxoethyl)-1-(thietane-3-yl)-1H-1,2,4-triazole-4-th Bromide in Relation to the Hemostasis System in vivo","authors":"Y. Wang, N. R. Bulatova, E. E. Klen, G. A. Rozit, I. L. Nikitina, E. Smolyarchuk, K. A. Zavadich, I. D. Krylova, A. Samorodov","doi":"10.33380/2305-2066-2024-13-1-1653","DOIUrl":"https://doi.org/10.33380/2305-2066-2024-13-1-1653","url":null,"abstract":"Introduction. A characteristic manifestation of vascular brain damage is depressive disorders that accompany both acute and chronic disorders of cerebral circulation. Depression not only reduces the patient's quality of life, but also complicates the treatment of basic vascular disease, increases the risk of stroke and death. Therefore, complex therapy of vascular depression includes not only antidepressants, but also basic means to correct the consequences of disorders of cerebral blood flow, including with antiplatelet activity. In this regard, the development of a new molecule based on thietane-containing heterocycles, combining the properties of an antidepressant and an antiplatelet agent.Aim. To conduct a preclinical evaluation of 4-(2-(4-nitrophenyl)-2-oxoethyl)-1-(thietane-3-yl)-1H-1,2,4-triazol-4 bromide when administered to rats.Materials and methods. A study was conducted of the effect of 4-(2-(4-nitrophenyl)-2-oxoethyl)-1-(thietan-3-yl)-1H-1,2,4-triazol-4-bromide on the hemostasis system during intravenous and intragastric administration to healthy white non-linear sexually mature male rats (n = 160). Thromboelastography was performed on a TEG 5000 device, activated with a 0.2 M solution of calcium chloride, Born aggregometry and standard clotting tests to assess the coagulation component of hemostasis.Result and discussion. The findings show that 4-(2-(4-nitrophenyl)-2-oxoethyl)-1-(thietane-3-yl)-1H-1,2,4-triazole-4-th bromide with peroral administration exceeded acetylsalicylic acid by 2.8 times in terms of ED50, and by 1.8 times with intravenous way of administration accordingly. A similar effect of pentoxifylline in the intravenous route of administration was recorded at a concentration of 27.8 mg/kg versus 12.4 mg/kg of compound I. The results of a complex method to assess the state of the hemostasis system indicate a more pronounced antiaggregational effect of compound I compared with pentoxifylline and acetylsalicylic acid.Conclusion. Preclinical studies of 4-(2-(4-nitrophenyl)-2-oxoethyl)-1-(thietane-3-yl)-1H-1,2,4-triazole-4 bromide, was demonstrated that a combination of antidepressant and antiplatelet activity, which can serve as a basis for further drug development.","PeriodicalId":11259,"journal":{"name":"Drug development & registration","volume":"9 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139958583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：