AN EXPERIMENTAL SYSTEM FOR THE SIMULTANEOUS ESTIMATION OF MITOSTATIC AND LYMPHOTOXIC EFFECTS OF IMMUNOSUPPRESSANTS AND CYTOSTATICS

Sublethally (600 R) irradiated (CBA x C57BL)F1 mice were grafted intravenously with parental lymph node cells in doses ranging from 0.2 x 106 to 12 x 106. The transplantation of these lymphoid cells leads to inactivation of the recipient's endogenous CFU (as measured by the diminution of the number of colonies registered on the 10th day after irradiation). A 50% inactivation was observed when the graft size of the CBA cells was 0.52 x 106. This figure for C57BL cells was 10 times more. This experimental system evaluates two simultaneously developing processes: the multiplication of endogenous CFU and the homograft reaction of transplanted lymphocytes against them. Both processes can be quantitatively estimated simultaneously in the same experiment by the determination of the number of colonies in corresponding experimental groups. Thus it was possible in a single experiment to compare quantitatively the effect of immunosuppressants on two points: (a) mitostatic action (suppression of CFU) and (b) lymphotoxic action. The latter, a true immunosuppressive effect, represents suppression of GVH activity of lymphoid cells and is demonstrated by abolition of the inhibition of endogenous colony formation. In the present system we have tested 6-MP, ALS, cyclophosphamide, hydrocortisone, and other drugs. The definite mitostatic and lymphotoxic doses of drugs are ascertained. Cyclophosphamide and ALS proved to be drugs with high dose ranges of selective lymphotoxic action. Hydrocortisone acetate had a more narrow range of selective lymphotoxic effect. 6-MP and Imuran (azathioprine) failed to exert any selective action on lymphoid elements. They possessed pronounced mitostatic efficiency, however

Lifespan and growth of Astarte borealis (Bivalvia) from Kandalaksha Gulf, White Sea, Russia

Marine bivalves are well known for their impressive lifespans. Like trees, bivalves grow by accretion and record age and size throughout ontogeny in their shell. Bivalves, however, can form growth increments at several different periodicities depending on their local environment. Thus, establishing lifespans and growth rates of marine bivalves requires a proper identification of annual growth increments. Here, we use isotope sclerochronology to decipher the accretionary growth record of modern Astarte borealis from the White Sea, Russia (N 67°05.70′; E 32°40.85′). Unlike winter growth increments observed in many other cold-temperate and boreal bivalve and limpet species, prominent growth increments in A. borealis corresponded to the most negative values in the oxygen isotope (δ18O) time series indicating that they formed during summer. Furthermore, summer growth increments do not coincide with the external concentric ridges on the shell making the latter feature an unreliable indicator of age. Similar to many other polar bivalves, A. borealis shows slow growth and long life. The von Bertalanffy growth equation for our sample is Ht = 29.39*(1 − e(− 0.11(t−(− 1.86))). Lifespans of individuals examined here (n = 18) range from 16 to 48 years. Given its impressive longevity and widespread polar distribution, A. borealis may be a potentially valuable skeletal archive for monitoring environmental conditions in the Arctic Ocean and boreal seas in the face of changing climate

Study of interaction between the polyoxidonium immunomodulator and the human immune system cells

Abstract Polyoxidonium (PO) is a high-molecular weight physiologically active compound with pronounced immunomodulating activity, an N-oxidized polyethylene-piperazine derivative. The aim of our work was to study cellular and molecular mechanisms of the action of PO on the human peripheral blood leukocytes. By means of flow cytometry it was established that the binding of fluorescein-isothiocyanate-labeled PO (FITC-labeled PO) occurs more rapidly with monocytes and neutrophils than with lymphocytes (7-to 8-fold weaker as compared with monocytes). Using colloidal gold-labeled PO and electron microscopy it was shown with that the preparation penetrates into leukocytes by endocytosis. PO is localized in endoplasmic vesicles of cellular cytosol. Analysis of one of the crucial signal transducer, the intracellular Ca 2+ , performed with the Fluo-3 fluorescent dye, showed that PO does not induce Ca 2+ mobilization from the intracellular calcium stores and influx of extracellular Ca 2+ . The study of the intracellular hydrogen peroxide (H 2 O 2 ) production with the 2V ,7V -dichlorfluorescein indicator demonstrated that PO significantly increases the level of intracellular H 2 O 2 in monocytes and neutrophils, however, this increase is much less as compared with phorbol myristate acetate stimulation. The analysis of immunomodulating effect produced by PO proved its stimulating activity on some cytokines production in vitro, e.g. interleukin 1h (IL-1h), tumor necrosis factor (TNF)-a and IL-6. A dose-dependent increase in the intracellular killing by blood phagocytes was established under the action of PO.

Особенности фармакокинетики антисмысловых олигонуклеотидных препаратов

This review covers the pharmacokinetic characteristics of the various antisense oligonucleotide drugs. A comparison of the pharmacokinetics of drugs first and second generation. As well as the influence on the pharmacokinetics of the chemical modification of the molecule.В обзоре рассмотрены фармакокинетические особенности различных антисмысловых олигонуклеотидных препаратов. Проведено сравнение фармакокинетики препаратов первого и второго поколения. А так же рассмотрено влияние на фармакокинетику химической модификации молекулы

Studying the pharmacokinetics of biotechnological medicinal products on the example of monoclonal antibodies

Therapeutic monoclonal antibodies (mAbs), which are developed to treat many pathologies, including cancer, autoimmune and infectious diseases, are one of the fastest growing classes of medicinal products. Given the large number of mAbs in the pipeline and continued interest from pharmaceutical companies, the mAb market is expected to continue to grow in the coming years. To maximise both the therapeutic benefit and the safety of medicinal products in this class, it is essential that their pharmacological properties be carefully characterised and understood.The aim of the study was to analyse literature data on approaches to studying the pharmacokinetics of mAbs. This review presents data on the main physicochemical and pharmacological properties of mAbs and compares them with small molecules. The article describes the influence of various factors on mAb pharmacokinetics.For example, such factors include the method of administration, hydrophilicity, and charge of the mAb, individual characteristics of the patient (body weight, plasma albumin levels, genetic characteristics, etc.), and concurrent administration of other medicinal products. The authors evaluated the role of intra- and inter-individual variability of pharmacokinetic parameters. The rapid development of this group of medicinal products and the emergence of new promising molecules are indicative of the need to study the pharmacokinetics and pharmacodynamics of mAbs in detail and to maximise both the therapeutic benefit and the safety of the medicinal products in this class

Микробициды для топической иммунопрофилактики ВИЧ-инфекции

Microbicides are antiseptic topical drugs that help directly or indirectly inhibit the penetration of an infectious agent into the human body, thereby preventing the sexual transmission of HIV-infection and other sexually transmitted diseases. Microbicides have an antiviral mechanism of action in the sexual transmission of HIV and affect the components of mucosal immunity in the vagina. In this article, the pharmaceutical and biomedical aspects of microbicide application are examined and diverse classifications of microbicides are presented. For each group of chemicals, the most important representatives and their mechanisms of action are described. This article also presents the structure and function of mucosal immunity, and shows the importance of the mucosal immune response in the sexual transmission of HIV. This work also exhibits the experimental models for testing of candidate microbicides. For each compound described, a review of preclinical research and clinical trials is provided, covering its development as a microbicide. This paper gives an overview of microbicides, a new class of chemically diverse immunobiological medications reducing the risk of sexual transmission of HIV. The use of microbicides is believed to curb the HIV/AIDS epidemic in the nearest future.Микробициды являются антисептическими топическими лекарственными средствами, способствующими напрямую или опосредованно сдерживать проникновение инфекционного агента в организм человека, тем самым предотвращая половую передачу вируса иммунодефицита человека (ВИЧ) и других заболеваний, передающихся половым путем. Они обладают не только прямым местным противовирусным механизмом действия при половой передаче ВИЧ, но и влияют на компоненты мукозального иммунитета во влагалище.В данной статье авторами рассмотрены фармацевтические и биомедицинские аспекты применения кандидатных микробицидов, представлены разнообразные классификации этих препаратов, описаны наиболее значимые представители каждой химической группы, указаны механизмы их действия. Помимо этого даны представления о структуре и функции мукозального иммунитета и показана значимость мукозального иммунного ответа на вирус при половой передаче ВИЧ-инфекции. Отдельно рассматриваются экспериментальные модели, которые применяются для тестирования кандидатных микробицидов. Для каждого описанного в статье химического соединения представлен краткий обзор доклинических и клинических исследований по разработке на его основе микробицида. Даны общие представления о таком новом разнообразном классе медицинских иммунобиологических препаратов, как микробициды, которые должны в ближайшем будущем уменьшить риск половой передачи ВИЧ и сдержать эпидемию ВИЧ-инфекции и синдрома приобретенного иммунодефицита (СПИД)

CXC chemokines and antimicrobial peptides in rhinovirus-induced experimental asthma exacerbations

RATIONALE: Rhinoviruses (RVs) are the major triggers of asthma exacerbations. We have shown previously that lower respiratory tract symptoms, airflow obstruction, and neutrophilic airway inflammation were increased in experimental RV-induced asthma exacerbations. OBJECTIVES: We hypothesized that neutrophil-related CXC chemokines and antimicrobial peptides are increased and related to clinical, virologic, and pathologic outcomes in RV-induced exacerbations of asthma. METHODS: Protein levels of antimicrobial peptides (SLPI, HNP 1–3, elafin, and LL-37) and neutrophil chemokines (CXCL1/GRO-α, CXCL2/GRO-β, CXCL5/ENA-78, CXCL6/GCP-2, CXCL7/NAP-2, and CXCL8/IL-8) were determined in bronchoalveolar lavage (BAL) fluid of 10 asthmatics and 15 normal controls taken before, at day four during and 6 weeks post-experimental infection. RESULTS: BAL HNP 1–3 and Elafin were higher, CXCL7/NAP-2 was lower in asthmatics compared with controls at day 4 (P = 0.035, P = 0.048, and P = 0.025, respectively). BAL HNP 1–3 and CXCL8/IL-8 were increased during infection (P = 0.003 and P = 0.011, respectively). There was a trend to increased BAL neutrophils at day 4 compared with baseline (P = 0.076). BAL HNP 1–3 was positively correlated with BAL neutrophil numbers at day 4. There were no correlations between clinical parameters and HNP1–3 or IL-8 levels. CONCLUSIONS: We propose that RV infection in asthma leads to increased release of CXCL8/IL-8, attracting neutrophils into the airways where they release HNP 1–3, which further enhances airway neutrophilia. Strategies to inhibit CXCL8/IL-8 may be useful in treatment of virus-induced asthma exacerbations

Analysis of pneumococcal serotypes distribution to determine a model composition for a Russian pneumococcal conjugate vaccine

Diseases caused by Streptococcus pneumoniae, as well as antibiotic resistance of its serotypes, are the leading cause of death amongst children worldwide. To prevent pneumococcal infection, the population is immunised with conjugate vaccines containing different amounts of polysaccharides of certain serotypes. Development of a full-cycle Russian vaccine is vital because the active pharmaceutical ingredients for the vaccines registered in the Russian Federation are produced abroad, and only the final stages of production of vaccines of this group are performed in the territory of the Russian Federation. Considering the phenomenon of serotype replacement associated with the long-term widespread use of pneumococcal conjugate vaccines, it is necessary to carefully select the serotype composition for the new vaccine. The aim of this work was to analyse the serotype distribution of pneumococci in the Russian Federation and other countries in order to select optimal serotypes for the Russian vaccine for human use, taking into account vaccination schedules for each age group. This review presents an analysis of the pneumococcal serotype distribution in the Russian Federation in the pre-vaccination era, as well as after the introduction of routine vaccination. In addition, the review includes data on the serotype distribution in the Eurasian Economic Union countries. The authors described a model composition containing at least sixteen serotypes. It will increase effectiveness of immune protection of the population, providing a more complete coverage of serotypes, considering their prevalence in the Russian Federation. Based on the analysis, the serotype composition for the sixteen-valent pneumococcal conjugate vaccine is proposed for further production and preclinical and clinical trials. A new Russian pneumococcal conjugate vaccine will ensure vaccination of all population groups within the National Immunisation Schedule of the Russian Federation

Исследование фармакокинетики биотехнологических препаратов на примере моноклональных антител

Therapeutic monoclonal antibodies (mAbs), which are developed to treat many pathologies, including cancer, autoimmune and infectious diseases, are one of the fastest growing classes of medicinal products. Given the large number of mAbs in the pipeline and continued interest from pharmaceutical companies, the mAb market is expected to continue to grow in the coming years. To maximise both the therapeutic benefit and the safety of medicinal products in this class, it is essential that their pharmacological properties be carefully characterised and understood.The aim of the study was to analyse literature data on approaches to studying the pharmacokinetics of mAbs. This review presents data on the main physicochemical and pharmacological properties of mAbs and compares them with small molecules. The article describes the influence of various factors on mAb pharmacokinetics.For example, such factors include the method of administration, hydrophilicity, and charge of the mAb, individual characteristics of the patient (body weight, plasma albumin levels, genetic characteristics, etc.), and concurrent administration of other medicinal products. The authors evaluated the role of intra- and inter-individual variability of pharmacokinetic parameters. The rapid development of this group of medicinal products and the emergence of new promising molecules are indicative of the need to study the pharmacokinetics and pharmacodynamics of mAbs in detail and to maximise both the therapeutic benefit and the safety of the medicinal products in this class.Терапевтические моноклональные антитела (МкАт) являются одним из самых быстроразвивающихся классов лекарственных средств, которые разрабатываются для лечения многих патологий, включая рак, аутоиммунные и инфекционные заболевания. Учитывая большое количество находящихся в настоящее время в разработке МкАт и сохраняющийся интерес со стороны фармацевтических компаний, ожидается, что рынок МкАт будет продолжать расти и в последующие годы. Для максимизации как терапевтической пользы, так и безопасности препаратов этого класса крайне важно, чтобы их фармакологические свойства были тщательно охарактеризованы.Цель работы — анализ литературных данных о подходах в изучении фармакокинетических параметров моноклональных антител.Представлены данные об основных физико-химических и фармакологических свойствах МкАт. Проведен сравнительный анализ характеристик МкАт и низкомолекулярных лекарственных веществ. Показано влияние на фармакокинетические параметры МкАт различных факторов, таких как способ введения, гидрофильность и заряд МкАт, индивидуальные особенности пациентов (масса тела, уровень альбумина в плазме крови, генетические особенности и др.), совместное применение с другими лекарственными средствами. Оценена роль межиндивидуальной и внутрииндивидуальной вариабельности фармакокинетических параметров МкАт. Сделан вывод о том, что в условиях стремительных темпов разработки препаратов данной группы и появления новых перспективных молекул особо важное значение приобретает необходимость подробного изучения и оптимизации фармакокинетических и фармакодинамических свойств для повышения как терапевтической пользы, так и безопасности препаратов класса МкАт