Drug For Various Types Research Articles

Abstract 5260: Combination activity of eribulin liposomal formulation and anti-PD-1 antibody after tumor regrowth during anti-PD-1 antibody treatment in mice

Abstract Eribulin (ERI) has been reported a microtubule dynamics inhibitor with unique tumor microenvironment modulations such as vascular remodeling activity. In the previous meeting (AACR2022, 2023), we reported that ERI and liposomal formulation of ERI (ERI-LF) also have immunomodulatory activity that induces CD8+ T cells via its vascular remodeling activity and ERI-LF showed more potent immune modulation and combination activities with anti-PD-1 antibody (PD-1 Ab) than ERI in syngeneic mice models and humanized mice models. Although immune-checkpoint inhibitors (ICI) are using as a key drug for various types of cancers in clinical setting, several clinical questions regarding suitable therapies after ICI therapy and efficacy of ICI rechallenge are remaining. In this study, we evaluated anti-tumor activities of combination of ERI-LF and PD-1 Ab in two syngeneic transplantation models using mouse non-small lung cancer cells, P-glycoprotein-knockout (Pgp-KO) KLN205 cells and Pgp-KO LL2 cells. As a result, combination of 1mg/kg ERI-LF (Q7D×2) with PD-1 Ab (200 ug/head, twice a week ×2 weeks) showed significant stronger antitumor activity compared with each monotherapy in only Pgp-KO KLN205 model, in which ERI-LF increased intratumoral microvascular density as a vascular remodeling activity, not in Pgp-KO LL2 model. We next conducted continuous treatment of PD-1 Ab in Pgp-KO KLN205 model to investigate tumor regrowth during treatment of PD-1 Ab. In this model, tumor growth was inhibited by PD-1 Ab until about two weeks after initiation of the treatment and then this inhibitory activity disappeared after two weeks even by continuous treatment of PD-1 Ab. We performed flow cytometry analysis (FCM) for tumor-infiltrating immune cells and RNAseq analysis using regrowing tumors compared with non-treatment tumors. Expressions of mRNA of several immune inhibitory receptors were upregulated in tumors with regrowth, although CD4+ cells and CD8+ cells were also increased in FCM using tumor samples. Furthermore, we investigated anti-tumor activity of combination of ERI-LF and PD-1 Ab against tumors which changed from inhibitory phase to regrowth phase during PD-1 Ab treatment in Pgp-KO KLN205 model. The combination of ERI-LF at 1mg/kg (Q7D×3) and PD-1 Ab (200 ug/head, twice a week ×3 weeks) also showed potent anti-tumor activity against tumors with regrowth by prior PD-1 Ab treatment as well as PD-1 Ab-naïve tumor, suggesting that this combination therapy might be effective after prior ICI therapy. Currently, Phase 1b/2 clinical trial of ERI-LF plus nivolumab in patients with selected solid cancers (NCT04078295) is underway. Patients with or without prior ICI therapy were enrolled in a small cell lung cancer cohort of this clinical study. Our preclinical results might provide a scientific rationale for a uniqueness of ERI-LF as a post ICI therapy. Citation Format: Moe Tamura, Yuki Niwa, Taro Semba. Combination activity of eribulin liposomal formulation and anti-PD-1 antibody after tumor regrowth during anti-PD-1 antibody treatment in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5260.

Evaluation of the Interactions of Cabozantinib with Topoisomerase Enzymes by in vitro Enzyme Activity Assays, and its Effects on Cancer Cell Proliferation

The discovery of many drugs in recent years provides a definitive solution in the treatment of various diseases, but today, despite the discovery of many effective anticancer drugs, there are various types of cancer that have limitations in treatment and are still not completely curable. Since most of these limitations are due to cancer cells gaining resistance or compounds only being effective in certain types of cancer cells, the search for more effective anticancer drugs that are also effective in these types of cancer is inevitable. Cabozantinib is in medical use as a highly effective anticancer drug in various types of cancer, such as medullary thyroid cancer and kidney cancer. The anticancer properties of the Cabozantinib compound have attracted more attention in recent years, however, more studies are needed to define the anticancer activities of this compound. In our study, the interactions of Cabozantinib with topoisomerase enzymes, were demonstrated through in vitro enzyme activity tests, and the anti-proliferative effect of Cabozantinib was studied on MCF7, A549 and PC3 cell lines. By analyzing the interactions of the Cabozantinib with topoisomerases, the action mechanisms of the compound at the molecular level was evaluated.

Clinical and biochemical changes and their correction in patients with metabolic phenotype of osteoarthritis and insomnia

BACKGROUND: Currently, OA is considered a polyetiological disease, where several phenotypes are distinguished based on the leading role of a specific risk factor. It is assumed that each clinical phenotype corresponds to its own fundamental changes in various organs and systems. Modern experimental evidence of chondro-osteogenic activity allows us to consider melatonin as a potential drug for various types of osteoarticular pathology.AIM: To study clinical and biochemical changes and effects of melatonin in the metabolic phenotype of OA and insomnia.MATERIALS AND METHODS: The study involved patients with a metabolic phenotype of OA and healthy volunteers. The subjects were collected complaints and anamnesis, as well as general clinical and orthopedic examination. In the blood serum, markers of bone and cartilage metabolism were determined. Patients were asked to answer the questions of clinical scales to assess the quality of sleep, the functional state of the joints and quality of life.RESULTS: The study involved 36 patients. Participants were divided into 3 groups: group health patients — patients without articular pathology, sleep quality disorders and normal body mass index; control group- patients with metabolic phenotype of OA, insomnia and basic treatment for 30 days; experimental group — patients with a metabolic phenotype of OA and insomnia, whose basic treatment included melatonin (Melaxen®) at a dosage of 3 mg for 30 days. Statistically significant differences were observed between the initial levels of acid phosphatase (AP), bone isoenzyme alkaline phosphatase (ALP) and calcium (Ca) in the control and experimental groups. According to the results of screening for the detection of insomnia among patients with the metabolic phenotype of, there were statistically significant insomnological disorders compared to the group health patients, as well as significant differences in terms of pain, symptoms, activity and quality of life in general according to the KOOS and SF-36 scales. Correlation analysis showed moderate correlations with biochemical parameters in patients with OA metabolic phenotype groups. After the treatment there was a certain increase in the level of Ca and a decrease in the activity of ALP and АP in patients of experimental group in comparison with patients of control groups. There was a positive trend in the range of criteria of the KOOS and SF-36 scale in experimental groups, pronounced decrease in pain syndrome (P), symptoms (S) and an increase in the levels of daily activity (A) and the total indicator (Sum) in comparison with patients of control groups. Also as improved sleep quality on all scales in comparison with the control group. In control group, problems with the quality and quantity of sleep remained at the same level.CONCLUSION: In patients with the most pronounced indicators of clinical manifestations of OA, more active processes of bone remodeling. The higher the level of bone resorption markers, the greater the severity of the clinical course in patients with osteoarthritis, and the worse the quality of sleep in general. The addition of melatonin to the treatment regimen was associated with a decrease in serum activity of the bone isoenzyme of alkaline phosphatase, acid phosphatase, an increase in calcium levels, as well as with an improvement in sleep and clinical symptoms ОА.

DNA Gyrase as a Target for Quinolones.

Bacterial DNA gyrase is a type II topoisomerase that can introduce negative supercoils to DNA substrates and is a clinically-relevant target for the development of new antibacterials. DNA gyrase is one of the primary targets of quinolones, broad-spectrum antibacterial agents and are used as a first-line drug for various types of infections. However, currently used quinolones are becoming less effective due to drug resistance. Common resistance comes in the form of mutation in enzyme targets, with this type being the most clinically relevant. Additional mechanisms, conducive to quinolone resistance, are arbitrated by chromosomal mutations and/or plasmid-gene uptake that can alter quinolone cellular concentration and interaction with the target, or affect drug metabolism. Significant synthetic strategies have been employed to modify the quinolone scaffold and/or develop novel quinolones to overcome the resistance problem. This review discusses the development of quinolone antibiotics targeting DNA gyrase to overcome bacterial resistance and reduce toxicity. Moreover, structural activity relationship (SAR) data included in this review could be useful for the development of future generations of quinolone antibiotics.

Self-Medication Practices from the Perspective of Tunisian Cardiovascular Patients – A Community Pharmacy-Based Survey

Tunisia, a developing country, is facing in recent years a growing burden of chronic diseases, mainly cardiovascular diseases (CVDs). Self-care is essential in the long-term management of these diseases, and the practice of self-medication is a key component of the self-care process. This study aimed to analyze self-medication practices among patients with cardiovascular comorbidities in a region of Tunisia. The study was conducted in two community pharmacies in the region of Beja, Tunisia, as an interview based on a questionnaire for patients who self-reported the presence of a CVDs or the use of drugs to treat such disease. Out of 160 cardiovascular patients enrolled, over 90% self-reported the practice of self-medication with drugs of various types (paracetamol, ibuprofen, diclofenac, amoxicillin + clavulanic acid, codeine, etc.), for medical symptoms considered trivial (headache, fever, cough, toothache, urinary discomfort, etc.). Over 70% of patients invoked both the existence of a previous medical prescription / recommendation and saving time and money as justifying reasons for self-medication practices. The abovementioned medicines are self-reported to be used concomitantly with the chronic therapies used for CVDs, and respectively other associated comorbidities (dyslipidemia, obesity, diabetes, asthma, etc.). The high frequency of self-medication that has been highlighted is clear evidence that this practice is part of the daily health care routine of these patients. Thus, the therapist, doctor or pharmacist, has a very important role in the process of informing, advising and educating these patients with cardiovascular comorbidities in order to practice responsible self-medication.

Molecular targeted drugs, comprehensive classification and preclinical models for the implementation of precision immune oncology in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a complex heterogeneous disease with high morbidity and mortality. Recent progress in molecular targeted drugs including multikinase inhibitors and immune checkpoint inhibitors has demonstrated substantial survival improvement in patients with advanced HCC, but it remains as a challenging issue to discover surrogate markers for precisely distinguishing responders and non-responders. Genome-based medicine has changed cancer treatment from empirical use of cytotoxic agents to theoretical use of molecular targeted drugs in various types of cancer, while not in HCC due to lack of druggable targets. Integrated genomic and transcriptomic analysis reveal that HCC is divided into three major subtypes, proliferative, CTNNB1-mutated and metabolic disease-associated, with distinctive molecular and immunological features, and an increasing number of studies provide evidence for the close correlation between the subtype and the response to molecular targeted drugs using both of clinical data and preclinical models. Dozens of immunocompetent mouse models, such as hydrodynamic tail vain injection models and implantable syngeneic models, reflect molecular characteristics and tumor immune microenvironment of the subtypes, and help us to evaluate the efficacy of single and combination therapies and understand the molecular mechanisms underlying vulnerability and resistance to them. Thus, the consensus classification and relevant preclinical models could accelerate the establishment of predictive biomarkers and the development of subtype-specific therapies.

Efficacy and Safety of Topical Urea for Treatment Atopic Dermatitis as a Reference in the National Drugs Formulary

Atopic dermatitis (AD) is a chronically relapsing skin disease that occurs most commonly during early infancy and childhood. One of the most important clinical features of AD which results from a dysfunctional epidermal barrier (EB) is very dry skin (xerosis). Moisturizers are often used as supplements to topical and/or systemic anti-inflammatory drugs in various types of skin conditions and disorders. Humectan, this class of moisturizer is used to improve the appearance and texture of skin by filling in the crevices between corneocytes. One of the humectant included in the list of the National Drugs Formulary that is needed and must be available at health service facilities as a reference in the implementation of National Health Insurance (NHI) is urea. The literature searches using Pubmed, Academia, Google scholar and published in the last 10 years. Urea is effectively increasing skin hydration as well as niacinamide, significantly reducing local Scoring Atopic Dermatitis (SCORAD) and stratum corneum (SC) hydration. Urea had a decrease in transepidermal water loss (TEWL) which was not significantly better than lanolin and ceramide. The ceramide had a lower mean Visual Analogue Scale (VAS) score for irritation compared with the urea. More participants also preferred the ceramide-based cream over the urea. Urea is an effective and safe treatment although not as well as ceramide. Ceramide has been shown to be more effective and less irritating than urea. Ceramid can be quite expensive, while urea is a moisturizer that is easily found and accessible to the public.

Development and Validation of Reversed-Phase HPLC Method for the Determination of Epirubicin and Its Application to the Pharmacokinetic Study of Epirubicin Loaded Polymeric Nanoparticle Formulations in Rats.

Epirubicin, commonly used as anticancer drug for various types of tumors like breast, liver, lung, stomach, ovaries, and bladder for its improved antitumor efficacy and safety. A rapid, sensitive, and reliable bioanalytical method was developed and validated for epirubicin using conventional reverse phase HPLC with UV detection. The developed method was successfully applied to investigate the pharmacokinetics of epirubicin after intravenous administration of a reference epirubicin and its designed nano-formulations to rats. C18 column was used in an isocratic mode for analyte elution at a flow rate of 1.0 mL/min with UV detection of 234 nm. The mobile phase was composed of acetonitrile 22% (channel A) and 0.025% tri fluoro-acetic acid in water (channel B). Ondansetron was added as an internal standard, and the plasma samples were analyzed after protein precipitation. A concentration range of 0.016-1.024 μg/mL was selected for the construction of calibration curves, with LLOQ of 0.016 μg/mL. Results showed that the value of AUC, half-life, and mean residence time of designed nano-formulation were bounce to 10, 9, and 11 times higher, when compared to the reference epirubicin after intravenous dose of 10 mg/kg of epirubicin to rats, respectively. The designed epirubicin nano-formulations achieved clinically significant pharmacokinetic values in rats. Current method will help epirubicin future research using clinical samples and drug bioequivalence studies on various novel formulations for drug safety purposes.

Review of formulation and evaluation of self-micro emulsifying drug delivery system (SMEDDS)

Approximately half of the new drug applicants that reach formulation have poor water solubility. Oral delivery has been the main route of drug administration for the chronic treatment of numerous diseases. In different cases, in oral conveyance, 50 % of the medication compound is hampered because of the high lipid soluble or fat soluble of the medication itself. Around 40 % of new drug applicants show low solubility in water, which prompts poor oral bioavailability, high Intra and Intersubject changeability, and deficiency of dose proportionalityAim of review. The main aim of this review article is to gather the information related to design and evaluation of SMEDDS. These information can be utilized to enhance the bioavailability of the poorly aqueous soluble drug for various types of orally administered drugs. In this review article, various literature are reviewed and summerised in single paper to serve as reference guide to various research scholars and researchers working on self-micro-emulsifying drug delivery systems.Materials and Methods. To prepare this manuscript various keywords were searched in different search engine such as Google, Yahoo and Bing etc. This review article reviews the recent work done in the field of SMEDDS. It comprises review of literatures available in public domain and formulation of SMEDDS and its characterization is summarized in this article.Result. The various strategies to developed poor aqueous soluble drug for improvement of bioavailability for example, salt development and molecular size reduction of the compound might be one technique to enhance the dissolution rate of the drug. In any case, these methods have their limitations. SMEDDS is one of the novel applications for the delivery of low water soluble and low bioavailability of drug. SMEDDS is a method to improve the aqueous solubility of the medication; SMEDDS are described as isotropic blenders of oils, surfactants, and co-surfactant. Upon slightly stir followed by dilution with distilled water, for example, gastrointestinal liquids, these techniques can define clear o/w micro emulsion. SMEDDS is first choice and key technology for developing the lipophilic drug and other different factors that chance to affect the oral bioavailability.Conclusions. This review paper attempts to describe the preparation of SMEDDS and furthermore discusses the development of pseudo ternary phase diagram for SMEDDS. It describes the mechanism and method of preparation involved in SMEDDS. The capability of oral absorption of drug compound from the SMEDDS relies upon numerous formulation−related parameters, for example, surfactant concentration, oil/surfactant ratio, and hydrophobicity of emulsion, globule size and charge, in vitro, in vivo all of which basically characterized the ability of self-emulsification. SMEDDS are administered as unit dosage form and it also protect the degradation of drug

Reliable screening and classification of phosphodiesterase type 5 inhibitors in dietary supplements using gas chromatography / mass spectrometry combined with specific common ions

Illegal dietary supplements adulterated with phosphodiesterase type 5 inhibitors (PDE-5i) are increasingly widely distributed through internet markets and underground routes. For this reason, it demands development of reliable screening methods to determine a wide range of PDE-5i drugs in various types of dietary supplements. Herein, we developed a screening method using gas chromatography-mass spectrometry (GC–MS) for simultaneous detection of 53 PDE-5i drugs in supplements. Common formulations (such as capsule, powder, pill, and tablet) of supplements with complicated matrices were treated by simple liquid–liquid extraction and trimethylsilyl (TMS) derivatization. With the aid of TMS derivatization, 53 PDE-5i drugs could be successfully separated and detected within 15 min, using a short microbore GC column (15 m). Moreover, owing to enhanced detection sensitivity and selectivity of PDE-5i TMS derivatives, 0.5 mg of sample was sufficient to screen and confirm targeted PDE-5i drugs. In this study, specific common ions according to structural characteristics of PDE-5i drugs were found under the electron ionization (EI) of their TMS derivatives. These specific common fragments could reflect the common pharmacophores for 4 classes of PDE-5i drugs (sildenafil, other sildenafil, vardenafil, and tadalafil analogues). Based on characteristic EI fragment ions, extracted common ion chromatograms (ECICs) and discriminant analysis (DA) were effectively used for reliable screening and classification of various types of PDE-5i drugs. Specific ECICs and DA using characteristic EI fragments here will aid in identification of newly emerging PDE-5i counterfeits in supplements. This study will be helpful to supervise illegal adulteration of PDE-5i drugs in dietary supplements to protect public health and consumer safety.

New uracil analog U-332 is an inhibitor of NF-\u03baB in 5-fluorouracil-resistant human leukemia HL-60 cell line

Background5-Fluorouracil (5-FU) is an antimetabolite that interferes with DNA synthesis and has been widely used as a chemotherapeutic drug in various types of cancers. However, the development of drug resistance greatly limits its application. Overexpression of ATP-binding cassette (ABC) transporters in many types of cancer is responsible for the reduction of the cellular uptake of various anticancer drugs causing multidrug resistance (MDR), the major obstacle in cancer chemotherapy. Recently, we have obtained a novel synthetic 5-FU analog, U-332 [(R)-3-(4-bromophenyl)-1-ethyl-5-methylidene-6-phenyldihydrouracil], combining a uracil skeleton with an exo-cyclic methylidene group. U-332 was highly cytotoxic for HL-60 cells and showed similar cytotoxicity in the 5-FU resistant subclone (HL-60/5FU), in which this analog almost completely abolished expression of the ATP-binding cassette (ABC) transporter, multidrug resistance associate protein 1 (ABCC1). The expression of ABC transporters is usually correlated with NF-κB activation. The aim of this study was to determine the level of NF-κB subunits in the resistant HL-60/5-FU cells and to evaluate the potential of U-332 to inhibit activation of NF-κB family members in this cell line.MethodsAnti-proliferative activity of compound U-332 was assessed by the MTT assay. In order to disclose the mechanism of U-332 cytotoxicity, quantitative real-time PCR analysis of the NF-κB family genes, c-Rel, RelA, RelB, NF-κB1, and NF-κB2, was investigated. The ability of U-332 to reduce the activity of NF-κB members was studied by ELISA test.ResultsIn this report it was demonstrated, using RT-PCR and ELISA assay, that members of the NF-κB family c-Rel, RelA, RelB, NF-κB1, and NF-κB2 were all overexpressed in the 5-FU-resistant HL-60/5FU cells and that U-332 potently reduced the activity of c-Rel, RelA and NF-κB1 subunits in this cell line.ConclusionsThis finding indicates that c-Rel, RelA and NF-κB1 subunits are responsible for the resistance of HL-60/5FU cells to 5-FU and that U-332 is able to reverse this resistance. U-332 can be viewed as an important lead compound in the search for novel drug candidates that would not cause multidrug resistance in cancer cells.

Spectrum of seizure disorder in children between 1-18 years age at a tertiary care hospital: a longitudinal study

Background: To study the spectrum of seizures and types of anti-epileptic drugs in various types of seizures in children. Methods: A hospital based longitudinal study was conducted in the department of Pediatrics over two-years of period. A total of 161 cases presenting with seizures were studied for clinical features, imaging studies, EEG and pharmacotherapy given for various types of seizures (Monotherapy / combination therapy). Results: In the present study, the patient’s age ranged from 1year to 18 years. There were 72 (44.7%) females and 89 (55.2%) males. The male to female ratio was 0.8. Investigation like EEG, neuroimaging which included MRI / CT SCAN BRAIN were done. Out of 161 cases, EEG was done in all the cases, 89.44% (144) had EEG abnormality. 11% (17) presented with no EEG abnormality and MRI was done in 80.21% (129), out of which 53.48 % (68) were abnormal, CT scan was done in 19.87 % (32) of which 21.87% (7) were abnormal. Maximum used pharmacotherapeutic agent was sodium valproate (46.3 %) for generalised tonic clonic (GTCS) and minimum was combination of 3 anti-epileptic drugs (7%). Conclusion: Seizures in children are a common indication for hospital admission. They can be provoked or unprovoked. Early detection of the cause of seizures helps in instituting appropriate treatment. Children with seizures should be on regular long term follow up and treatment and proper response to therapy should be evaluated. Evaluation of the type of seizure with specific EEG findings helps in early and appropriate initiation of AED.

P2.01-058 Pharmacokinetic Parameter Variability of Docetaxel between Individuals and Its Relationship with Hematological Toxicity

Docetaxel is the commonly used chemotherapy drugs of various types of tumors. However, the major adverse effect of which is the dose-limiting hematologic toxicity. In clinical practice, 3/4 grade neutropenia and febrile (FN) is the severe side effects threatening the patient life. This research aims to analyze the variability of docetaxel’s medicine area under the curve (AUC) between individuals and its relationship with hematological toxicity in advanced NSCLC, which sets up the mathematical model to predict its hematological toxicity by docetaxel AUC to lay the theoretical foundation for individual adjustment in future. Select 32 patients with advanced NSCLC in Shandong Cancer Hospital that receiving docetaxel chemotherapy treatment from 2014-10 to 2015-12. Adopt Mycare® reagent kit to determine the blood concentration, and calculate the docetaxel AUC over model software of non-mixed effects. After standardized treatment, analyze the AUC variability between individuals, relationship of AUC with decreased amount of neutrophils before or after the chemotherapy, and the relationship of AUC with 3/4 grade neutropenia. And make the fitting with different methods to set up the mathematical model in relationship with decreased percentage of neutrophils after AUC prediction chemotherapy and incidence rate of 3/4 grade neutropenia. 1. The AUC of 32 patients in the first cycle after standardized treatment that use docetaxel is between 1.8ug.h/ml-4.7ug.h/ml in average of 3.32±0.12ug.h/ml. The difference between the maximum value and minimum one is 2.6 times. 2. AUC value has the tendency that increases as cycle number increases. However, the number of chemotherapy cycle has no statistical significance of AUC influence (F=0.186, P=0.824). 3. The model predicting the decreased percentage of neutrophils with docetaxel AUC is : y1 = 1.4812x2 + 3.0217x + 29.061 (cycle 1), y2 = 4.3981x2 + 14.006x + 50.532 (cycle 2), y3 = 2.0683x2 + 2.1257x + 19.604(cycle 3), y4 = 4.683x2 - 19.273 + 61.398 (cycle 4); The model predicting the incidence rate of 3/4 grade neutrophils is y=19.383ln(x)+2.4005. (x=AUC). This research sets up the mathematical model to predict the decreased percentage of neutrophils and incidence rate of 3/4 grade neutropenia by docetaxel AUC, which provides basis for screening high-risk patients who may suffer seriously hematological toxicity and lay the theoretical foundation for individualized adjustment based on doxetaxel AUC. In addition, as the first cycle of doxetaxel AUC has important reference value, it suggests that all patients receiving docetaxel chemotherapy at the first time must receive AUC test.

Vertigo in clinical practice – common methodology and pathogenetically founded differentiated treatment approaches

Актуальность головокружения в клинической практике определяется высоким уровнем распространенности и значительным ухудшением качества жизни пациентов с этой патологией. В статье рассмотрено и проанализировано головокружение, его причины и патогенетически обоснованные дифференцированные подходы к лечению. Целью данной работы явилось изучение эффективности применения препарата Тагиста (бетагистин) в сравнении с плацебо у пациентов с поражениями вестибулярной системы на разных уровнях, вызванными различными причинами. Материалы и методы. В исследование было включено 200 человек, 105 из них были рандомизированы в группу изучаемого препрата, 95 — в группу плацебо. Все больные основной группы, кроме стандартной терапии, получали курс лечения препаратом Тагиста (24 мг 2 раза в день) в течение 14 дней. Параллельно с оценкой эффективности препарата Тагиста выполнена сравнительная оценка его безопасности. К первичным критериям эффективности были отнесены: оценка выраженности и длительности головокружения (Dizziness Handicap Inventory), определение двигательной активности (шкала Тинетти), оценка по шкале качества жизни (SF-36, EQ-5D). Результаты и выводы. Статистически значимых различий в эффективности препарата Тагиста при центральном и периферическом вестибулярных синдромах выявлено не было. Анализ действия препарата Тагиста свидетельствует о его разностороннем влиянии на различные патогенетические механизмы головокружения и, следовательно, о патогенетической обоснованности применения препарата при разных типах вестибулярного головокружения. Статистически достоверная положительная динамика при терапии препаратом Тагиста в дозировке 48 мг в сутки у больных основной группы сопровождалась минимальным количеством побочных эффектов. The relevance of dizziness in the clinical practice is determined by the high prevalence and significant deterioration in the quality of life of patients with this pathology. The article reviewed and analyzed dizziness, its causes and pathogenetically justified differentiated treatment approaches. The objective of this work was to examine the effectiveness of the drug Tagista (betahistine) compared to placebo in patients with lesions of the vestibular system at various levels caused by different factors. Materials and methods. The study included 200 people, 105 of them were randomized to the study group, 95 — to the placebo group. All patients of the study group received Tagista (24 mg 2 times a day) for 14 days in addition to standard treatment. Besides the evaluation of Tagista efficacy, the assessment of its safety was also conducted. The primary effectiveness criteria included: assessment of dizziness severity and duration (Dizziness Handicap Inventory), evaluation of motor activity (Tinneti scale), the quality of life assessment (SF-36, EQ-5D). Results and Conclusions. There was no statistically significant difference in the effectiveness of Tagista in the central and peripheral vestibular syndromes. Analysis of Tagista action indicates its diverse effects on different pathogenetic mechanisms of dizziness and, therefore, pathogenetic substantiation of using this drug in various types of vestibular dizziness. Statistically significant positive dynamics during the therapy with Tagista at a dose of 48 mg a day in patients of the study group was associated with minimal side effects.

The protective effect of lemon fruit extract on histopathological changes induced in small intestines and pancreas of male mice by cyclophosphamide.

IntroductionCyclophosphamide (CP) is alkylating agent and the most commonly used chemotherapeutic drug for various types of cancer; it causes severe toxicity. The aim of the research was to assess the protective effect of lemon fruit extract (LFE) against the side effects of the anti-cancer drug “cyclophosphamide” (CP).MethodsThis experimental study was conducted in 2015. Thirty male mice were divided into six groups: group A (control): intraperitoneal injection of saline, group B: oral LFE (10ml/kg), group C: intraperitoneal injection of CP (10 mg/kg), group D: intraperitoneal injection of CP (20 mg/kg), group E: intraperitoneal injection of CP (10 mg/kg) and oral LFE (10 ml/kg), and group F: intraperitoneal injection of CP (20 mg/kg) and oral LFE (10 ml/kg). All groups were treated daily for five consecutive days.ResultsThe results of the group treated with the drug C and D was that, in their intestines, the effect was uneven between a severe to a sharp effect, and there was a lack of dense connective tissue and its collagen fibers and fat cells, the intestinal glands or crypt of Lieberkühn appeared few in number and distorted in composition when compared with control A, as the pancreas appeared divided into several lobes containing small numbers of pancreatic Acini, padded with secretory pyramid-shaped cells, although some of them appeared exaggerated. While treatment in group E and F resulted in the intestines and pancreas appearing to be semi-normal; regarding the pancreas, it showed an observed improvement more than the response of the intestines.ConclusionThe results support the protective effect of lemon fruit extract against CP-induced intestinal and pancreatic injury.

Anti-angiogenic effects of resveratrol in combination with 5-fluorouracil on B16 murine melanoma cells.

5-Fluorouracil (5-FU) has been used as a chemotherapeutic drug for various types of cancer, although the development of resistance remains a major limitation for its use in clinical settings. In the present study, the anti-angiogenic effects of resveratrol and 5-FU either alone or in combination were examined in a B16 murine melanoma model. Co-treatment using resveratrol and 5-FU inhibited cell proliferation more efficiently compared with use of either drug alone and the antiproliferative effect coincided with changes in the expression levels of AMP-activated protein kinase (AMPK), cyclooxygenase-2, vasodilator-stimulated phosphoprotein (VASP) and vascular endothelial growth factor (VEGF). Furthermore, co-treatment with resveratrol and 5-FU reduced tumor growth compared with that in the control group and this growth-inhibitory effect was associated with changes in the expression levels of AMPK, VASP and VEGF. Immunohistochemical staining for angiogenesis demonstrated that co-treatment with resveratrol and 5-FU reduced the number of microvascular vessels compared with that in the control group. These results suggested that co-treatment with resveratrol and 5-FU suppressed cell growth and angiogenesis in B16 murine melanoma tumors.

Silencing XIAP suppresses osteosarcoma cell growth, and enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin.

X-chromosome-linked inhibitor of apoptosis protein (XIAP) is an important member of the inhibitors of apoptosis (IAP) family. It has been shown that XIAP promotes the invasion, metastasis, growth and survival of malignant cells, and confers resistance to some chemotherapeutic drugs in various types of cancer. However, little is known regarding its detailed role in osteosarcoma (OS). In the present study, we first investigated the expression of XIAP in OS tissues, and an increased expression of XIAP in OS tissues compared to adjacent non-tumor tissue was identified. Additionally, its expression level correlated with key pathological characteristics including clinical stage, tumor size and metastasis. Subsequently, small interfering RNA (siRNA) was used to block XIAP expression to evaluate the effect of XIAP siRNA on cell proliferation, colony formation, cell cycle, apoptosis, tumorigenicity, and the combined effects of doxorubicin or cisplatin in OS cell lines (MG63 cells). Downregulation of XIAP expression using the RNA silencing approach efficiently decreased cell proliferation and colony formation, and induced cell apoptosis and cell cycle in the G0/G1 stage. In addition, this downregulation inhibited tumor growth in a nude murine model. The resuls also showed that treatment with XIAP-shRNA in combination with doxorubicin or cisplatin enhanced chemosensitivity. These results suggested that XIAP may aid the diagnosis of OS and may be an effective strategy for gene therapy of this disease.

Protective effect of Selenium nanoparticle against cyclophosphamide induced hepatotoxicity and genotoxicity in Swiss albino mice

Cyclophosphamide (CP) is the most commonly used chemotherapeutic drug for various types of cancer. However, its use causes severe cytotoxicity to normal cells in human. It is well known that the undesirable side effects are caused due to the formation of reactive oxygen species. Selenium is an essential micronutrient for both animals and humans and has antioxidant and membrane stabilizing property, but selenium is also toxic above certain level. Nano selenium has been well proved to be less toxic than inorganic selenium as well as certain organoselenium compounds. The objective of the study is to evaluate the protective role of Nano-Se against CP-induced hepatotoxicity and genotoxicity in Swiss albino mice. CP was administered intraperitoneally (25 mg/kg b.w.) and Nano-Se was given by oral gavages (2 mg Se/kg b.w.) in concomitant and pretreatment scheme. Intraperitoneal administration of CP induced hepatic damage as indicated by the serum marker enzymes aspartate and alanine transaminases and increased the malonaldehyde level, depleted the glutathione content and antioxidant enzyme activity (glutathione peroxidase, glutathione-s-transferase, superoxide dismutase and catalase), and induced DNA damage and chromosomal aberration. Oral administration of Nano-Se caused a significant reduction in malonaldehyde, ROS level and glutathione levels, restoration of antioxidant enzyme activity, reduction in chromosomal aberration in bone marrow, and DNA damage in lymphocytes and also in bone marrow. Moreover, the chemoprotective efficiency of Nano-Se against CP induced toxicity was confirmed by histopathological evaluation. The results support the protective effect of Nano-Se against CP-induced hepatotoxicity and genotoxicity.

Simultaneous determination of 5 psychotropic drugs of various types in an autopsy case of acute multiple drug poisoning

We attempted the simultaneous determination of 5 drugs, mirtazapine, sertraline, chlorpromazine, amoxapine and zolpidem, detected in a gas chromatography–mass spectrometry screening test in an autopsy case. The solid-phase extraction of the analytes from biological samples was achieved using Oasis®HLB cartridges (Waters, Milford, MA, USA). Gas chromatography was performed on a HP-5MS fused silica capillary column (30m×0.25mm i.d., 0.25μm film thickness, Agilent Technologies). The mass spectrometer was operated with an electron energy of 70eV in electron impact mode. The qualitative and quantitative analyses were performed in full-scan mode and the selected ion monitoring mode, respectively. The total ion chromatogram showed good separation of these drugs. Linear graphs were obtained with good correlation coefficients for these drugs from 0.001 to 2.0μg/mL (r2=0.9909–0.9986) using imipramine-d6 as an internal standard. The recoveries of these drugs were found to be 62.8–88.0% in spiked whole blood. Mirtazapine, sertraline, chlorpromazine, amoxapine and zolpidem were found in post-mortem samples of the deceased at concentrations of 2.67, 0.07, 0.25, 0.32 and 0.68μg/mL, respectively. The concentration of mirtazapine was within the lethal level and those of amoxapine and zolpidem were within the toxic level. We diagnosed that the cause of death was acute multiple drug poisoning. The simple and practical procedure used in this study is useful for the simultaneous determination of psychotropic drugs of various types in post-mortem biological samples.

Identification of inositol polyphosphate 4-phosphatase type II as a novel tumor resistance biomarker in human laryngeal cancer HEp-2 cells

Although tumor resistance remains a significant impediment to successful radiotherapy, associated regulatory markers and detailed molecular mechanisms underlying this phenomenon are not well defined. In this study, we identified inositol polyphosphate 4-phosphatase type II (INPP4B) as a novel marker of radioresistance by systematically analyzing Unigene libraries of laryngeal cancer. INPP4B was highly expressed in radioresistant laryngeal cancer cells and was induced by treatment with either radiation or anticancer drugs in various types of cancer cells. Ectopic INPP4B overexpression increased radioresistance and anticancer drug resistance by suppressing apoptosis in HEp-2 cells. Conversely, INPP4B depletion with small interfering RNA resensitized HEp-2 as well as A549 and H1299 cells to radiation- and anticancer drug-induced apoptosis. Furthermore, radiation-induced INPP4B expression was blocked by inhibition of extracellular signal-regulated kinase (ERK). INPP4B depletion significantly attenuated radiation-induced increases in Akt phosphorylation, indicating an association of INPP4B-mediated radioresistance with Akt survival signaling. Taken together, our data suggest that ERK-dependent induction of INPP4B triggers the development of a tumor-resistance phenotype via Akt signaling and identify INPP4B as a potentially important target molecule for resolving the radioresistance of cancer cells.