Period Of Drug Administration Research Articles

The clinical effectiveness of conservative surgical management in medication-related osteonecrosis of the Jaw

ObjectivesConsensus has not yet been reached on the therapy for medication-related osteonecrosis of the jaw (MRONJ). We assessed the effectiveness of conservative surgical management, which involves removing the necrotic bone and performing a gingivectomy, followed by localized cleaning to facilitate the separation of the sequestrum. Additionally, we revalidated the treatment algorithm utilized by our department. MethodsWe examined 160 patients diagnosed with MRONJ at three hospitals. The data for this study were collected retrospectively. These patients were followed up for a minimum of 2 years. ResultsThe outcome 2 years after starting conservative surgical management was: cure: 117 cases; improvement: 22 cases; unchanged: 12 cases; and deterioration: 9 cases. The cure rate was 72.3% and 83.0% at 2 and 5 years after therapy initiation, respectively, and significantly lower at age ≥ 74 years compared to age < 74 years (P < 0.001), with malignant tumour as the primary disease when compared to osteoporosis (P < 0.001), and with ≥ 4 years of administration compared to < 4 years (P = 0.0301). On multivariate analysis, the trigger (P < 0.05), primary disease (P = 0.001), and administration period (P < 0.01) were independent prognostic factors. ConclusionsConservative surgical management is effective for MRONJ regardless of stage, especially in patients with age < 74 years, osteoporosis, and short drug-administration periods, and could become a first-line therapy for all stages.

Experience in using Aterixen® in clinical practice. Results of the "SUPRA" observation program

Background. The new medical product Aterixen (XC221GI) has appeared on the pharmaceutical market in 2022. It was revealed, at preclinical stage, that the main anti-inflammatory drug's effect was assured by its effect on production of anti-inflammatory cytokines IL-6, IL-8 and chemokines IP-10 (CXCL10), MIG (CXCL9). The results of double-blind randomized placebo-controlled studies have shown high efficacy of the drug in the management of patients with new coronavirus infection (COVID-19) of different severity.&#x0D; Aim. To evaluate experience of Atherixen practical use among physicians and general practitioners.&#x0D; Materials and methods. The observational program included patients aged from 18 to 60 years with confirmed diagnosis of mild COVID-19. All patients have signed voluntary informed consent to participate in the study. The study consisted of 2 periods: screening period and drug administration period. All patients received Aterixen (100 mg tablets), 1 tablet 2 times per day for 14 days within the standard therapy outlined in the Temporary methodological recommendations on prevention, diagnosis, and treatment of COVID-19. Efficacy was assessed by mean disease duration and physician and patient treatment satisfaction via five-point Likert scale.&#x0D; Results. The average disease duration did not exceed 9.5 days. It indicates the ability of Aterixen to prevent the transition of the disease to moderate and severe forms. The degree of physician and patient treatment satisfaction via five-point Likert scale in the vast majority of cases corresponded to the highest grades. Moreover, no adverse events were reported during the study and all patients had high tolerability.

EVALUATION OF CLINICAL EFFECTIVENESS OF THE DRUG SILIOSTIN IN BROILER CHICKEN DYSCHONDROPLASIA

An experiment was conducted at the poultry farm "Ivanov A. S." to study the clinical effectiveness of the new osteotropic drug Siliostin in broiler chicken dischondroplasia. Siliostin is a complex pharmaceutical composition containing sources of organosilicon and inorganic compounds, flavonoids, organic acids, vitamins, and a range of osteotropic macro and microelements. Two groups of Cobb-500 crossbred broiler chickens were formed for the experiment experimental and control (n = 60). Over 21 days, the birds in the experimental group received Siliostin at a dose of 2% of the mass of consumed complete feed, while the control group chickens were fed only on the primary ration feeds. The therapeutic effectiveness of Siliostin was evaluated based on criteria such as clinical condition, flock integrity, body weight, and serum blood biochemistry indicators. It was established that the use of the drug in cases of clinical manifestation of dischondroplasia in broiler chickens contributes to the improvement of the physiological condition of sick birds, normalisation of indicators of biochemical homeostasis, and also has a positive effect on feed activity and intensive body weight gain. Moreover, after the end of the drug administration period and until the completion of the production cycle (60 days), the positive dynamics in the parameters mentioned above were maintained, and no repeated cases of dischondroplasia were observed in the experimental group of broilers.

Safety confirmation of induced pluripotent stem cell-derived cardiomyocyte patch transplantation for ischemic cardiomyopathy: first three case reports.

With the expected increase in patients with heart failure and ischemic 15 cardiomyopathy, the development of myocardial regenerative medicine using cell transplantation as a novel treatment method is progressing. This first-in-human clinical trial aimed to confirm the safety of cardiomyocyte patch transplantation derived from allogeneic induced pluripotent stem (iPS) cells based on the results of several preclinical studies. The inclusion criteria were left ventricular ejection fraction of 35% or less; heart failure symptoms of New York Heart Association class III or higher despite existing therapies such as revascularization; and a 1-year observation period that included a 3-month immunosuppressive drug administration period after transplantation of iPS cell-derived cardiomyocyte patches to evaluate adverse events, cardiac function, myocardial blood flow, heart failure symptoms, and immune response. In the first three cases of this trial, no transplanted cell-related adverse events were observed during the 1-year observation period, and improvement in heart failure symptoms was observed. In addition, improvements in left ventricular contractility and myocardial blood flow were observed in two of the three patients. Regarding immune response, an increase in transplant cell-specific antibody titer was observed in all three patients after immunosuppressive drug administration. In one patient with poor improvement in cardiac function and myocardial blood flow, an increase in antibody titer against HLA-DQ was observed even before cell transplantation. Our case findings demonstrate that the transplantation of iPS cell-derived cardiomyocyte patches for ischemic cardiomyopathy can be safely performed; however, further investigation of the therapeutic effect and its relationship with an immune response is needed by accumulating the number of patients through continued clinical trials.

Impact of microsampling on toxicological evaluation in rodent safety studies.

Recently, animal welfare has been attracting worldwide attention, and implementation of 3Rs (replacement, reduction, and refinement) is prioritized in every way possible in the drug development. Microsampling, in which small amounts of blood are collected, is attracting attention in this context. ICH S3A Q&A focused on microsampling was published in November 2017 to help accelerate the application of microsampling for toxicokinetic assessment. The increased sensitivity of drug measurement apparatuses such as mass spectrometers has made it possible to measure drug concentrations with small amounts of blood samples. In this review, we summarized the reports on toxicological influence of microsampling in rodents (rats and mice) with or without drug administration or recovery period after blood collection and influences that may arise from differences in the blood sampling site or blood sampling volume. We also summarized some perspectives on further implementation of microsampling in toxicology studies. The use of microsampling in regulatory toxicology studies has gradually increased, although at a lower rate than in discovery studies. Since more animals are used in GLP toxicology studies than in discovery studies, the effect of reducing the number of animals by microsampling is expected to be greater in the toxicology studies. This report aims to promote the application of microsampling to nonclinical studies, as it is beneficial for improving animal welfare and can contribute to the 3Rs.

Evaluation of effectiveness of pharmacological treatment in pelvic congestion syndrome.

Pelvic congestion syndrome (PCS) is a pain syndrome characterized by positional pelvic pain and is associated with pelvic and vulvar varicosities as well as symptoms of dyspareunia and postcoital pain. Since the etiology of PCS is complex, the treatment should be individualized. Despite both pharmacological and interventional methods being used, there is significant predominance of minimally invasive therapies e.g. embolization. The study considers the answer to the question of whether pharmacological therapy is altogether effective. Using a combination of keywords, a PubMed search was performed for the years 1987-2022. The relevant articles were appointed and included in this narrative review. Despite the multitude of alternatives for pharmacological treatment, the systemic side effects of the medications used, as well as the interactions between drugs, affect patients' compliance and persistence. Furthermore, the quality of the currently existing evidence, considering the efficacy of the given substances, is low. Because of the adverse effects and thus the limited drug administration period, there is currently insufficient research on long-term effectiveness of the PCS pharmacological treatment. Therefore, prospective, comparative studies with larger patient population sizes are necessary to provide the possibility of efficient pharmacological therapy.

IMPORTANCE OF RASOUSHADHIS IN AYURVEDA: A REVIEW

If used wisely, science is a boon to humanity and, if misused, can be hazardous. Ayurveda is one of the primordial systems of medical science that has elaborated the causes and methods of drug-induced consequences and preventive measures. Every system has some flaws, which need to be noted and rectified no matter how excellent the system is. In rasoushadhis (herbomineral formulations) preparation, specific techniques like shodhana, jarana and marana etc., have been developed to prepare more bio-assimilable forms of rasaushadha dravya. The indications, dose, vehicle, period of drug administration, interval or duration of treatment, diagnosis of the disease, nature or prakriti of the patient, pathya-apathya (favourable-unfavourable regimen) etc., are significant factors that the physician should always consider before they recommend these rasoushadhis to the patients. This review compiles the standard procedures which are adopted during the preparation of rasoushadhis like Shodhana, and Marana, the utility of rasoushadhis in Ashtanga Ayurveda, skin diseases, lifestyle disorders etc. and the rational use of rasoushadhis to understand and highlight the importance and uniqueness of rasoushadhis.

Adavosertib (AZD1775) does not prolong the QTc interval in patients with advanced solid tumors: a phase I open-label study

PurposeAdavosertib is a small-molecule, ATP-competitive inhibitor of Wee1 kinase. Molecularly targeted oncology agents have the potential to increase the risk of cardiovascular events, including prolongation of QT interval and associated cardiac arrhythmias. This study investigated the effect of adavosertib on the QTc interval in patients with advanced solid tumors.MethodsEligible patients were ≥ 18 years of age with advanced solid tumors for which no standard therapy existed. Patients received adavosertib 225 mg twice daily on days 1–2 at 12-h intervals and once on day 3. Patients underwent digital 12-lead electrocardiogram and pharmacokinetic assessments pre-administration and time-matched assessments during the drug administration period. The relationship between maximum plasma drug concentration (Cmax) and baseline-adjusted corrected QT interval by Fridericia (QTcF) was estimated using a prespecified linear mixed-effects model.ResultsTwenty-one patients received adavosertib. Concentration–QT modeling of ΔQTcF and the upper limit of the 90% confidence interval corresponding to the geometric mean of Cmax observed on days 1 and 3 were below the threshold for regulatory concern (not > 10 ms). No significant relationship between ΔQTcF (vs baseline) and adavosertib concentration was identified (P = 0.27). Pharmacokinetics and the adverse event (AE) profile were consistent with previous studies at this dose. Eleven (52.4%) patients experienced 17 treatment-related AEs in total, including diarrhea and nausea (both reported in six [28.6%] patients), vomiting (reported in two [9.5%] patients), anemia, decreased appetite, and constipation (all reported in one [4.8%] patient).ConclusionAdavosertib does not have a clinically important effect on QTc prolongation.ClinicalTrials.govNCT03333824.

ROLE OF AYURVEDIC HERBAL AND HERBO-MINERAL FORMULATIONS IN FEMALE INFERTILITY- A REVIEW ARTICLE

Background (Introduction): Infertility is a global health issue affecting millions of people of reproductive age worldwide. According to WHO, available data suggests that between 48 million couples and 186 million individuals have infertility globally. According to ayurveda, womb preparation is the most important factor to attain fertility. Herbo-metallic formulations prepared using SOPs can play a significant role in eliminating doshas in a short duration of time. They are known for their minimum dose, maximum efficacy, and least side effects. They help to keep all the hormones and the reproductive system in an equilibrium state. They remove all the toxins from the body and regularize menstrual cycles. They possess Rasayan (Immuno-modulatory) and Yogavahi (Nano-carriers; Act accordingly) properties. Aims/objective: To evaluate the role of Herbo-metallic formulations in infertility. Methodology: All the material and data are collected from ancient treatises, Research papers under google scholar, pubmed, Elsevier, etc. search engines. Results: Various research have been reviewed for the impact of Rasaushadhi (Herbo-mineral/metallic formulations) on fertility and the result found to be quiet satisfying as they are Ushana in virya (Potency) and act directly on target organ (Reproductive tract) in shorter duration is prepared as per the classical procedure. Discussion: For healthy progeny, ritu (Menstrual cycle), kshetra (Reproductive tract), beeja (Ovum/sperm), and ambu (Nutrition) factors must be in homeostasis. Metallic preparations can be harmful and toxic if they are not prepared properly. The indications, dose, vehicle(Anupan), period of drug administration, interval or duration of treatment, disease diagnosed, nature or Prakruti of the patient, Pathya-apathya, etc. are major factors that should always be considered by the physician before prescribing Rasaushadhi to the patients. Conclusion: As herbo-mineral formulations play a very significant role in ayurveda and they are capable to cure severe disorders in a minimum dose and time. Therefore, this article reviews several Rasaushadhis along with their pharmacokinetics concerning infertility.

Duration of Zidovudine Consumption Correlates with Anemia in People Living with HIV

Anemia is the most common hematological disorder associated with Human Immunodeficiency Virus (HIV). WHO recommends zidovudine (AZT) as one of the first-line drugs for this infection. It is important to note that the drug has the adverse effect of causing anemia. Therefore, this study correlates AZT consumption duration and the incidence of anemia in HIV-infected individuals. This cross-sectional study was conducted at health service facilities using 213 participants. The data were obtained from medical records, and the assessed parameter was hemoglobin (Hb) level after less or more than a year of zidovudine administration. Furthermore, they were analyzed using a Pearson’s coefficient contingency test (p&lt;0.05) to evaluate the correlation between groups with and without anemia at each period of drug administration. The results showed a significant correlation (p&lt;0.05) between sex and age with anemia incidence in HIV patients administered AZT. The duration of this drug intake in HIV-infected individuals was correlated with anemia (p= 0.024; OR=0.369). This indicates the use of AZT for at least one year may be a protective factor for the incidence of anemia in patients with HIV compared to the group consuming this drug for less than one year.

Abstract CT180: Activation of innate and adaptive immune response with a clinical stage TLR7 agonist prodrug PRTX007

Abstract Background. PRTX007 is an orally administered prodrug of PRX034, a toll-like receptor 7 (TLR7) agonist that elicits an unprecedented pattern of systemic immune induction in non-human primates and in humans. Notably, there is no evidence of NF-Kβ-mediated systemic inflammation at drug levels that stimulate IFN-responsive pathways and corresponding downstream cellular processes, including activation of CD8+ T cells and NK cells. We have previously reported interim results from a Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) study of PRTX007. PRTX007 demonstrated a favorable safety profile with no serious adverse events (SAEs) and a lack of the adverse events (AEs) historically associated with TLR7 agonists. Robust systemic immune induction was achieved, without counter-regulation or evidence of systemic inflammation, in participants receiving PRTX007 in the 300 - 500 mg MAD cohorts. This report describes new results from the 750 mg MAD cohort, the highest MAD dose level in this now-completed study. Methods. Phase 1, single-center, prospective, randomized, double-blind, placebo-controlled study of 9 SAD and 4 MAD cohorts of PRTX007 administered QOD orally to healthy adult participants. Primary objectives were safety and tolerability. Secondary objectives were evaluation of pharmacokinetics (PK) and pharmacodynamics. In total, 104 of the 130 participants in this study received study drug. Results. AEs were limited to non-dose-related mild headache, minor dose-related increases in ALT (&amp;lt;2X ULN) that rapidly resolved, and mild-moderate fever that were transiently observed in 1 of 8 participants. The PKs of PRTX007 and PRX034 are well-behaved with exposure increasing proportionally to PRTX007 dose without accumulation upon repeated dosing (mean PRX034 AUC (hr*ng/ml) on D1: 13,432; D13: 13,796). Coordinated expression of interferon-stimulated genes and genes known to be related to TLR7 agonism were observed in immune cells in blood in all participants. Increases in IL-1RA, MCP-1 and IP10 in plasma were also observed. IL-6, TNFα and IL- 1β remained essentially unchanged from pretreatment levels. The proportion of CD8+ T cells and NK cells, with significant expression of the proliferation marker Ki67 and activation marker CD38, increased markedly from pretreatment to end of dosing in all participants. Ki67+ expressing CD8+ T cells increased from 1.1% to 9.8% and Ki67+ expressing NK cells increased from 3.6% to 10.3% during the two-week period of drug administration. CD38+ CD8+ T cells increased from 11.8% to 21.9% and CD38+ NK cells increased from 59.4% to 80.0% during the corresponding period. Conclusion. PRTX007 demonstrated a favorable safety profile in all SAD and MAD cohorts. In the 750 mg MAD cohort, activation of the innate and adaptive immune response including important effector cell populations were observed without systemic increases in proinflammatory factors. Citation Format: Charlotte R. Lemech, Christopher Argent, Curtis L. Scribner, Andrew Sharabi, Richard Daniels, James R. Appleman. Activation of innate and adaptive immune response with a clinical stage TLR7 agonist prodrug PRTX007 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT180.

The role of SIRT2 inhibition on the aging process of brain in male rats

BackgroundThough the exact mechanisms regarding brain aging and its relation to neurodegenerative disorders are not precise, oxidative stress, the key regulators of apoptosis and autophagy, such as bcl-2 and beclin 1, seem to be the potential players in the aging of the cerebral cortex and hippocampus. As a type of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, sirtuin 2 (SIRT2) has been associated to age-related diseases. However, the exact role of SIRT2 in brain aging is not well studied. The objective of the current study was to study the role of SIRT2 inhibition on brain aging through the neuroprotective mechanisms. MethodsWe tested the effects of AGK-2, a SIRT2 inhibitor, on oxidative stress parameters, apoptosis and autophagy regulators including bcl-2, bax, beclin1 in young and old rats. 24 Wistar albino rats (3 months-old and 22 months-old) were divided into four groups; Young-Control (4% DMSO+PBS), Young-AGK-2 (10 µM/bw, ip), Aged-Control, and Aged-AGK-2. Following the 30 days of drug administration period the rats were sacrificed and the cerebral cortex, hippocampus, and cerebellum were isolated. Total antioxidant status (TAS) and total oxidant status (TOS) were measured as oxidative stress parameters in all three brain regions. SIRT2, bcl-2, and bax protein expression levels were measured by western blot and gene expression level of beclin 1, Atg5, and SIRT2 by real-time PCR. ResultsThe bcl-2, bcl-2/bax ratio, beclin 1, and TAS in the cerebral cortex of the aged group were significantly decreased; however, the TOS, oxidative stress index (OSI), and SIRT2 expression in the cerebral cortex and hippocampus increased. SIRT2 inhibition by AGK-2 reduced TOS and OSI levels in all brain regions and increased bcl-2, bcl-2/bax ratio. In aged animals, AGK-2 also increased the beclin 1 levels in the cortex and hippocampus. ConclusionOur results indicate that SIRT2 has an essential role in brain aging. The inhibition of SIRT2 by AGK-2 may increase cell survival and decrease aging related processes in the cerebral cortex and hippocampus via decreasing oxidative stress, and increasing bcl-2 and beclin 1 expression.

Assessment of The Toxicological Profile of The New Dioxidine Dosage Form (Solution for Topical and External Use, 0.025%)

The general toxicity was studied with an assessment of local tolerability, immunotoxicity, and pharmacological safety of the new medicine Dioxidine®, a solution for topical and external use, 0.25 mg/ml (0.025%) for the treatment of acute tonsillopharyngitis (JSC «Valenta Pharm», Russia). The experiment included 48 rabbits (divided in equal proportion by sex) randomized into 3 groups (n=16 in each group), whose back wall of the pharynx was irrigated with the studied substances for 28 days. Group 1 — control (aqueous solution of NaCl 0.9% for infusions at a daily dose of 4.0 ml/animal); group 2 — dioxidine (1.8 ml/animal); group 3 — dioxidine (4.0 ml/animal). The animals were observed for the entire period of drug administration — up to the 28 th day of the experiment, as well as during the delayed observation period — up to the 58 th day. The following indicators were recorded: lethality, daily monitoring of general condition and behavior, weight, feed and water consumption, respiratory rate, heart rate, blood pressure, electrocardiogram, mass coefficients of internal organs. Immunotoxicity, poisoning symptoms, adrenal insufficiency, as well as animal autopsy results were assessed. Clinical and biochemical blood tests, blood coagulation system analysis, urine analysis, macroscopic and histological examination of internal organs were performed. The absence of statistically significant differences in all evaluated indicators between the group of animals receiving dioxidine solution for topical and external use, 0.25 mg/ml (0.025%) at a dose of 1.8 ml/animal (equivalent to 15 therapeutic doses for humans), the group receiving dioxidine at a dose of 4.0 ml/animal (equivalent to 35 therapeutic doses for humans) and the control group allowed us to draw conclusions concerning the absence of signs of general toxicity, including toxic effects on the adrenal glands, cardiotoxicity, immunotoxicity, and toxic effects on other organs and organ systems, as well as local irritant and toxic effects after repeated irrigation of dioxidine on the back wall of the pharynx in rabbits for 28 days and during the period of delayed observation.

Sintesis, Karakterisasi Struktur, dan Kajian Molecular Docking Senyawa Turunan 4’-Metoksi Flavonol sebagai Antagonis Reseptor Estrogen Alpha (ER-a) pada Kanker Payudara

A long period of drug administration in breast cancer chemotherapy can cause various side effects. These situations encourage researchers to search for and develop alternative anticancer drugs through various approaches. This study aimed to synthesize a flavonol derivative (TF4) and to study the interactions of the synthesized compound with ER-α as one of the targeted receptors in breast cancer treatment. The synthesis was carried out using the stirring method and the study of interactions of TF4 with ER-α was performed through molecular docking against ER-α crystal structures bound to an antagonist (PDB ID: 3ERT) and agonist (PDB ID: 1A52). The synthesis of TF4 produced crude product in 58 % yield and pure product in 6 % yield. The structure of TF4 was confirmed by spectroscopic analyses including UV, FT-IR, 1D, and 2D NMR. The docking results showed that the TF4 does not form any conventional hydrogen bond with ER-α. However, it can form carbon-hydrogen (C--H) bonds and van der Walls interactions with several important residues on the active site of ER-α. In addition, the binding free energy values of TF4 (-9.14 and -9.50 kcal/mol) are more negative than estradiol (E2) as one of the natural ligands for ER-α. Thus, it can be estimated that TF4 can be bounded easier on the active site of ER-α than its natural ligand. It may presume that it can act as an estrogen antagonist because of the similarity in interactions and binding poses compared to TAM, TOR, dan 4-OHT as reference drug molecules.

A Randomized Phase 2 Study of 5-Aminolevulinic Acid Hydrochloride and Sodium Ferrous Citrate for the Prevention of Nephrotoxicity Induced by Cisplatin-Based Chemotherapy of Lung Cancer

Introduction: Cisplatin-based chemotherapy was established in the 1980s, and it has been improved by the development of a short hydration protocol in lung cancer therapy. However, cisplatin-based chemotherapy is still associated with renal toxicity. Because 5-aminolevulinic acid (5-ALA) with sodium ferrous citrate (SFC) is known to be a mitochondrial activator and a heme oxygenase-1 (HO-1) inducer, 5-ALA with SFC is speculated to mitigate cisplatin-induced renal inflammation. Methods: We investigated the effects of oral administration of 5-ALA with SFC for preventing cisplatin-based nephrotoxicity in patients with lung cancer and evaluated its benefits for patients who received cisplatin-based chemotherapy. The primary endpoint was the significance of the difference between the serum creatinine (sCr) levels of the patients administered 5-ALA with SFC and those given placebo after course 1 of chemotherapy. The difference in the estimated glomerular filtration rate (eGFR) between the two groups was also evaluated as the secondary endpoint. Results: The double-blind, randomized two-arm studies were conducted at 15 medical facilities in Japan; 54 male and 20 female patients with lung cancer who received cisplatin-based chemotherapy between the ages of 42 and 75 years were included in the study. The compliance rate was greater than 94% in the primary assessment and subsequent drug administration periods. All enrolled patients completed the four cycles of cisplatin-based chemotherapy with short hydration. The average level of sCr on day 22 of course 1 was 0.707 mg/dL in the group treated with 5-ALA and SFC and 0.735 mg/dL in the placebo group, respectively, and the sCr in the test group was significantly lower than that in the placebo group (p = 0.038). In addition, the eGFR was significantly higher in the SPP-003 group than in the placebo group up to day 1 of course 3 (84.66 and 75.68 mL/min/1.73 m², respectively, p = 0.02) and kept better even after the last administration of the study drug (82.37 and 73.49 mL/min/1.73 m², respectively, p = 0.013). Conclusions: The oral administration of 5-ALA with SFC is beneficial to patients undergoing cisplatin-based chemotherapy for lung cancer with short hydration.

Degeneration of Granule Neurons In The Dentate Gyrus (Dg) Area In The Hippocampus In Male Rats Under The Influence of Simvastatin

Background: Simvastatin is a lipophilic statin used to prevent and treat hypercholesterolemia. This study aimed to evaluate the effect of simvastatin on the appearance specifications of the DG region Hippocampus. Method: For the experiment, 36 male Wistar rats with an average weight of 300-250 g were divided into six groups (each group comprised six heads). Groups: 1): Control group, 2): Vitamin D dose 5 µg/kg, 3): Simvastatin group dose 1 mg/kg, 4): Simvastatin group dose 10 mg/kg, 5): Simvastatin group dose 1 mg/kg + vitamin D dose 5 µg/kg, 6): Simvastatin group dose 10 mg/kg + vitamin D dose 5 µg/kg. The duration of drug use was 28 days. At the end of the drug administration period, the animals were slaughtered, and then the brain tissue of the animals was extracted to prepare microscopic sections. Results: Microscopic studies show a negative effect of 10 mg/kg simvastatin on DG neurons. Conclusion: The microscopic studies in the present study indicate that high doses of simvastatin cause degeneration of neurons in the DG region of the hippocampus.

Ifenprodil for the treatment of methamphetamine use disorder: An exploratory, randomized, double-blind, placebo-controlled trial.

AimNo effective pharmacological interventions have been developed for patients with methamphetamine use disorder. Ifenprodil is a blocker of G protein‐activated inwardly rectifying potassium channels, which play a key role in the mechanism of action of addictive substances. We conducted a randomized, double‑blind, exploratory, dose‐ranging, placebo‐controlled trial to examine the clinical efficacy of ifenprodil for the treatment of methamphetamine use disorder.MethodsParticipants were assigned to three groups: placebo, 60 mg/d ifenprodil, or 120 mg/d ifenprodil. The drug administration period was 84 days. The primary outcome was the use or nonuse of methamphetamine during the drug administration period in the placebo group vs 120 mg/d ifenprodil group. We also assessed drug use status, relapse risk based on the Stimulant Relapse Risk Scale (SRRS), drug craving, and methamphetamine in urine as secondary outcomes. We further evaluated drug use status and SRRS subscale scores in patients who were not taking addiction medications during the study.ResultsIfenprodil did not affect the primary or secondary outcomes. However, the additional analyses showed that the number of days of methamphetamine use during the follow‐up period and scores on the emotionality problems subscale of the SRRS improved in the 120 mg/d ifenprodil group. The safety of ifenprodil was confirmed in patients with methamphetamine use disorder.ConclusionThe present findings did not confirm the efficacy of ifenprodil for methamphetamine use disorder treatment based on the primary or secondary outcomes, but we found evidence of its safety and efficacy in reducing emotionality problems.Clinical trial registrationThe study was registered at the University Hospital Medical Information Network Clinical Trial Registry (no. UMIN000030849) and Japan Registry of Clinical Trials (no. jRCTs031180080). The main registration site is jRCT (https://jrct.niph.go.jp/).

СРАВНИТЕЛЬНАЯ ОЦЕНКА ПРОТИВОЛУЧЕВОЙ ЭФФЕКТИВНОСТИ ФЛАГЕЛЛИНА ПО ВЫЖИВАЕМОСТИ И МИКРОЯДЕРНОМУ ТЕСТУ

Purpose: Comparative evaluation of the effectiveness of the domestic drug flagellin (development of the State Research Institute of High-Purity Biological Products, St. Petersburg) in an extended range of drug administration periods before and after irradiation, as well as evaluation of the possibility of using the micronucleus test as a biomarker of its effectiveness.&#x0D; Material and methods: The work was performed on male ICR CD1 mice weighing 20–22g. The radioprotective effectiveness of flagellin was evaluated by the 30-day survival rate of experimental animals in comparison with control groups. The cytogenetic effect was evaluated by a micronucleus test in polychromatophilic erythrocytes (MJ-PCE) of mouse bone marrow. Irradiation was performed on the RUST M1 X-unit at a dose rate of 1.1 Gy/min in the dose range from 7 to 10 Gy for survival assessment and at a dose of 1 Gy for the micronucleus test. Flagellin was administered intraperitoneally at 0.2 mg/kg for 18 h and 30 min before irradiation, 10 and 30 min after irradiation. The animals of the control groups were injected with a solvent – phosphate-albumin buffer at the same time and in the same volume.&#x0D; Results: The most effective was the use of flagellin for 30 min and 10 min in relation to radiation (survival at 8.5 Gy 92 % and 78 %, at 9 Gy 81 % and 55 %, respectively) with survival in the control 29 % and 0. In the most studied version of the introduction of flagellin 30 minutes before exposure, the FID values at the level of generally accepted estimates LD16, LD50, LD84, were 1.3; 1.2 and 1.2, respectively.&#x0D; Conclusions: It is of interest to further expand the time range of the use of flagellin, especially after irradiation. The use of the method of estimating the proportion of polychromatophilic erythrocytes with micronuclei in the bone marrow allowed us to identify the optimal timing of drug administration much faster than in terms of survival (MJ-PCR test was performed 24 hours after irradiation). The MJ-PHE indicator can be considered as a potential biomarker of drug-induced increased radioresistance (this was previously shown in our studies for betaleukin, indralin, and riboxin).

Depletion of clomiphene residues in eggs and muscle after oral administration to laying hens

ABSTRACT The selective oestrogen receptor modulator (SERM) clomiphene is therapeutically used to induce ovulation. While prohibited as a doping agent in sports, it is frequently detected in sports drug testing urine samples. Few reports exist on clomiphene’s (illicit) use in the farming industry to increase the egg production rate of laying hens, which creates a risk that eggs as well as edible tissue of these hens contain residues of clomiphene. To investigate the potential transfer of clomiphene into eggs and muscle tissue, laying hens were orally administered with clomiphene citrate at 10 mg/day for 28 days. To determine clomiphene residues in eggs, chicken breast and chicken thigh, the target analyte was extracted from homogenised material with acetonitrile and subjected to ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. The test method reached a limit of quantification (LOQ) of 1 µg/kg and was characterised concerning specificity, precision, trueness and linearity. Analyses were performed on whole egg, egg white and yolk separately, and chicken muscle from breast and thigh. Clomiphene was detectable in eggs two days after the beginning of the drug administration period. The drug concentrations increased to 10–20 µg per egg within one week, and after withdrawal of clomiphene, residues decreased after 4 days, but traces of clomiphene were still detectable until the end of the study (14 days after the last administration). In the chicken’s muscle tissue, clomiphene levels up to 150 µg/kg (thigh) and 36 µg/kg (breast) were found. Six days after the last dose, tissue clomiphene concentrations fell below the LOQ. Overall, these results underline the concerns that clomiphene may be transferred into animal-derived food and future research will therefore need to focus on assessing and minimising the risk of unintentional adverse analytical findings in doping controls.

Serum concentrations, pharmacokinetic/pharmacodynamic modeling, and effects of dexamethasone on inflammatory mediators following intravenous and oral administration to exercised horses

Corticosteroids are potent anti-inflammatory drugs and as such are commonly administered to performance and racehorses. The objectives of the current study were to describe blood and urine concentrations and the pharmacokinetics and effects on cortisol and inflammatory mediator concentrations, following intravenous and oral administration to 12 exercised horses. Horses received an intravenous administration of 40 mg of dexamethasone sodium phosphate and 20 mg of dexamethasone tablets with a 4 week washout in between administrations. Blood and urine samples were collected prior to and for up to 96 hours post drug administration. Whole blood samples were collected at various time points and challenged with lipopolysaccharide or calcium ionophore to induce ex vivo synthesis of eicosanoids. The concentrations of dexamethasone and eicosanoids were measured using LC-MS/MS and the concentrations from both routes of administration fit simultaneously using a three-compartment pharmacokinetic model. A turnover model with inhibition of Kin gave an adequate fit to the dexamethasone-cortisol PKPD data. Serum and urine dexamethasone concentrations were at the limit of quantitation at 96 and 48 hours post administration, respectively. The volume of distribution, systemic clearance, and terminal half-life was 0.907 L/kg, 7.89 mL/h/kg, and 1.34 h, respectively. The IC50 for cortisol suppression was 0.007 ng/mL. Stimulation of dexamethasone treated blood with lipopolysaccharide and calcium ionophore resulted in an inhibition of inflammatory biomarker production for a prolonged period of time post drug administration. The results of this study suggest that dexamethasone has a prolonged anti-inflammatory effect following intravenous or oral administration to horses.