Administration Of Substances Research Articles

A Pharmacokinetic Study of the Interaction Between Regorafenib and Paracetamol in Male Rats

Background: In clinical practice, the prevalent problem of polypharmacy could result in increased risks of drug–drug interactions. Regorafenib (REG) is commonly co-administered with paracetamol (PA) as a treatment protocol in cancer patients with pain therapy. Purpose: This study aimed to demonstrate the effect of paracetamol on the pharmacokinetic parameters of regorafenib and its metabolites following a single administration of both substances in rats. Additionally, the influence of REG and its metabolites on the pharmacokinetics of paracetamol was also determined. Methods: Twenty-four rats were divided randomly into three groups: REG group (IIREG, regorafenib 20 mg/kg, n = 8), PA group (IIIPA, paracetamol 100 mg/kg, n = 8), and REG+PA co-administration group (IREG+PA, REG 20 mg/kg and PA 100 mg/kg, n = 8). The concentrations of regorafenib, regorafenib-N-oxide (M-2), and N-desmethyl-regorafenib-N-oxide (M-5) were determined using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS). The plasma concentrations of PA and its glucuronide (GPA) and sulfate (SPA) metabolites were measured using the validated high-performance liquid chromatography method with ultraviolet detection (HPLC–UV). The pharmacokinetic parameters were calculated using a non-compartmental model. The statistical evaluation was performed in the SAS program. Results: After the administration of PA, the Cmax and AUC0–∞ of REG increased by 890% and 1140%, respectively; for M-2, they increased by 220% and 170%, and for M-5, by 2130% and 1730% (Cmax and AUC0–∞, respectively). A difference in the ratio of M-2/REG for AUC0–∞ and Cmax between the groups was observed, but not for M-5/REG. The AUC0–∞ for PA and GPA decreased by 20.7% and 51.1%, respectively, when PA was co-administered with REG. But the AUC0–∞ for SPA increased by 91.35% in the IREG+PA group. A difference in the ratio of GPA/PA for Cmax and for SPA/PA for AUC0–t and AUC0–∞ between the groups was observed. Conclusions: Paracetamol increased the plasma exposure of regorafenib, M-2, and M-5, which may exacerbate the drug’s side effects. In contrast, REG reduced paracetamol exposure and contributed to its faster elimination, which may reduce the analgesic and antipyretic effects of paracetamol. These findings suggest clinical relevance for oncology patients requiring analgesic treatment.

Alcohol and cannabis co-use: Probing subjective response in eliciting cross-substance craving

The co-use of alcohol and cannabis is rising in prevalence, yet the mechanisms driving individuals to co-use are not well understood. Subjective response to alcohol or cannabis may predict the desire to use either substance. However, which specific facets of subjective response predict cross-substance craving remains unclear. The present study investigated whether acute administration of alcohol or cannabis facilitates cue-induced craving for the other substance, with an emphasis on the underlying subjective response mechanisms contributing to co-use. This is a secondary analysis of a behavioral pharmacology study that combined alcohol/cannabis administration with a cross-substance cue-reactivity paradigm in individuals who were heavy alcohol and heavy cannabis co-users. Over two sessions, twenty-nine individuals (17M/12F) self-administered alcohol or cannabis (in a crossover design), and then completed a cue-reactivity exercise with the other substance. Analyses tested how changes in subjective response variables following substance administration predicted cross-substance cue-induced craving. Following alcohol administration, greater subjective ratings of positive mood predicted significantly greater cue-induced cannabis craving (β = 1.14, SE = 0.41, t = 2.80, p = 0.010). Following cannabis administration, lower subjective effects ratings of positive mood/arousal predicted significantly greater cue-induced alcohol craving (β = −1.08, SE = 0.38, t = −2.85, p = 0.009; β = −2.38, SE = 1.13, t = −2.10, p = 0.047). This study identified subject response mechanisms contributing to cross-substance cue induced craving. These mechanisms include increases in positive mood following alcohol use and decreases in positive mood and arousal, akin to increases in relaxation, following cannabis use.

Targeted RT study: results on early toxicity of targeted therapies and radiotherapy

Purpose/objectiveCurrently, there are few prospective data on the tolerability of combining targeted therapies (TT) with radiation therapy (RT). The objective of this prospective study was to assess the feasibility and toxicity of pairing RT with concurrent TT in cancer patients. The aim was to enhance the existing evidence base for the simultaneous administration of targeted substances together with radiotherapy.MethodsProspective study enrollment was conducted at a single institution between March 1, 2020, and December 31, 2021, for all patients diagnosed with histologically confirmed cancer who underwent external beam radiotherapy in combination with targeted therapy. The study, known as the “targeted RT study,” was registered in the German Clinical Trials Register under DRKS00026193. Systematic documentation of the toxicity profiles of different targeted therapies was performed, and the assessment of acute toxicity followed the guidelines of the National Cancer Institute Common Terminology Criteria for Adverse Events Version v5.0.ResultsA total of 334 patients underwent 683 radiation therapy series. During the course of RT, 51 different TT substances were concurrently administered. External beam radiotherapy was employed for various anatomical sites. The combination of RT and concurrent TT administration was generally well tolerated, with no instances of severe acute toxicity observed. The most commonly reported toxicity was fatigue, ranging from mild to moderate Common Terminology Criteria for Adverse Events (CTCAE) °I-°III. Other frequently observed toxicities included dermatitis, dyspnea, dysphagia, and dry cough. No toxicity greater than moderate severity was recorded at any point. In only 32 patients (4.7% of evaluated RT series), the concurrent substance administration was discontinued due to side effects. However, these side effects did not exceed mild severity according to CTCAE, suggesting that discontinuation was a precautionary measure. Only one patient receiving Imatinib treatment experienced a severe CTCAE °III side effect, leading to discontinuation of the concurrent substance due to the sudden occurrence of melaena during RT.ConclusionIn conclusion, the current study did not demonstrate a significant increase or additional toxicity when combining radiotherapy and concurrent targeted therapy. However, additional research is required to explore the specific toxicity profiles of the various substances that can be utilized in this context.Trial registration numberDRKS00026193. Date of registration 12/27/2022 (retrospectively registered).

Functional properties of dietary quercetin in cardiovascular health and disease

AbstractThe increasing incidence of cardiovascular diseases has resulted in an escalating need for natural dietary supplements with cardioprotective properties. This review provides a thorough analysis of laboratory and clinical studies conducted on dietary quercetin, a widely available flavonoid, and its influence on the management of cardiovascular health and disease. The references cited in this review were obtained from reputable databases, including SciFinder, Web of Science, and ClinicalTrials.gov, with a specific focus on the period spanning from 1999 to 2023 pertaining to this subject matter. Notably, a bibliometric approach was used to analyze the bibliometric attribute trends of the research on quercetin associated with vascular health for the first time. Numerous investigations conducted on animal and human subjects at different phases of cardiac illness have consistently shown that the administration of quercetin substances improves cardiac function, suggesting the potential efficacy of quercetin in the management of heart disease. Evidently, the consumption of quercetin through dietary sources holds promise in conferring significant cardiovascular benefits through physiological mechanisms and biochemical signaling pathways, thus positioning it as a promising dietary contender for the prevention of cardiovascular disorders. Renewable food resources, including lovage leaves, elderberry, and radish leaves, which are abundant in quercetin, exhibit significant potential for the development and production of novel healthcare products with the objective of preventing cardiovascular disorders. This review is anticipated to provide valuable insights for the advancement of cardioprotective functional foods in the foreseeable future.

Reinforcing systems of the brain and quantification of their work

BACKGROUND: The reinforcing systems of the brain are represented by the ventral forbrain dopaminergic bundle, which innervates the emotiogenic structures of the limbic system. Their study shows the reproduction of unconditioned (self-stimulation, self-administration) and conditioned reflex (preference for place, temperature, color) reactions. The quantitative assessment of the brain’s reinforcing systems remains unclear. For self-stimulation of brain structures, the change of the pedal presses in the Skinner chamber and some calculated coefficients are used, for example, the “mismatch coefficient”, which characterizes the temporal characteristics of the pedal pressings. AIM: To develop, test, and substantiate an additional objective quantitative method for assessing the reinforcing systems of the brain, called the “addiction coefficient”, based on an analysis of the effect of three psychoactive compounds (amphetamine, morphine and ethanol) in different doses on self-stimulation of the lateral hypothalamus in rats. MATERIALS AND METHODS: The main method for studying the reinforcing systems of the brain was the reaction of self-stimulation of the lateral hypothalamus in Wistar rats, which was modulated by the administration of psychoactive substances. The psychomotor stimulant amphetamine (phenamine) hydrochloride (0.5, 1, 2, and 4 mg/kg), narcotic analgesic morphine hydrochloride (1, 2, 4, and 8 mg/kg), and ethanol (0.5, 1, 2, and 4 g/kg) administered intraperitoneally were used as inductors of reinforcing. The control was the administration of of 0.9% NaCl solution (0.1, 0.2, 0.4, and 0.8 ml/rat). RESULTS: The use of different controls, characterized by an increase or decrease in the self-stimulation reaction in response to the introduction of 0.9% NaCl solution, showed that calculated coefficients, including the “mismatch coefficient”, can change in different directions and do not objectively reflect the reinforcing effects of pharmacological substances. The proposed “addiction coefficient”, which reflected the component of psychic dependence, changed unidirectionally toward an increase. The degree of this increase can be tens and hundreds of percent of the control and is significantly independent of the initial values of self-stimulation. As expected, the “addiction coefficient” increased most clearly after amphetamine administration and less significantly after morphine and ethanol injections. CONCLUSIONS: The “addiction coefficient” of a psychoactive substance, calculated as the ratio of the increase in pedal presses to the value of the “mismatch coefficient”, is a clear quantitative indicator when assessing the reinforcing properties of psychoactive substances in the self-stimulation reaction of the lateral hypothalamus. The “addiction coefficient” does not significantly depend on the initial level of self-stimulation and is recommended for a comparative assessment of the reinforcing properties of primarily related psychoactive compounds.

Diagnosis of Lymphatic Metastasis in Breast Cancer Using Nanoparticle Technology - Diagnosis, Therapy, Imaging, Treatment

Breast cancer is a major cause of patient death rates, frequently leading to life-changing repercussions even after survival is attained. This paper aims to investigate therapeutic alternatives employing nanoparticles to specifically target and treat lymphatic metastasis, which is a highly dangerous characteristic of breast cancer. This work explores the effectiveness and importance of using nanoparticle-based therapeutics to prevent the harmful consequences of breast cancer progression. The paper begins by discussing the progress of lymphatic metastasis and then delves into the use of nanoparticle technology in imaging techniques, diagnostic methods, and therapy tactics. This section provides detailed information on primary targeting treatments, including chemotherapy specifically targeting cancer stem cells, induction of tumour cell death, suppression of Epithelial-Mesenchymal Transition (EMT), manipulation of the Tumour Microenvironment (TME), and improvement of the immune response. In addition, the research explores the use of nanoparticle technology in treatment plans, specifically focusing on its super magnetic capabilities and the application of gold nanoparticles, nanodiamonds, and other related qualities. Nanoparticle technology presents an optimistic strategy to address lymphatic metastasis in breast cancer. Nanoparticles can be used to deliver drugs or therapeutic substances directly to cancerous tumours, specifically targeting cancer cells to either destroy them or slow their growth. This strategy provides a solution for the administration of pharmaceuticals or substances that may provide challenges when delivered using conventional methods. Furthermore, nanoparticles facilitate the visualisation of tumours, aiding healthcare professionals in evaluating the severity of malignancy and formulating suitable treatment strategies. A comprehensive discussion has been conducted on several nanoparticles employed for inhibiting the dissemination of cancer cells from the primary organ to secondary organs. After successfully overcoming breast cancer, patients remain susceptible to post-surgical metastases in vital organs such as the lungs, brain, and bones. The advancements achieved through nanoparticle technology are highly significant. The discussion has focused on experimental evidence offered by researchers who mostly conducted studies on mice to support their findings.

Effect of Flavonols of Aronia melanocarpa Fruits on Morphofunctional State of Immunocompetent Organs of Rats under Cyclophosphamide-Induced Immunosuppression.

Aronia melanocarpa berries contain many compounds with potential benefits for human health. The food flavonoids quercetin and rutin, found in significant amounts in the fruits of A. melanocarpa, are known to have favourable effects on animal and human organisms. However, data on the effect of flavonols isolated from black chokeberry on immune functions during immunosuppression are not available in the literature. Thus, the aim of this study was to evaluate the effect of flavonol fraction isolated from A. melanocarpa fruits, in comparison with pure quercetin and rutin substances, on the dysfunctional state of rat thymus and spleen in immunodeficiency. The study was performed on Wistar rats. The animals were orally administered solutions of the investigated substances for 7 days: water, a mixture of quercetin and rutin and flavonol fraction of A. melanocarpa. For induction of immunosuppression, the animals were injected once intraperitoneally with cyclophosphamide. Substance administration was then continued for another 7 days. The results showed that under the influence of flavonols, there was a decrease in cyclophosphamide-mediated reaction of lipid peroxidation enhancement and stimulation of proliferation of lymphocytes of thymus and spleen in rats. At that, the effect of the flavonol fraction of aronia was more pronounced.

Extracellular vesicles in disorders of hemostasis following traumatic brain injury.

Traumatic brain injury (TBI) is a global health priority. In addition to being the leading cause of trauma related death, TBI can result in long-term disability and loss of health. Disorders of haemostasis are common despite the absence of some of the traditional risk factors for coagulopathy following trauma. Similar to trauma induced coagulopathy, this manifests with a biphasic response consisting of an early hypocoagulable phase and delayed hypercoagulable state. This coagulopathy is clinically significant and associated with increased rates of haemorrhagic expansion, disability and death. The pathophysiology of TBI-induced coagulopathy is complex but there is biologic plausibility and emerging evidence to suggest that extracellular vesicles (EVs) have a role to play. TBI and damage to the blood brain barrier result in release of brain-derived EVs that contain tissue factor and phosphatidylserine on their surface. This provides a platform on which coagulation can occur. Preclinical animal models have shown that an early rapid release of EVs results in overwhelming activation of coagulation resulting in a consumptive coagulopathy. This phenomenon can be attenuated with administration of substances to promote EV clearance and block their effects. Small clinical studies have demonstrated elevated levels of procoagulant EVs in patients with TBI correlating with clinical outcome. EVs represent a promising opportunity for use as minimally invasive biomarkers and potential therapeutic targets for TBI patients. However, additional research is necessary to bridge the gap between their potential and practical application in clinical settings.

Quantitative SPECT/CT imaging of actinium-225 for targeted alpha therapy of glioblastomas

BackgroundA new, alternative option for patients with recurrent glioblastoma is targeted alpha therapy (TAT), in the form of a local administration of substance P (neurokinin type 1 receptor ligand, NK-1) labelled with 225Ac. The purpose of the study was to confirm the feasibility of quantitative SPECT imaging of 225Ac, in a model reproducing specific conditions of TAT. In particular, to present the SPECT calibration methodology used, as well as the results of validation measurements and their accuracy. Additionally, to discuss the specific problems related to high noise in the presented case.Materials and methodsAll SPECT/CT scans were conducted using the Symbia T6 equipped with HE collimators, and acquired with multiple energy windows (three main windows: 440 keV, 218 keV, and 78 keV, with three lower scatter energy windows). A Jaszczak phantom with fillable cylindrical sources of various sizes was used to investigate quantitative SPECT/CT imaging characteristics. The planar sensitivity of the camera, an imaging calibration factor, and recovery coefficients were determined. Additionally, the 3D printed model of the glioblastoma tumour was developed and imaged to evaluate the accuracy of the proposed protocol.ResultsUsing the imaging calibration factor and recovery coefficients obtained with the Jaszczak phantom, we were able to quantify the activity in a 3D-printed model of a glioblastoma tumour with uncertainty of no more than 10% and satisfying accuracy.ConclusionsIt is feasible to perform quantitative 225Ac SPECT/CT imaging. However, there are still many more challenges that should be considered for further research on this topic (among others: accurate determination of ICF in the case of high background noise, better method of background estimation for recovery coefficient calculations, other methods for scatter correction than the dual-energy window scatter-compensation method used in this study).

The predictive value of heart rate in determining clinical course after a bupropion overdose

Introduction Bupropion is a popular antidepressant due to its favorable side effect profile and indications for smoking cessation and weight loss. Due to the possibility of delayed onset seizure and other adverse outcomes after bupropion overdose, patients are often observed for periods of 12-24 hours following suspected ingestion. Tachycardia is a clinical predictor that holds promise in differentiating cases at risk for seizures from low-risk cases that do not require prolonged observation. This study assessed whether heart rate within the first eight hours of presentation can identify cases that do not require extended observation. Methods This is a retrospective cohort study of all supra-therapeutic bupropion cases from two hospital systems between 2010 and 2022. Results Data from 216 charts were included. Seizures, hypotension, and dysrhythmias occurred in 19 percent (n = 41), 1.4 percent (n = 3), 0.9 percent (n = 2) respectively. One patient died. Delayed adverse effects were rare (n = 4); they occurred from 14 hours to 28 hours post-ingestion. Maximum heart rate in eight hours was associated with a risk of adverse outcomes. (odds ratio, 1.07; 95 percent confidence interval: 1.05 to 1.09; P < 0.001). An eight hour maximum heart rate threshold of 104 beats/minute had a negative predictive value of 100 percent (95 percent confidence interval: 96.7 percent to 100 percent) for the occurrence of delayed adverse effects. All patients with delayed effects had tachycardia within five hours of emergency department arrival. Discussion Delayed adverse outcomes of seizures, hypotension, dysrhythmia, and death were uncommon in this cohort. Heart rate during the first eight hours of observation performs reliably as a screening test to identify patients at low risk for delayed adverse outcomes. This study is limited by its retrospective nature, the inability to ascertain time of ingestion for most cases and the lack of confirmatory laboratory testing. Conclusion This study supports the use of an eight hour observation period when there are no other clinical signs of toxicity to warrant admission and if no co-ingestion or administration of substances that mask tachycardia are present.

The rat telemetry assay and venous catheter access buttons for use in cardiovascular safety pharmacology assessments – Surgical methods, refinements and colony maintenance

IntroductionRat telemetry is the assay of choice to assess the potential effects of novel drug candidates on cardiovascular parameters during early drug discovery. Telemetry device implantation can be combined with venous catheter and access button implantation when intravenous administration of the drug substance is required. MethodsRats (Sprague Dawley or Han Wistar) were implanted with telemetry devices for arterial blood pressure measurement using either direct aortic catheterisation (n = 131) or aortic catheterisation via the femoral artery (n = 17). Bipolar leads for ECG recording were also implanted in some of the animals (n = 102). Femoral vein catheters and access buttons were implanted as a separate surgery after the initial telemetry implantation (n = 43). Results128 animals (86%) were implanted successfully with telemetry devices without any notable surgical or post-surgical problems. When considering the 2 different catheterisation methods separately, the success rate of the direct aortic approach was 88% compared to 76% with the aortic placement via the femoral artery. Lameness was the most common post-surgical problem. Blood loss during surgery and ischaemic patches on the tail were also observed at a low incidence with the direct aortic approach. Catheter pull-out occurred in some rats before the first signal check reducing the overall success rate for blood pressure measurement using the direct aortic approach to 85%. A 95% success rate was observed for catheter and access button implantation. DiscussionA high success rate is possible when implanting telemetry devices in rats with and without venous catheters and access buttons. We have attempted to provide solutions to problems and describe refinements to the procedure which may further improve surgical outcomes.

The hypothermic effect of the antihypoxant 2-aminobenztiazole

BACKGROUND: One of the compounds studied at the Department of Pharmacology of the Kirov Military Medical Academy is a compound with a proven antihypoxic effect of 2-aminobenzothiazole (2-ABT). The mechanism of action of this substance is partially associated with the central action, and its protective effect may potentially be due to the general hypothermic effect.&#x0D; AIM: To determine the effect of 2-ABT on body temperature.&#x0D; MATERIALS AND METHODS: Experiments were carried out on 24 adult males of white outbred mice. 2-ABT was previously dissolved in 0.9% sodium chloride solution and administered intraperitoneally to mice at doses of 32.5 mg/kg (with proven antihypoxic effect), 21.7 mg/kg or 10.8 mg/kg. Rectal temperature was measured with an electronic thermometer DT-623 (China) before administration of the test substance, as well as 5, 30 and 60 minutes after the injection.RESULTS: Compound 2-ABT has a pronounced dose-dependent hypothermic effect. This effect is maximally expressed in a dose in which the compound has a proven antihypoxic property – 32.5 mg/kg. The hypothermic effect manifests itself within 5 minutes after administration, the maximum decrease in body temperature is observed after 30 minutes, while the effect persists for an hour.&#x0D; CONCLUSION: 2-ABT may be a promising compound for the creation of a drug for drug-induced (controlled) hypothermia.

Cardiovascular and Respiratory Effects of Cannabis Use by Route of Administration: A Systematic Review

Aim: Knowledge of the cardiovascular and respiratory effects of cannabis use by route of administration is unclear. This evidence is necessary to increase clinical and public health awareness given the recent trend in cannabis legalization, normalization, and surge in the availability and usage of various forms of cannabis products. Methods: Search was conducted in Web of Science, ProQuest, Psych INFO, Scopus, Embase, and Medline databases, and subsequently in the references of retrieved articles. Peer-reviewed articles published between 2009 and 2023, that reported on cardiovascular and respiratory effects of cannabis use by route of administration were included. Studies with no report of the route of administration and combined use of other illicit substances were excluded. The review was guided by Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Results: Of the 1873 articles retrieved, 42 met inclusion criteria encompassing six case reports, 21 reviews, and 15 empirical studies. Four administration routes were identified: smoking, vaping, oral ingestion, and dabbing. Smoking was the most common route of administration and was associated with both respiratory effects, such as bronchitis, dyspnea, and chronic obstructive lung disease, and cardiovascular effects including tachycardia, ventricular arrhythmias, and myocardial infarction. Cannabis edibles were associated with minimal respiratory effects. Tachycardia was the most common cardiovascular effect and was associated with all routes of administration. Conclusion: Cannabis use does cause cardiovascular and respiratory effects, but the conclusion remains tentative of the cardiovascular and respiratory effects by route of administration due to methodological limitations of the studies.

Engineering resveratrol-loaded chitosan nanoparticles for potential use against Helicobacter pylori infection

Helicobacter pylori (H. pylori) is a microorganism directly linked to severe clinical conditions affecting the stomach. The virulence factors and its ability to form biofilms increase resistance to conventional antibiotics, growing the need for new substances and strategies for the treatment of H. pylori infection. The trans-resveratrol (RESV), a bioactive polyphenol from natural sources, has a potential activity against this gastric pathogen. Here, Chitosan nanoparticles (NP) containing RESV (RESV-NP) were developed for H. pylori management. The RESV-NP were prepared using the ionic gelation method and characterized by Dynamic Light Scattering (DLS), Nanoparticle Tracking Analysis (NTA) and, Cryogenic Transmission Electron Microscopy (Cryo – TEM). The encapsulation efficiency (EE) and in vitro release rate of RESV were quantified using high-performance liquid chromatography (HPLC). RESV-NP performance against H. pylori was evaluated by the quantification of the minimum inhibitory/bactericidal concentrations (MIC/MBC), time to kill, alterations in H. pylori morphology in its planktonic form, effects against H. pylori biofilm and in an in vitro infection model. RESV-NP cytotoxicity was evaluated against AGS and MKN-74 cell lines and by hemolysis assay. Acute toxicity was tested using Galleria mellonella model assays. RESV-NP showed a spherical shape, size of 145.3 ± 24.7 nm, polydispersity index (PDI) of 0.28 ± 0.008, and zeta potential (ZP) of + 16.9 ± 1.81 mV in DLS, while particle concentration was 3.12 x 1011 NP/mL (NTA). RESV-NP EE was 72 %, with full release within the first 5 min. In microbiological assays, RESV-NP presented a MIC/MBC of 3.9 µg/mL, a time to kill of 24 h for complete eradication of H. pylori. At a concentration of 2xMIC (7.8 µg/mL), RESV-NP completely eradicated the H. pylori biofilm, and in an in vitro infection model, RESV-NP (4xMIC – 15.6 µg/mL) showed a significant decrease in bacterial load (1 Log10CFU/mL) when compared to the H. pylori J99 control. In addition, they did not demonstrate a toxic character at MIC concentration for both cell lines. The use of the RESV-NP with mucoadhesion profile is an interesting strategy for oral administration of substances targeting gastric disorders, linked to H. pylori infections.

SYNTHESIS AND ANALGESIC ACTIVITY OF METHYL-1-ANTIPYRYL-4-AROYL-2,3-DIOXO-2,3,5,10-TETRAHYDROBENZO[B]PYRROLO[2,3-E][1,4]DIAZEPINE-10A(1H) –CARBOXYLATES

In order to obtain new biologically active compounds, methyl-1-antipyryl-4-aroyl-2,3-dioxo-2,3,5,10-tetrahydrobenzo[b]pyrrolo[2,3-e][1,4]diazepine was synthesized-10a(1H)-carboxylates by reacting 1-antipyryl-4-aroyl-5-methoxycarbonyl-1H-pyrrole-2,3-diones with o-phenylenediamine. The structures of the obtained compounds were confirmed by 1H NMR, IR spectroscopy, X-ray diffraction and elemental analysis. The presence of several electrophilic centers in the structure of antipyryl-substituted 1H-pyrrole-2,3-diones gives them a high reactivity with respect to binucleophilic reagents. Apparently, the described interaction is carried out by the initial nucleophilic attack of one aminogroup of o-phenylenediamine on the C5 carbon atom of the pyrrole-2,3-dione ring, followed by the attack of another aminogroup on the carbonyl carbon atom of the aroyl fragment, closing the diazepine ring. The described reaction is a convenient preparative method for the synthesis of previously undescribed methyl-1-antipyryl-4-aroyl-2,3-dioxo-2,3,5,10-tetrahydrobenzo[b]pyrrolo[2,3-e][1,4]diazepine-10a(1H)-carboxylates, which are of interest as pharmacological substances. The described interaction proceeds quickly and with high yields. The obtained compounds were screened for analgesic activity, as a result of which a more pronounced effect was found in some products compared to the reference drug (diclofenac sodium). A preliminary assessment of acute toxicity was carried out, according to which the derivatives of 2,3,5,10-tetrahydrobenzo[b]pyrrolo[2,3-e][1,4]diazepine proved to be safe for further studies. The survival rate of animals in all groups is 100% after 24 h and 100% after 14 days. Screening of analgesic activity was performed by the hot plate method. Registration of time was carried out from the moment of placement on a hot surface until the appearance of a behavioral response to nociceptive stimulation 60 and 120 min after the administration of substances. For citation: Lyadov V.A., Makrushin D.E., Denislamova E.S., Maslivets A.N., Triandafilova G.A., Solodnikov S.I. Synthesis and analgesic activity of methyl-1-antipyryl-4-aroyl-2,3-dioxo-2,3,5,10-tetrahydrobenzo[b]pyrrolo[2,3-e][1,4]diazepine-10a(1H) –carboxylates. ChemChemTech [Izv. Vyssh. Uchebn. Zaved. Khim. Khim. Tekhnol.]. 2024. V. 67. N 5. P. 17-23. DOI: 10.6060/ivkkt.20246705.6939.

Randomized, Placebo-controlled Homeopathic Drug-proving of SARS CoV-2 nosode (BiosimCovex) in healthy volunteers

Introduction&#x0D; The Homeopathic Pathogenetic Trial (HPT, Drug-proving) is a systematic examination and recording of the symptoms experienced by healthy volunteers after an administration of an investigational medicinal substance. Randomized, placebo-controlled HPT was conducted using BiosimCovex (SARS CoV-2 nosode) in healthy volunteers. &#x0D; Materials and methods&#x0D; BiosimCovex 30c was given orally in a randomized, placebo-controlled trial to examine the safety and pathogenetic effects of 30 volunteers (18- 65 years of age and both genders). Volunteers were administered a dose of 6 pills of the nosode once a day for two weeks followed by 30 days observation period. Pre and post-examination (physical), vital signs, and laboratory investigations were done with a run-in period of 7 days. Symptoms experienced by the volunteers were recorded and analyzed, and Qualitative and Quantitative indices per volunteer were reported. Trial registered at http://ctri.nic.in (CTRI/2022/06/043392).&#x0D; Results&#x0D; BiosimCovex nosode exhibited quantitatively distinct symptoms, which can be applied in clinical practice. The number of symptoms reported in the verum arm was 73 (placebo 11). The incidence of the Pathogenetic effect per volunteer in the verum group was 8.1 vs that of the placebo 5.5. The Qualitative Pathogenetic Index was 0.295 in the verum group as compared to the placebo 0.193. The symptoms observed matched with the symptoms produced in an open-label Phase 1 study conducted during the COVID-19 pandemic and also with that of the viral infection. There were no serious/fatal adverse events during the study. Safe use was documented.&#x0D; Conclusion&#x0D; BiosimCovex nosode developed during a pandemic condition produced specific symptoms in the homeopathic pathogenetic trial which could be used in clinical practice.

Harnessing the Power of Stimuli-Responsive Nanoparticles as an Effective Therapeutic Drug Delivery System.

The quest for effective and reliable methods of delivering medications, with the aim of improving delivery of therapeutic agent to the intended location, has presented a demanding yet captivating field in biomedical research. The concept of smart drug delivery systems is an evolving therapeutic approach, serving as a model for directing drugs to specific targets or sites. These systems have been developed to specifically target and regulate the administration of therapeutic substances in a diverse array of chronic conditions, including periodontitis, diabetes, cardiac diseases, inflammatory bowel diseases, rheumatoid arthritis, and different cancers. Nevertheless, numerous comprehensive clinical trials are still required to ascertain both the immediate and enduring impacts of such nanosystems on human subjects. This review delves into the benefits of different drug delivery vehicles, aiming to enhance comprehension of their applicability in addressing present medical requirements. Additionally, it touches upon the current applications of these stimuli-reactive nanosystems in biomedicine and outlines future development prospects.

Resveratrol Alleviates the Early Challenges of Implant-Based Drug Delivery in a Human Glial Cell Model.

Brain diseases are oftentimes life-threatening and difficult to treat. The local administration of drug substances using brain implants can increase on-site concentrations and decrease systemic side effects. However, the biocompatibility of potential brain implant materials needs to be evaluated carefully as implants can trigger foreign body reactions, particularly by increasing the microglia and astrocyte reactivity. To date, these tests have been frequently conducted in very simple in vitro models, in particular not respecting the key players in glial cell reactions and the challenges of surgical implantation characterized by the disruption of oxygen and nutrient supply. Thus, we established an in vitro model in which we treated human glial cell lines with reduced oxygen and glucose levels. The model displayed cytokine and reactive oxygen species release from reactive microglia and an increase in a marker of reactive astrocytes, galectin-3. Moreover, the treatment caused changes in the cell survival and triggered the production of hypoxia-inducible factor 1α. In this comprehensive platform, we demonstrated the protective effect of the natural polyphenol resveratrol as a model substance, which might be included in brain implants to ease the undesired glial cell response. Overall, a glial-cell-based in vitro model of the initial challenges of local brain disease treatment may prove useful for investigating new therapy options.

The Influence of Demographic Factors of Nigerian Dentists on their Satisfaction with Duration of Orthodontic Treatment and Knowledge of Accelerated Orthodontics

Background: The duration of orthodontic treatment and the knowledge of accelerated orthodontics are very important to the dental practitioner but there are limited information on the relationship between their satisfaction with duration of orthodontic treatment and knowledge of accelerated orthodontics.&#x0D; Aim: To assess the associations between the demographics of the Nigerian dental practitioners and their satisfactions with the duration of orthodontic treatment and their knowledge of accelerated orthodontics.&#x0D; Materials and Methods: Electronic and physical methods of surveying the Nigerian dental practitioners were carried out between January and June 2023. The contents of the questionnaire involving satisfaction with duration of orthodontic treatment and the knowledge of accelerated orthodontics were analysed for associations with the participants’ demographics, using the IBM SPSS version 25. Descriptive statistics, the ANOVA and independent t-test were used with the significance level set at P &lt; .05.&#x0D; Results: No statistically significant associations were found between the dentists’ satisfaction with duration of orthodontic treatment and their age, gender and years of practice as dentists (P &gt; .05). Also, no statistically significant associations were found between the dentists’ knowledge of the methods of accelerated orthodontics and age (P &gt; .05). Statistically significant associations were found between the male gender and knowledge of administration of biological substances and piezocision, while the highest number of methods of accelerated orthodontics was statistically significantly associated with the years of practice of dentistry (P &lt; .05).&#x0D; Conclusion: Although no significant associations were found between the participants’ demographics and satisfaction with duration of orthodontic treatment, gender gave significant associations with knowledge of two methods of accelerated orthodontics, while years of practice of dentistry revealed the most significant associations with knowledge of accelerated orthodontics.

Neuropeptide substance P alters stem cell fate to aid wound healing and promote epidermal stratification through asymmetric stem cell divisions.

Loss of sensory innervation delays wound healing and administration of the neuropeptide substance P improves re-epithelialization. Keratinocyte hyperproliferation post-wounding may result from symmetric stem cell (SC) self-renewal, asymmetric SC self-renewal, committed progenitor divisions, or a combination of these. However, the effects of sensory denervation and of neuropeptides on SC proliferation are not known. Here we show that early after wounding both asymmetric and symmetric SC self-renewal increase, without significant committed progenitor (CP) activation. Decreased sensory innervation is associated with a decrease in both SC and CP proliferation. Based on previous work showing that substance P is decreased in capsaicin-treated mice and improves wound healing in normal skin, we examined the effects of substance P on SC and CP proliferation during wound healing. Substance P restored asymmetric SC proliferation in skin with decreased sensory innervation, both at baseline and following wounding. Epidermis with decreased sensory innervation was severely thinned. Consistent with this, substance P-induced asymmetric SC proliferation resulted in increased stratification in skin with both normal and decreased innervation. Lapatinib prevented the substance P-induced increase in asymmetric SC divisions in murine epidermis, as well as the increase in epidermal stratification, suggesting that asymmetric SC divisions are required for epidermal stratification.