Dose-dependent Adverse Effects Research Articles

Green and chemical syntheses of silver nanoparticles: Comparative and comprehensive study on characterization, therapeutic potential, and cytotoxicity

The emergence of metallic nanoparticles through green synthesis has garnered significant recognition, shaping global research efforts towards eco-friendly practices, often termed as the green revolution. Specifically, the green synthesis of silver nanoparticles (AgNPs) has made considerable strides in the past decade, becoming a prominent fixture in the realm of science and technology. The study explores the synthesis and characterization of silver nanoparticles (AgNPs) using Cassia fistula L. flowers extract through chemical co-precipitation (CM_AgNPs) and green methods (CFF_AgNPs). Characterization techniques, including scanning electron microscopy (SEM), transmission electron microscopy (TEM), attenuated total reflectance fourier-transform infrared (FTIR), and X-ray diffraction (XRD), revealed irregular morphologies with agglomeration, polycrystalline nature, and intrinsic functional groups involved in capping AgNPs. Antioxidant assessment demonstrated superior antioxidative activity (84.48 %) in green-synthesized nanoparticles compared to chemically synthesized ones (75.87 %), and they exhibited dose-dependent anti-inflammatory effects with IC50 values CFF_AgNPs_30.19 μg/mL and CM_AgNPs _34.14 μg/mL respectively. The lower IC50 value of CFF_AgNPs_30.19 μg/mL signifies finer and better activity due to the presence of phytochemicals present in it. Whereas for CM_AgNPs the IC50 value is a 34.14 μg/mL which is solely due to AgNPs. To ensure the promising therapeutic aspects of AgNPs with a careful assessment of their safety profile, cytotoxicity of AgNPs on HEP3B cancer cells was evaluated through MTT assay, lactate dehydrogenase (LDH) release, and reactive oxygen species (ROS) level measurement. In the in vitro cytotoxicity evaluation, HEP3B demonstrated more pronounced dose-dependent adverse effects upon exposure to CFF_AgNPs compared to CM_AgNPs. This study underscores the bioactive potential of Cassia fistula L. mediated AgNPs, suggesting promising applications in biomedicine with environmental sustainability. The findings contribute to the growing interest in green synthesis methods for metallic nanoparticles and their potential benefits in various fields.

Impact of Lithium on the Immune System: An Investigation of T-Cell Subpopulations and Cytokine Responses in Rats.

The aim of this study was to investigate the dose-dependent adverse effects of long-term dietary lithium administration on specific aspects of the defense system in rats. Additionally, the study aimed to explore the inflammatory activities of lithium beyond its recognized anti-inflammatory properties. Forty Wistar Albino rats were involved, which were randomly allocated into the control and four treatment groups. The control group received standard rat feed, and the experimental groups' diet was added 1g/kg, 1.4g/kg, 1.8g/kg, and 2.2g/kg lithium bicarbonate, respectively. CD4+, CD8+, and CD161 + cells were assessed by flow cytometry. TNF-α, IFN-γ, IL-1β, and IL-2 and IL-4, IL-6, and IL-10 levels were measured. The proportion of CD4 + cells and the CD4+/CD8 + ratio (P = 0.005 and P = 0.038, respectively) were reduced with the highest dose of lithium compared to the control group. The data regarding pro-inflammatory cytokines showed a dose-dependent increase in serum TNF-α and IFN-γ levels (P = 0.023 and P = 0.001, respectively). On the other hand, serum IL-1β and IL-2 levels were decreased in a dose-dependent manner (P = 0. 001 and P = 0. 001, respectively). As for anti-inflammatory cytokines, a dose-dependent decrease was determined in serum IL-4 level (P = 0.002), while no significant changes were noted in IL-6 and IL-10 levels (P = 0.507 and P = 0.732, respectively). In conclusion, lithium adversely impacted the cellular defense system. Furthermore, apart from its anti-inflammatory properties, lithium exhibited cytokine-mediated inflammatory activities. Therefore, lithium's potential adverse effects on the immune system should be considered in immunodeficient patients and those with an inflammatory status treated with high doses of lithium.

Clomiphene citrate administered in peri-conception phase causes fetal loss and developmental impairment in mice.

Clomiphene citrate is a common treatment for ovulation induction in subfertile women, but its use is associated with elevated risk of adverse perinatal outcomes and birth defects. To investigate the biological plausibility of a causal relationship, this study investigated in mice the consequences for fetal development and pregnancy outcome of peri-conception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 h after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in three independent cohorts. Viable pregnancy was reduced by 30%, late gestation fetal weight was reduced by 16%, and ∼30% of fetuses exhibited delayed development and/or congenital abnormalities not seen in control dams, including defects of the lung, kidney, liver, eye, skin, limbs, and umbilicus. Clomiphene citrate also caused a 30 h average delay in time of birth, and elevated rate of pup death in the early postnatal phase. In surviving offspring, growth trajectory tracking and body morphometry analysis at 20 weeks of age showed post-weaning growth and development comparable to controls. A dysregulated inflammatory response in the endometrium was observed and may contribute to the underlying pathophysiological mechanism. These results demonstrate that in utero exposure to clomiphene citrate during early pregnancy can inhibit implantation and impact fetal growth and development, causing adverse perinatal outcomes. The findings raise the prospect of similar iatrogenic effects in women where clomiphene citrate may be present in the peri-conception phase unless its use is well-supervised.

Effects of Orexin Receptor Antagonist on Cognitive Function in Adults: A Systematic Review

Background:: Orexin receptor antagonists (ORAs) are the emerging class of hypnotics used for the treatment of insomnia. However, from the available literature, the effect of ORA on cognitive functions is not clear yet. Therefore, the current study aimed to systematically evaluate the effect of ORA on cognitive function from available clinical studies. Methods:: The extensive literature search was conducted in various databases, including Pubmed, Embase, Cochrane Library, and clinicaltrials.gov, using suitable keywords. The quality of the included studies was evaluated using the Cochrane risk of bias tool (ROB2). Results:: We obtained a total of 450 articles from different databases. Finally, 07 articles met the inclusion criteria and were included in the current systematic review for qualitative analysis. Available literature showed conflicting results, with few studies showing no impact of ORA on cognitive function, while others reported dose-dependent adverse effects of ORA on cognitive function. The risk of bias in included studies was found to be low. Conclusion:: In conclusion, ORA is generally safe in clinical doses. However, it is important to note that there is a dose-dependent decline in cognitive function after the administration of ORA. Therefore, clinicians must be careful while prescribing ORA and adjust the dose as per the needs of the individual patients and the potential risk factors.

Effect of 2.45 GHz Microwave Radiation on the Inner Ear: A Histopathological Study on 2.45 GHz Microwave Radiation and Cochlea.

The present study aims to determine the possible low dose-dependent adverse effects of 2.45 GHz microwave exposure and Wi-Fi frequency on the cochlea. Twelve pregnant female rats (n=12) and their male newborns were exposed to Wi-Fi frequencies with varying electric field values of 0.6, 1.9, 5, 10 V/m, and 15 V/m during the 21-day gestation period and 45 days after birth, except for the control group. Auditory brainstem response testing was performed before exposure and sacrification. After removal of the cochlea, histopathological examination was conducted by immunohistochemistry methods using caspase (cysteine-aspartic proteases, cysteine aspartates, or cysteine-dependent aspartate-directed proteases)-3, -9, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Kruskal-Wallis and Wilcoxon tests and multivariate analysis of variance were used. Auditory brainstem response thresholds in postexposure tests increased statistically significantly at 5 V/m and above doses. When the number of apoptotic cells was compared in immunohistochemistry examination, significant differences were found at 10 V/m and 15 V/m doses (F(5,15)=23.203, P=.001; Pillai's trace=1.912, η2=0.637). As the magnitude of the electric field increased, all histopathological indicators of apoptosis increased. The most significant effect was noted on caspase-9 staining (η2 c9=0.996), followed by caspase-3 (η2 c3=0.991), and TUNEL staining (η2 t=0.801). Caspase-3, caspase-9, and TUNEL-stained cell densities increased directly by increasing the electric field and power values. Apoptosis and immune activity in the cochlea depend on the electric field and power value. Even at low doses, the electromagnetic field in Wi-Fi frequency damages the inner ear and causes apoptosis.

Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia.

Many chemotherapeutic drugs, including paclitaxel, produce neuropathic pain in patients with cancer, which is a dose-dependent adverse effect. Such chemotherapy-induced neuropathic pain (CINP) is difficult to treat with existing drugs. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidative responses and activates phosphorylated Nrf2 (pNrf2). We determined the analgesic effects of bardoxolone methyl (BM), an Nrf2 activator, and the role of pNrf2 on CINP. CINP was induced in rats by intraperitoneally injecting paclitaxel on 4 alternate days in rats. BM was injected systemically as single or repeated injections after pain fully developed. RNA transcriptome, mechanical hyperalgesia, levels of inflammatory mediators and pNrf2, and location of pNrf2 in the dorsal root ganglia (DRG) were measured by RNA sequencing, von Frey filaments, Western blotting, and immunohistochemistry in rats and human DRG samples. In addition, the mitochondrial functions in 50B11 DRG neuronal cells were measured by fluorescence assay. Our RNA transcriptome of CINP rats showed a downregulated Nrf2 pathway in the pain condition. Importantly, single and repeated systemic injections of BM ameliorated CINP. Paclitaxel increased inflammatory mediators, but BM decreased them and increased pNrf2 in the DRG. In addition, paclitaxel decreased mitochondrial membrane potential and increased mitochondrial volume in 50B11 cells, but BM restored them. Furthermore, pNrf2 was expressed in neurons and satellite cells in rat and human DRG. Our results demonstrate the analgesic effects of BM by Nrf2 activation and the fundamental role of pNrf2 on CINP, suggesting a target for CINP and a therapeutic strategy for patients.

SERS spectroscopy as a tool for the study of thiopurine drug pharmacokinetics in a model of human B leukemia cells

Thiopurine drugs are immunomodulatory antimetabolites relevant for pediatric patients characterized by dose-dependent adverse effects such as myelosuppression and hepatotoxicity, often related to inter-individual differences, involving the activity of important enzymes at the basis of their biotransformation, such as thiopurine S-methyltransferase (TPMT).Surface Enhanced Raman Scattering (SERS) spectroscopy is emerging as a bioanalytical tool and represents a valid alternative in terms of affordable costs, shorter analysis time and easier sample preparation in comparison to the most employed methods for pharmacokinetic analysis of drugs.The aim of this study is to investigate mercaptopurine and thioguanine pharmacokinetics by SERS in cell lysates of a B-lymphoblastoid cell line (NALM-6), that did (TPMT*1) or did not (MOCK) overexpress the wild-type form of TPMT as an in vitro cellular lymphocyte model to discriminate between cells with different levels of TPMT activity on the base of the amount of thioguanosine nucleotides (TGN) metabolites formed.SERS analysis of the cell lysates was carried out using SERS substrates constituted by Ag nanoparticles deposited on paper and parallel samples were used for quantification of thiopurine nucleotides with liquid chromatography-tandem mass spectrometry (LC-MS/MS).A direct SERS detection method has been set up that could be a tool to study thiopurine drug pharmacokinetics in in vitro cellular models to qualitatively discriminate between cells that do and do not overexpress the TPMT enzyme, as an alternative to other more laborious techniques.Results underlined decreased levels of TGN and increased levels of methylated metabolites when TPMT was overexpressed, both after mercaptopurine and thioguanine treatments.A strong positive correlation (Spearman's rank correlation coefficient rho = 0.96) exists between absolute quantification of TGMP (pmol/1 x 106 cells), obtained by LC-MS/MS, and SERS signal (intensity of TGN at 915 cm−1).In future studies, we aim to apply this method to investigate TPMT activity in pediatric patients’ leukocytes.

Cytotoxic effects of dose dependent inorganic magnesium oxide nanoparticles on the reproductive organs of rats

Introduction Magnesium oxide nanoparticles (MgO NPs) have a variety of applications that have contributed to their elevated popularity, however, the safety and toxic effects on humans are also of concern with these increased applications. There is insufficient data regarding the effect of MgO NPs on reproductive organs, which are crucial aspects to the body’s vital physiological functions. The present study was undertaken in male and female rats to assess the reproductive toxicological potential of two doses (low versus high) of MgO NPs on testicular and ovarian tissues. The toxicity was evaluated using histological, hormonal, and oxidative parameters. Material and Methods In this work, magnesium oxide nanoparticles (MgO NPs) were synthesized by the sol-gel route and were characterized by X ray diffraction analysis (XRD) and Fourier transform infra-red spectroscopy (FTIR). Forty-eight adult Wister albino rats were used in this experiment which were divided into groups of male and female, and then further into control, low dose MgO NPs, and high dose MgO NPs. The low dose used was 131.5 mg/kg b.w. (1/10 LD50) while the high dose used was 263 mg/kg b.w. (1/5 LD50). All doses were given orally by gastric tube. After 4 weeks, blood samples were collected to investigate the level of sex hormones and both ovarian and testicular tissues were examined for variable oxidative parameters and histopathological changes by light microscopy. Results The obtained findings showed that high dose of MgO NPs produced considerable changes in sex hormones and stress parameters in both male and female rats in comparison to the low dose and control groups. Histomorphometric analysis demonstrated the presence of histopathological alterations in the testicular and ovarian tissues. Conclusion The results of this study showed dose-dependent adverse effects of MgO NPs on the testis and ovary both functionally and histopathologically as compared to the control rats.

Sonodynamic Cytokine Nanocomplexes with Specific Stimulation towards Effector T cell for Combination Cancer Immunotherapy.

Cytokine therapy mediates the interaction between immune cells and non-immune cells in tumor microenvironment (TME), forming a promising approach in cancer therapy. However, the dose-dependent adverse effects and non-selective stimulation of cytokines limit their clinical use. We herein report a sonodynamic cytokine nano-immunocomplex (SPNAI) that specifically activates effector T cells (Teffs) for antitumor immunotherapy. By conjugating anti-interleukin-2 (anti-IL-2) antibodies S4B6 on the semiconducting polymer nanoparticles to afford SPNA, this nanoantibody SPNA can bind with IL-2 to form SPNAI which can block the interaction between IL-2 and regulatory T cells (Tregs), selectively activating Teffs in TME. Moreover, SPNAI generates 1O2 to trigger immunogenic cell death of cancer cells upon sono-irradiation, which promotes the maturation of dendritic cells and the proliferation of Teffs. This SPNAI-mediated combination sonodynamic immunotherapy thus elevates the ratio of Teffs/Tregs in TME, resulting in inhibition of tumor growth, suppression of lung metastasis and prevention of tumor relapse.

In Vitro high-throughput toxicological assessment of E-cigarette flavors on human bronchial epithelial cells and the potential involvement of TRPA1 in cinnamon flavor-induced toxicity

Electronic cigarettes (ECs) are considered a less hazardous alternative to tobacco smoking but are not harmless. Growing concerns about the safety profiles of flavors in e-liquids underpin the need for this study. Here, we screened 53 nicotine-free flavored e-liquids (across 15 flavor categories) across a 3-point concentration range (0.25%, 0.5%, and 1% v/v) in a high-throughput fashion in human bronchial epithelial (HBEC-3KT) submerged cell cultures to identify ‘toxic hits’ using in vitro endpoint assays comprising cell count, cell viability, and lactate dehydrogenase (LDH). We observed significant, dose-dependent adverse effects only with cinnamon, vanilla tobacco, and hazelnut e-liquids compared to media-only and PG/VG vehicle controls. Hence, we further analyzed these three flavors for their effects on HBEC-3KT proliferation, mitochondrial health, and oxidative stress. A significant decrease in cell proliferation after 36 h was observed for each e-liquid toxic hit compared to media-only and PG/VG controls. Hazelnut (at all concentrations) and vanilla tobacco (1%) increased cytoplasmic reactive oxygen species generation compared to media-only and PG/VG controls. Conversely, all three flavors at 0.5% and 1% significantly decreased mitochondrial membrane potential compared to PG/VG and media-only controls. Chemical analysis revealed that all three flavors contained volatile organic compounds. We hypothesized that the cytotoxicity of cinnamon might be mediated via TRPA1; however, TRPA1 antagonist AP-18 (10 μM) did not mitigate these effects, and cinnamon significantly increased TRPA1 transcript levels. Therefore, pathways mediating cinnamon’s cytotoxicity warrant further investigations. This study could inform public health authorities on the relative health risks assessment following exposure to EC flavor ingredients.

Recent update on the protective potentials of resveratrol against cisplatin-induced ototoxicity: a systematic review.

Although cancer treatment with cisplatin is effective, dose-dependent adverse effects such as ototoxicity occurs often, which limits its clinical use. The use of resveratrol may alleviate the cisplatin-induced ototoxic effects. This study is aimed to review the potential otoprotective effects of resveratrol against cisplatin-induced ototoxicity. According to the PRISMA guideline, a systematic search was accomplished to identify all relevant scientific papers on "the role of resveratrol against cisplatin-induced ototoxicity" in different electronic databases up to May 2021. Fifty-five articles were screened based on a pre-defined set of inclusion and exclusion criteria. Eight eligible studies were finally included in the current systematic review. The in-vitro findings revealed that cisplatin administration significantly decreased the HEI-OC1 cell viability compared to the untreated cells; however, resveratrol co-treatment (in a dose-dependent manner) could protect HEI-OC1 cells against cisplatin-induced decrease in cell viability. Furthermore, the in-vivo finding showed a decreased value of DPOAE, and increased values of ABR threshold, ABR-I, ABR-IV, and ABR I-IV interval in cisplatin-treated animals; in contrast, resveratrol co-administration demonstrated an opposite pattern on these parameters. Thus, it can be mentioned that resveratrol co-treatment alleviates cisplatin-induced ototoxicity. Mechanically, resveratrol exerts its otoprotective effects through various mechanisms such as anti-oxidant, anti-apoptosis, and anti-inflammatory.

#5835 A LOW DOSE GLUCOCORTICOID, LOW DOSE CYCLOPHOSPHAMIDE, RITUXIMAB TREATMENT PROTOCOL AS INDUCTION THERAPY IN ANCA ASSOCIATED VASCULITIS PATIENTS

Abstract Background and Aims There has been a considerable improvement in the survival of patients with ANCA associated vasculitis (AAV) since the introduction of immunosuppressive therapy. Nowadays early deaths are attributable to infection while cardiovascular disease, infection and malignancy are the most common causes in long term mortality in these patients. High-dose glucocorticoids and cyclophosphamide have numerous dose-dependent adverse effects and are associated with those events. The aim of this study is to investigate the efficacy and safety a low dose glucocorticoids, low dose cyclophosphamide, rituximab treatment protocol in AAV patients. Method This is a single-centre cohort study of patients on a combination of reduced-dose oral glucocorticoids, rituximab and low-dose pulsed intravenous cyclophosphamide followed by a maintenance regimen of rituximab and tapered steroid for the treatment of AAV (table). Data shown as median (IQR). Results Nine patients (3 women) aged 62.4 (55/67.8) years, with serum creatinine (sCre) 2.15 (1.8/2.5) mg/dL, eGFR CKD-EPI 28 (20/39) ml/min/1.73 m2, albuminuria 0.98 (0.57/1.45) gr/24 h and BVAS 14 at baseline were treated with the mentioned protocol. Seven patients had MPO and 2 had double MPO/PR3 positivity. Two were already on dialysis and 4 had pulmonary involvement. The median follow-up was 19 (12.5/39) months. One patient required the addition of plasma exchange and extended treatment due to aggressive disease and one was lost to follow-up after four months. The rest of the 7 patients were dialysis free with a sCre 2.15 (1.8/2.5) mg/dL, eGFR 28 (20/39) ml/min/1.73 m2 at the end of follow-up. Patient and renal survival were 88% and 100% respectively. 85.7% of patients achieved ANCA-negative status and all remained B cell deplete at 6 and 18 months. There were no major relapses, while two patients had infection related hospitalization. No unexpected side effects were observed during follow-up. Conclusion These findings confirm the literature that a combined regimen provides early disease control with low relapse rates, without significant adverse effects from immunosuppression. A regimen like this may provide the basis for further refinement of remission induction protocols in AAV, potentially allowing early withdrawal of corticosteroids.

Efficacy and safety of gefapixant for chronic cough: a meta-analysis of randomised controlled trials.

The efficacy and safety of gefapixant in adults with chronic cough remain unclear. Our objective was to assess the efficacy and safety of gefapixant using updated evidence. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and Embase databases were searched from inception through September 2022. Subgroup analysis based on dose of gefapixant (i.e. ≤20, 45-50 and ≥100 mg twice daily for low, moderate and high doses, respectively) was performed to explore a potential dose-dependent effect. Five studies involving seven trials showed the efficacy of moderate- or high-dose gefapixant for reducing objective 24-h cough frequency (estimated relative reduction 30.9% and 58.5%, respectively) (i.e. primary outcome) and awake cough frequency (estimated relative reduction 47.3% and 62.8%, respectively). Night-time cough frequency was only reduced with high-dose gefapixant. Consistently, the use of moderate- or high-dose gefapixant significantly alleviated cough severity and improved cough-related quality of life, but increased the risk of all-cause adverse events (AEs), treatment-related AEs and ageusia/dysgeusia/hypogeusia. Subgroup analysis showed dose dependency in both efficacy and AEs with a cut-off dose being ≥45 mg twice daily. This meta-analysis revealed dose-dependent efficacy and adverse effects of gefapixant against chronic cough. Further studies are required to investigate the feasibility of moderate-dose (i.e. 45-50 mg twice daily) gefapixant in clinical practice.

Taste-masked formulation of sodium phenylbutyrate (ACER-001) for the treatment of urea cycle disorders

Urea cycle disorders (UCDs) are a group of rare inherited metabolic diseases caused by a deficiency of one of the enzymes or transporters that constitute the urea cycle. Defects in these enzymes lead to acute accumulation (hyperammonemic crises, HAC) or chronically elevated levels (hyperammonemia) of ammonia in the blood and/or various tissues including the brain, which can cause persistent neurological deficits, irreversible brain damage, coma, and death. Ongoing treatment of UCDs include the use of nitrogen-scavenging agents, such as sodium phenylbutyrate (salt of 4-phenylbutyric acid; NaPBA) or glycerol phenylbutyrate (GPB). These treatments provide an alternative pathway for nitrogen disposal through the urinary excretion of phenylacetylglutamine. ACER-001 is a novel formulation of NaPBA with polymer coated pellets in suspension, which is designed to briefly mask the unpleasant bitter taste of NaPBA and is being developed as a treatment option for patients with UCDs. Four Phase 1 studies were conducted to characterize the bioavailability (BA) and/or bioequivalence (BE) of ACER-001 (in healthy volunteers) and taste assessment relative to NaPBA powder (in taste panelists). ACER-001 was shown to be bioequivalent to NaPBA powder under both fed and fasting conditions. Lower systemic exposure of phenylacetate (PAA) and phenylbutyrate (PBA) was observed when ACER-001 was administered with a high-fat meal relative to a fasting state suggesting that the lower doses of PBA administered under fasting conditions may yield similar efficacy with potentially fewer dose dependent adverse effects relative to higher doses with a meal. ACER-001 appeared to be adequately taste-masked, staying below the aversive taste threshold for the first 3min after the formulation was prepared and remaining palatable when taken within 5min.

Enhanced chemotherapeutic efficacy of docetaxel in human lung cancer cell line via GLUT1 inhibitor.

The dose-dependent adverse effects of anticancer agents neednew methods with lesser toxicity. The objective of the current research was to evaluate the efficacy of GLUT1 inhibitor, as an inhibitor of glucose consumption in cancer cells, in augmenting the efficiency of docetaxel with respect to cytotoxicity and apoptosis. Cell cytotoxicity was assessed by using methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Annexin V/PI double staining was employed to evaluate apoptosis percentage. Quantitative real-time polymerase chain reaction(RT-PCR) analysis was accomplished to detect the expression of genes involved in the apoptosis pathway. The IC50 values for docetaxel and BAY-876 were 3.7 ± 0.81and 34.1 ± 3.4 nM, respectively. The severity of synergistic mutual effects of these agents on each other was calculated by synergy finder application. It showed that the percentage of apoptotic cells following co-administration of docetaxel and BAY-876 increased to 48.1 ± 2.8%. In comparison without GLUT1 co-administration, the combined therapy decreased significantly the transcriptome levels of the Bcl-2 and Ki-67 and a remarkable increase in the level of the Bax as proapoptotic protein(p < 0.05). Co-treatment of BAY-876 and docetaxel depicted a synergistic effect which was calculated using the synergy finder highest single agent(HSA) method (HSA synergy score: 28.055). These findings recommend that the combination of GLUT-1 inhibitor and docetaxel can be considered as a promising therapeutic approach for the treatment of patients with lung cancer.

THE SAFETY OF GLUCOCORTICOIDS IN THE TREATMENT OF INFAMMATORY RHEUMATIC DISEASE : A SYSTEMATIC REVIEW

Glucocorticoids have been utilized as a component of the treatment for rheumatoid arthritis ever since their introduction some decades ago. It has been established that glucocorticoids are effective in lowering the inflammatory activity induced by this condition and in slowing the course of erosive joint degradation. Both of these benefits can be attained by taking the medication. Unfortunately, they also have a wide variety of potentially adverse consequences, the severity of which may vary depending on the dosage and the length of the therapy. Nevertheless, the benefits of these medications far outweigh the risks associated with them. As a result of the rise in popularity of many alternative therapy alternatives, the use of glucocorticoids as a treatment method is currently being debated (such as biologic and targeted synthetic disease-modifying antirheumatic medicines). It is possible to provide corticosteroids by injecting them directly into the joint. Many people are opposed to the use of glucocorticoids because of the dose-dependent adverse effects that they can have, despite the fact that they continue to be an essential component in the treatment of a wide variety of inflammatory rheumatic diseases. The usage of glucocorticoids for an extended period of time is connected with a greater risk of experiencing adverse consequences. These problems are associated with an increased chance of developing cardiovascular disease, diabetes, and possibly mortality.

Low-Dose Lithium Supplementation Influences GSK3β Activity in a Brain Region Specific Manner in C57BL6 Male Mice.

Lithium, a commonly used treatment for bipolar disorder, has been shown to have neuroprotective effects for other conditions including Alzheimer's disease via the inhibition of the enzyme glycogen synthase kinase-3 (GSK3). However, dose-dependent adverse effects of lithium are well-documented, highlighting the need to determine if low doses of lithium can reliably reduce GSK3 activity. The purpose of this study was to evaluate the effects of a low-dose lithium supplementation on GSK3 activity in the brain of an early, diet-induced Alzheimer's disease model. Male C57BL/6J mice were divided into either a 6-week or 12-week study. In the 6-week study, mice were fed a chow diet or a chow diet with lithium-supplemented drinking water (10 mg/kg/day) for 6 weeks. Alternatively, in the 12-week study, mice were fed a chow diet, a high-fat diet (HFD), or a HFD with lithium-supplemented drinking water for 12 weeks. Prefrontal cortex and hippocampal tissues were collected for analysis. Results demonstrated reduced GSK3 activity in the prefrontal cortex as early as 6 weeks of lithium supplementation, in the absence of inhibitory phosphorylation changes. Further, lithium supplementation in an obese model reduced prefrontal cortex GSK3 activity as well as improved insulin sensitivity. Collectively, these data provide evidence for low-dose lithium supplementation to inhibit GSK3 activity in the brain. Moreover, these results indicate that GSK3 activity can be inhibited despite any changes in phosphorylation. These findings contribute to an overall greater understanding of low-dose lithium's ability to influence GSK3 activity in the brain and its potential as an Alzheimer's disease prophylactic.

Safety assessment of the functional feed additive phenylcapsaicin in a commercial broiler diet

Introduction: Intestinal colonisation of Salmonella is a major concern in the poultry industry, and a low dose of the high-purity synthetic capsaicin analogue phenylcapsaicin (PheCap) has the potential to be a phytobiotic alternative to antibiotics in reducing floor Salmonella in commercial broiler chicken houses. In this study we present the first safety assessment of PheCap at doses relevant for the poultry industry. Methods: In a completely randomized block design, Ross 308 male broilers were offered feed containing 0, 10, 15, or 150 mg PheCap/kg. Growth rates, mortality, haematology, clinical chemistry, foot pad lesions, litter quality and gross pathological examination of organs and tissues were evaluated for signs of toxicity over a two-phase, 35-day growth period. Results: No differences in feed intake and broiler growth were found, with broilers in the control group having the highest mortality. There was a statistically significant increase in the European Production Efficiency Factor (EPEF) for the 10 (p = 0.02) and 15 mg PheCap/kg feed (p = 0.003) treatment doses. No dose dependent adverse effects were found for any of the treatment doses. The No Observed Adverse Effect Level (NOAEL) of PheCap is probably higher than that of the highest weekly averaged daily intake of 36.3 mg/kg BW/day observed in the present study. Conclusions: The inclusion of PheCap in broiler feed at doses relevant for the commercial poultry industry is assumed not have any negative effects on broiler health.

Approach to acute psychosis in older adults.

Approach to acute psychosis in older adults.

Practical Psychopharmacology: Using a Knowledge of Pharmacokinetics to More Rapidly Stabilize Patients at Lower Drug Doses.

Three drug dosing strategies can be employed to address dose-dependent drug adverse effects. The usual strategy is to continue the drug but at a lower dose; it would then take 5 half-lives of the drug for the new steady state to be attained and for a dose-dependent adverse effect to correspondingly attenuate. Such slow offset of the adverse effect could be disadvantageous for drugs such as fluoxetine, penfluridol, and cariprazine that have long half-lives. A second strategy is to stop the drug and to resume it at a lower dose when the adverse effect attenuates as the drug blood level falls. This strategy introduces subjectivity in timing the reintroduction of the drug, requires closer patient monitoring, and risks nonadherence and relapse. The third strategy is to stop the drug for a prespecified number of days and to then reintroduce it at a lower dose. From a knowledge of pharmacokinetics, it can be shown that stopping a drug for just 1 half-life and then resuming it at half the dose results in the immediate achievement of steady state; that is, there is no need to wait for 4 additional half-lives as with the usual strategy of dose reduction without dosing interruption. A limitation of this pharmacokinetically driven dosing strategy, however, is that it would work well in the average patient but not in those with outlying pharmacokinetic parameters.