Dose-dependent Adverse Effects Research Articles

Impact of Tigecycline on Coagulation in Severe Infections and Effect of Vitamin K1 Intervention: A Retrospective Single-Center Analysis.

BACKGROUND Tigecycline is a tetracycline antibiotic used to treat gram-positive and gram-negative bacterial infections, and bleeding is a dose-dependent adverse effect. Vitamin K1 is a fat-soluble vitamin used to treat hemorrhagic conditions. This retrospective study from a single center included 920 patients treated with tigecycline for bacterial infections between January 2017 and December 2022 and aimed to evaluate the incidence of coagulopathy and the use of vitamin K1. MATERIAL AND METHODS A total of 220 patients were included and divided into a high-dose group (100 mg, every 12 h) and normal-dose group (50 mg, every 12 h) according to the treatment dose of tigecycline. Clinical characteristics and changes in coagulation indicators during tigecycline treatment were collected. Seventy-two patients were treated with vitamin K1, and the changes in coagulation indicators before and after treatment were compared. ANOVA and t test were used to analyze the effects of different doses of tigecycline on coagulation function and the intervention of vitamin K1. RESULTS Among 920 patients, the incidence of coagulopathy was 23.91%. In both groups, coagulopathy occurred on days 5 to 7 after administration, and the high-dose group had worse coagulation function than the normal-dose group, including activated partial thrombin time, prothrombin time, and fibrinogen (P<0.05). After treatment with vitamin K1, fibrinogen increased and activated partial thrombin time and prothrombin time were shortened in both groups (P<0.05 or P<0.01). CONCLUSIONS Tigecycline caused coagulopathy with dose and time dependence. Vitamin K1 can improve tigecycline-induced coagulopathy.

Beta-blockers and their impact on metabolic processes

The aim of the study is to determine the effect of beta-blockers on lipid status, triglycerides and Body Mass Index (BMI) in patients using beta-blockers in the treatment of arterial hypertension. Our study included 120 patients at the Public Health Institution "Dom zdravlja" Živinice. The participants were monitored over a period of 3 years. Measurements were made after 12, 24 and 36 months of treatment. Patients were divided into two groups. The experimental group included 60 patients, who used beta-blockers in the treatment of arterial hypertension. The control group included 60 patients who used other antihypertensives as their first choice medication in the treatment of arterial hypertension. By monitoring cholesterol and triglyceride levels in patients using beta-blockers and other antihypertensive medications, and comparing these values within the group, no statistically significant difference in cholesterol and triglyceride levels was found in patients who used beta-blockers after 12, 24, and 36 months of treatment. There was also no statistically significant effect of therapy on the change in cholesterol and triglyceride values at observed time intervals, nor was there a statistically significant difference between these values. BMI monitoring showed a statistically significant difference between patients using beta-blockers and other antihypertensive drugs, with patients using beta-blockers having a higher BMI after 36 months of treatment. There was no statistically significant difference in BMI between patients using bisoprolol and carvedilol and patients using other beta-blockers, but patients using bisoprolol and carvedilol had lower BMI values. In studies conducted in recent years, it has been noted that many beta-blockers cause dose-dependent adverse metabolic effects on glucose and lipid metabolism, with the most adverse metabolic effects observed in patients treated with conventional non-selective beta-blockers. On the other hand, more favorable metabolic profile have drugs with β1 selective activity, such as atenolol and metoprolol, especially those with intrinsic sympathomimetic activity such as pindolol. In fact, with these beta-blockers, the adverse metabolic effects appear to be less prominent. In conclusion, beta-blockers do not lead to an increase in cholesterol and triglycerides, but they do lead to an increase in BMI in patients with arterial hypertension

Bupivacaine 0.25% versus Bupivacaine 0.125% with Dexmedetomidine for Transversus Abdominis Plane Block for Post-operative Analgesia in Cesarean Section

Abstract Background Although beneficial in acute and chronic pain management, the use of local anaesthetics is limited by its duration of action and the dose dependent adverse effects on the cardiac and central nervous system. Adjuvants or additives are often used with local anaesthetics for its synergistic effect by prolonging the duration of sensory-motor block and limiting the cumulative dose requirement of local anaesthetics. The armamentarium of local anesthetic adjuvants have evolved over time from classical opioids to a wide array of drugs spanning several groups and varying mechanisms of action. Objectives The aim of this study is to compare two different concentration of Bupivacaine 0.25% versus 0.125% added to Dexmedetomidine as adjuvant in TAP block on quality of analgesia for postoperative pain for parturients undergoing elective CS as regard: VAS score for pain after TAB block, hemodynamics stability, first dose of rescue analgesia and the side effects. Results We found that Bupivacaine 0.125% with dexmedetomidine is recommended regarding their analgesic properties, and moreover, Bupivacaine 0.25% with dexmedetomidine was proved to prolong the analgesic effect of TAP block in elective CS even with the higher concentrations of local anesthetics is our concern. Conclusion TAP block with bupivacaine 0.125% with dexmetomidine is an effective combination used for postoperative pain relief after elective Cs with lower incidence of LAST, hemodynamic stability and lower opioids consumption.

RimabotulinumtoxinB: An Update.

Botulinum type-A toxin is a well established aesthetic and medical treatment. While the usage of type-B toxin is less common, there is a growing interest in using type-B toxin, especially in those who are treatment resistant. To evaluate the primary FDA-approved clinical applications of rimabotulinumtoxinB, along with established and emerging off-label clinical indications. Articles were reviewed from PubMed database and Food and Drug Adminstration guidelines. Facial rhytids tend to use a higher conversion ratio between type A and type B toxin, due to type B toxin's weaker affinity to muscles and higher affinity for sweat glands. Specially, a 1:100 to 1:50 ratio was utilized for glabellar rhytids, a 1:25 to 1:50 ratio for periocular rhytids, a 1:50 to 1:66.6 ratio for cervical dystonia, a 1:20 to 1:50 ratio for hyperhidrosis, and a 1:25 to 30 ratio for sialorrhea. Type B toxin has demonstrated its safety and efficacy in treating facial rhytids, cervical dystonia, sialorrhea and hyperhidrosis, with potential for novel applications under investigation. Regardless of injection location and clinical applications, dry mouth and dysphagia remained the most common side effects. Across all indications, type B toxin appeared to have a faster onset of action, a dose-dependent clinical duration, and a dose-dependent adverse effect profile.

Misoprostol-induced seizures following self-abortion: a rare, but repeated occurrence

Misoprostol is a synthetic prostaglandin E1 (PGE) analogue used for medical termination of pregnancy, managing miscarriage, inducing labour, cervical ripening, and treating postpartum haemorrhage. Generally, it is safe and well-tolerated, with dose-dependent adverse effects such as nausea, vomiting, diarrhoea, abdominal pain, fever, and headache that usually resolve within a few days. However, seizures are a rare complication, occurring primarily in patients with a history of epilepsy or a predisposition to seizures and is associated with high doses and rapid administration. This case report highlights the repercussions of a misoprostol overdose used for pregnancy termination, leading to seizures induced by hyperthermia. The first patient required temporary invasive ventilation and resuscitation but recovered, whereas the second patient receiving a lower dose, exhibited milder symptoms. Both patients received psychosocial counselling prior to discharge.

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 Periconception 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 the consequences in mice for fetal development and pregnancy outcome of periconception clomiphene citrate administration at doses approximating human exposures. A dose-dependent adverse effect of clomiphene citrate given twice in the 36 hours after mating was seen, with a moderate dose of 0.75 mg/kg sufficient to cause altered reproductive outcomes in 3 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-hour 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 postweaning growth and development similar 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 compromise 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 periconception 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.

Development of a simple high-performance liquid chromatography-ultraviolet detection method for selpercatinib determination in human plasma.

Selpercatinib is a selective rearranged during transfection (RET) kinase inhibitor effective for the treatment of RET-positive non-small cell lung cancer, thyroid cancer, and other cancers. However, its clinical use requires careful management because of dose-dependent adverse effects and pharmacokinetic interactions. Given the multiple factors influencing selpercatinib blood levels, we hypothesized that establishing a therapeutic drug monitoring system for selpercatinib could help reduce adverse events and optimize efficacy. Therefore, we herein developed a high-performance liquid chromatography-ultraviolet (HPLC-UV) method for measuring selpercatinib blood levels to facilitate therapeutic drug monitoring in clinical practice. Proteins were precipitated with acetonitrile, and selpercatinib and the internal standard (gefitinib) were separated via HPLC-UV. The calibration curve was linear over 0.5-8.0 µg/mL with a coefficient of determination (r²) equaling 0.9996. Intra- and interday validation coefficients were both under 2.80%. The corresponding measurement precision ranged from - 1.50% to 12.60% and - 1.32% to 7.50%, respectively, with recoveries exceeding 94.43%. Thus, this study establishes a simple and sensitive method for quantifying selpercatinib in human plasma. Future studies will analyze plasma samples from patients treated with selpercatinib and utilize this method to explore the relationships among plasma concentration, efficacy, and adverse events to define the therapeutic concentration range.

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.

#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.