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Clinical Scenario: Ankle sprains are one of the most common injuries in athletics, and many lead to recurrent sprains, chronic ankle instability, and persistent symptoms. Treatment improvements are needed. Platelet-rich plasma (PRP) involves formulating autologous plasma with higher platelet concentration to be injected in the desired tissue. There is currently high-quality evidence supporting the use of PRP with lateral epicondylitis and knee osteoarthritis to accelerate the healing process and decrease pain. Clinical Question: Does the injection of PRP relieve pain faster and improve function compared with no injection or placebo in patients with a lateral ankle sprain? Summary of Key Findings: A computerized search yielded 191 studies; of these, 3 studies fit the inclusion and exclusion criteria. PRP injection reduces pain and increases function after lateral ankle sprain 5 to 8 weeks after intervention. Clinical Bottom Line: The use of PRP after lateral ankle sprain to decrease pain and increase function is supported with moderate evidence. Strength of Recommendation: Based on the Strength of Recommendation Taxonomy, evidence from the included studies is considered as level B, reflecting limited quality patient-oriented evidence. [ABSTRACT FROM AUTHOR]

Background: Recent studies suggest that low-molecular-weight heparin (LMWH) may play a role in mitigating the severity of acute pancreatitis (AP). This systematic review and meta-analysis aims to synthesise existing evidence on the effectiveness and safety of LMWH in the treatment of moderately-severe and severe AP. Methods: This systematic review and meta-analysis was conducted in accordance with the 2020 update of the PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. The systematic search was conducted in MEDLINE, the Cochrane Central Register of Controlled Trials, Scopus, and EMBASE, covering studies published up to February 2024. Randomised controlled trials (RCTs) and observational studies (n-RCTs) that reported the differences in the outcomes of AP for patients receiving LMWH in addition to the standard treatment (Intervention), compared to patients managed by standard treatment without LMWH (Control) were eligible. A random-effects model was used to calculate the pooled relative risk (RR) and mean differences (MD) with the corresponding 95% CI. Results: Thirteen studies were included in the meta-analysis, all published between 2004 and 2022. Eight studies were RCTs, and five were n-RCTs. Data from 13,709 patients (6.971 Interventions and 6.738 Controls) were analysed. The comparison of Intervention and Control groups showed the superiority of LMWH to standard treatments in terms of overall mortality (RR = 0.44, 95% CI = 0.31; 0.64, P < 0.0001, I2 = 51%), acute necrotic collections (RR = 0.24, 95% CI = 0.09; 0.62, P = 0.003, I2 = 0%), and organ failure (RR = 0.67, 95% CI = 0.48; 0.93, P = 0.02, I2 = 78%). The Intervention group showed superior outcomes compared with the Control group for gastrointestinal bleeding (RR = 0.64, 95% CI = 0.44; 0.94, P = 0.02, I2 = 0%), length of hospital stay (MD= − 6.08, 95% CI = − 10.08; − 2.07, P = 0.003, I2 = 98%), need for operative interventions (RR = 0.50, 95% CI = 0.29; 0.87, P = 0.01, I2 = 61%), and vascular thrombosis (RR = 0.43, 95% CI = 0.31; 0.61, P < 0.00001, I2 = 0%). Conclusions: Moderate to high-quality evidence suggests that early intervention with LMWH could improve the prognosis of non-mild AP in terms of mortality, organ failure, and decreased incidence of vascular thrombosis. In light of our findings, integrating LMWH into the treatment regimen for moderate-severe to severe AP is advocated. [ABSTRACT FROM AUTHOR]

Background: Breakthrough cancer pain (BTcP) has a negative impact on patients' quality of life, general activities, and is related to worse clinical outcomes. Fentanyl inhalant is a hand-held combination drug-device delivery system providing rapid, multi-dose (25μg/dose) administration of fentanyl via inhalation of a thermally generated aerosol. This multicenter, randomized, placebo-controlled, multiple-crossover, double-blind study evaluated the efficacy, safety, and tolerability of fentanyl inhalant in treating BTcP in opioid-tolerant patients. Methods: The trial was conducted in opioid-tolerant cancer patients with 1 ~ 4 BTcP outbursts per day. Each patient was treated and observed for 6 episodes of BTcP (4 with fentanyl inhalant, 2 with placebo). During each episode of targeted BTcP, patients were allowed up to six inhalations, with an interval of at least 4 min between doses. Primary outcome was the time-weighted sum of PID (pain intensity difference) scores at 30 min (SPID30). Results: A total of 335 BTcP episodes in 59 patients were treated. The mean SPID30 was -97.4 ± 48.43 for fentanyl inhalant-treated episodes, and -64.6 ± 40.25 for placebo-treated episodes (p < 0.001). Significant differences in PID for episodes treated with fentanyl inhalant versus placebo was seen as early as 4 min and maintained for up to 60 min. The percentage of episodes reported PI (pain intensity) scores ≤ 3, a ≥ 33% or ≥ 50% reduction in PI scores at 30 min, PR30 (pain relief scores at 30 min) and SPID60 favored fentanyl inhalant over placebo. Only 4.4% of BTcP episodes required rescue medication in fentanyl inhalant group. Most AEs were of mild or moderate severity and typical of opioid drugs. Conclusion: Treatment with fentanyl inhalant was shown to be a promising therapeutic option for BTcP, with significant pain relief starting very soon after dosing. Confirmation of effectiveness requires a larger phase III trial. Trial registration: ClinicalTrials.gov: NCT05531422 registered on 6 September 2022 after major amendment, NCT04713189 registered on 14 January 2021. [ABSTRACT FROM AUTHOR]

Traditional Chinese medicine (TCM) is considered to be one of the most comprehensive and influential form of traditional medicine. It plays an important role in clinical treatment and adjuvant therapy for cancer. However, the complex composition of TCM presents challenges to the comprehensive and systematic understanding of its antitumor mechanisms, which hinders further development of TCM with antitumor effects. Omics technologies can immensely help in elucidating the mechanism of action of drugs. They utilize high-throughput sequencing and detection techniques to provide deeper insights into biological systems, revealing the intricate mechanisms through which TCM combats tumors. Multi-omics approaches can be used to elucidate the interrelationships among different omics layers by integrating data from various omics disciplines. By analyzing a large amount of data, these approaches further unravel the complex network of mechanisms underlying the antitumor effects of TCM and explain the mutual regulations across different molecular levels. In this study, we presented a comprehensive overview of the recent progress in single-omics and multi-omics research focused on elucidating the mechanisms underlying the antitumor effects of TCM. We discussed the significance of omics technologies in advancing research on the antitumor properties of TCM and also provided novel research perspectives and methodologies for further advancing this research field. [ABSTRACT FROM AUTHOR]

Problem: Leishmaniasis is a disease caused by protozoan parasites of the genus Leishmania and has a high prevalence and impact on global health. Currently, the available drugs for its treatment have drawbacks, such as high toxicity, resistance of the parasite, and high cost. Therefore, the search for new, more effective, and safe drugs is a priority. The effectiveness of an anti-leishmanial drug is analyzed through in vitro studies in which a technician manually counts the intracellular form of the parasite (amastigote) within macrophages, which is slow, laborious, and prone to errors. Objective(s): To develop a computational system that facilitates the detection and counting of amastigotes in microscopy images obtained from in vitro studies using image processing techniques. Methodology: Segmentation of objects in the microscope image that might be Leishmania amastigotes was performed using the multilevel Otsu method on the saturation component of the hue, saturation, and intensity color model. In addition, morphological operations and the watershed transform combined with the weighted external distance transform were used to separate clustered objects. Then positive (amastigote) objects were detected (and consequently counted) using a classifier algorithm, the selection of which as well as the definition of the features to be used were also part of this research. MATLAB was used for the development of the system. Results and discussion: The results were evaluated in terms of sensitivity, precision, and the F-measure and suggested a favorable effectiveness of the proposed method. Conclusions: This system can help researchers by allowing large volumes of images of amastigotes to be counted using an automatic image analysis technique. [ABSTRACT FROM AUTHOR]

Background: Vascular dementia (VaD) is one of the most prevalent, burdensome, and costly forms of dementia. Pharmacological treatment is often the first-line choice for clinicians; however, there is a paucity of comparative information regarding the multiple available drug options. Methods and Analysis: A systematic review and network meta-analysis were conducted on randomized trials involving adult patients with VaD, sourced from PubMed, the Cochrane Library, EMBASE, Web of Science, OPENGREY, ClinicalTrials.gov, Wanfang Data, and CNKI. The primary outcomes included changes in Mini-Mental State Examination (MMSE) scores, activities of daily living (ADL) scores, and the incidence of adverse reactions. Efficacy and safety of intervention strategies were comprehensively analyzed using forest plots, cumulative ranking probability curves (SUCRA), and funnel plots, all generated with R software. Results: A total of 194 RCTs comparing 21 different anti-VaD drugs with placebos or no treatment were analysed. Regarding MMSE scores, the five most effective drugs were Butylphthalide, Huperzine A, Edaravone, Rivastigmine, and Memantine. For ADL scores, the top five drugs in efficacy were Huperzine A, Butylphthalide, Tianzhi granule, Nicergoline, and Idebenone. In terms of the incidence of adverse drug reactions, Co-dergocrine Mesylate, Tongxinluo capsule, Butylphthalide, Piracetam, and Oxiracetam demonstrated favourable safety profiles. Conclusion: This study enhances the understanding of the relative benefits and risks associated with various VaD treatments, providing a valuable reference for clinical decision-making. [ABSTRACT FROM AUTHOR]

This review article provides an in-depth examination of various aspects related to tirzepatide, a synthetic peptide given the positive signal by the "United States Food and Drug Administration" for managing type 2 diabetes. Beginning with an overview of diabetes introduction, epidemiology, and issues related to β-cell dysfunction, is explored in the narrative. It further delves into the significance of incretins in the context of diabetes and introduces tirzepatide as a novel "twincretin" owing to its dual agonistic activity on the glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptors. The document delves into the chemistry and structure of tirzepatide, providing insights into its unique composition of 39 amino acids derived from native GLP-1, GIP, and semaglutide sequences. Tirzepatide's pharmacology, with a focus on its pharmacokinetic characteristics, and its mechanism of action (MOA) are extensively discussed. Notably, tirzepatide exhibits a preference for GIP receptors, leading to effective reduction of hyperglycemia and positive effects on pancreatic β-cells. Clinical trials examining tirzepatide's impact on glycemic and obesity control are detailed, demonstrating its efficacy in reducing body weight and appetite. Furthermore, the review article explores tirzepatide's effects on cardiovascular and kidney function, highlighting potential renal benefits for diabetic and elevated cardiovascular risk individuals. The narrative also addresses the association between tirzepatide and NAFLD, emphasizing potential benefits in mitigating NAFLD outcomes. Additionally, a comprehensive overview of tirzepatide's side effects, supported by scientific trials, is presented in this article. In conclusion, this review article provides a thorough examination of tirzepatide's multifaceted impact on diabetes management, shedding light on its pharmacological properties, clinical implications, and potential side effects. The information presented contributes to a comprehensive understanding of tirzepatide's role in the evolving landscape of T2D therapeutics. [ABSTRACT FROM AUTHOR]

Background: Off-label intranasal administration of injectable dexmedetomidine has been widely applied in the pediatric sedation setting. However, the development of an improved drug delivery system that is easy to use is needed. We developed a novel dexmedetomidine nasal spray that can be administered directly without dilution or configuration for pediatric pre-anesthetic sedation. This nasal spray has a fixed dose and is stable during storage. To the best of our knowledge, this is the first licensed nasal spray preparation of dexmedetomidine worldwide. Objective: To evaluate the pre-anesthetic sedation efficacy and safety of the novel dexmedetomidine nasal spray in children. Methods: The study was conducted at 11 sites in China between 24 November 2021 and 20 May 2022 and was registered in ClinicalTrials.gov (NCT05111431, first registration date: 20/10/2021). Subjects (n = 159) between 2 and 6 years old who were to undergo elective surgery were randomized to the dexmedetomidine group (n = 107) or the placebo group (n = 52) in a 2:1 ratio. The dosage was 30 µg or 50 µg based on the stratified body weight. The primary outcome measure was the proportion of subjects who achieved the desired child-parent separation and Ramsay scale ≥ 3 within 45 min of administration. Safety was monitored via the assessments of adverse events, blood pressure, heart rate, respiratory rate and blood oxygen saturation. Results: The proportion of subjects achieving desired parental separation and Ramsay scale ≥ 3 within 45 min was significantly higher in the dexmedetomidine group (94.4%) vs the placebo group (32.0%) (P < 0.0001). As compared with placebo, dexmedetomidine treatment led to more subjects achieving Ramsay scale ≥ 3 or UMSS ≥ 2, and shorter time to reach desired parental separation, Ramsay scale ≥ 3 and UMSS ≥ 2 (all P < 0.0001). Adverse events were reported in 90.7% and 84.0% of subjects in the dexmedetomidine and placebo groups, respectively, and all the events were mild or moderate in severity. Conclusions: This novel dexmedetomidine nasal spray presented effective pre-anesthetic sedation in children with a tolerable safety profile. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to compare the tissue dissolving capacities of sodium and calcium hypochlorite [NaOCl and Ca(OCl)2] solutions applied without activation or with two irrigant activation methods. Materials and Methods: One hundred and eight dentin cavities were prepared. Preweighed tissue pieces were placed in these dentin cavities, and samples were divided into nine groups of twelve. In groups 1, 2, and 3, NaOCl was used with non-activation (NA), passive ultrasonic (PUA), and laser activation (LA). With the same techniques, Ca(OCl)2 was used in groups 4, 5, and 6, and distilled water was used in groups 7, 8, and 9. The weight loss of tissue samples was calculated and analyzed using Two-way ANOVA and Duncan tests. Results: Distilled water groups showed no tissue dissolution in any conditions. NaOCI and Ca(OCI)2 showed statistically similar dissolving effectiveness when used with the same technique. Activated groups dissolved significantly greater tissue than non-activated ones, the highest in LA. Conclusions: Ca(OCI)2 can be an alternative to NaOCl; for both, the first choice of activation may be the LA. [ABSTRACT FROM AUTHOR]

Introduction: Graves' disease (GD) is an autoimmune disorder characterized by hyperthyroidism due to increased thyroid-stimulating hormone receptor antibodies (TRAb).The treatment of GD often consists of radioactive iodine therapy, anti-thyroid drugs (ATD), or thyroidectomy. Since few studies have collected data on remission rates after treatment with ATD in Saudi Arabia, our study aimed to assess the efficacy and the clinical predictors of GD long-term remission with ATD use. Method: We conducted a retrospective chart review study of 189 patients with GD treated with ATD between July 2015 and December 2022 at the endocrine clinics in King Abdulaziz Medical City in Riyadh. All GD patients, adults, and adolescents aged 14 years and older who were treated with ATD during the study period and had at least 18 months of follow-up were included in the study. Patients with insufficient follow-up and those who underwent radioactive iodine (RAI) therapy or thyroidectomy as first-line therapy for GD were excluded from the study. Results: The study sample consisted of 189 patients, 72% of whom were female. The patients' median age was 38years (33, 49). A total of 103 patients (54.5%) achieved remission. The median follow-up period for the patients was 22.0 months (9, 36). Patients who achieved remission had lower mean free T4 levels (25.8pmol/l ± 8.93 versus 28.8pmol/l ± 10.82) (P value = 0.038) and lower median TRAb titer (5.1IU/l (2.9, 10.7)) versus (10.5IU/l (4.2, 22.5)) (P value = 0.001) than patients who did not achieve remission. Thirty-five out of 103 patients who achieved remission (34%) relapsed after ATD discontinuation. The patients who relapsed showed higher median thyroid uptake on 99mTc-pertechnetate scan than patients who did not relapse: 10.3% (5.19, 16.81) versus 6.0% (3.09, 12.38), with a P value of 0.03. They also received ATD for a longer period, 40.0 months (29.00, 58.00) versus 25.0 months (19.00, 32.50), with a P value of < 0.0001. Conclusion: The remission of GD was achieved in approximately half of the patients treated with ATD; however, approximately one-third of them relapsed. Lower Free T4 and TRAb levels at diagnosis were associated with remission. Longer ATD use and higher thyroid uptake upon diagnosis were associated with relapse after ATD discontinuation. Future studies are necessary to ascertain the predictors of ATD success in patients with GD. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is one of the most common diseases globally that may have side effects on liver and renal function. Pharmacological treatments to reduce adverse liver and renal effects are still limited. It has been proposed that silymarin may possess hepatoprotective and anti-inflammatory properties. The present trial aims to assess the hepatorenal protective efficacy of silymarin supplementation in cancer patients receiving chemotherapy in an outpatient setting. Method: This is a randomized, placebo-controlled clinical trial that recruited female breast cancer patients. Participants were randomly assigned to one placebo group and two intervention groups. The control group received 140 mg of placebo daily, while the two intervention groups received 140 mg silymarin daily. Follow-up assessments were conducted at baseline, 3 weeks, and 6 weeks. At the beginning of the study, the patients were subjected to a computed tomography (CT) scan, and the liver and renal parameters such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin, Blood urea nitrogen (BUN) and Creatinine (Cr) were examined through laboratory tests. Results: Despite two deaths and three dropouts, 100 patients completed the study. Silymarin showed significant effects on liver enzymes in the levels of ALP and bilirubin (P < 0.05), with no significant impact on renal function in the levels of Blood urea nitrogen (BUN) and Creatinine (Cr) (P > 0.05). The medication was well-tolerated, with minimal reported side effects (P > 0.05). Discussion: The study suggests that silymarin may have hepato-renal protective potential in breast cancer patients and improve patient tolerance to chemotherapy. The data presented on the efficacy and safety of silymarin may provide stronger foundation for further trials and for a possible use in clinical practice. Trial registration information: Registration Number: IRCT20201123049474N2, First Trial Registration: 16/08/2021, Access: https://www.irct.behdasht.gov.ir/trial/57641 [ABSTRACT FROM AUTHOR]

Background: Fentanyl is an opioid analgesic frequently used in the emergency department (ED) and is usually administered without knowing the QTC values of the patients or being monitored. However, the effect of fentanyl on QTC, prolongation or shortening, has not been elucidated. This study aimed to determine the effect of fentanyl on QTC. Methods: This is a prospective observational study in the ED of a tertiary hospital on patients who received intravenous fentanyl for procedures other than intubation. ECG was performed before and at 1, 5, 15, 30, and 60 min after the initiation of fentanyl administration, and QTC value was calculated. Primary outcomes were QTC prolongation, defined as an increase in the QTC to ≥ 500 ms or any increase in QTC by ≥ 60 ms. Results: The study included 109 patients. Of these, 60 patients were male, and the median age was 40. Compared with the baseline QTC value, statistically significant prolongation was detected at the 5th, 15th, 30th, and 60th minutes, with the maximum prolongation at 30 min, and the median was 13.08 ms. Most patients with QTC prolongation were female and over 40 years of age. Clinically, none of these patients developed malignant arrhythmias during the 60-minute monitored observation period. Conclusion: Fentanyl prolonged the QTC value statistically significantly. Although no patient developed malignant arrhythmia clinically, our results suggest that this QTC-prolonging effect should be considered when using fentanyl in patients at risk of torsades. [ABSTRACT FROM AUTHOR]

Background: Transcriptomics can reveal much about cellular activity, and cancer transcriptomics have been useful in investigating tumor cell behaviors. Patterns in transcriptome-wide gene expression can be used to investigate biological mechanisms and pathways that can explain the variability in patient response to cancer therapies. Methods: We identified gene expression patterns related to patient drug response by clustering tumor gene expression data and selecting from the resulting gene clusters those where expression of cluster genes was related to patient survival on specific drugs. We then investigated these gene clusters for biological meaning using several approaches, including identifying common genomic locations and transcription factors whose targets were enriched in these clusters and performing survival analyses to support these candidate transcription factor-drug relationships. Results: We identified gene clusters related to drug-specific survival, and through these, we were able to associate observed variations in patient drug response to specific known biological phenomena. Specifically, our analysis implicated 2 stem cell-related transcription factors, HOXB4 and SALL4, in poor response to temozolomide in brain cancers. In addition, expression of SNRNP70 and its targets were implicated in cetuximab response by 3 different analyses, although the mechanism remains unclear. We also found evidence that 2 cancer-related chromosomal structural changes may impact drug efficacy. Conclusion: In this study, we present the gene clusters identified and the results of our systematic analysis linking drug efficacy to specific transcription factors, which are rich sources of potential mechanistic relationships impacting patient outcomes. We also highlight the most promising of these results, which were supported by multiple analyses and by previous research. We report these findings as promising avenues for independent validation and further research into cancer treatments and patient response. [ABSTRACT FROM AUTHOR]

Background: Open liver resection necessitates a substantial upper abdominal inverted-L incision, resulting in severe pain and compromising patient recovery. Despite the efficacy of epidural analgesia in providing adequate postoperative analgesia, the potential epidural-related adverse effects should be carefully considered. This study aims to compare the efficacy and safety of continuous epidural analgesia and intravenous analgesia in open liver resection. Methods: A retrospective study was conducted, collecting data from patients who underwent open liver resection between 2007 and 2017. Propensity score matching was implemented to mitigate confounding variables, with patients being matched in a 1:1 ratio based on propensity scores. The primary outcome was the comparison of postoperative morphine consumption at 24, 48, and 72 hours between the two groups. Secondary outcomes included pain scores, postoperative outcomes, and epidural-related adverse effects. Results: A total of 612 patients were included, and after matching, there were 204 patients in each group. Opioid consumption at 24, 48, and 72 hours postoperatively was statistically lower in the epidural analgesia group compared to the intravenous analgesia group (p < 0.001). However, there was no significant difference in pain scores (p = 0.422). Additionally, perioperative hypotension requiring treatment, as well as nausea and vomiting, were significantly higher in the epidural analgesia group compared to the intravenous analgesia group (p < 0.001). Conclusions: Epidural analgesia is superior to intravenous morphine in terms of reducing postoperative opioid consumption within the initial 72 h after open liver resection. Nevertheless, perioperative hypotension, which necessitates management, should be approached with consideration and vigilance. Trial registration: The study was registered in the Clinical Trials Registry at www.clinicaltrials.gov/, NCT number: NCT06301932. [ABSTRACT FROM AUTHOR]

Background and objectives: About a quarter of migraine cases among women have menstrual migraine (MM), which is usually more severe, longer lasting, and less responsive to treatment than typical migraine. Randomized controlled trials (RCTs) have evaluated the efficacy of several medication in the acute and preventive treatment of MM; this meta-analysis compared the effectiveness of these treatments. Methods: We conducted systematic searches in the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase databases. The primary outcomes of acute treatment trials were pain relief at 2 and 24 h after treatment compared with placebo or another treatment. The three endpoints we checked for studying MM prevention were: no recurrence of headaches each month, a 50% reduction in monthly migraine days from baseline, and a decrease in the mean number of headache days per month. Results: Out of 342 studies, 26 RCTs met the criteria. Triptans, combined with or without other analgesics, were superior to placebo in providing pain relief in the acute treatment and prevention of MM. Among the treatments, sumatriptan and lasmiditan demonstrated superior pain relief at 2 h (OR: 4.62) and 24 h (OR: 4.81). Frovatriptan exhibited effectiveness in preventing headache recurrence, whereas galcanezumab and erenumab displayed significant preventive benefits in reducing headache days per month. Conclusion: Sumatriptan and lasmiditan are effective first-line treatments for acute MM. For prevention, frovatriptan may be the more effective of triptans. Compared with triptans, CGRP monoclonal antibodies, here including erenumab and galcanezumab, are more effective in reducing headache days, and therefore, in preventing MM. [ABSTRACT FROM AUTHOR]

In the conducted research study, solubility investigation was performed to elucidate the dissolution rate and behaviour of a drug incorporated within a solid dispersion matrix. The foremost objective was to appraise the impact of formulation parameters on the improvement of drug's solubility, the list of factors influencing the bioavailability. To this end, a systematic series of experiments were undertaken, wherein the drug was co-precipitated with a hydrophilic polymer carrier using various solvent systems and ratios. The resulting solid dispersions were meticulously characterized, employing state-ofthe-art analytical techniques. Subsequently, solubility profiles were generated through equilibrium solubility studies, encompassing a range of pH conditions and temperatures, to comprehensively evaluate the dissolution behaviour of the drug. Based on study, it was concluded that the solubility of Pazopanib Hydrochloride (Pazopanib base) is significantly increased from 0.001 mg/ml to ~8.000 mg/ml. the same was confirmed from the analytical tools. Analytical tools also confirm the conversion of crystalline form to amorphous form. The outcomes of these investigations provide essential insights into the potential utility of solid dispersion systems as a viable strategy for enhancing the solubility and, consequently, the therapeutic efficacy of the drug in question. [ABSTRACT FROM AUTHOR]

Objective: To analyse the clinical efficacy and adverse drug reactions (ADRs) of iron preparations. Methods: A total of 374 patients with iron deficiency anaemia admitted to our hospital between 1 January and 31 December 2020 were included in this study. They were divided into 2 groups based on their medication regimens: Group A (n = 187) took oral ferrous succinate tablets, and Group B (n = 187) received intravenous iron sucrose. The remission of major symptoms, laboratory test results, ADRs and other related data were collected after 4 weeks of treatment. Results: Compared with the pre-treatment baseline, haemoglobin (Hb), serum iron (SI), serum ferritin (SF) and the mean corpuscular volume (MCV) increased in both groups at 4 weeks of treatment (P < 0.05). After treatment, Group A had lower levels of Hb (108.41 ± 8.39 vs. 122.31 ± 6.04 g/L, t = 6.293, P < 0.001), SI (9.72 ± 4.24 vs. 15.62 ± 5.41 µmol/L, t = 5.482, P < 0.001) and SF (27.1 ± 10.82 vs. 39.82 ± 10.44 ug/L, t = 6.793, P < 0.001) compared with Group B. In contrast, there was no significant difference in the post‐treatment level of MCV (P > 0.05). The overall response rate significantly differed between the 2 groups (78.61% vs. 90.91%, χ2 = 10.949, P < 0.001). The incidence of ADRs of both groups were similar, and the difference was not statistically significant (χ2 = 0.035, P = 0.851). Conclusion: Iron sucrose demonstrates favourable efficacy and safety in treating iron deficiency anaemia. [ABSTRACT FROM AUTHOR]

Background and Objectives Envafolimab is the first and only globally approved subcutaneously injectable PD-L1 antibody for the treatment of instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors in adults, including those with advanced colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. The aim of this investigation was to examine the pharmacokinetic and exposure-response (E-R) profile of envafolimab in patients with solid tumors to support the approval of fixed and alternative dose regimens. Methods In this study, a population pharmacokinetic (PopPK) modeling approach will be employed to quantitatively evaluate intrinsic and extrinsic covariates. Additionally, PopPK-estimated exposure parameters were used to evaluate E-R relationship for safety and efficacy to provide a theoretical basis for recommending optimal treatment regimens. Simulations were performed on the dosing regimens of body weight-based regimen of 2.50 mg/kg QW, fixed dose 150 mg QW, and 300 mg Q2W for the selection of alternative dosing regimens. Data from 4 clinical studies (NCT02827968, NCT03101488, NCT03248843, and NCT03667170) were utilized. Results The PopPK dataset comprised 182 patients with 1810 evaluable envafolimab concentration records. Finally, a one-compartment model incorporating first-order absorption, first-order linear elimination, and time-dependent elimination according to an E max function was found to accurately describe the concentration-time data of envafolimab in patients with advanced solid tumors. Creatinine clearance and country were identified as statistically significant factors affecting clearance, but had limited clinical significance. A relative flat exposure-response relationship was observed between early measures of safety and efficacy to verify that no dose adjustment is required. Simulation results indicated that 2.50 mg/kg QW, 150 mg QW, and 300 mg Q2W regimen yield similar steady-state exposure. Conclusions No statistically significant difference was observed between weight-based and fixed dose regimens. Model-based simulation supports the adoption of a 150 mg weekly or 300 mg biweekly dosing regimen of envafolimab in the solid tumor population, as these schedules effectively balance survival benefits and safety risks. [ABSTRACT FROM AUTHOR]

Introduction Predictive markers of LV5FU2 maintenance benefit after first-line induction with FOLFIRINOX in patients with metastatic pancreatic cancer are necessary to select patients who will not be harmed by this strategy. Patients and Methods We focused on patients who received 12 cycles of FOLFIRINOX (arm A, N  = 88) or 8 cycles of FOLFIRINOX followed by LV5FU2 maintenance in controlled patients (arm B, N  = 91) from the PRODIGE-35 trial. Prognostic factors and predictors of efficiency were identified by using Cox regression. Median progression-free survival (PFS), overall survival (OS), and time to deterioration of quality of life (TTD-QoL) were evaluated. Results Poor independent prognostic factors were primary tumor in place, age <65 years and the presence of liver metastases for PFS, a baseline neutrophil/lymphocyte ratio (NLR) ≥5 and CA19.9 ≥500 UI/L for OS, independent of the treatment arm. Patients with one metastatic site had a longer PFS in arm A, whereas patients with ≥2 metastatic sites had a longer PFS in arm B. We also identified predictors of OS and TTD-QoL in arm B but these differences were not statistically significant. Conclusion Except for patients with one metastatic site who benefited more from 12 cycles of FOLFIRINOX, a maintenance strategy with LV5FU2 should be widely offered to mPC patients whose survival and QoL are preserved after 4 months of FOLFIRINOX. (ClinicalTrials.gov: NCT02352337). [ABSTRACT FROM AUTHOR]

Objective: To compare the outcomes associated with the use of probiotics, prebiotics, and synbiotics for the treatment of chronic constipation in adults. Methods: We searched eight electronic databases from database inception to July 11, 2023, to identify randomized controlled trials (RCTs) that report efficacy and safety for the treatment of chronic constipation. The risk of bias in the included RCTs was evaluated according to the Cochrane tool, and the certainty of the evidence was assessed using the Confidence in Network Meta-Analysis framework. The analysis was conducted using R version 4.3.0. Results: Out of the 37 RCTs, a total of 21 different types of interventions were reported, involving 3,903 patients. This NMA demonstrated that both prebiotics and synbiotics resulted in an increase in frequency of stool movements per week. Compared to placebo, lactulose (Mean difference [MD] = 3.39, 95% Confdence interval [CI] [1.13, 5.65], moderate certainty), mix2 (consisting of Lactulose and Bacillus coagulans) (MD = 3.63, 95% CI [1.37, 5.89], moderate certainty), mix6 (consisting of Lactulose and Bifidobacterium coagulans) (MD = 4.30, 95% CI [1.04, 7.54], low certainty), and mix7 (consisting of Lactulose, Bifidobacterium subtilis, and Enterococcus faecium) (MD = 4.58, 95% CI [1.35, 7.78], moderate certainty) exhibited a significant effect. Notably, mix7 demonstrated the highest probability of being the most effective intervention (94.8%). Furthermore, when compared to L. plantarum, four probiotics and two synbiotics showed significant advantages in the Patient Assessment of Constipation Symptoms (PAC-SYM) score. L. reuteri (MD = -13.74, 95% CI [-22.20, -4.66], very low certainty) exhibited a significant effect in improving the Patient Assessment of Constipation Quality of Life (PAC-QoL) score. In terms of safety, there were no statistically significant differences between the intervention and control groups in all adverse event analyses. Conclusions: Moderate to very low evidence supports the use of lactulose and synbiotics to increase the number of weekly stool movements in patients, particularly highlighting the significant impact of synbiotics in increasing the number of weekly stool movements in patients with constipation. The use of L. paracasei showed improvements in PAC-SYM scores, while L. reuteri demonstrated enhancements in PAC-QoL scores. [ABSTRACT FROM AUTHOR]

Objective: The aim of this meta-analysis was to investigate the effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on blood glucose and weight in adolescents with overweight/obesity and/or type 2 diabetes mellitus (T2DM) aged <18 years. Methods: PubMed, Embase, Web of Science, and Cochrane Library were searched for all randomized controlled trials (RCTs) up to August 2023 comparing GLP-1RAs with placebo in overweight/obese and/or T2DM adolescents and extracted relevant data for meta-analysis. Results: Fourteen RCTs were included in the meta-analysis with a total of 1,262 participants. Results revealed that the GLP-1RAs group had a more significant reduction in glycosylated hemoglobin A1c (HbA1c; risk difference (RD)=-0.34%, p<0.001) than the control group. However, there was no difference in fasting plasma glucose [fasting plasma glucose (FPG); RD=-2.07 mg/dL, p=0.065] between the two groups. Nonetheless, the experimental group that received exenatide showed no significant reduction in HbA1c (p=0.253) and FPG (p=0.611) between the two groups. The GLP-1RAs group had a more significant decline in body weight (RD=-4.28 kg, p=0.002) and body mass index (BMI) (RD=-1.63 kg/m2, p=0.002) compared to the control group. The experimental group was given liraglutide (RD=-2.31 kg, p=0.038) or exenatide (RD=-2.70 kg, p<0.001). Compared to the control group, the experimental group had a more significant drop in body weight than the control group. However, for the experimental group that received liraglutide, the BMI had a no significant reduction between the two groups (RD=-0.81 kg/m2, p=0.260). For the experimental group using exenatide, BMI declined more significantly in the intervention group than in the control group (RD=-1.14 kg/m2, p<0.001). Conclusion: This study showed that GLP-1RAs reduced HbA1c, FPG, and weight loss in overweight/obese and/or T2DM adolescents. Liraglutide was better than exenatide in terms of glucose reduction. Nevertheless, in terms of weight control, exenatide was more effective than liraglutide. [ABSTRACT FROM AUTHOR]

Objective This study aimed to assess the efficacy and safety of intravenous ramosetron for pain relief in patients with fibromyalgia (FM) unresponsive to conventional treatments. Methods In this prospective, double-blind, placebo-controlled trial, 80 FM patients were randomly allocated to receive either placebo (n  = 40) or ramosetron (n  = 40) at a dosage of 0.3 mg/day intravenously for five consecutive days. The primary outcome was the reduction in pain intensity at the end of the treatment period, evaluated using a visual analogue scale (VAS). Secondary outcome measures included the FM Impact Questionnaire, Beck Depression Inventory (BDI), Multi-Dimensional Health Assessment Questionnaire (MDHAQ), EQ-5D and State-Trait Anxiety Inventory on days 5 (end of treatment), 7, 10 and 28. Safety was continuously monitored throughout the study. Results At the end of the treatment phase, the ramosetron group demonstrated a significantly greater reduction in VAS pain scores compared with the placebo group (1.18 ± 1.60 vs 0.54 ± 1.59, P  < 0.05). Additionally, the ramosetron group exhibited significant improvements in BDI (4.42 ± 5.18 vs 1.33 ± 4.87, P  < 0.05) and MDHAQ pain scale (0.37 ± 0.74 vs 0.04 ± 0.52, P  < 0.05) scores. However, these improvements in pain VAS and BDI scores were not sustained through day 28. The safety profile of ramosetron was favorable, with gastrointestinal symptoms, particularly constipation, being the most commonly reported adverse events. Conclusions Intravenous administration of ramosetron provided safe and effective short-term relief of pain intensity in FM patients with inadequate response to standard treatments. [ABSTRACT FROM AUTHOR]

Objectives Autoreactive memory B cells (MBCs) contribute to chronic and progressive courses in autoimmune diseases like SLE. The efficacy of belimumab (BEL), the first approved biologic treatment for SLE and LN, is generally attributed to depletion of activated naïve B cells and inhibition of B-cell activation. BEL's effect on MBCs is currently unexplained. We performed an in-depth cellular and transcriptomic analysis of BEL's impact on the blood MBC compartment in patients with SLE. Methods A retrospective meta-analysis was conducted, pooling flow cytometry data from four randomized trials involving 1245 patients with SLE treated with intravenous BEL or placebo. Then, extensive MBC phenotyping was performed using high-sensitivity flow cytometry in patients with mild/moderate SLE and severe SLE/LN treated with subcutaneous BEL. Finally, transcriptomic characterization of surging MBCs was performed by single-cell RNA sequencing. Results In BEL-treated patients, a significant increase in circulating MBCs, in a broad range of MBC subsets, was established at week 2, gradually returning to baseline by week 52. The increase was most prominent in patients with higher SLE disease activity, serologically active patients and patients aged ≤18 years. MBCs had a non-proliferating phenotype with a prominent decrease in activation status and downregulation of numerous migration genes. Conclusion Upon BEL initiation, an increase of MBCs was firmly established. In the small cohort investigated, circulating MBCs were de-activated, non-proliferative and demonstrated characteristics of disrupted lymphocyte trafficking, expanding on our understanding of the therapeutic mechanism of B-cell-activating factor inhibition by BEL. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov , NCT00071487, NCT00410384, NCT01632241, NCT01649765, NCT03312907, NCT03747159. [ABSTRACT FROM AUTHOR]

Objectives To evaluate 1-year bimekizumab efficacy in PsA from the patient perspective using the 12-item PsA Impact of Disease (PsAID-12) questionnaire. Methods BE OPTIMAL (NCT03895203; biologic DMARD [bDMARD]-naïve), BE COMPLETE (NCT03896581; inadequate response/intolerance to TNF inhibitors [TNFi-IR]) and BE VITAL (NCT04009499; open-label extension) assessed bimekizumab 160 mg every 4 weeks in patients with PsA. Post hoc analyses of patient-reported disease impact, assessed by the PsAID-12 questionnaire, are reported to 1 year (collected to Week 40 in BE COMPLETE). Results Overall, 1,112 total patients were included (698 bimekizumab, 414 placebo). Rapid improvements observed with bimekizumab treatment at Week 4 continued to Week 16 and were sustained to 1 year. At 1 year, mean (SE) change from baseline in PsAID-12 total score was comparable between bimekizumab-randomized patients and patients who switched to bimekizumab at Week 16 (bDMARD-naïve bimekizumab –2.3 [0.1], placebo/bimekizumab –2.2 [0.1]; TNFi-IR bimekizumab –2.5 [0.1], placebo/bimekizumab –2.2 [0.2]). Proportions of bimekizumab-randomized patients achieving clinically meaningful within-patient improvement (≥3-point decrease from baseline) at Week 16 were sustained to 1 year (bDMARD-naïve 49.0%; TNFi-IR 48.5%) and were similar for placebo/bimekizumab patients (bDMARD-naïve 44.4%; TNFi-IR 40.6%). Across studies and arms, 35.3% to 47.8% of patients had minimal or no symptom impact at 1 year. Improvements were observed to 1 year across all single-item domains, including pain, fatigue and skin problems. Conclusion Bimekizumab treatment resulted in rapid and sustained clinically meaningful improvements in disease impact up to 1 year in bDMARD-naïve and TNFi-IR patients with PsA. Trial registration BE OPTIMAL: NCT03895203; BE COMPLETE: NCT03896581; BE VITAL: NCT04009499 (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Objectives To investigate the predictive factors for difficult-to-treat rheumatoid arthritis (D2T RA) and assess the efficacy of biologic DMARDs (bDMARDs) and Janus kinase inhibitors (JAKi). Methods Retrospective analysis was conducted on data from the ANSWER cohort comprising 3623 RA patients treated with bDMARDs or JAKi in Japan. Multivariate Cox proportional hazards modelling was used to analyse the hazard ratios (HRs) for treatment retention. Results Of the 3623 RA patients, 450 (12.4%) met the first two criteria of the EULAR D2T RA definition (defined as D2T RA in this study). Factors contributing to D2T RA included age over 75 (compared with those under 65, hazard ratio [HR] = 0.46; 95% CI: 0.31, 0.69), higher rheumatoid factor (RF) titres (HR = 1.005; 95% CI: 1.00, 1.01), higher clinical disease activity index (HR = 1.02; 95% CI: 1.01, 1.03), lower methotrexate dosage (HR = 0.97; 95% CI: 0.95, 0.99), and comorbidities like hypertension (HR = 1.53; 95% CI: 1.2, 1.95) and diabetes (HR = 1.37; 95% CI: 1.09, 1.73). Anti-IL-6 receptor antibodies (aIL-6R, HR = 0.53; 95% CI: 0.37, 0.75) and JAKi (HR = 0.64; 95% CI: 0.46, 0.90) were associated with fewer discontinuations due to ineffectiveness compared with TNF inhibitors. Oral glucocorticoid usage (HR = 1.65; 95% CI: 1.11, 2.47) was linked to increased discontinuation due to toxic adverse events. Conclusion Younger onset, higher RF titres, and comorbidities predicted D2T RA development. For managing D2T RA, aIL-6R and JAKi exhibited superior drug retention. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the effectiveness and safety of two different intravenous methylprednisolone (IVMP) pulse doses in patients with severe microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Methods We emulated a target trial using observational data from the nationwide registry in Japan. Patients with severe glomerulonephritis or diffuse alveolar haemorrhage were selected and pseudo-randomized into three groups using propensity score-based overlap weighting as follows: non-IVMP, IVMP 0.5 g/day and IVMP 1.0 g/day. The primary outcome was all-cause mortality, and the secondary outcomes were composite all-cause mortality and kidney failure, severe relapse and serious infection from 2 to 48 weeks after treatment initiation. To estimate the treatment effects, the Cox proportional hazard model and Fine–Gray subdistribution hazard model were used. Results In this emulated target trial, of 201 eligible patients (MPA, 175; GPA, 26), 6 (3%) died, 4 (2.0%) had kidney failure, 11 (5.5%) had severe relapse, and 40 (19.9%) had severe infections. Hazard ratios (HR) for IVMP 0.5 g/day and IVMP 1.0 g/day pulse groups compared with non-IVMP pulse were as follows: all-cause mortality 0.46 (95% CI: 0.07, 2.81) and 0.07 (95% CI: 0.01, 0.41), respectively; all-cause mortality/kidney failure 1.18 (95% CI: 0.26, 5.31) and 0.59 (95% CI: 0.08, 4.52), respectively; subdistribution HRs for severe relapse were 1.26 (95% CI: 0.12, 13.70) and 3.36 (95% CI: 0.49, 23.29), respectively; and for serious infection 1.88 (95% CI: 0.76, 4.65) and 0.94 (95% CI: 0.28, 3.13), respectively. Conclusion IVMP 1.0 g/day pulse may improve 48-week mortality in patients with severe MPA/GPA. [ABSTRACT FROM AUTHOR]

Objective To investigate the safety and efficacy of subcutaneous tocilizumab (SC-TCZ) treatment in a long-term extension (LTE) of clinical trials in polyarticular or systemic juvenile idiopathic arthritis (pJIA or sJIA). Methods Patients with pJIA or sJIA from two open-label, 52-week phase 1b core trials of SC-TCZ who had adequate response per investigator assessment entered the LTE and continued SC-TCZ treatment according to body weight–based dosing regimens until commercial availability or up to 5 years. Pharmacokinetics, pharmacodynamics, and efficacy were assessed for up to 3 years, and safety for up to 5 years in the LTE. Results Forty-four patients with pJIA and 38 patients with sJIA entered the LTE. Tocilizumab trough concentrations were maintained within the range expected to provide clinical benefit (mean values: pJIA, ∼10 μg/ml; sJIA, ∼75 μg/ml over 3 years). Pharmacodynamic parameters (interleukin-6, soluble interleukin-6 receptor, erythrocyte sedimentation rate, C-reactive protein) were maintained throughout the LTE at levels achieved in the core trials. Inactive disease per American College of Rheumatology provisional criteria was reported for 90% (17/19) and 53% (8/15) of patients with pJIA and 91% (10/11) and 92% (12/13) of patients with sJIA in the <30 and ≥30 kg body weight groups, respectively. Serious adverse events in the LTE were reported in six patients with pJIA (13.6%; five serious infections) and five patients with sJIA (13.2%; one serious infection). Conclusion Patients with pJIA or sJIA experienced long-term disease control with SC-TCZ treatment. Long-term safety was consistent with the known tocilizumab safety profile. Clinical trial registration clinicaltrials.gov, NCT02165345 [ABSTRACT FROM AUTHOR]

Objective To determine the safety and efficacy of anifrolumab in patients with systemic lupus erythematosus (SLE) classified based on the Lupus Low Disease Activity State (LLDAS) in real-world clinical practice. Methods This retrospective observational study involved SLE patients who started anifrolumab therapy. The primary end point was the retention rate over 26 weeks after initiating anifrolumab therapy; 45 patients followed up for 12 weeks or longer were analysed in the following groups to determine the safety and efficacy up to week 12 after treatment initiation: (i) non-LLDAS achievement group and (ii) minor flare group. Safety and efficacy were compared between the minor flare group and the standard of care (SoC) group (treated by adding glucocorticoids [GCs] or immunosuppressants) after adjustment with inverse probability of treatment weighting using propensity score (PS-IPTW). Results The retention rate of anifrolumab was 89.7% at week 26.The LLDAS achievement rates at week 12 were 42.9% and 66.7% in the non-LLDAS achievement and minor flare groups, respectively. In both groups, GC doses and SELENA–SLEDAI score significantly decreased. When the anifrolumab group with minor flare was compared with the SoC group or the GC dose increase group, the GC dose and SLEDAI score were significantly lower in the anifrolumab group than in either of the other groups; there was no significant difference in LLDAS achievement. Conclusion At week 26 after initiating anifrolumab therapy, ∼90% of patients remained on therapy. Anifrolumab might lower disease activity without initiating GCs and reduce GC doses, especially in patients who experience minor flares after LLDAS achievement. [ABSTRACT FROM AUTHOR]

The worldwide HIV cases were 39.0 million (33.1–45.7 million) in 2022. Due to genetic variations, HIV-1 is more easily transmitted than HIV-2 and favours CD4 + T cells and macrophages, producing AIDS. Conventional HIV drug therapy has many drawbacks, including adherence issues leading to resistance, side effects that lower life quality, drug interactions, high costs limiting global access, inability to eliminate viral reservoirs, chronicity requiring lifelong treatment, emerging toxicities, and a focus on managing infections. Conventional dosage forms have bioavailability issues due to intestinal P-glycoprotein (P-gp) efflux, which can reduce anti-retroviral drug efficacy and lead to resistance. Use of phyto-constituents with P-gp regulating actions has great benefits for semi-synthetic modification to create formulations with greater bioavailability and reduced toxicity, which improves drug effectiveness. Lipid-based nanocarriers, solid lipid nanoparticles, nanostructured lipid carriers, polymer-based nanocarriers, and inorganic nanoparticles may inhibit P-gp efflux. Employing potent P-gp inhibitors within nanocarriers as a Trojan horse approach can enhance the intracellular accumulation of anti-retroviral drugs (ARDs), which are substrates for efflux transporters. This technique increases oral bioavailability and offers lower-dose options, boosting HIV patient compliance and lowering costs. Molecular docking of the inhibitor with P-gp may anticipate optimum binding and function, allowing drug efflux to be minimised. [ABSTRACT FROM AUTHOR]

Objective: Our objective was to evaluate the association of serum biomarkers with baseline psoriatic arthritis (PsA) disease activity, pharmacodynamic effects of deucravacitinib on biomarker levels, and the relationship between biomarkers and clinical responses to deucravacitinib. Methods: The phase 2 trial (ClinicalTrials.gov identifier: NCT03881059) randomly assigned 203 patients with PsA 1:1:1 to placebo, deucravacitinib at 6 mg once daily (QD), or deucravacitinib at 12 mg QD. Serum biomarkers associated with the interleukin 23 (IL‐23) pathway (IL‐17A, β‐defensin [BD‐2], and IL‐19), type I interferon pathway, inflammation, and collagen matrix turnover were measured by immunoassay. Clinical responses (≥75% improvement from baseline in the Psoriasis Area and Severity Index [PASI75] and ≥20% improvement from baseline in American College of Rheumatology criteria [ACR20] responses) were measured at week 16. Hematologic variables were also assessed. Results: IL‐17A, BD‐2, and IL‐19 had a modest association with PASI scores (r = 0.4, r = 0.56, and r = 0.5, respectively) at baseline. In deucravacitinib groups, IL‐17A, BD‐2, IL‐19, C‐X‐C motif ligand 9 (CXCL9), CXCL10, C‐reactive protein, matrix metalloproteinase 3, and collagen type 4 degradation marker levels were significantly reduced at week 16 versus baseline (P < 0.01); higher levels of IL‐23 pathway–associated biomarkers predicted higher PASI75 and ACR20 response rates in deucravacitinib‐treated patients. Significantly higher PASI75 response rates were seen in patients with high baseline IL‐17A (odds ratio 15.76) and BD‐2 levels (odds ratio 15.41) versus low baseline IL‐17A and BD‐2 levels. Changes in hematologic variables that are characteristic of JAK inhibition were not observed with deucravacitinib. Conclusion: Deucravacitinib significantly impacted biomarkers associated with Tyk2 signaling pathways of key inflammatory cytokines, including IL‐23 and type I interferon, and those related to collagen matrix turnover. These biomarkers may predict treatment responses to deucravacitinib. [ABSTRACT FROM AUTHOR]

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Treatment of ocular diseases presents unique challenges and opportunities for the clinician and for the clinical pharmacologist. Ophthalmic pharmaceuticals, typically given as liquids, require consideration of solubility, physiological pH, and osmolarity, as well as sterility and stability, which in turn requires optimal pharmaceutics. Ocular tissue levels are challenging to obtain in humans, and the clinical pharmacokinetics is typically blood levels, which are primarily related to safety, rather than efficacy. The eye is a closed compartment with multiple physiological barriers with esterases and transporters, but relatively little cytochrome oxidases. Delivery routes include topical, intravitreal, and systemic. Patient dosing involves not only adherence issues common to all chronic diseases, but also performance requirements on eye drop instillation. Therapeutically, ocular diseases and their pharmacological treatments include both those analogous to systemic diseases (e.g., inflammation, infection, and neuronal degeneration) and those unique to the eye (e.g., cataract and myopia). [ABSTRACT FROM AUTHOR]

Cancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long‐term efficacy of these treatments. Our analysis aim was to develop a semi‐mechanistic longitudinal exposure‐tumor growth inhibition model for patients with mRCC to characterize and compare everolimus (mTORC1) and apitolisib's (dual PI3K/mTORC1/2) ability to inhibit tumor growth, and quantitate each drug's efficacy decay caused by emergence of tumor resistance over time. Model‐estimated on‐treatment tumor growth rate constant was 1.7‐fold higher for apitolisib compared to everolimus. Estimated half‐life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib, suggesting a faster rate of tumor re‐growth for apitolisib patients likely due to the emergence of resistance. Goodness‐of‐fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size–time profiles. Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model‐informed drug development for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to quantitatively compare the efficacy and safety of CDK4/6 inhibitors and PI3K/AKT/mTOR inhibitors for ER+/HER2− metastatic breast cancer. Methods: A parametric survival function was used to analyze the time course of overall survival (OS) and progression-free survival (PFS). The objective response rate (ORR) and the incidence of any grade and grade 3–4 adverse events were summarized using the random-effects model of a single-arm meta-analysis. Results: This study included 44 arms from 48 publications, with a total sample size of 7881 patients. Our study revealed that CDK4/6 inhibitors had a median OS of 40.7 months, a median PFS of 14.8 months, and an ORR of 40%, whereas PI3K/AKT/mTOR inhibitors had a median OS of 29.8 months, a median PFS of 8.3 months, and an ORR of 20%. Additionally, this study also found that the proportion of patients with visceral metastases and specific endocrine therapy used in combination significantly impact OS and PFS. In terms of adverse events, CDK4/6 inhibitors exhibited a relatively high incidence of hematological adverse events. Conclusion: Our study provides solid quantitative evidence for the first-line recommendation of CDK4/6 inhibitors combined with endocrine therapy for ER+/HER2− metastatic breast cancer in clinical guidelines. [ABSTRACT FROM AUTHOR]

Purpose: To describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships. Methods: The PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA). Results: The two-compartment model adequately described the PK of SB12 and ECU, and the subject's weight was chosen as a clinically significant covariate affecting drugs' clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid Emax and sigmoid Emax relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients. Conclusion: The population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12. [ABSTRACT FROM AUTHOR]

Background: Central nervous system (CNS) tumors are among the most common malignancies in various age ranges. Low-grade glioma (LGG) can account for nearly 30% of pediatric CNS malignancies. Progression or recurrence after the first-line treatments is common among these patients. Therefore, more treatments are required. Bevacizumab as an anti-VEGF antibody has come into the spotlight recently and is especially used in relapse or recurrence settings. This review aims to study the safety and efficacy of bevacizumab for patients with recurrent LGG. Methods: This study was conducted according to The Preferred Reporting Items for Systematic Reviews and Meta-Analyses. PubMed, Scopus, Web of Science, and Embase were comprehensively searched using the relevant key terms until 24th August 2023 to retrieve the studies that investigated clinical outcomes of bevacizumab in patients with recurrent LGG. All statistical analysis was performed by STATA v.17. Results: A total of 1306 papers were gathered, out of which 13 were incorporated in the meta-analysis. The pooled incidence rate of treatment according to the RANO scale was 70% (95% CI = 43–98%) for objective response rate, 26% (95% CI = 58–96%) for partial response, 21% (95% CI = 15–28%) for minor response, 14% (95% CI = 3–24%) for complete response, 48% (95% CI = 37–59%) for stable disease, and 8% (95% CI = 4–11%) for progressive disease. Furthermore, according to progressive survival after treatment, it was 4% (95% CI = −1 to 9%) for 6-month PFS, 41% (95% CI = 32–50%) for 2-year PFS, and 29% (95% CI = 22–35%) for 3-year PFS. Conclusion: According to the RANO scale and PFS, clinicians should be aware that Bevacizumab could be a favorable alternative therapy for recurrent LGG. Furthermore, bevacizumab exhibits minimal toxicity and high tolerability in recurrent LGG. [ABSTRACT FROM AUTHOR]

Intranasal (IN) medications offer a safe non-invasive way to rapidly deliver drugs in situations where intravenous (IV) access and intramuscular (IM) administration is challenging or not feasible. In the prehospital setting, this can be an essential alternative in time critical situations including trauma management, seizures, and agitated patients. However, there is a paucity of evidence summarizing its efficacy in this environment. This systematic review aims to assess the current evidence supporting the use of IN medicine (midazolam, ketamine, fentanyl, morphine, glucagon, and naloxone) in the prehospital setting alone. A systematic literature search (PROSPERO CRD42023440713) of PubMed, Web of Science, OVID Medline, "Cochrane Central Register of Controlled Trials," Cochrane reviews and Embase was performed from inception to June 2023 to identify studies where IN medications were administered to patients in the prehospital setting. All randomized controlled trials, observational cohort studies, case series, and case reports were included. Papers not written in English, review articles, abstracts, and non-published data (including letters to the editor) were excluded. The methodological quality of the included studies was interpreted using the Cochrane risk of bias tool and rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. No funding was received. From 4818 studies, 39 were included (seven for midazolam, five for ketamine, twelve for fentanyl, one for diamorphine, two for glucagon, and twelve for naloxone). A total of 24,097 patients were treated with IN medications across all the studies. There were five moderate quality, four low quality, and thirty very low quality studies. The potential efficacy of IN fentanyl and ketamine was demonstrated consistently throughout the studies with less clear evidence for midazolam, morphine, glucagon, and naloxone. This review was severely limited by the study quality, with most studies demonstrating "high concerns" for bias. Prehospital IN medication administration has wide-ranging potential, particularly for administering analgesia. There are likely to be certain populations, for example, pediatrics, that will benefit the most, although conclusions are limited by the quality of evidence currently available. We encourage additional research in this area, particularly with robust prospective double-blind RCTs. [ABSTRACT FROM AUTHOR]

Objective: The efficacy and safety of propranolol for retinopathy of prematurity (ROP) remain under debate. This network meta-analysis (NMA) focuses on whether a ranking may be established for different dose levels of propranolol as treatment of ROP in terms of stage progression as the primary outcome, with appearance of plus disease and need for anti-vascular endothelial growth factors (anti-VEGFs) or laser therapy as secondary endpoints. Methods: Fourteen studies (10 randomised controlled trials, three single-arm trials and one retrospective observational study) of 474 patients treated with oral or ocular propranolol were retrieved from databases up to April 2024. Meta-insight and model-based NMA were undertaken to evaluate the propranolol dose–response relationship. Studies were evaluated for model fit, risk of bias and Confidence of evidence In Network Meta-Analysis (CINeMA). Effect sizes were determined as odds ratio (OR) with 95% credible interval (CrI). Results: Bayesian analysis showed a trend towards improved effects for propranolol given at late stages (stages 2–3; S23) of ROP progression compared with its administration at earlier stages (stages 0–1; S01). OR values for oral propranolol 1.5 and 2 mg/kg/day given at S23 were 0.13 (95% CrI 0.04–0.37) and 0.16 (95% CrI 0.04–0.61), respectively, while given at S01 were 0.28 (95% CrI 0.02–2.96) and 0.78 (95% CrI 0.14–4.43), respectively. Similarly, OR of eye propranolol 0.2% at S23 was 0.37 (95% CrI 0.09–1.00) versus an S01 OR of 0.64 (95% CrI 0.21–2.04). Surface under the cumulative ranking curve (SUCRA) analyses confirmed best probability values for oral propranolol 1.5–2 mg/kg followed by eye propranolol 0.2%, all at S23. Model-based NMA showed nonlinearity in the dose–response for oral propranolol with a trend to greater maximal effect for its administration at late versus early stages. For secondary endpoints, lower risk values were found with oral propranolol 1.5 mg/kg/day at S23 for progression to plus disease (OR 0.14; 95% CrI 0.02–0.84) and need for anti-VEGFs (OR 0.23; 95% CrI 0.05–0.93) and laser (OR 0.16; 95% CrI 0.02–1.10) therapies also followed by eye propranolol 0.2%, and a similar profile was obtained with SUCRA analysis. Lower doses (0.5–1.0 mg/kg/day) of oral propranolol retained efficacy. Threat of adverse events was estimated as risk difference versus control with no difference for eye propranolol 0.2% and oral propranolol 0.5 mg/kg/day, modest increases of risk for oral propranolol 1.0 and 1.5 mg/kg/day and the highest risk difference for oral propranolol 2.0 mg/kg/day (0.06; 95% CI −0.01 to 0.13). Conclusion: A diminished risk of disease progression and need for additional treatment was obtained with propranolol in ROP, but safety is a potential concern. Propranolol eye micro-drops (0.2%) can be as efficacious as oral propranolol. Nonetheless, the evidence is limited due to the paucity and quality of the available studies. [ABSTRACT FROM AUTHOR]

The electrospun nanofiber system is correlated with high efficacy of drug delivery. This study aims to investigate the effect of nanofiber-based delivery of evodiamine, an indole alkaloid derived from Rutaceae plants Evodia rutaecarpa (Juss.) Benth, on intrahepatic cholangiocarcinoma (ICC), as well as to explore the molecular mechanisms. An electrospun nanofiber system carrying evodiamine was generated. Compared to evodiamine treatment alone, the nano-evodiamine exhibited more pronounced effects on suppressing proliferation, colony formation, invasiveness, migration, apoptosis resistance, cell cycle progression, and in vivo tumorigenesis of two ICC cell lines (HUCC-T1 and RBE). ICC cells exhibited increased expression of histone deacetylase 4 (HDAC4) while decreased tropomyosin 1 (TPM1). HDAC4 suppressed TPM1 expression by removing H3K9ac modifications from its promoter. Nano-evodiamine reduced HDAC4 protein levels in ICC cells, thus promoting transcription and expression of TPM1. Either overexpression of HDAC4 or downregulation of TPM1 negated the tumor-suppressive effects of nano-evodiamine. Collectively, this study demonstrates that the electrospun nanofiber system enhances the efficiency of evodiamine. Additionally, evodiamine suppresses the malignant properties of ICC cells. The findings may provide fresh insights into the application of electrospun nanofiber system for drug delivery and the effects of evodiamine on tumor suppression. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) represent a crucial component of targeted therapies in gastric cancer, potentially altering traditional treatment paradigms. Many ADCs have entered rigorous clinical trials based on biological theories and preclinical experiments. Modality trials have also been conducted in combination with monoclonal antibody therapies, chemotherapies, immunotherapies, and other treatments to enhance the efficacy of drug coordination effects. However, ADCs exhibit limitations in treating gastric cancer, including resistance triggered by their structure or other factors. Ongoing intensive researches and preclinical experiments are yielding improvements, while enhancements in drug development processes and concomitant diagnostics during the therapeutic period actively boost ADC efficacy. The optimal treatment strategy for gastric cancer patients is continually evolving. This review summarizes the clinical progress of ADCs in treating gastric cancer, analyzes the mechanisms of ADC combination therapies, discusses resistance patterns, and offers a promising outlook for future applications in ADC drug development and companion diagnostics. [ABSTRACT FROM AUTHOR]

Background: Aberrant TGF‐β signaling pathway can lead to invasive phenotype of colorectal cancer (CRC), resulting in poor prognosis. It is pivotal to develop an effective prognostic factor on the basis of TGF‐β‐related genes to accurately identify risk of CRC patients. Methods: We performed differential analysis of TGF‐β‐related genes in CRC patients from databases and previous literature to obtain TGF‐β‐related differentially expressed genes (TRDEGs). LASSO‐Cox regression was utilized to build a CRC prognostic feature model based on TRDEGs. The model was validated using two GEO validation sets. Wilcoxon rank‐sum test was utilized to test correlation of model with clinical factors. ESTIMATE algorithm and ssGSEA and tumor mutation burden (TMB) analysis were used to analyze immune landscape and mutation burden of high‐risk (HR) and low‐risk (LR) groups. CellMiner database was utilized to identify therapeutic drugs with high sensitivity to the feature genes. Results: We established a six‐gene risk prognostic model with good predictive accuracy, which independently predicted CRC patients' prognoses. The HR group was more likely to experience immunotherapy benefits due to higher immune infiltration and TMB. The feature gene TGFB2 could inhibit the efficacy of drugs such as XAV‐939, Staurosporine, and Dasatinib, but promote the efficacy of drugs such as CUDC‐305 and by‐product of CUDC‐305. Similarly, RBL1 could inhibit the drug action of Fluphenazine and Imiquimod but promote that of Irofulven. Conclusion: A CRC risk prognostic signature was developed on basis of TGF‐β‐related genes, which provides a reference for risk and further therapeutic selection of CRC patients. [ABSTRACT FROM AUTHOR]

Introduction: Limited awareness exists regarding real-world data (RWD) for palbociclib in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced/metastatic breast cancer in populations from certain countries outside of Western regions. Methods: A systematic scoping review was conducted using PubMed and Embase to evaluate RWD for palbociclib from countries outside of Western regions that are underrepresented in clinical trials. Search criteria were aligned with our research question for relevant English-language publications, without restrictions on publication date, followed by Phase 1 (title and abstract) and Phase 2 (full-text) screening of retrieved citations as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Data analyses of eligible studies were done separately for abstracts and full-text publications to enhance the precision and reliability of the results. Results: Database search yielded 1485 non-duplicate records, 46 qualified for inclusion, of which 47.8% were published as full text. The analysis of outcomes, based exclusively on full-text publications that collectively included 2048 patients treated with palbociclib, revealed the median progression-free survival (PFS) of 20.2–36.7 months, overall survival (OS) of 39.9 months (reported in one publication) and objective response rate (ORR) of 45.3–80.0% with first-line treatment. In ≥ second line, the median PFS, OS and ORR ranged from 7.0 to 24.2 months, 11 to 19.6 months, and 13.9% to 47.9%, respectively. The safety profile of palbociclib was similar to that reported in pivotal clinical studies, and no new safety concerns were identified. Conclusions: A comprehensive volume of evidence demonstrates that palbociclib's effectiveness and safety profile in real-world settings align with those observed in clinical trials, offering valuable insights for clinical decision-making in countries outside of Western regions underrepresented in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Breast cancer presents diverse molecular subtypes affecting treatment strategies. Human epidermal growth factor receptor 2 (HER2)-low, hormone receptor-positive (HR+) breast cancer poses a challenge due to limited targeted therapies. Current neoadjuvant treatment primarily utilizes chemotherapy, with conflicting results regarding efficacy in patients with HER2-low breast cancer. Trastuzumab deruxtecan (T-DXd) shows promise in HER2-low metastatic disease, and preliminary evidence suggests synergy with endocrine therapy. Objective: This editorial explores the hypothesis that neoadjuvant T-DXd with or without endocrine therapy offers efficacy in the clinical management of HR+/HER2-low breast cancer. Methods: We propose a phase II study with two treatment arms: T-DXd + letrozole and T-DXd alone. The primary endpoint is the radiological complete response rate. Secondary endpoints include pathological complete response rate, safety, event-free survival, and overall survival. Exploratory analyses will compare the arms to identify potential for optimizing treatment efficacy and minimizing side effects. Conclusions: This study design allows for initial assessment of T-DXd with or without endocrine therapy in the treatment of HER2-low breast cancer. The findings may pave the way for personalized treatment strategies and inform future research, potentially leading to a chemotherapy-sparing approach. [ABSTRACT FROM AUTHOR]

Introduction: A dynamic molecular biomarker that can identify early efficacy of immune checkpoint inhibitor (ICI) therapy remains an unmet clinical need. Here we evaluate if a novel circulating tumor DNA (ctDNA) assay, xM, used for treatment response monitoring (TRM), that quantifies changes in ctDNA tumor fraction (TF), can predict outcome benefits in patients treated with ICI alone or in combination with chemotherapy in a real-world (RW) cohort. Methods: This retrospective study consisted of patients with advanced cancer from the Tempus de-identified clinical genomic database who received longitudinal liquid-based next-generation sequencing. Eligible patients had a blood sample ≤ 40 days prior to the start of ICI initiation and an on-treatment blood sample 15–180 days post ICI initiation. TF was calculated via an ensemble algorithm that utilizes TF estimates derived from variants and copy number information. Patients with molecular response (MR) were defined as patients with a ≥ 50% decrease in TF between tests. In the subset of patients with rw-imaging data between 2 and 18 weeks of ICI initiation, the predictive value of MR in addition to rw-imaging was compared to a model of rw-imaging alone. Results: The evaluable cohort (N = 86) was composed of 14 solid cancer types. Patients received either ICI monotherapy (38.4%, N = 33) or ICI in combination with chemotherapy (61.6%, N = 53). Patients with MR had significantly longer rw-overall survival (rwOS) (hazard ratio (HR) 0.4, P = 0.004) and rw-progression free survival (rwPFS) (HR 0.4, P = 0.005) than patients with molecular non-response (nMR). Similar results were seen in the ICI monotherapy subcohort; HR 0.2, P = 0.02 for rwOS and HR 0.2, P = 0.01 for rwPFS. In the subset of patients with matched rw-imaging data (N = 51), a model incorporating both MR and rw-imaging was superior in predicting rwOS than rw-imaging alone (P = 0.02). Conclusions: xM used for TRM is a novel serial quantitative TF algorithm that can be used clinically to evaluate ICI therapy efficacy. [ABSTRACT FROM AUTHOR]

Introduction: Biological monoclonal antibodies play a pivotal role in cancer treatment, with biosimilars significantly enhancing their accessibility. In Brazil's ethnically diverse setting, real-world evidence is crucial for assessing the effectiveness and applicability of these therapies in routine clinical practice. Methods: We performed a multicentric, observational, prospective real-world study on biosimilar trastuzumab-dkst for adjuvant treatment of early HER2-positive breast cancer in Brazilian patients. Data were collected using a case-report form. Results: Of the 176 recruited, we present data from the first 59 patients (mean age 51.7 ± 12.9 years) who had completed treatment with trastuzumab-dkst. The mean time from diagnosis to the first adjuvant treatment with trastuzumab-dkst was 5.5 ± 2.7 months. Of the patients, 59% of patients achieved at least a 30-month follow-up. The 31.7-month invasive disease-free survival rate (IDFS) was 94.5% (95% CI 83.9–98.2%) and median IDFS was not achieved, since only three patients had invasive disease recurrence. The overall survival rate was 100% until the last assessment. The observed adverse events were similar to those presented by other studies using biosimilar or reference trastuzumab. Four serious adverse events (8.5%) were observed. A reduction in left ventricular ejection fraction of at least 10% was observed in 16.9% of participants. There was no treatment interruption, and three participants (5.1%) had their trastuzumab-dkst dose reduced. Conclusion: Our study reinforces the existing pivotal data, underscoring the real-world efficacy and safety of biosimilar trastuzumab-dkst in the adjuvant treatment for early HER2-positive breast cancer. The preliminary long-term effectiveness and safety data we present further validate trastuzumab-dkst's role as a cost-saving alternative in oncological care. These findings have important implications for improving patient access to crucial treatments and for the more efficient use of healthcare resources. ClinicalTrials.gov Registration: NCT03892655. [ABSTRACT FROM AUTHOR]

Introduction: Hepatic visceral crisis (VC), characterized by a rapid total bilirubin increase with disease progression, poses a life-threatening risk in advanced breast cancer (ABC). International consensus guidelines define VC and touch on impending VC (IVC). Limited data exist on systemic treatments for hepatic VC/IVC. This study explores the safety and efficacy of cisplatin monotherapy in patients with Human Epidermal Growth Factor Receptor 2- negative breast cancer (BC) and hepatic IVC/VC. Methods: In this retrospective single-center cohort study data of patients treated with cisplatin monotherapy (60–80 mg/m2, every 3–4 weeks) between 2016 and 2023 at a reference Cancer Centre in Southern Poland were analyzed. Results: 33 female patients (24/33 hormonal-positive) with the mean age 53.84 years were included. Participants progressed on median 2 prior palliative systemic treatment lines. In 10/23 patients hepatic VC and in 23/33 IVC (rapid, symptomatic liver progression; extensive liver involvement; alanine or aspartate aminotransferase > 2 × normal limit; significant increases in lactate dehydrogenase, alkaline phosphatase, or gamma-glutamyl transferase) were identified. Median progression-free survival was 1.87 months and median overall survival 2.67 months. 33% of the patients presented stable disease or partial response. Eight patients experienced adverse events grade ≥ 3: in five the dose of cisplatin was reduced; two stopped the treatment. Conclusion: Due to the hepatotoxicity of BC-active drugs, specific recommendations for systemic treatment are scarce. Our study explored cisplatin's potential use, finding it to be a viable option in patients with performance status 0 or 1 experiencing hepatic IVC/VC, irrespective of liver function parameters and other factors. [ABSTRACT FROM AUTHOR]

Introduction: RTXM83, a biosimilar of rituximab, was approved after physicochemical, functional, non-clinical, and clinical studies demonstrated their similarity; these studies included RTXM83-AC-01-11, a multicentric double-blind international prospective pivotal study. Long-term data on biosimilars can potentially elucidate their clinical robustness and facilitate their broader adoption. Methods: In this retrospective observational study, we analyzed a dataset from a Brazilian cohort previously randomized in the RTXM83-AC-01-11 study followed by the assessment of long-term outcomes in an observational extension phase from randomization in the RTXM83-AC-01–11 study to the last recorded evaluation. Patients with diffuse large B cell lymphoma (DLBCL) received either reference rituximab (R) or RTXM83 plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as adjuvant treatment. Results: The median follow-up period was 77.0 months. Patients with initial DLBCL stages III and IV comprised 50% of the R-CHOP group and 40% of the biosimilar group. Five (18.5%) patients, including two RTXM83-CHOP-treated and three R-CHOP-treated individuals, experienced late adverse events (AEs) of interest. No new safety signs were established. At the final assessment, the progression-free survival (PFS) rates were 93.3% and 50.0% in the RTXM83-CHOP and R-CHOP groups, respectively. Median PFS was not achieved in the RTXM83-CHOP group, which was 40.5 months in the R-CHOP group. The overall survival (OS) rates were 100% and 66.7% in the RTXM83-CHOP and R-CHOP groups, respectively. The median OS was not reached in any group. Conclusion: This study demonstrated the long-term safety and effectiveness of RTXM83 in treating DLBCL; outcomes comparable to those of the reference product and potentially improved access to treatment have been indicated. However, further research with more diverse patient groups can validate these findings and advocate the broader adoption of biosimilars in cancer care. Trial Registration: ClinicalTrials.gov Identifier: NCT04928573. June 16, 2021, "retrospectively registered". [ABSTRACT FROM AUTHOR]

Objective: To evaluate the efficacy and safety of a low‐dose, long‐term rituximab regimen in the treatment of idiopathic CIDP. Methods: This study included 15 CIDP patients treated with rituximab. Patients were administered 600 mg of rituximab intravenously every 6 months. Baseline evaluation was conducted before the initiation of rituximab treatment and subsequent evaluations were conducted 6 months after each rituximab infusion at on‐site visits. Clinical improvement was objectively determined by improvement of scale score at least decrease ≥1 INCAT or mRS or increase ≥4 MRC or ≥8 cI‐RODS after each infusion compared to baseline evaluation. Results: Fifteen CIDP patients were included and 10 of them were typical CIDP and five were distal CIDP. Nine in 15 (60%) patients after first infusion and three in six (50%) patients after second infusion exhibited significant clinical improvement compared to baseline evaluation. Additionally, rituximab facilitated a reduction or cessation of other medications in 73% of patients at last visit. The safety profile was favorable, with no reported adverse events. Conclusion: Rituximab presents a promising therapeutic option for idiopathic CIDP, offering both efficacy and safety with a low‐dose, long‐term regimen. [ABSTRACT FROM AUTHOR]

Objective: There is growing evidence that adding non-steroidal anti-inflammatory drugs to some psychopharmacological treatments may help to improve symptoms in patients suffering from major depressive disorder. The present study examined the therapeutic efficacy of adding celecoxib to escitalopram and the safety of doing so. Method: In this double-blind randomized controlled trial, 60 patients with major depressive disorder were randomly assigned to either treatment with escitalopram plus celecoxib (intervention group) or escitalopram and placebo. All patients were evaluated blind to treatment group with the Hamilton Depression Rating Scale (HDRS) before the intervention as well at 4 and 8 weeks after initiating treatment. Chi-square and paired t-test were used to examine between-group differences at those assessment times. Results: There was no significant difference in depressive symptoms between intervention and placebo groups at baseline. However, at 4 and 8 weeks after the beginning of treatment, there were significant between-group differences in HDRS scores, favoring the intervention group. No between-group differences were found in treatment-related side effects. Conclusions: Adding celecoxib to escitalopram may improve symptoms of depression in patients with major depressive disorder without increasing the risk of drug-related side effects. [ABSTRACT FROM AUTHOR]

Background: Obsessive-compulsive disorder (OCD) is a prevalent and burdensome mental health condition, often resistant to conventional treatments. Agomelatine (Valdoxan), a compound acting on serotonin and melatonin systems, has shown promise in treating those with treatment-resistant OCD based on anecdotal reports and case studies. Methods: A randomized, double-blind controlled trial was conducted with 60 patients diagnosed with treatment-resistant OCD. Participants were randomized into an intervention group (receiving agomelatine 50 mg/day) and a control group (receiving placebo). OCD symptoms were assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) over a 12-week period. Results: There were no significant differences in age, gender, or baseline Y-BOCS scores between intervention and control groups. Agomelatine did not demonstrate a significant improvement in OCD symptoms compared to placebo. Adverse events were comparable between groups, and liver enzyme levels remained within the normal range. Conclusion: This study, while not confirming superior efficacy compared to placebo, underscores the need for continued investigation into agomelatine's potential for treating specific subgroups of OCD patients, underscoring the need for more comprehensive and well-controlled trials in the future. [ABSTRACT FROM AUTHOR]