Oral Janus Kinase Inhibitors in Pediatric Atopic Dermatitis.

PURPOSE OF REVIEW: To analyze the efficacy and safety of Janus kinase inhibitors (JAKi) in the treatment of pediatric AD. RECENT FINDINGS: Adolescents with moderate and severe atopic dermatitis (AD) need systemic therapies, as stated several recent practice guidelines. (JAKi) have shown their efficacy in the treatment of adult AD, however, there is a lack of information concerning efficacy and safety of their use in pediatric AD. We found that the JAKi's abrocitinib (ABRO), baricitinib (BARI), and upadacitinib (UPA), are all an effective treatment option with a very fast onset of action for adolescents with moderate-to-severe AD. BARI was not effective in children between 2 and 10 years with moderate-to-severe AD. Fortunately, major safety issues with JAKi in adolescents with AD have not been documented in the trials, so far, contrasting with the reports in adults with AD, where these events have very rarely occurred. There are some reports of herpes zoster (HZ) infection in adolescents on JAKi, but it is not a major safety concern. Acne is a relatively common AE with UPA in adolescents; however, it is responsive to standard treatment. This review will help the clinician to choose among the JAKi according to the needs and clinical features of patients with moderate and severe AD. In the following years, with the advent of new biologicals and JAKi, these therapies will fall into place in each phase of the evolution of patients with AD.

[Severe atopic dermatitis in childhood in the era of personalized medicine]. / Dermatitis atópica severa en la infancia en la era de la medicina personalizada.

Atopic dermatitis (AD) is a chronic, non-infectious inflammatory dermatosis, with increasing prevalence in recent decades. Due to its chronic and recurrent nature, it diminishes the quality of life of patients and their families. In recent years, advances in the understanding of AD's pathophysiology have driven the development of targeted therapies such as monoclonal antibodies (mAbs) and Janus kinase inhibitors (JAKis) which modulate the immune system through specific signaling pathways, providing effective alternatives to traditional systemic immunosuppressive agents. Four targeted therapies have been approved in the USA for the treatment of severe/refractory cases: dupilumab, tralokinumab, abrocitinib, and upadacitinib. This manuscript aims to present an update on the pathophysiology of AD, describe the new treatments available, and provide an analysis of the initial results of the use of these treatments in the pediatric population. We concluded that the high cost of these treatments often limits their prescription to situations where cases of atopic dermatitis are resistant to other conventional therapeutic options or when the disease reaches a severe degree. This underscores the importance of careful and accurate decision-making in the medical management of AD to ensure the efficient use of these therapeutic resources.

Neuroprotective Potential of a Novel Soluble Guanylate Cyclase Stimulator the Riociguat Alone or in a Combination Manner with Resveratrol in Experimental Stroke Model in Rats / Potencial Neuroprotector del Novedoso Estimulador de Guanilato Ciclasa Soluble, el Riociguat solo o en Combinación con Resveratrol en un Modelo Experimental de Ataque Cerebrovascular en Ratas

SUMMARY: In this study we aimed to examine the effect of novel vasodilatory drug Riociguat co-administration along resveratrol to recover neurodegeneration in experimental stroke injury. For that purpose, thirty-five adult female rats were divided into five groups (Control, MCAO, MCAO + R, MCAO + BAY, MCAO + C) of seven animals in each. Animals in Control group did not expose to any application during the experiment and sacrificed at the end of the study. Rats in the rest groups exposed to middle cerebral artery occlusion (MCAO) induced ischemic stroke. MCAO + R group received 30 mg/kg resveratrol, and MCAO + BAY group received 10 mg/kg Riociguat. The MCAO + C group received both drugs simultaneously. The drugs were administered just before the reperfusion, and the additional doses were administered 24h, and 48h hours of reperfusion. All animals in this study were sacrificed at the 72nd hour of experiment. Total brains were received for analysis. Results of this experiment indicated that MCAO led to severe injury in cerebral structure. Bax, IL-6 and IL-1ß tissue levels were up-regulated, but anti-apoptotic Bcl-2 immunoexpression was suppressed (p<0.05). In resveratrol and Riociguat treated animals, the neurodegenerations and apoptosis and inflammation associated protein expressions were improved compared to MCAO group, but the most success was obtained in combined treatment exposed animals in MCAO + C group. This study indicated that the novel soluble guanylate stimulator Riociguat is not only a potent neuroprotective drug in MCAO induced stroke, but also synergistic administration of Riociguat along with resveratrol have potential to increase the neuroprotective effect of resveratrol in experimental cerebral stroke exposed rats.

En este estudio, nuestro objetivo fue examinar el efecto de la coadministración del nuevo fármaco vasodilatador Riociguat junto con resveratrol para recuperar la neurodegeneración en lesiones por ataques cerebrovasculares experimentales. Para ello, se dividieron 35 ratas hembras adultas en cinco grupos (Control, MCAO, MCAO + R, MCAO + BAY, MCAO + C) de siete animales en cada uno. Los animales del grupo control no fueron sometidos a ninguna aplicación durante el experimento y se sacrificaron al final del estudio. Las ratas de los grupos expuestas a la oclusión de la arteria cerebral media (MCAO) indujeron un ataque cerebrovascular isquémico. El grupo MCAO + R recibió 30 mg/kg de resveratrol y el grupo MCAO + BAY recibió 10 mg/kg de Riociguat. El grupo MCAO + C recibió ambos fármacos simultáneamente. Los fármacos se administraron antes de la reperfusión y las dosis adicionales se administraron a las 24 y 48 horas de la reperfusión. Todos los animales en este estudio fueron sacrificados a las 72 horas del experimento. Se recibieron cerebros totales para su análisis. Los resultados indicaron que la MCAO provocaba lesiones graves en la estructura cerebral. Los niveles tisulares de Bax, IL-6 e IL- 1ß estaban regulados positivamente, pero se suprimió la inmunoexpresión antiapoptótica de Bcl-2 (p <0,05). En los animales tratados con resveratrol y Riociguat, las neurodegeneraciones y las expresiones de proteínas asociadas a la apoptosis y la inflamación mejoraron en comparación con el grupo MCAO, sin embargo el mayor éxito se obtuvo en el tratamiento combinado de animales expuestos en el grupo MCAO + C. Este estudio indicó que el nuevo estimulador de guanilato ciclasa soluble Riociguat no solo es un fármaco neuroprotector potente en el ataque cerebrovascular inducido por MCAO, sino que también la administración sinérgica de Riociguat junto con resveratrol tiene el potencial para aumentar el efecto neuroprotector del resveratrol en ratas experimentales expuestas a un ataque cerebrovascular.

Cardiovascular Events, Malignancies, and Efficacy Outcomes in Latin American Patients With Rheumatoid Arthritis Receiving Tofacitinib or Tumor Necrosis Factor Inhibitors: A Post Hoc Analysis of the ORAL Surveillance Study.

BACKGROUND/OBJECTIVE: To assess safety/efficacy of tofacitinib and tumor necrosis factor inhibitors (TNFi) in patients from Latin America (LATAM) in ORAL Surveillance. METHODS: In ORAL Surveillance, 4362 patients with rheumatoid arthritis aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 or 10 mg twice daily or TNFi. This post hoc analysis stratified patients by geographical location (LATAM, n = 1202; non-LATAM, n = 3160). Incidence rates (IRs; patients with first event/100 patient-years) and hazard ratios for adverse events of special interest were reported. Efficacy outcomes included Clinical Disease Activity Index and American College of Rheumatology 20/50/70 responses. RESULTS: Risk factors associated with cardiovascular disease and malignancies were less prevalent in the LATAM cohort compared with the non-LATAM cohort. IRs for patients receiving tofacitinib (combined doses) versus TNFi were 0.54 versus 0.28 (LATAM) and 1.14 versus 0.92 (non-LATAM) for major adverse cardiovascular events; 0.58 versus 0.27 (LATAM) and 1.33 versus 0.95 (non-LATAM) for malignancies excluding nonmelanoma skin cancer; and 0.69 versus 0.35 (LATAM) and 0.63 versus 0.33 (non-LATAM) for all-cause death. IRs for nonmelanoma skin cancer and venous thromboembolism were also numerically higher with tofacitinib versus TNFi and in the non-LATAM cohort versus LATAM. Efficacy was similar across treatment groups within each cohort. CONCLUSIONS: Adverse events of special interest were generally less frequent in LATAM versus non-LATAM patients, reflecting differences in baseline characteristics, and higher with tofacitinib versus TNFi in both cohorts, consistent with the overall findings of ORAL Surveillance. Our findings emphasize the importance of assessing individual risk factors to guide benefit/risk assessment and treatment decisions. CLINICAL TRIAL REGISTRATION NUMBER: NCT02092467.

A consensus reverse docking approach for identification of a competitive inhibitor of acetyltransferase enhanced intracellular survival protein from Mycobacterium tuberculosis.

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a significant global health challenge. The emergence of multidrug-resistant (MDR) Mtb strains imposes the development of new therapeutic strategies. This study focuses on the identification and evaluation of potential inhibitors against Mtb H37Ra through a comprehensive screening of an in-house chemolibrary. Subsequently, a promising pyrimidine derivative (LQM495) was identified as promising and then further investigated by experimental and in silico approaches. In this context, computational techniques were used to elucidate the potential molecular target underlying the inhibitory action of LQM495. Then, a consensus reverse docking (CRD) protocol was used to investigate the interactions between this compound and several Mtb targets. Out of 98 Mtb targets investigated, the enhanced intracellular survival (Eis) protein emerged as a target for LQM495. To gain insights into the stability of the LQM495-Eis complex, molecular dynamics (MD) simulations were conducted over a 400 ns trajectory. Further insights into its binding modes within the Eis binding site were obtained through a Quantum mechanics (QM) approach, using density functional theory (DFT), with B3LYP/D3 basis set. These calculations shed light on the electronic properties and reactivity of LQM495. Subsequently, inhibition assays and kinetic studies of the Eis activity were used to investigate the activity of LQM495. Then, an IC50 value of 11.0 ± 1.4 µM was found for LQM495 upon Eis protein. Additionally, its Vmax, Km, and Ki parameters indicated that it is a competitive inhibitor. Lastly, this study presents LQM495 as a promising inhibitor of Mtb Eis protein, which could be further explored for developing novel anti-TB drugs in the future.

Pharmacological Modulation of the Cytosolic Oscillator Affects Glioblastoma Cell Biology.

The circadian system is a conserved time-keeping machinery that regulates a wide range of processes such as sleep/wake, feeding/fasting, and activity/rest cycles to coordinate behavior and physiology. Circadian disruption can be a contributing factor in the development of metabolic diseases, inflammatory disorders, and higher risk of cancer. Glioblastoma (GBM) is a highly aggressive grade 4 brain tumor that is resistant to conventional therapies and has a poor prognosis after diagnosis, with a median survival of only 12-15 months. GBM cells kept in culture were shown to contain a functional circadian oscillator. In seeking more efficient therapies with lower side effects, we evaluated the pharmacological modulation of the circadian clock by targeting the cytosolic kinases glycogen synthase kinase-3 (GSK-3) and casein kinase 1 ε/δ (CK1ε/δ) with specific inhibitors (CHIR99021 and PF670462, respectively), the cryptochrome protein stabilizer (KL001), or circadian disruption after Per2 knockdown expression in GBM-derived cells. CHIR99021-treated cells had a significant effect on cell viability, clock protein expression, migration, and cell cycle distribution. Moreover, cultures exhibited higher levels of reactive oxygen species and alterations in lipid droplet content after GSK-3 inhibition compared to control cells. The combined treatment of CHIR99021 with temozolomide was found to improve the effect on cell viability compared to temozolomide therapy alone. Per2 disruption affected both GBM migration and cell cycle progression. Overall, our results suggest that pharmacological modulation or molecular clock disruption severely affects GBM cell biology.

Toxicogenetic, biochemical, and physiological effects of azoxystrobin and carbendazim fungicides over Lactuca sativa L. and Phaseolus vulgaris L.

Fungicides are pesticides that are frequently used in agriculture because of their action against fungal diseases. However, the widespread application of pesticides around the world raises environmental and public health concerns, since these compounds are toxic and can pose risks to ecosystems and human health. The aim of this study was to evaluate the phytotoxic, cytogenotoxic, and biochemical effects of azoxystrobin and carbendazim on Lactuca sativa L. and their physiological effects on Phaseolus vulgaris L. by analyzing the cell cycle and chromosomal and nuclear alterations in L. sativa; the biochemical effects of azoxystrobin and carbendazim on Phaseolus vulgaris L. and their physiological effects on Phaseolus vulgaris L. by analyzing the cell cycle and chromosomal and nuclear alterations in L. sativa; the biochemical effects by analyzing the activity of antioxidant enzymes in L. sativa; and the physiological effects by analyzing chlorophyll content and chlorophyll a fluorescence in P. vulgaris. It was observed that both fungicides were phytotoxic and cytotoxic, reducing root growth and the mitotic index, cytogenotoxic, increasing the occurrence of chromosomal alterations, as well as inducing oxidative stress and an increase in chlorophyll fluorescence emission and altered energy absorption in the plants used as a test system. In view of this, studies such as the one presented here indicate that the use of pesticides, even in small quantities, can lead to damage to the metabolism of plant organisms.

Projecting long-term clinical outcomes with larotrectinib compared with immune checkpoint inhibitors in metastatic nonsmall cell lung cancer and differentiated thyroid cancer.

BACKGROUND: Larotrectinib is approved for patients with advanced NTRK gene fusion-positive solid tumors. Prior studies demonstrated promising results with larotrectinib compared with other systemic therapy. However, comparisons to checkpoint inhibitors, such as nivolumab or pembrolizumab, have not been done. OBJECTIVE: To estimate and compare expected life-years (LYs) and quality-adjusted LYs (QALYs) for patients with nonsmall cell lung cancer (NSCLC) eligible for larotrectinib vs patients with unknown NTRK gene fusion status on nivolumab or pembrolizumab. We also assessed patients with metastatic differentiated thyroid cancer (DTC), as pembrolizumab may be considered in certain circumstances. METHODS: We developed partitioned survival models to project long-term comparative effectiveness of larotrectinib vs nivolumab or pembrolizumab. Larotrectinib survival data were derived from an updated July 2021 analysis of 21 adult patients (≥18 years of age) with metastatic NTRK gene fusion-positive NSCLC and 21 with DTC. Survival inputs for nivolumab and pembrolizumab were obtained from published articles. Progression-free and overall survival were estimated using survival distributions (Exponential, Weibull, Log-logistic, and Log-normal). Exponential fits were chosen based on goodness-of-fit and clinical plausibility. RESULTS: In NSCLC, larotrectinib resulted in gains of 5.87 and 5.91 LYs compared to nivolumab and pembrolizumab, respectively, which translated to gains of 3.53 and 3.56 QALYs. In DTC, larotrectinib resulted in a gain of 5.23 LYs and 4.24 QALYs compared to pembrolizumab. CONCLUSIONS: In metastatic NSCLC and DTC, larotrectinib may produce substantial life expectancy and QALY gains compared to immune checkpoint inhibitors. Additional data with longer follow-up will further inform this comparison.

Beyond Clinical Trials: Understanding Neurotrophic Tropomyosin Receptor Kinase Inhibitor Challenges and Efficacy in Real-World Pediatric Oncology.

PURPOSE: Our study aimed to explore real-world treatment scenarios for children and adolescents with neurotrophic tropomyosin receptor kinase (NTRK)-fused tumors, emphasizing access, responses, side effects, and outcomes. PATIENTS AND METHODS: Pooled clinical data from 17 pediatric cases (11 soft-tissue sarcomas, five brain tumors, and one neuroblastoma) treated with larotrectinib and radiologic images for 14 patients were centrally reviewed. Testing for gene fusions was prompted by poor response to treatment, tumor progression, or aggressiveness. RESULTS: Six different NTRK fusion subtypes were detected, and various payment sources for testing and medication were reported. Radiologic review revealed objective tumor responses (OR) in 11 of 14 patients: Complete responses: two; partial responses: nine; and stable disease: three cases. Grades 1 or 2 Common Terminology Criteria for Adverse Events adverse effects were reported in five patients. Regarding the entire cohort's clinical information, 15 of 17 patients remain alive (median observation time: 25 months): four with no evidence of disease and 11 alive with disease (10 without progression). One patient developed resistance to the NTRK inhibitor and died from disease progression while another patient died due to an unrelated cause. CONCLUSION: This real-world study confirms favorable agnostic tumor OR rates to larotrectinib in children with NTRK-fused tumors. Better coordination to facilitate access to medication remains a challenge, particularly in middle-income countries like Brazil.

RuBi-Ruxolitinib: A Photoreleasable Antitumor JAK Inhibitor.

We describe the synthesis and biological testing of ruthenium-bipyridine ruxolitinib (RuBiRuxo), a photoreleasable form of ruxolitinib, a JAK inhibitor used as an antitumoral agent in cutaneous T-cell lymphomas (CTCL). This novel caged compound is synthesized efficiently, is stable in aqueous solution at room temperature, and is photoreleased rapidly by visible light. Irradiation of RuBiRuxo reduces cell proliferation and induces apoptosis in a light- and time-dependent manner in a CTCL cell line. This effect is specific and is mediated by a decreased phosphorylation of STAT proteins. Our results demonstrate the potential of ruthenium-based photocompounds and light-based therapeutic approaches for the potential treatment of cutaneous lymphomas and other pathologies.

AMPK inhibits voltage-gated calcium channel-current in rat chromaffin cells.

Metabolic changes are critical in the regulation of Ca2+ influx in central and peripheral neuroendocrine cells. To study the regulation of L-type Ca2+ channels by AMPK we used biochemical reagents and ATP/glucose-concentration manipulations in rat chromaffin cells. AICAR and Compound-C, at low concentration, significantly induce changes in L-type Ca2+ channel-current amplitude and voltage dependence. Remarkably, an overlasting decrease in the channel-current density can be induced by lowering the intracellular level of ATP. Accordingly, Ca2+ channel-current density gradually diminishes by decreasing the extracellular glucose concentration. By using immunofluorescence, a decrease in the expression of CaV1.2 is observed while decreasing extracellular glucose, suggesting that AMPK reduces the number of functional Ca2+ channels into the plasma membrane. Together, these results support for the first time the dependence of metabolic changes in the maintenance of Ca2+ channel-current by AMPK. They reveal a key step in Ca2+ influx in secretory cells.

Prophylactic treatment with the c-Abl inhibitor, neurotinib, diminishes neuronal damage and the convulsive state in pilocarpine-induced mice.

The molecular mechanisms underlying seizure generation remain elusive, yet they are crucial for developing effective treatments for epilepsy. The current study shows that inhibiting c-Abl tyrosine kinase prevents apoptosis, reduces dendritic spine loss, and maintains N-methyl-d-aspartate (NMDA) receptor subunit 2B (NR2B) phosphorylated in in vitro models of excitotoxicity. Pilocarpine-induced status epilepticus (SE) in mice promotes c-Abl phosphorylation, and disrupting c-Abl activity leads to fewer seizures, increases latency toward SE, and improved animal survival. Currently, clinically used c-Abl inhibitors are non-selective and have poor brain penetration. The allosteric c-Abl inhibitor, neurotinib, used here has favorable potency, selectivity, pharmacokinetics, and vastly improved brain penetration. Neurotinib-administered mice have fewer seizures and improved survival following pilocarpine-SE induction. Our findings reveal c-Abl kinase activation as a key factor in ictogenesis and highlight the impact of its inhibition in preventing the insurgence of epileptic-like seizures in rodents and humans.

Synergistic Renoprotective Effects of Green Tea Extract and Gemigliptin against Tacrolimus-Induced Nephrotoxicity in Mice / Efectos Renoprotectores Sinérgicos del Extracto de Té Verde y Gemigliptina contra la Nefrotoxicidad Inducida por Tacrolimus en Ratones

SUMMARY: Although tacrolimus (TAC) significantly reduces allograft rejection incidence in solid-organ transplantation, its long-term use is associated with an increased risk of TAC-induced nephrotoxicity. In this study, we investigated the renoprotective effects of green tea extract (GTE) with or without the dipeptidyl peptidase 4 inhibitor, gemigliptin, by assessing serum creatinine levels, the amount of proteinuria, and histopathology in TAC-induced nephrotoxicity. TAC-induced nephrotoxicity was induced by intraperitoneal TAC injection, GTE was administered via subcutaneous injection, and gemigliptin was administered orally. Mice with TAC-induced nephrotoxicity exhibited a significant increase in both serum creatinine levels and 24-hour urine protein. However, when treated with GTE via subcutaneous injection, mice showed a decrease in serum creatinine levels and the amount of proteinuria. When GTE was combined with gemigliptin, further renoprotective effects were observed in biochemical assessments, consistent with the attenuation of TAC-induced nephrotoxicity in histopathology. The expression of p53 protein was lower in the mice treated with the combination of GTE and gemigliptin compared to mice with TAC-induced nephrotoxicity. Our results demonstrate that the combination of GTE and gemigliptin treatment reveals synergistic renoprotective effects by decreasing the expression of p53 protein. These findings suggest that the combination of GTE and gemigliptin could potentially be used as a prophylactic or therapeutic strategy for TAC-induced nephrotoxicity.

Aunque tacrolimus (TAC) reduce significativamente la incidencia de rechazo de aloinjertos en trasplantes de órganos sólidos, su uso a largo plazo se asocia con un mayor riesgo de nefrotoxicidad inducida por TAC. En este estudio, investigamos los efectos renoprotectores del extracto de té verde (GTE) con o sin el inhibidor de la dipeptidil peptidasa 4, gemigliptina, mediante la evaluación de los niveles de creatinina sérica, la cantidad de proteinuria y la histopatología en la nefrotoxicidad inducida por TAC. La nefrotoxicidad inducida por TAC se indujo mediante inyección intraperitoneal de TAC, el GTE se administró mediante inyección subcutánea y la gemigliptina se administró por vía oral. Los ratones con nefrotoxicidad inducida por TAC mostraron un aumento significativo tanto en los niveles de creatinina sérica como en la proteína en orina de 24 horas. Sin embargo, cuando se trataron con GTE mediante inyección subcutánea, los ratones mostraron una disminución en los niveles de creatinina sérica y en la cantidad de proteinuria. Cuando se combinó GTE con gemigliptina, se observaron efectos renoprotectores adicionales en las evaluaciones bioquímicas, lo que concuerda con la atenuación de la nefrotoxicidad inducida por TAC en histopatología. La expresión de la proteína p53 fue menor en los ratones tratados con la combinación de GTE y gemigliptina en comparación con los ratones con nefrotoxicidad inducida por TAC. Nuestros resultados demuestran que la combinación de tratamiento con GTE y gemigliptina revela efectos renoprotectores sinérgicos al disminuir la expresión de la proteína p53. Estos hallazgos sugieren que la combinación de GTE y gemigliptina podría usarse potencialmente como estrategia profiláctica o terapéutica para la nefrotoxicidad inducida por TAC.

Randomized, Double-Blind Phase III Study of Pazopanib Versus Placebo in Patients With Metastatic Renal Cell Carcinoma Who Have No Evidence of Disease After Metastasectomy: ECOG-ACRIN E2810.

PURPOSE: Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. PATIENTS AND METHODS: Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. RESULTS: From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo (Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. CONCLUSION: Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.

Effectiveness and safety of biological and target synthetic drugs treatment for psoriatic arthritis: a systematic review with network meta-analysis.

BACKGROUND: Psoriatic arthritis (PA) is a chronic inflammatory systemic arthritis that can result in loss of functional capacity and joint deformation. This systematic review assessed the effectiveness and safety of biological and target synthetic drugs for treating PA. METHODS: We searched for randomized clinical trials (RCTs) that evaluated the use of Adalimumab, Etanercept, Infliximab, Golimumab, Secukinumab, Certolizumab Pegol and Tofacitinib in the main general databases and clinical trial registers databases. The primary outcomes were ACR 50, PsARC, and serious adverse events. Two independent reviewers performed study selection and data extraction. Network meta-analyses were conducted using a random effects model and frequentist approach. The CINeMA software was used to assess the certainty of evidence. RESULTS: We included 33 RCTs (n = 11,034). The results from the network meta-analysis for the ACR 50 at 6-months follow-up showed that all drugs were superior to placebo, with Secukinumab (high certainty of evidence), Infliximab (very low certainty of evidence) and Adalimumab (high certainty of evidence) ranking the highest. Regarding the PsARC (at 6-months follow-up), all drugs, except for Golimumab (very low certainty of evidence), were superior to placebo, with Etanercept (low certainty of evidence), Infliximab (low certainty of evidence) and Certolizumab Pegol (low certainty of evidence) being the most effective drugs. There were no significant differences in the risk of serious adverse events between the drugs and placebo. Golimumab (very low certainty of evidence), Secukinumab (low certainty of evidence), and Adalimumab (very low certainty of evidence) ranked the highest for safety. CONCLUSIONS: In conclusion, based on the balance between efficacy and safety, Secukinumab and Adalimumab may be the preferred options among the evaluated drugs for treating patients with PsA. However, caution is necessary when interpreting the safety findings, as they are supported by evidence of low to very low certainty. Consequently, the balance between benefits and potential risks may change as new safety evaluation studies become available. PROTOCOL REGISTRATION: PROSPERO: CRD42022315577.

Pesticides in surface water of the Ondas river watershed, western Bahia, Brazil: Spatial-seasonal distribution and risk assessment.

This study investigated the occurrence and seasonal distribution of different classes of pesticides in surface waters of the Ondas River Watershed, as well as potential risks to the aquatic health and human water consumption in the western region of Bahia state, Brazil. Two gas chromatography-mass spectrometry analytical methods were applied to monitor 34 pesticides in water samples collected during both the dry and rainy seasons at 17 sites. Upon individual analysis, only γ-HCH, methoxychlor, demeton-S, methyl parathion, fenitrothion, chlorpyrifos, and azoxystrobin exhibited statistically significant differences between seasons. During rainy season, concentration medians of residues were higher for γ-HCH (74.7 ng L-1), methoxychlor (25.1 ng L-1), and azoxystrobin (47.2 ng L-1), potentially linked to historical contamination or illegal use. Conversely, pesticides like methyl parathion, fenitrothion, and chlorpyrifos, belonging to the organophosphate class, showed higher concentration medians in the dry period, measuring 75.1, 5.50, and 10.8 ng L-1, respectively, probably due to region crop activities. The risk quotient (RQ) assessment for aquatic life indicated that 59.0% of the samples in the dry season and 76.0% in the rainy season had RQ values greater than one, signifying a critical scenario for species conservation. Regarding human consumption, elevated risks were observed for heptachlor in both sampling periods and for azoxystrobin during the rainy season, surpassing RQ levels above 1, indicating danger in untreated water ingestion. Additionally, 24.0% and 53.0% of the samples in the dry and rainy seasons, respectively, contained at least one pesticide exceeding the EU resolution limit (100 ng L-1). Therefore, considering this information, implementing mitigation measures to avoid the river's contamination becomes imperative.

Larotrectinib versus infigratinib for adult patients with both glioma and tyrosine kinase alterations after failure of initial therapies: Efficacy and safety analysis.

OBJECTIVES: To compare the efficacy and safety of larotrectinib with those of infigratinib in adult glioma patients with tyrosine kinase alterations. METHODS: Patients received oral infigratinib 125 mg (IN cohort, n = 125) or oral larotrectinib (LB cohort, n = 105) until unacceptable toxicity or disease progression. RESULTS: Duration of treatment was longer in the LB cohort than in the IN cohort (8 [9.5-6.25] months vs. 5.5 [6-5.25] months, p < 0.0001). Patients with partial responses (p = 0.0424) and overall survival (p = 0.03) were higher in the IN cohort than those in the LB cohort. The number of patients with disease progression was higher in the LB cohort (p = 0.0015). All the patients reported diarrhea, fatigue, vomiting, constipation, and decreased appetite. Patients in the IN cohort reported hyperphosphatemia, hyperlipasemia, stomatitis, dry skin, alopecia, dyspepsia, onycholysis, palmar-plantar erythrodysesthesia, nail disorders, and dry eyes. Patients in the LB cohort reported upper respiratory tract infections, pyrexia, cough, anemia, bacterial/viral infections, conjunctivitis, urinary tract infections, headaches, ataxia, dizziness, and muscle tremors. A total of 30 (24 %) and 40 (38 %) patients from the IN and the LB cohorts died at the follow-up of 18 months (p = 0.03). Patients who received bevacizumab initial therapy had higher overall survival (p = 0.048). CONCLUSIONS: Infigratinib has higher efficacy and overall survival than larotrectinib but has higher adverse effects in the management of both glioma and tyrosine kinase alterations after failure of initial therapies. Initial bevacizumab therapy is associated with a higher overall survival.

Aminopyrimidine Derivatives as Multiflavivirus Antiviral Compounds Identified from a Consensus Virtual Screening Approach.

Around three billion people are at risk of infection by the dengue virus (DENV) and potentially other flaviviruses. Worldwide outbreaks of DENV, Zika virus (ZIKV), and yellow fever virus (YFV), the lack of antiviral drugs, and limitations on vaccine usage emphasize the need for novel antiviral research. Here, we propose a consensus virtual screening approach to discover potential protease inhibitors (NS3pro) against different flavivirus. We employed an in silico combination of a hologram quantitative structure-activity relationship (HQSAR) model and molecular docking on characterized binding sites followed by molecular dynamics (MD) simulations, which filtered a data set of 7.6 million compounds to 2,775 hits. Lastly, docking and MD simulations selected six final potential NS3pro inhibitors with stable interactions along the simulations. Five compounds had their antiviral activity confirmed against ZIKV, YFV, DENV-2, and DENV-3 (ranging from 4.21 ± 0.14 to 37.51 ± 0.8 µM), displaying aggregator characteristics for enzymatic inhibition against ZIKV NS3pro (ranging from 28 ± 7 to 70 ± 7 µM). Taken together, the compounds identified in this approach may contribute to the design of promising candidates to treat different flavivirus infections.

Cost-Effectiveness of Onasemnogene Abeparvovec Compared With Nusinersen and Risdiplam in Patients With Spinal Muscular Atrophy Type 1 in Brazil: Custo-Efetividade do Onasemnogeno Abeparvoveque (AVXS-101) em Comparação ao Nusinersena e Risdiplam em Pacientes com Atrofia Muscular Espinhal Tipo 1 no Brasil.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of the onasemnogene abeparvovec in relation to nusinersen and risdiplam in the treatment of spinal muscular atrophy type 1 from the perspective of the Brazilian Unified Health System. METHODS: A Markov model was built on a lifetime horizon. Short-term data were obtained from clinical trials of the technologies and from published cohort survival curves (long term). Costs were measured in current 2022 local currency (R$) values and benefits in quality-adjusted life-years (QALYs). Utility values were derived from type 1 spinal muscular atrophy literature, whereas costs related to technologies and maintenance care in each health state were obtained from official sources of reimbursement in Brazil. Deterministic and probabilistic, as well as scenario, sensitivity analyses were performed. RESULTS: Compared with the less costly strategy (nusinersen), the use of onasemnogene abeparvovec resulted in an incremental cost of R$2.468.448,06 ($975 671.169 - purchasing power parity [PPP]) and a 3-QALY increment and incremental cost-effectiveness ratio of R$742.890,92 ($293 632.774 - PPP)/QALY. Risdiplam had an extended dominance from other strategies, resulting in an incremental cost-effectiveness ratio of R$926.586,22 ($366 239.612 - PPP)/QALY compared with nusinersen. Sensitivity analysis showed a significant impact of the follow-up time of the cohort and the cost of acquiring onasemnogene abeparvovec. CONCLUSIONS: Over a lifetime horizon, onasemnogene abeparvovec seems to be a potentially more effective option than nusinersen and risdiplam, albeit with an incremental cost. Such a trade-off should be weighed in efficiency criteria during decision making and outcome monitoring from the perspective of the Brazilian Unified Health System.