Protocatechualdehyde inhibits iron overload-induced bone loss by inhibiting inflammation and oxidative stress in senile rats.

The accumulating evidence has made it clear that iron overload is a crucial mechanism in bone loss. Protocatechualdehyde (PCA) has also been used to prevent osteoporosis in recent years. Whether PCA can reverse the harmful effects of iron overload on bone mass in aged rats is still unknown. Therefore, this study aimed to assess the role of PCA in iron overload-induced bone loss in senile rats. In the aged rat model, we observed that iron overload affects bone metabolism and bone remodeling, manifested by bone loss and decreased bone mineral density. The administration of PCA effectively mitigated the detrimental effects caused by iron overload, and concomitant reduction in MDA serum levels and elevation of SOD were noted. In addition, PCA-treated rats were observed to have significantly increased bone mass and elevated expression of SIRT3，BMP2，SOD2 and reduced expression of TNF-α in bone tissue. We also observed that PCA was able to reduce oxidative stress and inflammation and restore the imbalance in bone metabolism. When MC3T3-E1 and RAW264.7 cells induced osteoblast and osteoclasts differentiation, PCA intervention could significantly recover the restriction of osteogenic differentiation and up-regulation of osteoclast differentiation treated by iron overload. Further, by detecting changes in ROS, SOD, MDA, expression of SIRT3 and mitochondrial membrane potentials, we confirm that the damage caused to cells by iron overload is associated with decreased SIRT3 activity, and that 3-TYP have similar effects on oxidative stress caused by FAC. In conclusion, PCA can resist iron overload-induced bone damage by improving SIRT3 activity, anti-inflammatory and anti-oxidative stress.

Predictive and therapeutic value of lipoprotein-associated phospholipaseA2 in sarcopenia in chronic obstructive pulmonary disease.

BACKGROUND: Sarcopenia, characterized by progressive muscle dysfunction, is a common complication of chronic obstructive pulmonary disease (COPD). Our previous study revealed serum Lipoprotein-associated phospholipaseA2 (Lp-PLA2) level significantly increased in COPD and associated with exercise tolerance. This study further investigated the functions and target potential of Lp-PLA2 for sarcopenia in COPD. METHODS: The circulating Lp-PLA2 level/enzyme activity in COPD patients and age-matched healthy volunteers were measured. Clinical parameters on skeletal muscle were measured and their correlations with Lp-PLA2 were analyzed. We explored the involvement of Lp-PLA2 in vivo and treatment effectiveness of darapladib (a specific Lp-PLA2 inhibitor) in CS-induced muscle dysfunction models. RESULTS: Circulating Lp-PLA2 level/enzyme activity was elevated in COPD patients compared with healthy controls, negatively associated with skeletal muscle mass and function. In CS-induced muscle dysfunction murine models, up-regulated serum Lp-PLA2 level/enzyme activity was verified again. In CS-exposed mouse models, darapladib treatment reversed muscle mass loss and muscle dysfunction, meanwhile rescued upregulation of MuRF1 and atrogin-1, and activation of inflammatory factors, oxidant enzymes and NF-κB signaling. CONCLUSIONS: Lp-PLA2 could be a potential indicator for sarcopenia in COPD. Darapladib, a Lp-PLA2 inhibitor, can alleviate CS-induced skeletal muscle dysfunction and represents a potential therapeutic for sarcopenia in COPD.

Randomized placebo controlled trial of phytoterpenes in DMSO for the treatment of plantar fasciitis.

Plantar fasciitis is the most common cause of heel pain in adults with an overall prevalence of 0.85% in the adult population of the US, affecting over 2 million adults annually. Most current treatment modalities are not supported by sufficient evidence to recommend one particular strategy over another. Topical application of analgesics for soft tissue pain is well established, however the plantar fascia presents challenges in this regard due to thick skin, fibrotic tissue, and an often thickened fat pad. Sixty-two patients with plantar fasciitis were randomized to a placebo controlled trial testing the efficacy of a topical solution of plant terpenes containing camphor, menthol, eugenol, eucalyptol, and vanillin. Skin permeation of the mixture was enhanced with 15% dimethylsulfoxide (DMSO), 1% limonene, and rosemary oil. One ml of solution was applied topically twice daily, and pain scores evaluated on Day 0, Day 1, Day 3, and Day 10. Using the validated foot function index 78.1% of patients reported an 85% or greater decrease in their total pain score by day 10 while placebo treatment was without effect (One Way ANOVA, P < 0.01). This study adapts the treatment modality of topical analgesia for soft tissue pain to a problematic area of the body and shows therapeutic promise.ClinicalTrials.gov Identifier: NCT05467631.

Evaluation of the effect of voxelotor and darbepoetin alfa on hemoglobin levels in patients with sickle cell disease.

BACKGROUND: To date, there is limited evidence on patients utilizing both voxelotor and darbepoetin alfa and its impact on hemoglobin levels. The objective is to evaluate the effect of voxelotor and darbepoetin alfa on hemoglobin levels in patients with SCD. RESEARCH DESIGN AND METHODS: This was a retrospective chart review study that assessed the primary independent variable as the utilization of either voxelotor alone, darbepoetin alfa alone, or the concurrent administration of voxelotor and darbepoetin alfa. Descriptive statistics were utilized to obtain the mean standard deviation for numerical variables and proportions for categorical variables. RESULTS: A total of 23 participants were included in this study. When comparing baseline to 2 months and 3 months, participants on voxelotor alone experienced a 3% decrease and a 6.6% increase in hemoglobin, darbepoetin alfa alone group a 4.3% decrease and a 0.6% increase in hemoglobin and voxelotor and darbepoetin group a 4.4% decrease and a 0.5% decrease in hemoglobin levels. Fifty percent of the participants in the voxelotor group and 6 (66.7%) participants in the voxelotor plus darbepoetin alfa group experienced adverse drug events. CONCLUSIONS: Voxelotor resulted in a clinically significant difference in the percent change of hemoglobin from baseline to 3 months.

A potential therapeutic agent for the treatment of hyperuricemia and gout: 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide.

Uric acid, the metabolic product of purines, relies on xanthine oxidase (XOD) for production. XOD is a target for the development of drugs for hyperuricemia (HUA) and gout. Currently, treatment options remain limited for gout patients. 3, 4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a derivative of the natural product protocatechualdehyde with good biological activity. In this work, we identify a DHNB thiosemicarbazide class of compounds that targets XOD. 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazone can effectively inhibit XOD activity (IC50 value: 0.0437 µM) and exhibits a mixed inhibitory effect. In a mouse model of acute hyperuricemia, a moderate dose (10 mg/kg.w) of 3,4-dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide effectively controlled the serum uric acid content and significantly inhibited serum XOD activity. In addition, 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide showed favorable safety profiles, and mice treated with the target compound did not show any symptoms of general toxicity following a single dose of 500 mg/kg. In the allopurinol group, 50 % of the mice died. These results provide a structural framework and mechanism of XOD inhibition that may facilitate the design of hyperuricemia and gout treatments.

The influence of voxelotor on cerebral blood flow and oxygen extraction in pediatric sickle cell disease.

ABSTRACT: Voxelotor is an inhibitor of sickle hemoglobin polymerization that is used to treat sickle cell disease. Although voxelotor has been shown to improve anemia, the clinical benefit on the brain remains to be determined. This study quantified the cerebral hemodynamic effects of voxelotor in children with sickle cell anemia (SCA) using noninvasive diffuse optical spectroscopies. Specifically, frequency-domain near-infrared spectroscopy combined with diffuse correlation spectroscopy were used to noninvasively assess regional oxygen extraction fraction (OEF), cerebral blood volume, and an index of cerebral blood flow (CBFi). Estimates of CBFi were first validated against arterial spin-labeled magnetic resonance imaging (ASL-MRI) in 8 children with SCA aged 8 to 18 years. CBFi was significantly positively correlated with ASL-MRI-measured blood flow (R2 = 0.651; P = .015). Next, a single-center, open-label pilot study was completed in 8 children with SCA aged 4 to 17 years on voxelotor, monitored before treatment initiation and at 4, 8, and 12 weeks (NCT05018728). By 4 weeks, both OEF and CBFi significantly decreased, and these decreases persisted to 12 weeks (both P < .05). Decreases in CBFi were significantly correlated with increases in blood hemoglobin (Hb) concentration (P = .025), whereas the correlation between decreases in OEF and increases in Hb trended toward significance (P = .12). Given that previous work has shown that oxygen extraction and blood flow are elevated in pediatric SCA compared with controls, these results suggest that voxelotor may reduce cerebral hemodynamic impairments. This trial was registered at www.ClinicalTrials.gov as #NCT05018728.

Quantitative Model-Based Assessment of Multiple Sickle Cell Disease Therapeutic Approaches Alone and in Combination.

Three sickle cell disease (SCD) treatment strategies, stabilizing oxygenated hemoglobin (oxyHb), lowering 2,3-BPG, and inducing fetal hemoglobin (HbF) expression aim to prevent red blood cell (RBC) sickling by reducing tense-state sickle hemoglobin that contributes to polymer formation. Induction of 30% HbF is seen as the gold standard because 30% endogenous expression is associated with a lack of symptoms. However, the level of intervention required to achieve equivalent polymerization protection by the other strategies is uncertain, and there is little understanding of how these approaches could work in combination. We sought to develop an oxygen saturation model that could assess polymerization protection of all three approaches alone or in combination by extending the Monod-Wymann-Changeux model to include additional mechanisms. Applying the model to monotherapies suggests 51% sickle hemoglobin (HbS) occupancy with an oxyHb stabilizer or lowering RBC 2,3 BPG concentrations to 1.8 mM would produce comparable polymerization protection as 30% HbF. The model predictions are consistent with observed clinical response to the oxyHb stabilizer voxelotor and the 2,3-BPG reducer etavopivat. The model also suggests combination therapy will have added benefit in the case of dose limitations, as is the case for voxelotor, which the model predicts could be combined with 20% HbF or 2,3-BPG reduction to 3.75 mM to reach equivalent protection as 30% HbF. The proposed model represents a unified framework that is useful in supporting decisions in preclinical and early clinical development and capable of evolving with clinical experience to gain new and increasingly confident insights into treatment strategies for SCD.

Doping control approach: Identification of equine in vitro metabolites of voxelotor (GBT440), a hemoglobin S polymerization inhibitor.

RATIONALE: Sickle cell disease, a debilitating genetic disorder affecting numerous newborns globally, has historically received limited attention in pharmaceutical research. However, recent years have witnessed a notable shift, with the Food and Drug Administration approving three innovative disease-modifying medications. Voxelotor, also known as GBT440, is a promising compound that effectively prevents sickling, providing a safe approach to alleviate chronic hemolytic anemia in sickle cell disease. It is a novel, orally bioavailable small molecule that inhibits hemoglobin S polymerization by enhancing oxygen affinity to hemoglobin. The investigation demonstrated that voxelotor led to an unintended elevation of hemoglobin levels in healthy individuals by increasing serum erythropoietin levels. METHODS: Voxelotor and its metabolites in an in vitro setting utilizing equine liver microsomes were discussed. Plausible structures of the identified metabolites were inferred through the application of liquid chromatography in conjunction with high-resolution mass spectrometry. RESULTS: Under the experimental conditions, a total of 31 metabolites were detected, including 16 phase I metabolites, two phase II metabolites, and 13 conjugates of phase I metabolites. The principal phase I metabolites were generated through processes such as hydroxylation, reduction, and dissociation. The presence of glucuronide and sulfate conjugates of the parent drug were also observed, along with hydroxylated, reduced, and dissociated analogs. CONCLUSIONS: The data acquired will accelerate the identification of voxelotor and related compounds, aiding in the detection of their illicit use in competitive sports. It is crucial to emphasize that the metabolites detailed in this manuscript were identified through in vitro experiments and their detection in an in vivo study may not be guaranteed.

Plasma metabonomic study on the effect of Para­hydroxybenzaldehyde intervention in a rat model of transient focal cerebral ischemia.

Gastrodia elata Blume has been widely used to treat various central and peripheral nerve diseases, and Para­hydroxybenzaldehyde (PHBA) is one of the indicated components suggested to provide a neuroprotective effect. In our previous, it was shown that PHBA protected mitochondria against cerebral ischemia­reperfusion (I/R) injury in rats. In the present study, how PHBA regulated the metabolic mechanism in blood following cerebral I/R was assessed to identify an effective therapeutic target for the prevention and treatment of ischemic stroke (IS). First, a rat model of cerebral ischemia­reperfusion injury was established via middle cerebral artery occlusion/reperfusion (MCAO/R). The therapeutic effect of PHBA on brain I/R was evaluated by assessing the neurological function score, triphenyl tetrazolium chloride, hematoxylin and eosin, and Nissl staining. Next, a non­targeted metabolomic based on high­performance liquid chromatography quadrupole time­of­flight mass spectrometry was established to identify differential metabolites. Finally, a targeted metabolic spectrum was analyzed and the potential therapeutic targets were verified by Western blotting. The results showed that the neurological function score, cerebral infarction area, hippocampal morphology, and the number of neurons in the PHBA group were significantly improved compared with the model group. Metabonomic analysis showed that 13 different metabolites were identified between the model and PHBA group, which may be involved in the 'tricarboxylic acid cycle', 'glutathione metabolism', and 'mutual transformation of pentose and glucuronates', amongst others. Among these, the levels of the most significant differential metabolite, dGMP, decreased significantly following PHBA treatment. Western blotting was used to verify the expression of membrane­associated guanosine kinase PSD­95 and the subunit of glutamate AMPA receptor GluA1, which significantly increased after PHBA treatment. In addition, it was also found that PHBA increased the expression of the light chain­3 protein and autophagy effector protein 1, whilst the expression of sequestosome­1 decreased, indicating that PHBA promoted autophagy. Similarly, in TUNEL staining and detection of apoptosis­related proteins, it was found that MCAO/R upregulated the expression of Bax and cleaved­caspase­3 whilst downregulating the expression of Bcl­2 and increasing the apoptosis of hippocampal neurons; PHBA reversed this situation. These results suggest that cerebral I/R causes postsynaptic dysfunction by disrupting the interaction between PSD­95 and AMPARs, and the inhibition of the autophagy system eventually leads to the apoptosis of hippocampal neurons.

Voxelotor does not inhibit sickle hemoglobin fiber formation upon complete deoxygenation.

The drug voxelotor (commercially known as Oxbryta) has been approved by the US Food and Drug Administration for the treatment of sickle cell disease. It is known to reduce disease-causing sickling by inhibiting the transformation of the non-polymerizing, high-oxygen-affinity R quaternary structure of sickle hemoglobin into its polymerizing, low-affinity T quaternary structure. It has not been established whether the binding of the drug has anti-sickling effects beyond restricting the change of quaternary structure. By using a laser photolysis method that employs microscope optics, we have determined that fully deoxygenated sickle hemoglobin will assume the T structure. We show that the nucleation rates essential to generate the sickle fibers are not significantly affected by voxelotor. The method employed here should be useful for determining the mechanism of sickling inhibition for proposed drugs.

An expert review of voxelotor for the treatment of hemolytic anemia in patients with sickle cell disease: 'bridging the gap between laboratory data and patient related outcomes'.

INTRODUCTION: Until recently, the treatment of sickle cell disease (SCD) for a long time has been limited to hydroxycarbamide alone. SCD is characterized by hemoglobin (Hb) polymerization, hemolysis, and ischemia. Voxelotor, a first-in-class Hb modulator that increases Hb-oxygen affinity and reduces RBC polymerization, is approved for the treatment of hemolytic anemia in SCD patients. AREAS COVERED: This review is to examine the evidence supporting the laboratory and clinical benefits of voxelotor in SCD. The search keywords were as follows: hemolytic anemia, SCD, voxelotor/GBT 440. A total 19 articles were reviewed. Most studies report voxelotor's significant reduction in hemolysis; however, data related to positive effects on clinical outcomes, namely Vaso-occlusive crisis (VOCs), are sparse. We note the ongoing trials that have different endpoints related to the brain, kidney, and skin. Additional information from real-life post-marketing observational studies may shed more light on the benefits of voxelotor in SCD. Further research is required with the view to using related outcomes as end points e.g. VOCs, renal impairment. This is need to be undertaken in sub Saharan Africa, the epicentre of SCD. EXPERT OPINION: Our recommendation remains to offer and optimize hydroxycarbamide therapy and consider voxelotor in situations with severe anemia and related sequelae affecting the brain or kidney.

Structure-based computational design of novel covalent binders for the treatment of sickle cell disease.

The quest in finding an everlasting panacea to the pernicious impact of sickle cell disease (SCD) in the society hit a turn of success since the recent discovery of a small molecule reversible covalent inhibitor, Voxelotor. A drug that primarily promotes the stability of oxygenated hemoglobin and inhibit the polymerization of HbS by enhancing hemoglobin's affinity for oxygen has opened a new frontier in drug discovery and development. Despite eminent efforts made to reproduce small molecules with better therapeutic targets, none has been successful. To this end, we employed the use of structure-based computational techniques with emphasis on the electrophilic warhead group of Voxelotor to harness novel covalent binders that could elicit better therapeutic response against HbS. The PubChem database and DataWarrior software were used to design random molecules using Voxelotor's electrophilic functionality. Following the compilation of these chemical entities, a high-throughput covalent docking-based virtual screening campaign was conducted which revealed three (Compound_166, Compound_2301, and Compound_2335) putative druglike candidates with higher baseline energy value compared to the standard drug. Subsequently, in silico ADMET profiling was carried out to evaluate their pharmacokinetics and pharmacodynamics properties, and their stability was evaluated for 1 µs (1 µs) using molecular dynamics simulation. Finally, to prioritize these compounds for further development in drug discovery, MM/PBSA calculations was employed to evaluate their molecular interactions and solvation energy within the HbS protein. Despite the admirable druglike and stability properties of these compounds, further experimental validations are required to establish their preclinical relevance for drug development.

Overview of the Role of Vanillin in Neurodegenerative Diseases and Neuropathophysiological Conditions.

Nowadays, bioactive natural products play key roles in drug development due to their safety profile and strong antioxidant power. Vanillin is a natural phenolic compound found in several vanilla beans and widely used for food, cosmetic, and pharmaceutical products. Besides its industrial applications, vanillin possesses several beneficial effects for human health, such as antioxidant activity in addition to anti-inflammatory, anti-mutagenic, anti-metastatic, and anti-depressant properties. Moreover, vanillin exhibits neuroprotective effects on multiple neurological disorders and neuropathophysiological conditions. This study reviews the mechanisms of action by which vanillin prevents neuroinflammation and neurodegeneration in vitro and in vivo systems, in order to provide the latest views on the beneficial properties of this molecule in chronic neurodegenerative diseases and neuropathophysiological conditions.

Interactions of Curcumin's Degradation Products with the Aß42 Dimer: A Computational Study.

Amyloid-ß (Aß) dimers are the smallest toxic species along the amyloid-aggregation pathway and among the most populated oligomeric accumulations present in the brain affected by Alzheimer's disease (AD). A proposed therapeutic strategy to avoid the aggregation of Aß into higher-order structures is to develop molecules that inhibit the early stages of aggregation, i.e., dimerization. Under physiological conditions, the Aß dimer is highly dynamic and does not attain a single well-defined structure but is rather characterized by an ensemble of conformations. In a recent study, a highly heterogeneous library of conformers of the Aß dimer was generated by an efficient sampling method with constraints based on ion mobility mass spectrometry data. Here, we make use of the Aß dimer library to study the interaction with two curcumin degradation products, ferulic aldehyde and vanillin, by molecular dynamics (MD) simulations. Ensemble docking and MD simulations are used to provide atomistic detail of the interactions between the curcumin degradation products and the Aß dimer. The simulations show that the aromatic residues of Aß, and in particular 19FF20, interact with ferulic aldehyde and vanillin through π-π stacking. The binding of these small molecules induces significant changes on the 16KLVFF20 region.

Sickle Cell Disease: A Review.

Importance: Sickle cell disease (SCD) is an inherited disorder of hemoglobin, characterized by formation of long chains of hemoglobin when deoxygenated within capillary beds, resulting in sickle-shaped red blood cells, progressive multiorgan damage, and increased mortality. An estimated 300 000 infants are born annually worldwide with SCD. Most individuals with SCD live in sub-Saharan Africa, India, the Mediterranean, and Middle East; approximately 100 000 individuals with SCD live in the US. Observations: SCD is diagnosed through newborn screening programs, where available, or when patients present with unexplained severe atraumatic pain or normocytic anemia. In SCD, sickling and hemolysis of red blood cells result in vaso-occlusion with associated ischemia. SCD is characterized by repeated episodes of severe acute pain and acute chest syndrome, and by other complications including stroke, chronic pain, nephropathy, retinopathy, avascular necrosis, priapism, and leg ulcers. In the US, nearly all children with SCD survive to adulthood, but average life expectancy remains 20 years less than the general population, with higher mortality as individuals transition from pediatric to adult-focused health care systems. Until 2017, hydroxyurea, which increases fetal hemoglobin and reduces red blood cell sickling, was the only disease-modifying therapy available for SCD and remains first-line therapy for most individuals with SCD. Three additional therapies, L-glutamine, crizanlizumab, and voxelotor, have been approved as adjunctive or second-line agents. In clinical trials, L-glutamine reduced hospitalization rates by 33% and mean length of stay from 11 to 7 days compared with placebo. Crizanlizumab reduced pain crises from 2.98 to 1.63 per year compared with placebo. Voxelotor increased hemoglobin by at least 1 g/dL, significantly more than placebo (51% vs 7%). Hematopoietic stem cell transplant is the only curative therapy, but it is limited by donor availability, with best results seen in children with a matched sibling donor. While SCD is characterized by acute and chronic pain, patients are not more likely to develop addiction to pain medications than the general population. Conclusions and Relevance: In the US, approximately 100 000 people have SCD, which is characterized by hemolytic anemia, acute and chronic pain, acute chest syndrome; increased incidence of stroke, nephropathy, and retinopathy; and a life span that is 20 years shorter than the general population. While hydroxyurea is first-line therapy for SCD, L-glutamine, crizanlizumab, and voxelotor have been approved in the US since 2017 as adjunctive or second-line treatments, and hematopoietic stem cell transplant with a matched sibling donor is now standard care for severe disease.

Patient perception of voxelotor treatment benefit in sickle cell disease.

Patients with sickle cell disease (SCD) experience a range of clinical symptoms, including acute and chronic pain, fatigue, and respiratory problems, as well as chronic organ complications that can lead to disability and accelerated mortality. Voxelotor is a first-in-class therapy that targets sickle hemoglobin polymerization, the root cause of SCD. It is approved by the US Food and Drug Administration for treatment of SCD in patients aged 4 years and older and in the European Union and United Arab Emirates for the treatment of SCD in patients aged 12 years and older. Here, we report the single-center experience of both clinician-determined and patient-reported benefits of voxelotor in 27 consecutive patients treated for at least 8 weeks. Clinical Global Impression of Change and Patient Global Impression of Change rating scales were used to capture clinicians' and patients' perceptions of change in overall patient health-related quality-of-life with voxelotor treatment. Laboratory data were also collected to assess clinical response to treatment. As observed in previous clinical studies, hemoglobin concentrations and markers of hemolysis were improved in patients treated with voxelotor. Most patients reported marked improvement in disease symptoms, which correlated well with the clinicians' assessments. Although limited by the retrospective open-label study design, these findings suggest that voxelotor use has a positive impact on outcomes in patients with SCD.

Model-informed drug development of voxelotor in sickle cell disease: Population pharmacokinetics in whole blood and plasma.

Oxbryta (voxelotor) is a small-molecule inhibitor of sickle hemoglobin (Hb) polymerization approved for patients with sickle cell disease (SCD) aged greater than or equal to 12 years at a dose of 1500 mg once daily (q.d.). Voxelotor binds preferentially to Hb, and voxelotor partitioning into red blood cells is an effective predictor of Hb occupancy. The objectives of these analyses were to develop a population pharmacokinetic (PopPK) model for voxelotor in both plasma and whole blood in adults and adolescents to support the dose selection for optimal target engagement and to identify covariates that have a significant effect on voxelotor pharmacokinetics (PK) in plasma and whole blood. An integrated plasma and whole blood PopPK model with two compartments, first-order absorption and elimination, and a site-of-action effect compartment adequately described the concentration-time profiles of voxelotor in plasma and whole blood in patients treated up to 72 weeks. Covariates with significant effects on voxelotor PK included baseline blood volume on apparent volume of the central compartment and time-varying hematocrit and dose on whole blood partitioning, indicating that clinical markers of voxelotor effect can, in turn, influence its PK. Furthermore, the model confirmed that voxelotor PK in plasma and whole blood is linear with dose and time and comparable for adults and adolescents. No clinically important covariate effects on voxelotor PK that warranted dose adjustment were identified in this analysis. Overall, the PopPK analyses contributed significantly to the voxelotor label and support 1500 mg q.d. as the therapeutic dose in adults and adolescents with SCD.

Safety and efficacy of voxelotor in pediatric patients with sickle cell disease aged 4 to 11 years.

BACKGROUND: Sickle cell disease (SCD) is a devastating, multisystemic disorder that affects millions of people worldwide. The earliest clinical manifestations of SCD can affect infants as young as 6 months of age, and pediatric patients are at risk for acute and life-threatening complications. Early intervention with treatments that target the underlying pathophysiological mechanism of SCD, sickle hemoglobin (HbS) polymerization, are expected to slow disease progression and circumvent disease-associated morbidity and mortality. PROCEDURE: The HOPE-KIDS 1 trial (NCT02850406) is an ongoing four-part, phase 2a, open-label, single- and multiple-dose study to evaluate the pharmacokinetics, efficacy, and safety of voxelotor-a first-in-class HbS polymerization inhibitor-in patients aged 6 months to 17 years with SCD. Initial findings from a cohort of 45 patients aged 4 to 11 years who received voxelotor treatment for up to 48 weeks are reported. RESULTS: Hemoglobin (Hb) response, defined as a >1.0 g/dl increase from baseline, was achieved at week 24 by 47% (n = 16/34) of patients with Hb measurements at baseline and week 24. At week 24, 35% (n = 12/34) and 21% (n = 7/34) of patients had a >1.5 g/dl increase and a >2.0 g/dl increase from baseline in Hb concentration, respectively. Concurrent improvements in hemolytic markers were observed. Voxelotor was well tolerated in this young cohort, with no newly emerging safety signals. CONCLUSIONS: Based on its mechanism as an HbS polymerization inhibitor, voxelotor improves Hb levels and markers of hemolysis and has the potential to mitigate SCD-related complications; these results support its use in patients aged ≥4 years.

Real-world effectiveness of voxelotor for treating sickle cell disease in the US: a large claims data analysis.

BACKGROUND: Sickle cell disease (SCD) is a genetic disease that impacts patients' quality of life, healthcare costs, and life expectancy. Elevated sickle hemoglobin (HbS), which readily polymerizes, causes red blood cell sickling, leading to chronic hemolytic anemia and complications often requiring hospitalization and transfusions. In 2019, voxelotor, which inhibits HbS polymerization, was approved for SCD treatment. OBJECTIVES: This study uses real-world evidence to assess voxelotor's effectiveness in SCD patients in typical clinical practice from 2019 to 2021 using a national medical claims database (N = 3128). RESULTS: After initiating voxelotor, 60.8% of patients with available hemoglobin (Hb) laboratory data (n = 74) showed a Hb increase >1 g/dL. Mean transfusion rate per patient-year dropped 52% in patients with ≥1 transfusion before treatment (n = 190). In patients with ≥1 of the corresponding events (n = 1065), decreases were observed in mean vaso-occlusive crisis (VOC) frequency (-23%); mean VOC-related hospitalizations and length of stay (LOS) time (-34% and -30%, respectively); mean all-cause hospitalization and LOS time (-37% and -23%, respectively); outpatient visits (-10%); iron chelation use (-46%); and prescribed opioids (-13%). CONCLUSION: These data align with randomized controlled trial results showing voxelotor improvements and support that voxelotor may lower transfusion and VOC rates in clinical practice.

Natural products can be used in therapeutic management of COVID-19: Probable mechanistic insights.

The unexpected emergence of the new Coronavirus disease (COVID-19) has affected more than three hundred million individuals and resulted in more than five million deaths worldwide. The ongoing pandemic has underscored the urgent need for effective preventive and therapeutic measures to develop anti-viral therapy. The natural compounds possess various pharmaceutical properties and are reported as effective anti-virals. The interest to develop an anti-viral drug against the novel severe acute respiratory syndrome Coronavirus (SARS-CoV-2) from natural compounds has increased globally. Here, we investigated the anti-viral potential of selected promising natural products. Sources of data for this paper are current literature published in the context of therapeutic uses of phytoconstituents and their mechanism of action published in various reputed peer-reviewed journals. An extensive literature survey was done and data were critically analyzed to get deeper insights into the mechanism of action of a few important phytoconstituents. The consumption of natural products such as thymoquinone, quercetin, caffeic acid, ursolic acid, ellagic acid, vanillin, thymol, and rosmarinic acid could improve our immune response and thus possesses excellent therapeutic potential. This review focuses on the anti-viral functions of various phytoconstituent and alkaloids and their potential therapeutic implications against SARS-CoV-2. Our comprehensive analysis provides mechanistic insights into phytoconstituents to restrain viral infection and provide a better solution through natural, therapeutically active agents.