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Triple treatment with elexacaftor, tezacaftor, and ivacaftor in patients with cystic fibrosis who had one Phe508del allele and a minimal-function mutation resulted in sustained improvement in FEV 1 , sweat chloride concentration, and the number of pulmonary exacerbations.

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators correct the basic defect caused by CFTR mutations. Improvements in health outcomes have been achieved with the combination of a CFTR corrector and potentiator in people with cystic fibrosis homozygous for the F508del mutation. The addition of elexacaftor (VX-445), a next-generation CFTR corrector, to tezacaftor plus ivacaftor further improved F508del-CFTR function and clinical outcomes in a phase 2 study in people with cystic fibrosis homozygous for the F508del mutation. This phase 3, multicentre, randomised, double-blind, active-controlled trial of elexacaftor in combination with tezacaftor plus ivacaftor was done at 44 sites in four countries. Eligible participants were those with cystic fibrosis homozygous for the F508del mutation, aged 12 years or older with stable disease, and with a percentage predicted forced expiratory volume in 1 s (ppFEV1) of 40–90%, inclusive. After a 4-week tezacaftor plus ivacaftor run-in period, participants were randomly assigned (1:1) to 4 weeks of elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h versus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h alone. The primary outcome was the absolute change from baseline (measured at the end of the tezacaftor plus ivacaftor run-in) in ppFEV1 at week 4. Key secondary outcomes were absolute change in sweat chloride and Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score. This study is registered with ClinicalTrials.gov, NCT03525548. Between Aug 3 and Dec 28, 2018, 113 participants were enrolled. Following the run-in, 107 participants were randomly assigned (55 in the elexacaftor plus tezacaftor plus ivacaftor group and 52 in the tezacaftor plus ivacaftor group) and completed the 4-week treatment period. The elexacaftor plus tezacaftor plus ivacaftor group had improvements in the primary outcome of ppFEV1 (least squares mean [LSM] treatment difference of 10·0 percentage points [95% CI 7·4 to 12·6], p<0·0001) and the key secondary outcomes of sweat chloride concentration (LSM treatment difference −45·1 mmol/L [95% CI −50·1 to −40·1], p<0·0001), and CFQ-R RD score (LSM treatment difference 17·4 points [95% CI 11·8 to 23·0], p<0·0001) compared with the tezacaftor plus ivacaftor group. The triple combination regimen was well tolerated, with no discontinuations. Most adverse events were mild or moderate; serious adverse events occurred in two (4%) participants receiving elexacaftor plus tezacaftor plus ivacaftor and in one (2%) receiving tezacaftor plus ivacaftor. Elexacaftor plus tezacaftor plus ivacaftor provided clinically robust benefit compared with tezacaftor plus ivacaftor alone, with a favourable safety profile, and shows the potential to lead to transformative improvements in the lives of people with cystic fibrosis who are homozygous for the F508del mutation. Vertex Pharmaceuticals.

This study identified a new combination therapy for patients with cystic fibrosis homozygous for the Phe508del CFTR mutation. Treatment with ivacaftor, a CFTR potentiator, and lumacaftor, a CFTR corrector, resulted in improvement in pulmonary function and clinical status. Cystic fibrosis is a genetic disease that is associated with high rates of premature death. 1 – 4 It is a multisystem disease that is characterized by pancreatic insufficiency and chronic airway infections associated with loss of lung function, repeated pulmonary exacerbations, and, ultimately, respiratory failure. 5 Cystic fibrosis is caused by gene mutations that result in deficient or dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein, an anion channel that is normally present in the epithelial membrane. Phe508del (c.1521_1523delCTT; formerly F508del) is the most common CFTR mutation; approximately 45% of patients with cystic fibrosis are homozygous for this allele. 1 Cystic fibrosis is . . .

Abstract Rationale Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves CFTR function alone and in combination with ivacaftor. Objectives To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects with cystic fibrosis homozygous for F508del or compound heterozygous for F508del and G551D. Methods This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study (NCT01531673). Subjects homozygous for F508del received tezacaftor (10 to 150 mg) every day alone or in combination with ivacaftor (150 mg every 12 h) in a dose escalation phase, as well as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and G551D, taking physician-prescribed ivacaftor, received tezacaftor (100 mg every day). Measurements and Main Results Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28. Secondary endpoints included change in percent predicted FEV1 (ppFEV1) from baseline through Day 28 and pharmacokinetics. The incidence of adverse events was similar across treatment arms. Tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV1 in subjects homozygous for F508del, and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV1 in subjects compound heterozygous for F508del and G551D from baseline through Day 28 (P < 0.05 for all). Conclusions These results support continued clinical development of tezacaftor (100 mg every day) in combination with ivacaftor (150 mg every 12 h) in subjects with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT01531673).

BackgroundVX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro.MethodsA randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo.ResultsThe type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens.ConclusionsIn this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit.Clinical trial numberNCT00865904

Background Sepsis, an organ dysfunction caused by deregulated host response to infection, is a major health problem worldwide. Sepsis is associated with high rates of mortality, especially in critically ill patients. Curcumin may improve sepsis through its anti-inflammatory and antioxidant effects. This study aimed to investigate the effects of curcumin-piperine administration in critically ill septic patients. Method This double-blind randomized controlled trial (RCT) conducted on 66 patients with sepsis hospitalized in the intensive care unit (ICU). Patients were randomized to either the intervention group receiving two tablets of curcumin-piperine (each containing 500 mg curcuminoids and 5 mg piperine) ( n  = 33), or the placebo group receiving two matched tablets of placebo ( n  = 33) daily for 7 consecutive days along with enteral feeding. Clinical, laboratory, and biochemical indices were evaluated before and after the intervention. Statistical analyses were performed based on an intention-to-treat method. Result Mortality was observed in 10 patients in the curcumin-piperine group, and 12 patients in the control group. Curcumin-piperine significantly reduced bilirubin-total ( P  = 0.02), bilirubin-direct ( P  = 0.02), pH ( P  < 0.001), C-reactive protein ( P  = 0.04), erythrocyte sedimentation rate ( P  < 0.001), and platelet count ( P  = 0.01) compared with the placebo. A significantly lower reduction was found in red blood cell ( P  = 0.003), hemoglobin ( P  = 0.001), and hematocrit ( P  = 0.002) levels in the intervention vs. placebo group. In addition, mean corpuscular hemoglobin ( P  < 0.001) and mean corpuscular hemoglobin concentration ( P  = 0.001) were significantly higher in the intervention vs. placebo group. Conclusion Curcumin–piperine supplementation over a short period had beneficial effects on some inflammatory and laboratory indices in critically ill patients with sepsis. Trial registration IRCT20150613022681N4; available on: https://en.irct.ir/trial/52661 . Registration date: 2021-01-02, 1399/10/13.

Background Migraine is a highly prevalent neurological disorder related to severe, unilateral headache and symptoms such as vomiting, nausea, and photophobia. Growing evidence implicates oxidative stress and inflammation as key contributors to migraine pathophysiology, exacerbating symptoms and related mental health conditions. Mixodin is a novel bioactive formulation derived from natural compounds, including curcumin, piperine, and gingerol, which are well-established for their anti-inflammatory and antioxidant properties. While each component has shown potential in alleviating migraine-related symptoms, the combined therapeutic efficacy remains unclear. This study investigates whether the combined natural compounds in mixodin provide synergistic benefits in migraine management by targeting multiple underlying mechanisms. This study aims to examine the effects of mixodin supplementation on clinical symptoms, mental health, quality of life (QOL), inflammatory, and oxidative stress factors in patients with migraine. Methods This study is a randomized, double-blind, placebo-controlled clinical trial involving 60 patients diagnosed with migraine by a neurologist according to the ICHD-3 criteria. Eligible participants, aged 20 to 60 years, will be randomly assigned to one of two groups. The intervention group ( n  = 30) will receive two mixodin capsules daily for 8 weeks, each containing 300 mg of curcumin, 7.5 mg of gingerol, and 3.75 mg of piperine. The control group ( n  = 30) will receive two placebo capsules daily for the same duration. The primary outcome will be the clinical symptoms of migraine, including the frequency, severity, and duration of migraine attacks reported by patients. Secondary outcomes will include serum levels of high-sensitivity C-reactive protein (hs-CRP), calcitonin gene-related peptide (CGRP), total antioxidant capacity (TAC), total oxidant status (TOS), malondialdehyde (MDA), superoxide dismutase (SOD), nitric oxide (NO), and assessments of mental health status and QOL. Discussion This clinical trial aims to evaluate the effects of mixodin supplementation on inflammatory markers, oxidative stress, migraine-related symptoms, mental health, and QOL in patients with migraine. The results may suggestion insights into underlying mechanisms and support the development of evidence-based clinical guidelines that incorporate anti-inflammatory and antioxidant strategies to enhance therapeutic outcomes in migraine management. Trial registration Iranian Registry of Clinical Trials ( www.irct.ir ) (ID: IRCT20241009063312N1). Registration date: 2024–12–15. Trial status The protocol is Version 2.0, March 01, 2025. Recruitment began November 11, 2024, and is anticipated to be completed by June 22, 2025.

This study evaluates the effects of oral supplementation of curcumin alone and curcumin plus piperine on body composition, phase angle, and functional capacity in patients with mild to moderate inflammatory bowel disease (IBD). Patients with a diagnosis of IBD, aged 18 years or older with intact kidney and liver function, were into three groups: placebo, curcumin (1000 mg/day), and curcumin plus piperine (1000 mg/day + 10 mg/day). Anthropometric markers, body composition, phase angle (via tetrapolar bioelectrical impedance analysis), and hand-grip strength were assessed before and after the 12-week supplementation period. Statistical analyses included Chi-square test (χ²) and generalized estimating equation (GEE) adjusted for age. Of the 58 patients who started the study, 51 completed it. Initially, obesity was prevalent according to BMI (43.1%) and body fat percentage (62.7%), while 86.3% exhibited muscle depletion based on fat-free mass (FFM). Post-intervention, the curcumin plus piperine group showed a significant reduction in muscle depletion, with improvements in FFM (χ², p  = 0.019; GEE, p  = 0.049) and phase angle (χ², p  = 0.028) compared to the placebo group. In conclusion, our findings indicate that curcumin plus piperine significantly improves body composition by increasing muscle mass in patients with mild to moderate IBD, suggesting its potential as an adjuvant therapy. Trial registration : This trial was registered at ensaiosclinicos.gov.br as RBR89q4ydz on July 20, 2023. Website https://ensaiosclinicos.gov.br/ .

Purpose Indenoisoquinolines are non-camptothecin topoisomerase I (TopI) inhibitors that overcome the limitations of camptothecins: chemical instability and camptothecin resistance. Two dosing schedules of the novel indenoisoquinoline, indotecan (LMP400), were evaluated in patients with advanced solid tumors. Methods The maximum tolerated dose (MTD), toxicities, and pharmacokinetics of two indotecan drug administration schedules (daily for 5 days or weekly) were investigated. Modulation of TopI and the phosphorylation of histone H2AX (γH2AX) were assayed in tumor biopsies; γH2AX levels were also evaluated in circulating tumor cells (CTCs) and hair follicles to assess DNA damage response. Results An MTD of 60 mg/m 2 /day was established for the daily regimen, compared to 90 mg/m 2 for the weekly regimen. The TopI response to drug showed target engagement in a subset of tumor biopsies. Pharmacokinetics profiles demonstrated a prolonged terminal half-life and tissue accumulation compared to topotecan. Dose-dependent decreases in total CTCs were measured in seven patients. Formation of γH2AX-positive foci in CTCs (day 3) and hair follicles (4–6 h) was observed following treatment. Conclusions We established the MTD of two dosing schedules for a novel TopI inhibitor, indotecan. Target engagement was demonstrated as Top1 downregulation and γH2AX response. No objective responses were observed on either schedule in this small patient cohort. The principal toxicity of both schedules was myelosuppression; no significant gastrointestinal problems were observed. Increased DNA damage response was observed in CTCs, hair follicles, and a subset of tumor biopsies.

Background Oropharyngeal dysphagia (OD) is a major gastrointestinal motility disorder that causes severe nutritional and respiratory complications in elderly and neurological patients. In an earlier study, we found that stimulation of pharyngeal sensory neurons by capsaicinoids acting on transient receptor potential vanilloid 1 (TRPV1) improved the swallow response of dysphagic patients. The aim of this study was to explore the effect of piperine, a dual TRPV1/TRPA1 agonist, on the swallow response of dysphagic patients. Methods A videofluoroscopic study was performed to assess the signs of impaired safety and efficacy of swallow and the swallow response of 40 dysphagic patients while swallowing one series of nectar control boluses and two series of nectar boluses supplemented with piperine. Patients were randomized into two groups: one group received 150 μM piperine and the other group received 1 mM. Results Piperine improved the safety of swallow by: (a) reducing the prevalence of unsafe swallows by −34.48 % ( P  = 0.004) at 150 μM and −57.19 % ( P  < 0.001) at 1 mM, and the severity score of the penetration-aspiration scale from 3.25 ± 0.51 to 1.85 ± 0.27 ( P  = 0.003, 1 mM); and (b) shortening the time to laryngeal vestibule closure from 0.366 ± 0.024 to 0.270 ± 0.022 s with 150 μM piperine ( P  < 0.001) and from 0.380 ± 0.032 to 0.306 ± 0.028 s with 1 mM piperine ( P  < 0.05). Conclusions Supplementing the alimentary bolus with piperine speeds swallow response and strongly improves safety of swallow in patients with OD, with a maximal therapeutic effect at 1 mM. Our results suggest that activation of TRPV1/A1 in oropharyngeal sensory neurons is a very promising neurostimulation strategy for dysphagic patients.