BACKGROUND: Daratumumab, a monoclonal antibody targeting CD38, has been approved for use with standard myeloma regimens. An evaluation of subcutaneous daratumumab combined with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of transplantation-eligible patients with newly diagnosed multiple myeloma is needed. METHODS: In this phase 3 trial, we randomly assigned 709 transplantation-eligible patients with newly diagnosed multiple myeloma to receive either subcutaneous daratumumab combined with VRd induction and consolidation therapy and with lenalidomide maintenance therapy (D-VRd group) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (VRd group). The primary end point was progression-free survival. Key secondary end points were a complete response or better and minimal residual disease (MRD)-negative status. RESULTS: At a median follow-up of 47.5 months, the risk of disease progression or death in the D-VRd group was lower than the risk in the VRd group. The estimated percentage of patients with progression-free survival at 48 months was 84.3% in the D-VRd group and 67.7% in the VRd group (hazard ratio for disease progression or death, 0.42; 95% confidence interval, 0.30 to 0.59; P<0.001); the P value crossed the prespecified stopping boundary (P = 0.0126). The percentage of patients with a complete response or better was higher in the D-VRd group than in the VRd group (87.9% vs. 70.1%, P<0.001), as was the percentage of patients with MRD-negative status (75.2% vs. 47.5%, P<0.001). Death occurred in 34 patients in the D-VRd group and 44 patients in the VRd group. Grade 3 or 4 adverse events occurred in most patients in both groups; the most common were neutropenia (62.1% with D-VRd and 51.0% with VRd) and thrombocytopenia (29.1% and 17.3%, respectively). Serious adverse events occurred in 57.0% of the patients in the D-VRd group and 49.3% of those in the VRd group. CONCLUSIONS: The addition of subcutaneous daratumumab to VRd induction and consolidation therapy and to lenalidomide maintenance therapy conferred a significant benefit with respect to progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma. (Funded by the European Myeloma Network in collaboration with Janssen Research and Development; PERSEUS ClinicalTrials.gov number, NCT03710603; EudraCT number, 2018-002992-16.).
- MeSH
- bortezomib aplikace a dávkování škodlivé účinky MeSH
- dexamethason aplikace a dávkování škodlivé účinky MeSH
- lenalidomid aplikace a dávkování škodlivé účinky MeSH
- lidé MeSH
- mnohočetný myelom * farmakoterapie MeSH
- monoklonální protilátky aplikace a dávkování škodlivé účinky MeSH
- progrese nemoci MeSH
- protokoly antitumorózní kombinované chemoterapie * škodlivé účinky terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
BACKGROUND: In multiple myeloma (MM), improving our understanding of routine clinical practice and the effectiveness of agents outside of clinical trials is important. TOURMALINE-MM1 data resulted in approval of ixazomib for MM patients who have received ≥ 1 prior therapy. PATIENTS AND METHODS: UVEA-IXA comprised a retrospective chart review in the early access program, and a prospective 1-year follow-up period. Eligible patients had had a biochemical and/or symptomatic relapse after 1-3 prior lines of therapy; no anti-MM therapy for > 3 cycles at the start of ixazomib therapy; and an Eastern Cooperative Oncology Group performance score of 0-2. Lenalidomide- or proteasome inhibitor (PI)-refractory patients were ineligible. Primary endpoints were response and progression-free survival (PFS). RESULTS: Of 357 enrolled patients, 309 were evaluable; most patients received ixazomib alongside lenalidomide (98%) and dexamethasone (97%); 61% had received 2-3 prior lines of therapy. Median PFS was 15.6 months (95% confidence interval [CI]: 12.0-20.6) in all evaluable patients, and 19.6 (95% CI: 12.1-27.0) and 13.9 (95% CI: 10.1-18.1) months in patients who received 1 and ≥ 2 prior lines of therapy, respectively. The overall response rate was 67% in all evaluable patients, and 72% and 63%, respectively, in patients who received 1 and ≥ 2 prior lines of therapy. Median overall survival was 35.5 months. The ixazomib safety profile was consistent with previous reports. CONCLUSION: This study supports ixazomib-based therapy as an effective and tolerable treatment in the real-world. Outcomes were favorable in patients with 1 or ≥ 2 prior lines of therapy who were not lenalidomide- or PI-refractory.
- MeSH
- dexamethason terapeutické užití MeSH
- glycin analogy a deriváty MeSH
- lenalidomid terapeutické užití MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- mnohočetný myelom * MeSH
- prospektivní studie MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- retrospektivní studie MeSH
- sloučeniny boru * MeSH
- uvea MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The phase 3 ASPEN trial (NCT03053440) compared Bruton tyrosine kinase inhibitors (BTKis), zanubrutinib and ibrutinib, in patients with Waldenström macroglobulinemia (WM). Post-hoc biomarker analysis was performed using next-generation sequencing on pretreatment bone marrow samples from 98 patients treated with zanubrutinib and 92 patients treated with ibrutinib with mutated (MUT) MYD88 and 20 patients with wild-type (WT) MYD88 treated with zanubrutinib. Of 329 mutations in 52 genes, mutations in CXCR4 (25.7%), TP53 (24.8%), ARID1A (15.7%), and TERT (9.0%) were most common. TP53MUT, ARID1AMUT, and TERTMUT were associated with higher rates of CXCR4MUT (P < .05). Patients with CXCR4MUT (frameshift or nonsense [NS] mutations) had lower very good partial response (VGPR) and complete response rates (CR; 17.0% vs 37.2%, P = .020) and longer time to response (11.1 vs 8.4 months) than patients with CXCR4WT treated with BTKis. CXCR4NS was associated with inferior progression-free survival (PFS; hazard ratio [HR], 3.39; P = .017) in patients treated with ibrutinib but not in those treated with zanubrutinib (HR, 0.67; P = .598), but VGPR + CR rates were similar between treatment groups (14.3% vs 15.4%). Compared with ibrutinib, patients with CXCR4NS treated with zanubrutinib had a favorable major response rate (MRR; 85.7% vs 53.8%; P = .09) and PFS (HR, 0.30; P = .093). In patients with TP53MUT, significantly lower MRRs were observed for patients treated with ibrutinib (63.6% vs 85.7%; P = .04) but not for those treated with zanubrutinib (80.8% vs 81.9%; P = .978). In TP53MUT, compared with ibrutinib, patients treated with zanubrutinib had higher VGPR and CR (34.6% vs 13.6%; P < .05), numerically improved MRR (80.8% vs 63.6%; P = .11), and longer PFS (not reached vs 44.2 months; HR, 0.66; P = .37). Collectively, patients with WM with CXCR4MUT or TP53MUT had worse prognosis compared with patients with WT alleles, and zanubrutinib led to better clinical outcomes.
Environmental screening is essential due to the increased occurrence of harmful substances in the environment. Open Meter Duo (OMD) is an open-source field photo/fluorimeter that uses an RGB diode that imitates a color according to the selected wavelength and uses a UV LED from the security kit diode as an excitation light source. The prepared PCB shield with a 3D-printed aperture was connected to Arduino UNO R4 WiFi. This system was used for the fluorescent detection of cholinesterase activity with the indoxyl acetate method. Carbofuran-a toxic pesticide-and donepezil-a drug used to treat Alzheimer's disease-were tested as model inhibitors of cholinesterase activity. The limit of detection of indoxyl acetate was 11.6 μmol/L, and the IC50 values of the inhibitors were evaluated. This system is optimized for wireless use in field analysis with added cloud support and power source. The time of analysis was 5 min for the fluorimetric assay and 20 min for the optional photometric assay. The time of field operation was approximately 4 h of continuous measurement. This system is ready to be used as a cheap and easy control platform for portable use in drug control and point-of-care testing.
BACKGROUND: Atogepant, an oral calcitonin gene-related peptide receptor antagonist, has been approved for the preventive treatment of migraine, but its efficacy and safety in people who have been failed by conventional oral preventive migraine treatments has not yet been evaluated in a dedicated clinical trial. The ELEVATE trial evaluated the safety, tolerability, and efficacy of atogepant for the preventive treatment of episodic migraine in participants for whom two to four classes of conventional oral preventive treatments have failed. METHODS: ELEVATE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3b trial done at 73 sites in Canada, the Czech Republic, Denmark, France, Germany, Hungary, Italy, the Netherlands, Poland, Russia, Spain, the UK, and the USA. Adults (18-80 years) with episodic migraine who had previously been failed by two to four classes of conventional oral treatments for migraine prevention were randomly assigned (1:1) using interactive web response technology to oral atogepant 60 mg once a day or placebo, stratified by baseline monthly migraine days, number of treatment classes participants have been failed by, and region. The primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period in the off-treatment hypothetical estimand (OTHE) population, which included participants in the safety population (all participants who received ≥1 dose of study intervention) who had evaluable data available for the baseline period and for one or more of the 4-week post-baseline periods (whether on treatment or off treatment). The primary endpoint was analysed using a mixed model for repeated measures and a fixed-sequence procedure was used to control for multiple comparisons. The trial is registered with ClinicalTrials.gov (NCT04740827) and EudraCT (2019-003448-58), and is completed. FINDINGS: Between March 5, 2021, and Aug 4, 2022, 540 participants were screened, 315 were randomly assigned, and 313 participants (280 [89%] female, 33 [11%] male, and 300 [96%] White) received at least one dose of study intervention. In the OTHE population, which comprised 309 participants (155 assigned to placebo and 154 to atogepant), least squares mean changes from baseline in monthly migraine days across 12 weeks were -1·9 (SE 0·4) with placebo and -4·2 (0·4) with atogepant (least squares mean difference -2·4, 95% CI -3·2 to -1·5; adjusted p<0·0001). The most common treatment-emergent adverse event with atogepant was constipation in 16 (10%) of 156 participants (vs four [3%] of 157 for placebo). Serious adverse events occurred in four [3%] of 156 participants in the atogepant group vs none in the placebo group, and treatment-emergent adverse events resulting in treatment discontinuation occurred in three [2%] in the atogepant group vs two [1%] in the placebo group. INTERPRETATION: Atogepant 60 mg once a day was safe, well tolerated, and showed significant and clinically relevant reductions in mean monthly migraine days compared with placebo across 12 weeks in patients with episodic migraine who had previously been failed by two to four classes of conventional oral preventive treatments. Atogepant might be an effective preventive treatment option for patients in this difficult-to-treat population. FUNDING: Allergan (now AbbVie).
- MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- lidé MeSH
- migréna * farmakoterapie prevence a kontrola MeSH
- monoklonální protilátky * terapeutické užití MeSH
- piperidiny * MeSH
- pyridiny * MeSH
- pyrroly * MeSH
- spirosloučeniny * MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXA and REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asia and North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed. Primary outcomes were time-to-next treatment (TTNT) and progression-free survival (PFS). Results: Overall, 564 patients were included (median follow-up: 18.5 months). Median TTNT and PFS were 18.4 and 19.9 months; both outcomes were numerically longer for earlier versus later lines. Median treatment duration was 14.0 months. Overall response rate was 64.6%. No new safety concerns were noted. Conclusion: The effectiveness of IRd in routine practice appears similar to the efficacy observed in TOURMALINE-MM1. IRd benefit in earlier versus later lines was consistent with previous reports.
- MeSH
- dexamethason terapeutické užití MeSH
- glycin * analogy a deriváty MeSH
- lenalidomid terapeutické užití MeSH
- lidé MeSH
- mnohočetný myelom * farmakoterapie MeSH
- multicentrické studie jako téma MeSH
- prospektivní studie MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- retrospektivní studie MeSH
- sloučeniny boru terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- Alzheimerova nemoc * farmakoterapie MeSH
- cholinesterasové inhibitory chemie MeSH
- cholinesterasy MeSH
- lékové postižení jater * MeSH
- lidé MeSH
- neuroprotektivní látky * farmakologie terapeutické užití MeSH
- piperidiny * MeSH
- receptory N-methyl-D-aspartátu MeSH
- takrin chemie MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Alopecia areata is an autoimmune form of non-scarring hair loss. It is usually characterized by limited areas of hair loss. However, the disease may progress to complete scalp and body hair loss (alopecia totalis, alopecia universalis). In patients with alopecia areata hair loss significantly impacts the quality of life. Children and adolescents with alopecia areata often experience bullying, including physical aggression. The disease severity evaluation tools used in clinical practice are: the Severity of Alopecia Tool (SALT) score and the Alopecia Areata Scale (AAS). A SALT score equal to or greater than 20 constitutes a commonly accepted indication for systemic therapy in alopecia areata. When using the AAS, moderate to severe alopecia areata should be considered a medical indication for systemic treatment. Currently, the only two EMA-approved medications for alopecia areata are baricitinib (JAK 1/2 inhibitor) for adults and ritlecitinib (JAK 3/TEC inhibitor) for individuals aged 12 and older. Both are EMA-approved for patients with severe alopecia areata. Other systemic medications used off-label in alopecia areata include glucocorticosteroids, cyclosporine, methotrexate and azathioprine. Oral minoxidil is considered an adjuvant therapy with limited data confirming its possible efficacy. This consensus statement is to outline a systemic treatment algorithm for alopecia areata, indications for systemic treatment, available therapeutic options, their efficacy and safety, as well as the duration of the therapy.
- MeSH
- alopecia areata * farmakoterapie MeSH
- alopecie farmakoterapie MeSH
- azathioprin terapeutické užití MeSH
- dítě MeSH
- dospělí MeSH
- inhibitory Janus kinas * terapeutické užití MeSH
- kvalita života MeSH
- lidé MeSH
- minoxidil terapeutické užití MeSH
- mladiství MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
RATIONALE: Exposure to rewards can alter behavioral reactivity to them. For example, stimulants sensitize locomotor activation, whereas sexual experience sensitizes copulatory behaviors. Moreover, rewards can cross-sensitize one another. Although stimulants are known to cross-sensitize locomotor effects, the evidence for cross-sensitization between stimulants and sex is less clear. OBJECTIVES: This study determined the effects of single and repeated pre-exposure to methylphenidate (MPH) or sex on one another in adult male rats. METHODS: Cross-sensitization between MPH (5 mg/kg) and sex (30 min with sexually experienced female) was examined. Adult male rats were pre-exposed to 0, 1, or 10 trials of either sex or MPH before being exposed to the other reward. Locomotor chambers were used in MPH trials. Bilevel chambers were used in sexual trials, and sexual behaviors were video scored. RESULTS: The amount of prior sexual experience differentially influenced the ceiling of MPH-dependent sensitization; in the last drug trial, locomotion was highest in males given 1 previous sexual trial compared with 0 or 10. Compared with MPH-naive males, pre-exposure to MPH (1 and 10 trials) reduced the number of ejaculations without impacting sexual performance (intromission/mount latency and frequency). CONCLUSIONS: These findings indicate that the degree of pre-exposure to a reward can differentially affect reactivity to novel rewards. The results showed that previous findings of cross-sensitization between amphetamine and sex do not extend to MPH. However, exposure to MPH prior to sexual experience can increase the amount of sexual stimulation needed to achieve ejaculation.
- MeSH
- amfetamin farmakologie MeSH
- kopulace MeSH
- krysa rodu rattus MeSH
- methylfenidát * farmakologie MeSH
- stimulanty centrálního nervového systému * farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- chemoterapie konsolidační * MeSH
- imunologické faktory MeSH
- inhibitory proteasomu terapeutické užití MeSH
- klinické zkoušky jako téma MeSH
- lenalidomid terapeutické užití MeSH
- lidé MeSH
- mnohočetný myelom * terapie MeSH
- udržovací chemoterapie * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- směrnice pro lékařskou praxi MeSH
