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1.
Am J Hematol ; 99(7): 1257-1268, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38622840

RESUMO

In the phase 2 GRIFFIN trial (ClinicalTrials.gov identifier: NCT02874742), daratumumab added to lenalidomide, bortezomib, and dexamethasone (D-RVd) improved depth of response and progression-free survival (PFS) versus lenalidomide, bortezomib, and dexamethasone (RVd) alone in transplant-eligible (TE) patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) collected using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30-item (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module 20-item (QLQ-MY20), and EuroQol 5-Dimension 5-Level (EQ-5D-5L) tools on day 1 of cycles 1, 2, and 3; on day 21 of cycle 4 (end of induction therapy); on day 1 of cycle 5; on day 21 of cycle 6 (end of posttransplant consolidation therapy); and at months 6, 12, 18, and 24 of maintenance therapy. Meaningful improvements from baseline were seen in most of the PRO scales with both treatments after consolidation and were sustained for at least 2 years of maintenance treatment. Large reductions from baseline (~20 points) were especially observed in pain symptoms for both treatment groups, although these were numerically higher for patients receiving D-RVd during the majority of the time points. In addition, improvements in key scales, such as global health status, fatigue symptoms, and physical functioning, were also seen with both D-RVd and RVd. These improvements in health-related quality of life contribute to the totality of evidence supporting the improvement in clinical outcomes such as response rates and PFS with D-RVd in induction, consolidation, and maintenance therapy in TE patients with NDMM.


Assuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Lenalidomida , Mieloma Múltiplo , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Humanos , Mieloma Múltiplo/tratamento farmacológico , Bortezomib/administração & dosagem , Bortezomib/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Lenalidomida/administração & dosagem , Lenalidomida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Adulto
2.
Blood Cancer J ; 14(1): 69, 2024 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-38649340

RESUMO

In the MASTER study (NCT03224507), daratumumab+carfilzomib/lenalidomide/dexamethasone (D-KRd) demonstrated promising efficacy in transplant-eligible newly diagnosed multiple myeloma (NDMM). In GRIFFIN (NCT02874742), daratumumab+lenalidomide/bortezomib/dexamethasone (D-RVd) improved outcomes for transplant-eligible NDMM. Here, we present a post hoc analysis of patients with high-risk cytogenetic abnormalities (HRCAs; del[17p], t[4;14], t[14;16], t[14;20], or gain/amp[1q21]). Among 123 D-KRd patients, 43.1%, 37.4%, and 19.5% had 0, 1, or ≥2 HRCAs. Among 120 D-RVd patients, 55.8%, 28.3%, and 10.8% had 0, 1, or ≥2 HRCAs. Rates of complete response or better (best on study) for 0, 1, or ≥2 HRCAs were 90.6%, 89.1%, and 70.8% for D-KRd, and 90.9%, 78.8%, and 61.5% for D-RVd. At median follow-up (MASTER, 31.1 months; GRIFFIN, 49.6 months for randomized patients/59.5 months for safety run-in patients), MRD-negativity rates as assessed by next-generation sequencing (10-5) were 80.0%, 86.4%, and 83.3% for 0, 1, or ≥2 HRCAs for D-KRd, and 76.1%, 55.9%, and 61.5% for D-RVd. PFS was similar between studies and superior for 0 or 1 versus ≥2 HRCAs: 36-month PFS rates for D-KRd were 89.9%, 86.2%, and 52.4%, and 96.7%, 90.5%, and 53.5% for D-RVd. These data support the use of daratumumab-containing regimens for transplant-eligible NDMM with HCRAs; however, additional strategies are needed for ultra-high-risk disease (≥2 HRCAs). Video Abstract.


Assuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Mieloma Múltiplo/mortalidade , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Aberrações Cromossômicas , Adulto , Lenalidomida/uso terapêutico , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico
3.
Br J Haematol ; 204(6): 2227-2232, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38504552

RESUMO

Due in part to racial disparities and underrepresentation in clinical studies, optimal therapies for Black patients with multiple myeloma remain undefined. This final analysis of GRIFFIN by race showed that the addition of daratumumab (D) to lenalidomide/bortezomib/dexamethasone (RVd) provides clinical benefit among both Black and White transplant-eligible newly diagnosed patients compared with RVd alone. However, Black patients were more likely to discontinue ≥1 drug due to treatment-emergent adverse events. In summary, these findings suggest a benefit of D-RVd front-line therapy among Black and White patients and underscore the importance of equitable treatment access for all patients.


Assuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Bortezomib , Dexametasona , Lenalidomida , Mieloma Múltiplo , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Lenalidomida/uso terapêutico , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Dexametasona/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Bortezomib/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Negro ou Afro-Americano
4.
Lancet Haematol ; 10(10): e825-e837, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37708911

RESUMO

BACKGROUND: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis. METHODS: GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18-70 years, had an ECOG performance score of 0-2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1-14), subcutaneous bortezomib (1·3 mg/m2 on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1-4; day 1, cycles 5-6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1-21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022. FINDINGS: Between Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49·6 months (IQR 47·4-52·1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2·18 [95% CI 1·22-3·89], p=0·0079), and 4-year progression-free survival was 87·2% (95% CI 77·9-92·8) for D-RVd versus 70·0% (95% CI 55·9-80·3) for RVd, with a hazard ratio (HR) of 0·45 (95% CI 0·21-0·95, p=0·032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0·90 [95% CI 0·31-2·56], p=0·84). The most common grade 3-4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy. INTERPRETATION: Addition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies. FUNDING: Janssen Oncology.


Assuntos
Mieloma Múltiplo , Trombocitopenia , Humanos , Masculino , Mieloma Múltiplo/terapia , Bortezomib/efeitos adversos , Lenalidomida/uso terapêutico , Talidomida/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona , Trombocitopenia/etiologia
5.
Transplant Cell Ther ; 29(3): 174.e1-174.e10, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36494017

RESUMO

For eligible patients with newly diagnosed multiple myeloma (NDMM), standard of care includes induction therapy followed by autologous stem cell transplantation (ASCT). Daratumumab as monotherapy and in combination treatment is approved across multiple lines of therapy for multiple myeloma (MM), and lenalidomide is an effective and commonly used agent for induction and maintenance therapy in MM. However, there is concern that lenalidomide and daratumumab given as induction therapy might impair mobilization of stem cells for ASCT. Therefore, we assessed stem cell mobilization in patients following frontline induction therapy in the MASTER and GRIFFIN phase 2 clinical studies by examining stem cell mobilization yields, apheresis attempts, and engraftment outcomes for patients from each study. Adult transplantation-eligible patients with NDMM received induction therapy consisting of daratumumab plus carfilzomib/lenalidomide/dexamethasone (D-KRd) for four 28-day cycles in the single-arm MASTER trial or lenalidomide/bortezomib/dexamethasone (RVd) with or without daratumumab (D) for four 21-day cycles in the randomized GRIFFIN trial, followed by stem cell mobilization and ASCT in both studies. Institutional practice differed regarding plerixafor use for stem cell mobilization; the strategies were upfront (ie, planned plerixafor use) or rescue (ie, plerixafor use only after mobilization parameters indicated failure with granulocyte colony-stimulating factor [G-CSF] alone). Descriptive analyses were used to summarize patient characteristics, stem cell mobilization yields, and engraftment outcomes. In MASTER, 116 D-KRd recipients underwent stem cell mobilization and collection at a median of 24 days after completing induction therapy. In GRIFFIN, 175 patients (D-RVd, n = 95; RVd, n = 80) underwent mobilization at a median of 27 days after completing D-RVd induction therapy and 24 days after completing RVd induction therapy. Among those who underwent mobilization and collection, 7% (8 of 116) of D-KRd recipients, 2% (2 of 95) of D-RVd recipients, and 6% (5 of 80) of RVd recipients did not meet the center-specific minimally required CD34+ cell yield in the first mobilization attempt; however, nearly all collected sufficient stem cells for ASCT on remobilization. Among patients who underwent mobilization, plerixafor use, either upfront or as a rescue strategy, was higher in patients receiving D-KRd (97%; 112 of 116) and D-RVd (72%; 68 of 95) compared with those receiving RVd (55%; 44 of 80). The median total CD34+ cell collection was 6.0 × 106/kg (range, 2.2 to 13.9 × 106/kg) after D-KRd induction, 8.3 × 106/kg (range, 2.6 to 33.0 × 106/kg) after D-RVd induction, and 9.4 × 106/kg (range, 4.1 to 28.7 × 106/kg) after RVd induction; the median days for collection were 2, 2, and 1, respectively. Among patients who underwent mobilization, 98% (114 of 116) of D-KRd patients, 99% (94 of 95) of D-RVd patients, and 98% (78 of 80) of RVd patients underwent ASCT using median CD34+ cell doses of 3.2 × 106/kg, 4.2 × 106/kg, and 4.8 × 106/kg, respectively. The median time to neutrophil recovery was 12 days in all 3 treatment groups across the 2 trials. Because both trials used different criteria to define platelet recovery, data on platelet engraftment using the same criteria are not available. Four cycles of daratumumab- and lenalidomide-based quadruplet induction therapy had a minimal impact on stem cell mobilization and allowed predictable stem cell harvesting and engraftment in all patients who underwent ASCT. Upfront plerixafor strategy may be considered, but many patients were successfully collected with the use of G-CSF alone or rescue plerixafor.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos , Mieloma Múltiplo , Adulto , Humanos , Mieloma Múltiplo/terapia , Lenalidomida/uso terapêutico , Mobilização de Células-Tronco Hematopoéticas , Quimioterapia de Indução , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Transplante Autólogo , Bortezomib/uso terapêutico , Dexametasona/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico
6.
Future Oncol ; 18(36): 3983-3991, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36377712

RESUMO

Aim: To evaluate among multiple myeloma (MM) patients, the proportions with first-line bortezomib/lenalidomide/dexamethasone (VRd) dose modifications and the associated baseline patient characteristics. Patients & methods: Adult MM patients treated with first-line VRd were selected from the Optum claims database. VRd dose modifications were defined based on lenalidomide dose. Results: Among 1497 MM patients, 33% received VRd lite and 22% VRd reduced. Compared with VRd regular, VRd lite usage was more likely to be associated with patients aged ≥75 years and female sex; VRd reduced usage was more likely to be associated with female sex and frailty. Conclusion: A large proportion of MM patients received VRd dose modifications in the real-world, which could potentially result in reduced effectiveness of VRd.


Assuntos
Mieloma Múltiplo , Adulto , Humanos , Feminino , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Lenalidomida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Dexametasona/uso terapêutico
7.
Br J Haematol ; 199(3): 355-365, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36111391

RESUMO

Patients with multiple myeloma are at increased risk of vascular thromboembolic events (VTEs). This post hoc analysis evaluated VTEs in the randomised phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) that investigated lenalidomide/bortezomib/dexamethasone (RVd) ± daratumumab (D). Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation (ASCT) received D-RVd/RVd induction, high-dose therapy and ASCT, D-RVd/RVd consolidation and up to 2 years of lenalidomide maintenance therapy ± D. VTE prophylaxis was recommended (at least aspirin, ≥162 mg daily) in accordance with International Myeloma Working Group guidelines. In the safety population (D-RVd, n = 99; RVd, n = 102), VTEs occurred in 10.1% of D-RVd patients and 15.7% of RVd patients; grade 2-4 VTEs occurred in 9.1% and 14.7%, respectively. Median time to the first onset of VTE was longer for D-RVd versus RVd patients (305 days vs 119 days). Anti-thrombosis prophylaxis use was similar between arms (D-RVd, 84.8% vs RVd, 83.3%); among patients with VTEs, prophylaxis use at time of first VTE onset was 60.0% for D-RVd and 68.8% for RVd. In summary, the addition of daratumumab to RVd did not increase the incidence of VTEs, but the cumulative VTE incidence was relatively high in this cohort and anti-thrombotic prophylaxis use was suboptimal.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Tromboembolia Venosa , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Aspirina/uso terapêutico , Bortezomib , Dexametasona , Lenalidomida , Mieloma Múltiplo/terapia , Transplante Autólogo , Tromboembolia Venosa/prevenção & controle , Tromboembolia Venosa/induzido quimicamente
8.
BMC Cancer ; 22(1): 901, 2022 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-35982416

RESUMO

BACKGROUND: There is limited real-world evidence that describes patients with newly diagnosed multiple myeloma (NDMM) treated with the bortezomib, lenalidomide, and dexamethasone (VRd) triplet regimen. We evaluated patient characteristics and treatment outcomes among nontransplanted NDMM patients who received VRd as their first line of therapy (LOT) in US oncology practice settings. METHODS: This retrospective observational cohort study evaluated patients from the Flatiron MM Core Registry who received VRd as first LOT between November 1, 2015, and February 28, 2021. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. Associations between patient demographic and clinical characteristics and PFS were evaluated using a multivariable Cox proportional hazards model. RESULTS: A total of 2342 eligible patients with VRd as first LOT were identified (mean age, 67.0 years). Among all identified patients, 64.3% were ≥ 65 years of age, 25.5% were elderly (≥75 years), and 47.9% were frail. Among patients with available data, 21.2% had high-risk cytogenetics, and the majority had International Staging System (ISS) stage I/II disease (71.8%), and Eastern Cooperative Oncology Group performance status (ECOG PS) score 0/1 (81.2%). Median duration of therapy was 5.5 months. With median follow-up of 21.0 months, median PFS and time-to-next-treatment were 26.5 and 16.1 months, respectively. Higher risk of disease progression or death was seen in patients categorized as elderly (hazard ratio [HR] = 1.37; 95% confidence interval [CI]: 1.13-1.66 vs patients < 65 years), having high-risk cytogenetics (HR = 1.44; 95% CI: 1.19-1.75 vs standard risk), having ISS disease stages II and III (HR = 1.31; 95% CI: 1.06-1.63 and HR = 1.37; 95% CI: 1.10-1.70 versus stage I, respectively), and having worse ECOG PS score (≥2) (HR = 1.49; 95% CI: 1.22-1.81 versus functionally active patients). CONCLUSIONS: The majority of patients treated with VRd in this study were ≥ 65 years of age, were ISS stage I/II, had an ECOG PS score of 0/1, and had standard cytogenetic risk. Median PFS observed in real-world practice was notably shorter than that observed in the SWOG S0777 clinical trial. In nontransplanted patients treated with VRd as first LOT, a higher risk of disease progression or death was associated with older age, having high-risk cytogenetics, worse disease stage, and worse ECOG PS score.


Assuntos
Mieloma Múltiplo , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib , Dexametasona , Progressão da Doença , Humanos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/terapia , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos
10.
Future Oncol ; 18(40): 4443-4456, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36799429

RESUMO

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a publication about Black participants of the GRIFFIN clinical study that was published in Blood Cancer Journal in April 2022. The GRIFFIN clinical study looked at the treatment combination of daratumumab plus a standard therapy for multiple myeloma (called RVd therapy, which stands for lenalidomide, bortezomib, and dexamethasone) in adult patients who had not been treated before for multiple myeloma and so were considered to have newly diagnosed multiply myeloma. Multiple myeloma is a blood cancer of plasma cells. Based on the participants' age, medical history, and indicators of good general health, the participants in the GRIFFIN study were also eligible to receive autologous stem cell transplant as part of their therapy. This summary describes results for the Black participants of the GRIFFIN clinical study who received daratumumab plus RVd therapy (called D-RVd) to see if D-RVd therapy is better than RVd therapy at reducing the amount of multiple myeloma cancer cells in a patient's body. WHY DID THE RESEARCHERS EVALUATE THE RESULTS FOR BLACK PATIENTS IN THE GRIFFIN STUDY?: Due to racial disparities leading to historically low representation of minority groups in clinical studies, optimal treatments are not defined for Black patients with newly diagnosed multiple myeloma. Since previously published results from the overall population in the GRIFFIN study indicated that D-RVd therapy was better than RVd therapy, the researchers wanted to determine if this was also the case among Black participants. WHAT WERE THE RESULTS?: Out of 207 participants in the GRIFFIN study, 15% (32 participants) were Black and 78% (161 participants) were White. In both Black and White participants, D-RVd therapy reduced the amount of myeloma cancer cells more than RVd therapy. Additionally, D-RVd and RVd therapy had similar safety results for Black and White participants. WHAT DO THE RESULTS MEAN?: This analysis of GRIFFIN by race shows that Black people benefit from the daratumumab-containing D-RVd therapy as much as White people. Additionally, D-RVd therapy had similar safety results to RVd therapy for both Black and White people. Clinical Trial Registration: NCT02874742 (ClinicalTrials.gov).


Assuntos
Neoplasias Hematológicas , Mieloma Múltiplo , Adulto , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Bortezomib/uso terapêutico , Lenalidomida/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/administração & dosagem , Neoplasias Hematológicas/tratamento farmacológico , População Negra
11.
Cochlear Implants Int ; 20(4): 207-216, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30947632

RESUMO

OBJECTIVE: The goal of this work is to describe the first experience in the UK with the slim pre-curved perimodiolar electrode Nucleus CI532 in a continuous series of patients in terms of surgical and clinical reliability and early performance outcomes. METHOD: In this retrospective review we describe the complication rate (including electrode array tip fold-over), NRT thresholds, hearing preservation, power efficiency and CI performance outcomes in a continuous series of 40 cochlear implants CI532 performed between October 2016 and November 2017 in 17 adults and 13 children with severe to profound hearing loss. RESULTS: Preliminary data from these groups reveals some low-frequency hearing preservation in the CI532 group although none of the patients were conventional hearing preservation candidates. NRT thresholds, power efficiency, and BKB sentences in quiet were measured at 3 and 6 months post activation. There were no significant differences in these results. The average BKB score in quiet increases from 22% pre-operatively to 58% at 3 months and 70% at 6 months. In addition, although hearing preservation was not an objective, low-frequency thresholds were preserved in 20% of cases at 3 and 6 months post-operatively. Complications were observed in 5 cases, one case with non-device related aerocoele and four related to the device array: two cases of tip roll over, one case of the electrode array being placed extra-cochlea, and one case with the electrode buckling into the middle ear. The last 2 cases were dealt with per-operatively. DISCUSSION: Our preliminary results with the CI532 implant indicate that it may be reliably placed with standard surgical techniques but care is needed during the deployment of the electrode. Further initial data suggest that switch on and early electrophysiological measures are comparable to the existing CI 512 device. However whilst preliminary, our data suggest that it may be possible to use this electrode for hearing preservation. However, further studies are required to determine its definitive advantage over other electrode designs. CONCLUSION: CI532 is a reliable device offering good initial results and could be an option for hearing preservation although further studies are required.


Assuntos
Implantes Cocleares , Perda Auditiva Bilateral/reabilitação , Desenho de Prótese , Adulto , Criança , Eletrodos Implantados , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/etiologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Reino Unido
12.
Eur J Med Chem ; 138: 830-853, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28735214

RESUMO

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of indazole-based N-alkylthiazolidenediones, which function in biochemical assays as selective inverse agonists against this receptor. Series optimization provided several potent analogues that inhibited the recruitment of a co-activator peptide fragment in vitro (IC50s < 50 nM) and reduced fasted circulating insulin and triglyceride levels in a sub-chronic pre-diabetic rat model when administered orally (10 mg/kg). A multi-parametric optimization strategy led to the identification of 50 as an advanced lead, which was more extensively evaluated in additional diabetic models. Chronic oral administration of 50 in two murine models of obesity and insulin resistance improved glucose control and reduced circulating triglycerides with efficacies similar to that of rosiglitazone. Importantly, these effects were attained without the concomitant weight gain that is typically observed with the latter agent. Thus, these studies provide additional support for the development of such molecules for the potential treatment of metabolic diseases.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Hipoglicemiantes/farmacologia , Indazóis/farmacologia , Receptores de Estrogênio/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Indazóis/administração & dosagem , Indazóis/química , Ligantes , Masculino , Camundongos , Camundongos Obesos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Zucker , Relação Estrutura-Atividade , Receptor ERRalfa Relacionado ao Estrogênio
14.
J Med Chem ; 58(9): 3859-74, 2015 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-25850459

RESUMO

Reported herein is the design, synthesis, and pharmacologic characterization of a class of TRPV1 antagonists constructed on a benzo[d]imidazole platform that evolved from a biaryl amide lead. This design composes three sections: a 2-substituted 5-phenyl headgroup attached to the benzo[d]imidazole platform, which is tethered at the two position to a phenyl tail group. Optimization of this design led to the identification of 4 (mavatrep), comprising a trifluoromethyl-phenyl-vinyl tail. In a TRPV1 functional assay, using cells expressing recombinant human TRPV1 channels, 4 antagonized capsaicin-induced Ca(2+) influx, with an IC50 value of 4.6 nM. In the complete Freund's adjuvant- and carrageenan-induced thermal hypersensitivity models, 4 exhibited full efficacy, with ED80 values of 7.8 and 0.5 mg/kg, respectively, corresponding to plasma levels of 270.8 and 9.2 ng/mL, respectively. On the basis of its superior pharmacologic and safety profile, 4 (mavatrep) was selected for clinical development for the treatment of pain.


Assuntos
Analgésicos/química , Benzimidazóis/química , Canais de Cátion TRPV/antagonistas & inibidores , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Disponibilidade Biológica , Carragenina , Cães , Adjuvante de Freund , Células HEK293 , Haplorrinos , Temperatura Alta , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/fisiopatologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
15.
Cochlear Implants Int ; 15(6): 333-6, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24840806

RESUMO

OBJECTIVE AND IMPORTANCE: Patients who have undergone solid organ transplantation and continuing immunosuppressant medication are at a higher risk of wound problems and infections following cochlear implantation. This risk is theoretically even further increased in multi-organ transplant recipients due to the increased doses of immunosuppressive medications that these patients are administered. CLINICAL PRESENTATION AND INTERVENTION: Here, we present the first reported case of successful cochlear implantation in a patient who had previously undergone successful combined liver and kidney transplant. She had no significant complications from the surgery and had good audiological outcomes 3 months post-operatively. CONCLUSION: As we continue our advances in the use of cochlear implant technology, our report adds to the growing evidence of its benefits in transplant recipients. However, there are important pre- and peri-operative considerations in this group of patients which can improve safety and outcome.


Assuntos
Implante Coclear , Transplante de Rim , Transplante de Fígado , Idoso , Terapia Combinada , Feminino , Perda Auditiva/complicações , Perda Auditiva/terapia , Humanos , Imunossupressores/uso terapêutico , Doenças Renais Policísticas/complicações , Doenças Renais Policísticas/terapia , Percepção da Fala , População Branca
16.
Curr Top Med Chem ; 9(7): 599-610, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19689368

RESUMO

FMS is the exclusive receptor tyrosine kinase for colony-stimulating factor-1 (CSF-1, also known as M-CSF), which regulates the survival, proliferation, differentiation, and function of macrophage lineage cells. Since CSF-1 is over-expressed in many tumors and at sites of inflammation, small molecule inhibitors of CSF-1 appear to offer an attractive strategy for reducing macrophage numbers associated with cancer as well as autoimmune and inflammatory disease, such as rheumatoid arthritis (RA). Numerous FMS inhibitors with structurally distinct chemotypes have been developed and exhibit potent in vitro activity, but only a limited number of compounds have progressed clinically due to poor selectivity. To date, only a handful of FMS inhibitors have been tested in models of metastatic bone disease and RA. This review will summarize the biology of FMS and its function in bone physiology, inflammation, immunity, and cancer. In addition, efforts directed towards identifying FMS-selective small molecule inhibitors as well as the advancement of non-selective inhibitors in the clinic will be highlighted. Furthermore, emerging monoclonal antibody-based therapeutic strategies specifically targeting M-CSF will be described.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Fator Estimulador de Colônias de Macrófagos/fisiologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Receptores de Fator Estimulador de Colônias/antagonistas & inibidores , Animais , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Osso e Ossos/fisiologia , Humanos , Especificidade por Substrato
17.
Expert Opin Investig Drugs ; 17(12): 1865-82, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19012502

RESUMO

BACKGROUND: The hdm2 oncogene product, HDM2 (also known as MDM2), is an ubiquitin protein ligase that suppresses the transcriptional activity of the tumor suppressor p53 and promotes its degradation. Approximately 50% of all human tumors harbor mutations or deletions in the TP53 gene. In the remaining half of all human cancers that express the wild-type protein, aberrations of p53 regulators such as HDM2 account for p53 inhibition. Therefore, small-molecule inhibitors of the HDM2-p53 protein-protein interaction appear to offer an attractive strategy for cancer therapy. OBJECTIVE: This review focuses on recent progress in the field of small-molecule inhibitors of the p53-HDM2 protein-protein interaction for the treatment of cancer. RESULTS/CONCLUSION: The development of pharmacological inhibitors has been challenging. Although many small-molecule HDM2 inhibitors have shown potent in vitro activity, only a limited number of compounds have displayed acceptable pharmacokinetic properties for in vivo evaluation. To date, the most studied chemotypes have been cis-imidazolines (e.g., Nutlins), benzodiazepines (BDPs) and spiro-oxindoles. The cis-imidazolines were the first reported potent, selective small-molecule inhibitors of the p53-MDM2 interaction, and continue to show therapeutic potential. Additionally, p53-based strategies involving inhibition of MDM2-mediated p53 ubiquitylation and restoration of DNA-binding activity of mutant p53 protein, as well as combination therapies, will be briefly described. Finally, a structurally distinct chemotype currently in Phase I clinical trials will be presented.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Bibliotecas de Moléculas Pequenas/uso terapêutico , Proteína Supressora de Tumor p53/metabolismo , Animais , Antineoplásicos/química , Humanos , Ligação Proteica , Proteínas Proto-Oncogênicas c-mdm2/química , Bibliotecas de Moléculas Pequenas/química
18.
Bioorg Med Chem Lett ; 18(9): 2865-70, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18420408

RESUMO

2-Cyano-6-fluorophenylacetamide was explored as a novel P2 scaffold in the design of thrombin inhibitors. Optimization around this structural motif culminated in 14, which is a potent thrombin inhibitor (K(i)=1.2nM) that exhibits robust efficacy in canine anticoagulation and thrombosis models upon oral administration.


Assuntos
Acetamidas , Motivos de Aminoácidos , Anticoagulantes/administração & dosagem , Desenho de Fármacos , Nitrilas , Trombina/antagonistas & inibidores , Trombose/tratamento farmacológico , Acetamidas/síntese química , Acetamidas/farmacocinética , Acetamidas/uso terapêutico , Administração Oral , Animais , Anticoagulantes/síntese química , Anticoagulantes/farmacocinética , Sítios de Ligação , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Haplorrinos , Humanos , Ligação de Hidrogênio , Modelos Químicos , Nitrilas/síntese química , Nitrilas/farmacocinética , Nitrilas/uso terapêutico , Ratos , Relação Estrutura-Atividade
19.
Am J Nephrol ; 26(4): 381-7, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16873994

RESUMO

BACKGROUND/AIM: Recent studies have suggested that statins may play a role in the protection against renal failure which is independent of cholesterol reduction. Activation of RhoGTPases is a key step in renal tubular cells' epithelial-to-mesenchymal transition (EMT) which contributes to renal interstitial fibrosis. We hypothesized that statins could act by inhibiting the synthesis of the isoprenoids, such as geranylgeranyl pyrophosphate, which is essential for membrane attachment and biological activity of RhoGTPases, RhoA and Rac1. METHODS: Human proximal tubular epithelial cells (HK2) were used to examine the inhibitory effect of statins on EMT induced with medium conditioned by activated peripheral blood mononuclear cells. RESULTS: Our study demonstrates that the statins lovastatin, simvastatin, and pravastatin inhibit HK2 cells to undergo EMT. Inhibition of EMT in HK2 cells with these statins resulted in a reduction of RhoA and Rac1 activation in both the cytoplasmic and membrane-bound forms, in preservation of the expression of the epithelial cell markers E-cadherin and cytokeratin-19, and in a decrease in Fn-EDA expression, a marker for the myofibroblast phenotype. The decreased levels of activated RhoA and Rac1 in both the cytoplasmic and membrane fractions of the cells were reversed by geranylgeranyl pyrophosphate and mevalonate, and thus attributable to the inhibition of isoprenylation of RhoGTPases by statins. CONCLUSION: This phenomenon could explain the beneficial effect of statins on EMT and on renal fibrosis prevention.


Assuntos
Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/efeitos dos fármacos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos
20.
J Am Soc Nephrol ; 16(7): 1977-84, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15901767

RESUMO

ESRD is characterized by an interstitial infiltrate of inflammatory cells in association with tubular atrophy, epithelial mesenchymal transdifferentiation (EMT), and interstitial fibrosis. Human proximal tubular epithelial cells (HK2 cells) undergo EMT in response to activated PBMC conditioned medium (aPBMC-CM), showing acquisition of a fibroblastoid morphology, increased fibronectin-EDA (EDA) expression, loss of junctional E-cadherin localization, and cytokeratin 19 (K19) expression. The signaling pathway(s) that regulates EMT in response to aPBMC-CM is not well understood. This study shows that aPBMC-CM induces a rapid activation of RhoA, Rac1, and Cdc42 activity in HK2 cells from 15 min to 48 h. Moreover, infection with adenovirus expressing constitutively active RhoA, Rac1, and Cdc42 significantly increased the expression of EDA and downregulated expression of E-cadherin and K19. Dominant negative RhoA expression suppressed aPBMC-CM-induced upregulation of EDA but did not restore the expression of E-cadherin and K19. Constitutively active RhoA activated the Rho kinase and its downstream effectors, whereas constitutively active Rac1 and Cdc42 activated the P21-activated protein kinase in epithelial cells. In further experiments, HK2 cells were treated with toxin B, exoenzyme C3, Y-27632, and HA1077. These strategies, inhibiting the Rho/Rho kinase pathway, as well as the Rac1/Cdc42/P21-activated protein kinase pathway, blocked transdifferentiation of HK2 cells in response to aPBMC-CM. To conclude, these results indicate that aPBMC-CM activates RhoA, Rac1, and Cdc42 and their downstream effectors, leading to HK2 cells undergoing transdifferentiation. Therefore, activation of small RhoGTPases is a key step in the mechanism of EMT and likely to be a contributor to tubulointerstitial fibrosis.


Assuntos
Diferenciação Celular/fisiologia , Células Epiteliais/fisiologia , Túbulos Renais Proximais/fisiologia , Mesoderma/fisiologia , Proteína cdc42 de Ligação ao GTP/metabolismo , Proteínas rac1 de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Células Cultivadas , Meios de Cultivo Condicionados , Fibrose , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/patologia , Leucócitos Mononucleares , Transdução de Sinais , Proteína cdc42 de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/genética
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