Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 37
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
J Biopharm Stat ; 33(4): 466-475, 2023 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-36717961

RESUMO

Interpretation of safety data for clinical trials that were ongoing at the onset of the COVID-19 pandemic or were started subsequent to the beginning of the pandemic may be affected in a variety of ways. Pandemic-related issues can influence the extent of study participation and introduce data collection gaps. A SARS-CoV-2 infection among study subjects as a post-randomization event may introduce a number of confounding factors that can alter the frequency of adverse events, in some cases appearing as an increase in the frequency of an adverse event associated with a study drug relative to a comparator. The authors discuss clinical challenges and statistical concerns, specifically the estimand framework, including examples for consideration, to address these challenges in safety evaluation wrought by the COVID-19 pandemic. Our aim is to shed light on the importance of starting an early dialogue among the drug development team on the evaluation of safety, critical for benefit-risk evaluation throughout the drug development process.


Assuntos
COVID-19 , Humanos , Pandemias , SARS-CoV-2 , Medição de Risco
2.
Blood Cells Mol Dis ; 81: 102389, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31835175

RESUMO

ß-thalassemia (ß-Thal) is caused by defective ß-globin production leading to globin chain imbalance, aggregation of free alpha chain in developing erythroblasts, reticulocytes, and mature circulating red blood cells. The hypochromic thalassemic red cells exhibit increased cell dehydration in association with elevated K+ leak and increased K-Cl cotransport activity, each of which has been linked to globin chain imbalance and related oxidative stress. We therefore tested the effect of genetic inactivation of K-Cl cotransporters KCC1 and KCC3 in a mouse model of ß-thalassemia intermedia. In the absence of these transporters, the anemia of ß-Thal mice was ameliorated, in association with increased MCV and reductions in CHCM and hyperdense cells, as well as in spleen size. The resting K+ content of ß-Thal red cells was greatly increased, and Thal-associated splenomegaly slightly decreased. Lack of KCC1 and KCC3 activity in Thal red cells reduced red cell density and improved ß-Thal-associated osmotic fragility. We conclude that genetic inactivation of K-Cl cotransport can reverse red cell dehydration and partially attenuate the hematologic phenotype in a mouse model of ß-thalassemia.


Assuntos
Simportadores/genética , Talassemia beta/genética , Anemia/prevenção & controle , Animais , Desidratação , Modelos Animais de Doenças , Eritrócitos/química , Eritrócitos/patologia , Camundongos , Fragilidade Osmótica , Fenótipo , Esplenomegalia , Simportadores/metabolismo , Talassemia beta/patologia , Cotransportadores de K e Cl-
3.
Blood Cells Mol Dis ; 79: 102346, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31352162

RESUMO

Excessive red cell dehydration contributes to the pathophysiology of sickle cell disease (SCD). The densest fraction of sickle red cells (with the highest corpuscular hemoglobin concentration) undergoes the most rapid polymerization of deoxy-hemoglobin S, leading to accelerated cell sickling and increased susceptibility to endothelial activation, red cell adhesion, and vaso-occlusion. Increasing red cell volume in order to decrease red cell density can thus serve as an adjunct therapeutic goal in SCD. Regulation of circulating mouse red cell volume and density is mediated largely by the Gardos channel, KCNN4, and the K-Cl cotransporters, KCC3 and KCC1. Whereas inhibition of the Gardos channel in subjects with sickle cell disease increased red cell volume, decreased red cell density, and improved other hematological indices in subjects with SCD, specific KCC inhibitors have not been available for testing. We therefore investigated the effect of genetic inactivation of KCC3 and KCC1 in the SAD mouse model of sickle red cell dehydration, finding decreased red cell density and improved hematological indices. We describe here generation of mice genetically deficient in the three major red cell volume regulatory gene products, KCNN4, KCC3, and KCC1 in C57BL6 non-sickle and SAD sickle backgrounds. We show that combined loss-of-function of all three gene products in SAD mice leads to incrementally increased MCV, decreased CHCM and % hyperchromic cells, decreased red cell density (phthalate method), increased resistance to hypo-osmotic lysis, and increased cell K content. The data show that combined genetic deletion of the Gardos channel and K-Cl cotransporters in a mouse SCD model decreases red cell density and improves several hematological parameters, supporting the strategy of combined pharmacological inhibition of these ion transport pathways in the adjunct treatment of human SCD.


Assuntos
Anemia Falciforme/sangue , Eritrócitos/efeitos dos fármacos , Eritrócitos/metabolismo , Animais , Tamanho Celular/efeitos dos fármacos , Desidratação/tratamento farmacológico , Modelos Animais de Doenças , Eritrócitos/patologia , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/deficiência , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Camundongos , Simportadores/deficiência , Simportadores/genética , Cotransportadores de K e Cl-
4.
Mol Genet Metab ; 126(2): 121-130, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30528227

RESUMO

BACKGROUND: Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a lysosomal disorder wherein deficient heparan-N-sulfatase (HNS) activity results in the accumulation of heparan sulfate in the central nervous system and is associated with progressive neurodegeneration in early childhood. We report on the efficacy, pharmacokinetics, safety, and tolerability of intrathecal (IT) administration of recombinant human HNS (rhHNS) from a phase IIb randomized open-label trial. METHODS: Twenty-one patients, randomized 1:1:1 to rhHNS IT 45 mg administered every 2 weeks (Q2W), every 4 weeks (Q4W), or no treatment, were assessed for amelioration in neurocognitive decline as determined by the Bayley Scales of Infant and Toddler Development®, Third Edition. The primary efficacy goal was defined as ≤10-point decline (responder) in at least three patients in a dosing cohort after 48 weeks. Other efficacy assessments included adaptive behavioral function, assessments of cortical gray matter volume, and glycosaminoglycan (GAG) levels in urine. RESULTS: A clinical response to rhHNS IT was observed in three treated patients (two in the Q2W group, one in the Q4W group). Cerebrospinal fluid heparan sulfate and urine GAG levels were reduced in all treated patients. However, most secondary efficacy assessments were similar between treated patients (n = 14; age, 17.8-47.8 months) and untreated controls (n = 7; age, 12.6-45.0 months). Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths. CONCLUSION: rhHNS IT treatment reduced heparan sulfate and GAG levels in treated patients. Though the primary neurocognitive endpoint was not met, important lessons in the design and endpoints for evaluation of cognitive and behavioral diseases resulted. TRIAL REGISTRATION: ClinicalTrials.govNCT02060526; EudraCT 2013-003450-24.


Assuntos
Injeções Espinhais , Mucopolissacaridose III/tratamento farmacológico , Sulfatases/uso terapêutico , Sistema Nervoso Central , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Glicosaminoglicanos/urina , Humanos , Lactente , Masculino , Mucopolissacaridose III/líquido cefalorraquidiano , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Sulfatases/efeitos adversos
6.
Blood ; 126(3): 354-62, 2015 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-26048911

RESUMO

Cutaneous T-cell lymphoma (CTCL) is an aggressive neoplasm with limited treatments for patients with advanced disease. The mucin 1 C-terminal subunit (MUC1-C) oncoprotein plays a critical role in regulating cell proliferation, apoptosis, and protection from cytotoxic injury mediated by reactive oxygen species (ROS). Although CTCL cells exhibit resistance to ROS-induced apoptosis, the expression and functional significance of MUC1 in CTCL have not been previously investigated. Present studies demonstrate that MUC1-C is overexpressed in CTCL cell lines and primary CTCL cells but is absent in resting T cells from healthy donors and B-cell lymphoma cells. We have developed a cell-penetrating peptide that disrupts homodimerization of the MUC1-C subunit necessary for its nuclear translocation and downstream signaling. We show that treatment of CTCL cells with the MUC1-C inhibitor is associated with downregulation of the p53-inducible regulator of glycolysis and apoptosis and decreases in reduced NAD phosphate and glutathione levels. In concert with these results, targeting MUC1-C in CTCL cells increased ROS and, in turn, induced ROS-mediated late apoptosis/necrosis. Targeting MUC1-C in CTCL tumor xenograft models demonstrated significant decreases in disease burden. These findings indicate that MUC1-C maintains redox balance in CTCL cells and is thereby a novel target for the treatment of patients with CTCL.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Linfoma Cutâneo de Células T/metabolismo , Mucina-1/metabolismo , Peptídeos/farmacologia , Neoplasias Cutâneas/metabolismo , Animais , Proteínas Reguladoras de Apoptose , Western Blotting , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Glutationa/metabolismo , Humanos , Técnicas Imunoenzimáticas , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma Cutâneo de Células T/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mucina-1/química , Mucina-1/genética , NADP/metabolismo , Necrose , Estresse Oxidativo , Monoéster Fosfórico Hidrolases , RNA Mensageiro/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Am J Hematol ; 92(3): 317-321, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28066929

RESUMO

Acute myeloid leukemia (AML) is characterized by a clonal expansion of undifferentiated myeloid precursors resulting in impaired hematopoiesis and bone marrow failure. In 2016, the World Health Organization (WHO) published revisions to the classification of myeloid neoplasms and acute leukemias. Similar to the 2008 classification, the updated classification incorporates clinical features, morphology, immunophenotyping, and cytogenetics, with greater emphasis on molecular genetics, to define disease entities. This brief review addresses the various components of pathologic assessment to establish a diagnosis of AML and to help risk stratify patients, with an emphasis on newer techniques used in the detection of mutations with prognostic significance, as well as assays employed in the evaluation of minimal residual disease following treatment.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Classificação , Citogenética , Humanos , Imunofenotipagem , Biologia Molecular , Neoplasia Residual/diagnóstico , Medição de Risco , Organização Mundial da Saúde
9.
Arch Pathol Lab Med ; 2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37638547

RESUMO

CONTEXT.­: Increased band neutrophils in blood smear differential counts ("bandemia") are entrenched in medicine as a flag for sepsis. However, laboratory hematology experts have long advocated for discontinuation of reporting bands separately from segmented neutrophils because of poor sensitivity and specificity, poor interobserver agreement, and availability of alternative biomarkers for sepsis. OBJECTIVE.­: To describe band neutrophil reporting practices and reproducibility of band classification among laboratories participating in the College of American Pathologists (CAP) proficiency testing (PT) program. DESIGN.­: A survey questionnaire was distributed to hematology PT participants. A subsequent morphologic challenge included 12 preselected cell identifications of segmented neutrophils, bands, and metamyelocytes, and a 100-cell manual differential count of a digitally scanned blood smear. RESULTS.­: Among laboratories that reported manual differentials, most respondents reported bands (4554 of 5268; 86.4%). Only 3222 of 4412 respondents (73.0%) provided band reference ranges. Though participants classified "easy" band neutrophils well (78.0%-98.3%), categorization of cell identifications for "moderate" and "difficult" bands was poor (3.1%-39.0% of laboratories), with classification instead as segmented neutrophils. This pattern was seen regardless of laboratory demographic characteristics. Marked variability in band counts was observed on the 100-cell differential count for both CAP PT participants and CAP Hematology and Clinical Microscopy Committee (HCMC) members (coefficients of variation, 55.8% and 32.9%, respectively). Variability was significantly improved when segmented and band neutrophils were grouped together (coefficients of variation, 6.2% and 5.0%, respectively). CONCLUSIONS.­: Most CAP PT-participating laboratories report band counts, many without reference ranges. The survey confirms significant interlaboratory variability of band enumeration when bands are separately identified from segmented neutrophils. This study reaffirms the CAP Hematology and Clinical Microscopy Committee's strong recommendation to group segmented and band neutrophils together in manual differential counts.

11.
Am J Clin Pathol ; 156(6): 1073-1082, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34075395

RESUMO

OBJECTIVES: Lupus anticoagulant (LA) detection requires (1) prolongation of a phospholipid (PL)-dependent clot-based screening assay, (2) noncorrection upon adding normal pooled plasma, and (3) a confirmatory PL dependency test. Paired LA assays run screening and confirmatory tests simultaneously, with their test ratio (TR) or differences used to evaluate test results. We evaluated patients whose paired testing demonstrated PL dependence suggestive of LA, yet the low PL screen was not prolonged. METHODS: Clinical and laboratory parameters are compared across (1) true positive (screen prolonged, TR positive) vs borderline (screen not prolonged, TR positive); (2) low-, moderate-, and high-TR subgroups; and (3) dilute Russell viper venom time (dRVVT) vs silica clotting time (SCT). RESULTS: Borderline samples are not statistically different from true positives in their rate of repeat LA positivity or association with other anti-PL antibodies. Compared with true positives, borderline dRVVT is more frequent in pregnancy, women, and younger age. Elevated activated partial thromboplastin time is more frequent in true-positive dRVVT and SCT vs borderline and with an increasing dRVVT TR. LA persistence is more frequent with an increasing SCT TR. In addition, dRVVT true positivity is more frequent with thromboembolic events, while SCT is more frequent with autoimmunity and pregnancy complications. CONCLUSIONS: Negative low-PL screens may not necessarily lack LA. A reevaluation of the laboratory criteria for LA detection may be needed.


Assuntos
Síndrome Antifosfolipídica , Inibidor de Coagulação do Lúpus , Anticorpos Antifosfolipídeos , Síndrome Antifosfolipídica/diagnóstico , Testes de Coagulação Sanguínea , Feminino , Humanos , Inibidor de Coagulação do Lúpus/análise , Tempo de Tromboplastina Parcial , Fosfolipídeos , Tempo de Protrombina
12.
Pathology ; 53(3): 349-366, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33685720

RESUMO

The revised fourth edition of the World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues (2017) reflects significant advances in understanding the biology, genetic basis and behaviour of haematopoietic neoplasms. This review focuses on some of the major changes in B-cell and T-cell non-Hodgkin lymphomas in the 2017 WHO and includes more recent updates. The 2017 WHO saw a shift towards conservatism in the classification of precursor lesions of small B-cell lymphomas such as monoclonal B-cell lymphocytosis, in situ follicular and in situ mantle cell neoplasms. With more widespread use of next generation sequencing (NGS), special entities within follicular lymphoma and mantle cell lymphoma were recognised with recurrent genetic aberrations and unique clinicopathological features. The diagnostic workup of lymphoplasmacytic lymphoma and hairy cell leukaemia has been refined with the discovery of MYD88 L265P and BRAF V600E mutations, respectively, in these entities. Recommendations in the immunohistochemical evaluation of diffuse large B-cell lymphoma include determining cell of origin and expression of MYC and BCL2, so called 'double-expressor' phenotype. EBV-positive large B-cell lymphoma of the elderly has been renamed to recognise its occurrence amongst a wider age group. EBV-positive mucocutaneous ulcer is a newly recognised entity with indolent clinical behaviour that occurs in the setting of immunosuppression. Two lymphomas with recurrent genetic aberrations are newly included provisional entities: Burkitt-like lymphoma with 11q aberration and large B-cell lymphoma with IRF4 rearrangement. Aggressive B-cell lymphomas with MYC, BCL2 and/or BCL6 rearrangements, so called 'double-hit/triple-hit' lymphomas are now a distinct entity. Much progress has been made in understanding intestinal T-cell lymphomas. Enteropathy-associated T-cell lymphoma, type II, is now known to not be associated with coeliac disease and is hence renamed monomorphic epitheliotropic T-cell lymphoma. An indolent clonal T-cell lymphoproliferative disorder of the GI tract is a newly included provisional entity. Angioimmunoblastic T-cell lymphoma and nodal T-cell lymphomas with T-follicular helper phenotype are included in a single broad category, emphasising their shared genetic and phenotypic features. Anaplastic large cell lymphoma, ALK- is upgraded to a definitive entity with subsets carrying recurrent rearrangements in DUSP22 or TP63. Breast implant-associated anaplastic large cell lymphoma is a new provisional entity with indolent behaviour. Finally, cutaneous T-cell proliferations include a new provisional entity, primary cutaneous acral CD8-positive T-cell lymphoma, and reclassification of primary small/medium CD4-positive T-cell lymphoma as lymphoproliferative disorder.


Assuntos
Herpesvirus Humano 4/isolamento & purificação , Linfoma de Células B/classificação , Linfoma não Hodgkin/classificação , Linfoma de Células T/classificação , Transtornos Linfoproliferativos/classificação , Fosfatases de Especificidade Dupla/genética , Rearranjo Gênico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Fatores Reguladores de Interferon/genética , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Linfoma de Células T/genética , Linfoma de Células T/patologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/patologia , Fosfatases da Proteína Quinase Ativada por Mitógeno/genética , Mutação , Fator 88 de Diferenciação Mieloide/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Análise de Sequência de DNA , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Organização Mundial da Saúde
13.
Neurol Ther ; 10(2): 693-709, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33991326

RESUMO

INTRODUCTION: In a pivotal study, apomorphine sublingual film (APL; KYNMOBI®) was an effective and generally well-tolerated on-demand treatment of "OFF" episodes in patients with Parkinson's disease (PD), approved across the dose range of 10-30 mg. Pharmacokinetics and comparative bioavailability of APL and two subcutaneous (SC) apomorphine formulations (SC-APO [APOKYN®] and SC-APO-GO [APO-go® PEN]) were evaluated in a randomized, three-way crossover, open-label study (NCT03292016). METHODS: Patients with PD and "OFF" episodes received an open-label randomized sequence of single doses of SC-APO and SC-APO-GO at the currently prescribed dose (2/3/4/5 mg) and APL doses with similar plasma exposure (15/20/25/30 mg) with ≥ 1-day washout between formulations. Plasma pharmacokinetics of apomorphine and apomorphine sulfate (major inactive metabolite) were measured 0-6 h postdose. RESULTS: Median time to maximum plasma concentration (tmax) of apomorphine was 0.63-0.75 h for APL and 0.25-0.38 h for SC-APO and SC-APO-GO. Geometric mean maximum plasma concentration (Cmax) of apomorphine was 4.31-11.2 ng/ml across APL doses and was generally lower compared with SC apomorphine formulations within dose groups. Area under the concentration-time curve from time 0 to infinity (AUC∞) was similar across apomorphine formulations within most dose groups. Relative bioavailability of APL was ~ 17% of SC apomorphine by AUC∞; SC-APO and SC-APO-GO had similar bioavailability (98% and 83% by AUC∞ and Cmax, respectively). Apomorphine sulfate exposure was ~ three-fold higher for APL versus SC-APO and SC-APO-GO by AUC∞ and Cmax. CONCLUSION: In patients with PD and "OFF" episodes, APL demonstrated lower Cmax and relative bioavailability but similar exposures (AUCs) versus SC apomorphine within the approved dose range. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03292016.

14.
Parkinsonism Relat Disord ; 79: 110-116, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32927285

RESUMO

INTRODUCTION: The efficacy and safety of apomorphine sublingual film (APL-130277; APL) for the on-demand treatment of "OFF" episodes associated with Parkinson's disease (PD) was demonstrated in a double-blind trial. Herein we describe the ability of patients to receive effective and tolerable APL dose titration during the open-label titration phase. METHODS: Adult patients with levodopa-responsive PD and "OFF" episodes were enrolled. In practically defined "OFF," patients were observed for a FULL "ON" after their usual morning carbidopa/levodopa (CD/LD) dose and then after titration with APL following each increasing dose (10-35 mg). Antiemetic medication was administered for 3 days before initiation of titration and was continued throughout titration. Motor responses were evaluated predose and postdose using Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III score. Safety outcomes were evaluated. RESULTS: Among 141 patients who enrolled in the study and received APL during open-label titration, 109 (77.3%) achieved a FULL "ON" (66.1% at 10-20 mg) and 10 did not. Patients who successfully completed APL dose titration tended to be younger, had a longer mean time since PD diagnosis, and had lower levodopa requirements than those who discontinued during titration for any reason. Change in MDS-UPDRS Part III scores from predose to 30 min postdose after titration with the effective dose of APL (n = 109) was similar across all dose groups. In a post hoc analysis, the magnitude of motor response with APL was ~2-fold higher than with CD/LD 15 min postdose, and the observed peak response occurred earlier with APL than with the trend seen for CD/LD (45 vs 90 min, respectively). Overall, the most common (≥10%) treatment-emergent adverse events (TEAEs) during APL dose titration were nausea (20.6%), yawning (12.1%), dizziness (11.3%), and somnolence (11.3%). Twelve patients discontinued due to TEAEs during APL dose titration, most commonly (≥2%) because of dizziness (2.8%), nausea (2.1%), and somnolence (2.1%). CONCLUSION: Among eligible patients with PD and "OFF" episodes who had their APL dose successfully titrated to an effective and tolerable level, most were able to do so within the first 3 titrated doses but some required further dose escalations. The use of APL can provide benefit for the treatment of "OFF" episodes.


Assuntos
Apomorfina/farmacologia , Agonistas de Dopamina/farmacologia , Doença de Parkinson/tratamento farmacológico , Administração Sublingual , Idoso , Apomorfina/administração & dosagem , Apomorfina/efeitos adversos , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Índice de Gravidade de Doença
15.
Lancet Neurol ; 19(2): 135-144, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31818699

RESUMO

BACKGROUND: Many patients with Parkinson's disease have potentially disabling off episodes that are not predictably responsive to levodopa. In this study, we assessed the safety and efficacy of apomorphine sublingual film as an on-demand therapy for off episodes in patients with Parkinson's disease. METHODS: This randomised, double-blind, placebo-controlled study was done by movement disorder specialists at 32 sites in the USA and one in Canada. Patients with Parkinson's disease who had 2 h or more of off time per day with predictable morning off periods, were responsive to levodopa, and were on stable doses of anti-parkinsonian medication were eligible. In an open-label titration phase, increasing doses of apomorphine sublingual film (10-35 mg) were administered until a tolerable full on response was achieved. Patients were then randomly assigned (1:1) with an interactive web-response system to receive the effective dose of apomorphine sublingual film or matching placebo in a 12-week, double-blind maintenance phase. Randomisation was not stratified, and the block size was four. All patients and study personnel were masked to treatment assignments. The primary endpoint was the in-clinic change from predose to 30 min post-dose in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part 3 (motor) score at week 12, analysed on a modified intention-to-treat population by use of a mixed-effect model for repeated measures. Safety analyses were done on all enrolled patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT02469090. FINDINGS: Between June 18, 2015, and Dec 11, 2017, 109 patients were enrolled and randomly assigned to receive apomorphine sublingual film (n=54) or placebo (n=55). All patients received the assigned study treatment, and 34 (63%) of 54 patients receiving apomorphine sublingual film and 46 (84%) of 55 receiving placebo completed the study. Least squares mean (SE) change from predose to 30 min post-dose in MDS-UPDRS part 3 score at week 12 was -11·1 (SE 1·46, 95% CI -14·0 to -8·2) with apomorphine sublingual film and -3·5 (1·29, -6·1 to -0·9) with placebo (difference -7·6, SE 1·96, 95% CI -11·5 to -3·7; p=0·0002). Mild-to-moderate oropharyngeal events were the most common side-effect, reported in 17 (31%) of 54 patients receiving apomorphine sublingual film and in four (7%) of 55 patients receiving placebo, leading to treatment discontinuation in nine (17%) patients treated with apomorphine and in one (2%) patient treated with placebo. Other treatment-emergent adverse events were transient nausea (in 15 [28%] patients receiving apomorphine sublingual film), somnolence (seven [13%]), and dizziness (five [9%]). Orthostatic hypotension, syncope, dyskinesia, hallucinations, prolongation of the QT interval, and impulse control disorders were infrequent (prevalence ≤2% of all patients) or did not occur. One patient treated with apomorphine sublingual film (with known cardiac risk factors) had a fatal cardiac arrest. INTERPRETATION: Although nearly a third of patients discontinued treatment primarily because of oropharyngeal side-effects, apomorphine sublingual film provided an efficacious, on-demand treatment for off episodes for most patients with Parkinson's disease in this trial. The long-term safety and efficacy of apomorphine sublingual film are currently being investigated. FUNDING: Cynapsus Therapeutics and Sunovion.


Assuntos
Apomorfina/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Administração Sublingual , Adulto , Idoso , Antiparkinsonianos/uso terapêutico , Apomorfina/administração & dosagem , Canadá , Método Duplo-Cego , Discinesias/tratamento farmacológico , Feminino , Humanos , Levodopa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Estados Unidos
17.
Epilepsy Res ; 158: 106216, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31675622

RESUMO

OBJECTIVE: To evaluate the impact of eslicarbazepine acetate (ESL) monotherapy on markers of bone and lipid metabolism. METHODS: We conducted a post-hoc analysis of data pooled from two Phase III, dose-blind, conversion-to-ESL (1600 mg and 1200 mg) monotherapy studies in patients with focal seizures. Laboratory measurements included lipids (total cholesterol [TC]; high-density lipoprotein cholesterol [HDL-C]; low-density lipoprotein cholesterol; and triglycerides) and markers of bone metabolism (alkaline phosphatase; 25-hydroxyvitamin D; osteocalcin; and parathyroid hormone [PTH]); measurements were taken at baseline, Week 18, and Month 12, and analyzed according to enzyme-inducing antiepileptic drugs (EIAEDs) use at baseline (+EIAED and -EIAED subgroups). RESULTS: Data from 337 treatment-compliant patients were used for the Week 18 analyses (+EIAED subgroup, n = 119; -EIAED subgroup, n = 218); data from 161 treatment-compliant patients were used for the Month 12 analyses (+EIAED subgroup, n = 53; -EIAED subgroup, n = 108). At baseline, alkaline phosphatase and PTH concentrations were higher in the + EIAED versus -EIAED subgroup. Changes from baseline in markers of bone turnover were generally insignificant, except for some elevation in alkaline phosphatase in the -EIAED subgroup (18 weeks and 12 months) and osteocalcin in both subgroups (18 weeks only). Regarding lipids, TC and HDL-C concentrations were higher in the + EIAED versus -EIAED subgroup at baseline. Concentrations of markers of lipid metabolism fell in the + EIAED group and rose in the -EIAED group, reaching very similar values that were intermediate between the -EIAED and + EIAED baseline values. CONCLUSIONS: Based on this retrospective analysis, ESL seems to have had only a modest and primarily clinically insignificant impact on plasma lipids. More prospective data are needed to definitively ascertain the effects of ESL on bone metabolism.


Assuntos
Anticonvulsivantes/uso terapêutico , Osso e Ossos/metabolismo , Dibenzazepinas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Adolescente , Adulto , Biomarcadores/análise , Feminino , Humanos , Lipídeos , Masculino , Pessoa de Meia-Idade , Triglicerídeos/metabolismo , Adulto Jovem
18.
J Neurovirol ; 14(5): 455-8, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18989816

RESUMO

The polyomavirus JC (JCV) is the etiologic agent of progressive multifocal leukoencephalopathy (PML). JCV remains quiescent in kidneys, where it displays a stable archetypal regulatory region (RR). Conversely, rearranged JCV RR, including tandem repeat patterns found in the central nervous system (CNS) of PML patients, have been associated with neurovirulence. The precise site and mechanism of JCV RR transformation is unknown. We present herein a patient with rheumatoid arthritis treated with methotrexate, who developed PML and had a rapid fatal outcome. JCV DNA polymerase chain reaction (PCR) was positive in cerebrospinal fluid (CSF), bone marrow, blood, and urine. Double-immunohistochemical staining demonstrated that 9% of bone marrow CD138(+) plasma cells sustained productive infection by JCV, accounting for 94% of JCV-infected cells. JCV RR analysis revealed archetype and rearranged RR forms in bone marrow, whereas RR with tandem repeat was predominant in blood. These results suggest that the bone marrow may be a potential site of JCV pathogenic transformation. Further studies will be needed to determine the prevalence of JCV in bone marrow of immunosuppressed individuals at risk of PML and characterize the RR and phenotype of these JCV isolates.


Assuntos
Medula Óssea/virologia , DNA Viral/líquido cefalorraquidiano , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/fisiopatologia , Sequências Reguladoras de Ácido Nucleico/genética , Idoso , Artrite Reumatoide/complicações , Artrite Reumatoide/genética , Encéfalo/virologia , Líquido Cefalorraquidiano/virologia , DNA Viral/análise , DNA Viral/sangue , DNA Viral/genética , Rearranjo Gênico , Humanos , Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/genética , Leucoencefalopatia Multifocal Progressiva/virologia , Imageamento por Ressonância Magnética , Masculino , Dados de Sequência Molecular , Sequências de Repetição em Tandem/genética
19.
Clin Lymphoma Myeloma ; 8(2): 117-20, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18501106

RESUMO

A 30-year-old, HIV-positive man with a previous history of an atypical nasopharyngeal Burkitt lymphoma developed fluorodeoxyglucose (FDG) avidity on a routine FDG-positron emission tomography (PET)/computed tomography scan performed 10 months after the completion of all treatment. This new FDG-avid disease was in the area of his initial disease. Flow cytometric assessment of a fine needle aspiration showed a CD10-expressing B-cell population with kappa predominance. The corresponding cytology smears had large atypical lymphoid cells along with smaller lymphocytes and macrophages. Because of the patient's previous history of a CD10(+), high-grade B-cell lymphoma, the cytologic and flow cytometric findings were considered highly suspicious for a B-cell lymphoma. Because the differential diagnosis included a relapsed Burkitt lymphoma versus a second, unrelated lymphoma (the former with a dismal prognosis) it was deemed prudent to obtain more tissue via an open biopsy for confirmation of diagnosis and exact subclassification. An open biopsy, however, revealed a reactive lymph node with enlarged geographic follicles; no lymphoma was demonstrable and c-Myc studies were negative. The patient remains without evidence of disease. Retrospectively, the original flow cytometric assessment was believed to likely represent sampling of hyperplastic germinal centers with significantly expanded CD10(+) B cells. The FDG uptake and the kappa predominance further confounded the interpretation. This case illustrates the pitfalls of standard diagnostic techniques, including PET scanning, cytology, and flow cytometry, particularly in the setting of HIV. It further underscores the importance of adequate clinical correlation and a low threshold for performing open biopsies in such patients.


Assuntos
Citometria de Fluxo , Fluordesoxiglucose F18 , Soropositividade para HIV/complicações , Soropositividade para HIV/diagnóstico por imagem , Neoplasias Nasofaríngeas/diagnóstico por imagem , Adulto , Humanos , Masculino , Neoplasias Nasofaríngeas/patologia , Tomografia por Emissão de Pósitrons
20.
Clin Case Rep ; 6(9): 1818-1824, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30214771

RESUMO

Clinicopathologic and cytogenetic findings of an unusual EBV+ve, HHV8-ve germinotropic lymphoma, with a nongerminal center immunophenotype occurring in an immunocompetent individual, are presented. A comprehensive literature search revealed a single report of three similar cases. These may represent a unique subset of EBV-positive large B-cell lymphomas in immunocompetent individuals.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA