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1.
J Thromb Thrombolysis ; 49(1): 121-131, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31664662

RESUMO

Andexanet-alpha is a specific reversal agent for direct factor Xa inhibitors (dFXaI). We aimed to project utilization rates and cost of andexanet for reversal of dFXaI-related major hemorrhage compared to 4-factor prothrombin complex concentrates (4F-PCC). A retrospective, multicenter review was conducted between 1/1/2014 and 7/15/2018 of patients who received 4F-PCC for reversal of dFXaI-related life-threatening hemorrhages. Total hospital reimbursements/patient were calculated based on national average MS-DRG payments adjusting for Medicare discounts. The projected cost for andexanet (based on dose and insurance) and % reimbursement/patient was compared to the actual cost of 4F-PCC. Hemostasis at 24 h (excellent/good vs. poor) and 30-day thrombotic complications were assessed. Of 126 patients who received 4F-PCC to reverse dFXaI, 46 (~ 10 per-year) met inclusion criteria. The median projected cost of andexanet was $22,120/patient, compared to $5670/patient for 4F-PCC (P < 0.001). The median hospital reimbursement was $11,492/hospitalization. The projected cost of andexanet alone would exceed the entire hospital reimbursement in 74% of patients by a median of $7604, while 4F-PCC cost exceeded the total hospital payments in 7% of patients in the same cohort (P < 0.001). Hemostasis was excellent/good in 72% of patients post-4F-PCC, compared to 82% in andexanet trials. Thromboembolic events occurred in 4% of patients following 4F-PCC versus 10% in andexanet trials. The projected cost of andexanet would exceed the national average hospital reimbursement/patient in nearly 75% of patients by over $7500/hospitalization. 4F-PCC was significantly less expensive, had lower rates of thrombosis, but also lower rates of good/excellent hemostasis compared to published data for andexanet.


Assuntos
Fatores de Coagulação Sanguínea , Inibidores do Fator Xa , Fator Xa , Hemorragia , Proteínas Recombinantes , Centros de Atenção Terciária/economia , Idoso , Idoso de 80 Anos ou mais , Fatores de Coagulação Sanguínea/administração & dosagem , Fatores de Coagulação Sanguínea/economia , Custos e Análise de Custo , Fator Xa/administração & dosagem , Fator Xa/economia , Inibidores do Fator Xa/administração & dosagem , Inibidores do Fator Xa/efeitos adversos , Inibidores do Fator Xa/economia , Feminino , Hemorragia/induzido quimicamente , Hemorragia/tratamento farmacológico , Hemorragia/economia , Hemorragia/epidemiologia , Humanos , Masculino , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/economia , Estudos Retrospectivos
2.
Ann Pharmacother ; 47(11): 1569-76, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24259603

RESUMO

OBJECTIVE: Refractory status epilepticus (RSE) requires aggressive management with multiple antiepileptic drugs (AEDs) often requiring the initiation of continuous infusions of propofol, midazolam, or pentobarbital to achieve adequate control in addition to intermittent agents. Ketamine has been implicated in several case reports as a successful agent for treating RSE given that it blocks the N-methyl-D-aspartate receptor, which is overexpressed in prolonged status epilepticus. CASE SUMMARY: We describe a previously healthy 27-year-old woman who presented with prolonged RSE requiring the initiation of multiple AEDs, including high-dose propofol and midazolam continuous infusions. As a result of hypotension from propofol and inadequate seizure control with midazolam, the patient was successfully transitioned to a pentobarbital infusion in combination with multiple AEDs. Although the patient achieved control of her RSE, her course was complicated by the development of an anticonvulsant hypersensitivity syndrome (AHS) with transaminitis. Limited with the options of AED that could have been used, it was decided to initiate the patient on a continuous ketamine infusion plus midazolam and slowly wean the patient off pentobarbital as well as to avoid further use of phenytoin and phenobarbital. DISCUSSION: The patient was successfully transitioned off pentobarbital to a ketamine infusion plus midazolam with complete seizure control after several dose escalations. Her AHS and transaminitis resolved on a ketamine infusion for a total of 12 days, and she was successfully discharged from the hospital after 60 days in the ICU. CONCLUSION: This is the first case report to describe a successful transition to a ketamine infusion in a patient with AHS and transaminitis.


Assuntos
Anticonvulsivantes/efeitos adversos , Síndrome de Hipersensibilidade a Medicamentos/etiologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Ketamina/uso terapêutico , Estado Epiléptico/tratamento farmacológico , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/uso terapêutico , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Feminino , Humanos , Infusões Intravenosas , Ketamina/administração & dosagem , Midazolam/administração & dosagem , Midazolam/uso terapêutico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Estado Epiléptico/diagnóstico , Estado Epiléptico/imunologia , Resultado do Tratamento
3.
PLoS Pathog ; 4(2): e28, 2008 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-18282092

RESUMO

Methamphetamine (Meth) is abused by over 35 million people worldwide. Chronic Meth abuse may be particularly devastating in individuals who engage in unprotected sex with multiple partners because it is associated with a 2-fold higher risk for obtaining HIV and associated secondary infections. We report the first specific evidence that Meth at pharmacological concentrations exerts a direct immunosuppressive effect on dendritic cells and macrophages. As a weak base, Meth collapses the pH gradient across acidic organelles, including lysosomes and associated autophagic organelles. This in turn inhibits receptor-mediated phagocytosis of antibody-coated particles, MHC class II antigen processing by the endosomal-lysosomal pathway, and antigen presentation to splenic T cells by dendritic cells. More importantly Meth facilitates intracellular replication and inhibits intracellular killing of Candida albicans and Cryptococcus neoformans, two major AIDS-related pathogens. Meth exerts previously unreported direct immunosuppressive effects that contribute to increased risk of infection and exacerbate AIDS pathology.


Assuntos
Apresentação de Antígeno/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/toxicidade , Células Dendríticas/efeitos dos fármacos , Macrófagos Peritoneais/efeitos dos fármacos , Metanfetamina/toxicidade , Fagocitose/efeitos dos fármacos , Animais , Apresentação de Antígeno/imunologia , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/imunologia , Candida albicans/imunologia , Fracionamento Celular , Células Cultivadas , Cloroquina/farmacologia , Cryptococcus neoformans/imunologia , Células Dendríticas/microbiologia , Células Dendríticas/fisiologia , Feminino , Terapia de Imunossupressão , Macrófagos Peritoneais/microbiologia , Macrófagos Peritoneais/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fagocitose/imunologia
4.
Neurotox Res ; 19(1): 63-72, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19957214

RESUMO

In Parkinson's disease (PD), there is a progressive loss of neuromelanin (NM)-containing dopamine neurons in substantia nigra (SN) which is associated with microgliosis and presence of extracellular NM. Herein, we have investigated the interplay between microglia and human NM on the degeneration of SN dopaminergic neurons. Although NM particles are phagocytized and degraded by microglia within minutes in vitro, extracellular NM particles induce microglial activation and ensuing production of superoxide, nitric oxide, hydrogen peroxide (H2O2), and pro-inflammatory factors. Furthermore, NM produces, in a microglia-depended manner, neurodegeneration in primary ventral midbrain cultures. Neurodegeneration was effectively attenuated with microglia derived from mice deficient in macrophage antigen complex-1, a microglial integrin receptor involved in the initiation of phagocytosis. Neuronal loss was also attenuated with microglia derived from mice deficient in phagocytic oxidase, a subunit of NADPH oxidase, that is responsible for superoxide and H2O2 production, or apocynin, an NADPH oxidase inhibitor. In vivo, NM injected into rat SN produces microgliosis and a loss of tyrosine hydroxylase neurons. Thus, these results show that extracellular NM can activate microglia, which in turn may induce dopaminergic neurodegeneration in PD. Our study may have far-reaching implications, both pathogenic and therapeutic.


Assuntos
Progressão da Doença , Melaninas/metabolismo , Microglia/metabolismo , Degeneração Neural/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Animais , Dopamina , Feminino , Humanos , Camundongos , Camundongos Knockout , Microglia/patologia , Degeneração Neural/patologia , Neurônios/patologia , Doença de Parkinson/patologia , Gravidez , Ratos , Ratos Endogâmicos F344
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