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1.
Neurosurgery ; 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32097466

RESUMO

Marijuana is increasingly utilized for the treatment of multiple medical problems, including back pain, in the United States. Although there is strong preclinical evidence supporting the promise of cannabinoids in the treatment of back pain, there is a paucity of clinical data supporting their use in clinical practice. Opioids are an important medication for the treatment of acute and chronic back pain, but utilization of opioid-based regimens have likely contributed to the growing opioid epidemic. The significant risk of morbidity, mortality, and dependence secondary to opioid medications have increased the interest in nonopioid medications, including cannabinoid-based pain regimens, in treating back pain. This review will provide an overview on the pharmacology, drug delivery methods, clinical evidence, and safety considerations critical to understanding the potential role of cannabinoids in the treatment of back pain.

2.
J Neurointerv Surg ; 12(1): 67-71, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31530652

RESUMO

INTRODUCTION: Postprocedural thrombosis is a rare complication after flow diverting stent (FD) implantation for aneurysm treatment with few reported cases in the literature. Management strategies and outcomes associated with this complication have not been reported. METHODS: A multicenter retrospective series of cases of acute postprocedural FD thrombosis were compiled and prevalence was calculated based on procedural volumes over a 7 year period. Acute postprocedural FD thrombosis was defined as the development of neurologic deficit with angiographic imaging demonstrating acute thrombus within the index FD stent at least 2 hours following completion of the implantation procedure. RESULTS: A total of 10 cases of postprocedural thrombosis were identified at five participating centers among a total of 768 patients treated (prevalence 1.3%). Thrombosis occurred a median of 5.5 days after implantation (range 0-83 days). 9/10 patients underwent emergent angiography with intent to perform endovascular reperfusion. A variety of different endovascular treatments were used, including aspiration thrombectomy, retrievable stent thrombectomy, balloon angioplasty, and intra-arterial thrombolytic infusion, without any procedural complications. There were no instances of FD migration, stent kinking, or aneurysm rupture. 90% of patients achieved Thrombolysis in Cerebral Infarction 2B or greater revascularization. Favorable clinical outcomes (modified Rankin Scale score of 0-2) at 3 months were achieved in 88% of patients. CONCLUSION: Acute postprocedural thrombosis of an FD is a rare complication that occurs in approximately 1-2% of patients after aneurysm treatment. Patients presenting with acute postprocedural FD thrombosis should be aggressively managed using large vessel occlusion thrombectomy techniques, as good angiographic and clinical outcomes are possible.

3.
Int Econ Rev (Philadelphia) ; 60(2): 547-593, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31333276

RESUMO

We examine the effect of financial constraints on firm investment and cash flow. We combine data from the Spanish Mercantile Registry and the Bank of Spain Credit Registry to classify firms according to whether they are family-owned, not family-owned, or belong to a family-linked network of firms and according to their number of banking relations (with none, one, or several banks). Our empirical strategy is structural, based on a dynamic model solved numerically to generate the joint distribution of firm capital (size), investment and cash flow, both in cross-sections and in panel data. We consider three alternative financial settings: saving only, borrowing and lending, and moral hazard constrained state-contingent credit. We estimate each setting via maximum likelihood and compare across these financial regimes. Based on the estimated financial regime, we show that family firms, especially those belonging to networks based on ownership, are associated with a more flexible market or contract environment and are less financially constrained than non-family firms. This result survives stratifications of family and non-family firms by bank status, region, industry and time period. Family firms are better able to allocate funds and smooth investment across states of the world and over time, arguably done informally or using the cash flow generated at the level of the network. We also validate our structural approach by demonstrating that it performs well in traditional categories, by stratifying firms by size and age and find that smaller and younger firms are more constrained than larger and older firms.

5.
Am J Transplant ; 18(9): 2305-2313, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29767445

RESUMO

Preventing conversion of donor-specific anti-HLA antibodies (DSAs) from an IgM-to-IgG could a way to prevent chronic rejection. We evaluated whether belatacept-treated patients (belatacept less-intensive [LI] or more-intensive [MI] regimens) have a lower rate of conversion than do cyclosporine A (CsA)-treated patients. We included 330 HLA-mismatched patients from 2 phase 3 trials with either (a) complete donor/recipient HLA-A, -B, -DR, and -DQ loci typing or (b) incomplete HLA typing with IgG DSAs detected pretransplant or posttransplant. IgM and IgG DSAs were tested with single antigen beads at 0, 6, 12, 24, and 36 months posttransplant. The overall (preexisting or de novo) rates of IgM- and IgG-positive DSAs were 29% and 34%, respectively. The pretransplant IgM and IgG DSA-positive frequencies were similar between treatment groups. The IgG-positive dnDSA rate was significantly higher in the CsA-treated group (34%) compared with the belatacept-LI (8%) and belatacept-MI (11%) (P < .001) groups. In IgM-positive dnDSA patients, the IgG-positive dnDSA rate of conversion was 2.8 times higher in the CsA group than in the combined belatacept groups (P = .006). However, the observed association between belatacept treatment and more limited conversion of IgM-to-IgG dnDSAs was based on a limited number of patients and requires further validation.


Assuntos
Rejeição de Enxerto/etiologia , Antígenos HLA/imunologia , Imunoglobulina A/imunologia , Imunoglobulina M/imunologia , Imunossupressores/uso terapêutico , Isoanticorpos/efeitos adversos , Transplante de Rim/efeitos adversos , Abatacepte/uso terapêutico , Calcineurina/uso terapêutico , Feminino , Seguimentos , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto/efeitos dos fármacos , Sobrevivência de Enxerto/imunologia , Teste de Histocompatibilidade , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/imunologia , Falência Renal Crônica/cirurgia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Doadores de Tecidos
6.
Arthritis Rheumatol ; 70(8): 1331-1342, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29534336

RESUMO

OBJECTIVE: To develop an objective, readily measurable pharmacodynamic biomarker of glucocorticoid (GC) activity. METHODS: Genes modulated by prednisolone were identified from in vitro studies using peripheral blood mononuclear cells from normal healthy volunteers. Using the criteria of a >2-fold change relative to vehicle controls and an adjusted P value cutoff of less than 0.05, 64 up-regulated and 18 down-regulated genes were identified. A composite score of the up-regulated genes was generated using a single-sample gene set enrichment analysis algorithm. RESULTS: GC gene signature expression was significantly elevated in peripheral blood leukocytes from normal healthy volunteers following oral administration of prednisolone. Expression of the signature increased in a dose-dependent manner, peaked at 4 hours postadministration, and returned to baseline levels by 48 hours after dosing. Lower expression was detected in normal healthy volunteers who received a partial GC receptor agonist, which is consistent with the reduced transactivation potential of this compound. In cohorts of patients with systemic lupus erythematosus and patients with rheumatoid arthritis, expression of the GC signature was negatively correlated with the percentages of peripheral blood lymphocytes and positively correlated with peripheral blood neutrophil counts, which is consistent with the known biology of the GC receptor. Expression of the signature largely agreed with reported GC use in these populations, although there was significant interpatient variability within the dose cohorts. CONCLUSION: The GC gene signature identified in this study represents a pharmacodynamic marker of GC exposure.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Glucocorticoides/administração & dosagem , Leucócitos Mononucleares/efeitos dos fármacos , Prednisolona/administração & dosagem , Administração Oral , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Humanos , Contagem de Leucócitos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Masculino , Testes Farmacogenômicos , Regulação para Cima/efeitos dos fármacos
7.
Prof Case Manag ; 23(4): 204-212, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29401178

RESUMO

PURPOSE: The purpose of this study was to explore the difference in maximal lifting capability between 2 modes of lifting (traditional crate and XRTS Lever Arm) over multiple days. The differences in absolute strength values were compared with existing criteria for sincere effort during distraction-based lifting. In addition, rate of perceived exertion (RPE) is presented for the 2 modes of lifting on each day. PRIMARY PRACTICE SETTING: Workers' compensation. METHODOLOGY AND SAMPLE: Forty-four subjects between the ages of 20 and 44 years participated in this study. Investigators established 1 repetition maximum (RM) for each subject performing the crate lift. Subjects were randomly assigned 5 weights ranging from 10% to 100% of their determined 1RM and asked to give their rating of perceived exertion after each lift. The same procedure was repeated 2-5 days later using the XRTS Lever Arm. Paired t tests and Spearman's correlation coefficient were used for data analysis. Alpha was set at less than .05. RESULTS: There was a statistically significant difference (p < .04) between maximal lift values for the 2 lifting modes. The percent difference between the modes of lifting was 10.5% ± 6.4%. In addition, there was a positive correlation between the RPE on the 2 modes of lifting (p = .87). IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: A functional capacity evaluation (FCE) is typically ordered after the completion of physical rehabilitation and before releasing a patient to full or modified duty. In addition to assessing the ability to function within normal job demands, an assessment of effort by the participant typically takes place during an FCE. Case managers and physicians are presented with information, allowing them to make comparisons between functional lifting abilities displayed during treatment sessions and the FCE. These comparisons may often take place with the subpoena of medical records and may be discussed during the deposition or trial process. If an FCE takes place at a different facility than the physical therapy or work conditioning treatment, 2 different modes of lifting may take place based on the equipment within each facility. The results of this study indicate that the 2 modes of lifting on separate days meet established criteria for lift comparison testing during FCEs.


Assuntos
Tomada de Decisões , Remoção , Adulto , Administração de Caso , Frequência Cardíaca , Humanos , Esforço Físico , Reprodutibilidade dos Testes , Adulto Jovem
8.
Clin Pharmacol Drug Dev ; 7(2): 207-216, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28750160

RESUMO

Isavuconazonium sulfate is the water-soluble prodrug of the active triazole isavuconazole. Two phase 1 studies were conducted to identify the metabolic profile and mass balance of isavuconazole and BAL8728 (inactive cleavage product). Seven subjects in study 1 (isavuconazole mass balance) received a single oral dose of [cyano-14 C]isavuconazonium sulfate corresponding to 200 mg isavuconazole. Six subjects in study 2 (BAL8728 mass balance) received a single intravenous dose of [pyridinylmethyl-14 C]isavuconazonium sulfate corresponding to 75 mg BAL8728. Pharmacokinetic parameters of radioactivity in whole blood and plasma and of isavuconazole and BAL8728 in plasma were assessed. Radioactivity ratio of blood/plasma, percentage of dose, and cumulative percentage of radioactive dose recovered in urine and feces for isavuconazole and BAL8728 were assessed. Metabolic profiling was carried out by high-performance liquid chromatography and mass spectrometry. Mean plasma isavuconazole pharmacokinetic parameters included apparent clearance (2.3 ± 0.7 L/h), apparent volume of distribution (301.8 ± 105.7 L), and terminal elimination half-life (99.9 ± 44.6 hours). In study 1, isavuconazole-derived radioactivity was recovered approximately equally in urine and feces (46.1% and 45.5%, respectively). In study 2, BAL8728-derived radioactivity was predominantly recovered in urine (96.0%). Isavuconazole (study 1) and M4 (cleavage metabolite of BAL8728; study 2) were the predominant circulating components of radioactivity in plasma.


Assuntos
Antifúngicos/farmacocinética , Nitrilos/farmacocinética , Pró-Fármacos/farmacocinética , Piridinas/farmacocinética , Triazóis/farmacocinética , Adolescente , Adulto , Antifúngicos/sangue , Disponibilidade Biológica , Radioisótopos de Carbono , Voluntários Saudáveis , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade , Nitrilos/sangue , Piridinas/sangue , Triazóis/sangue , Adulto Jovem
9.
Am Econ J Microecon ; 10(1): 1-40, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31396364

RESUMO

This paper provides a theory-based empirical framework for understanding the risk and return on productive capital assets and their allocation across activities in an economy characterized by idiosyncratic and aggregate risk and thin formal markets for real and financial assets. We apply our framework to households running business enterprises in Thai villages with extensive networks, taking advantage of panel data: income, assets, consumption, gifts, and loans. We decompose risk and estimate the risk premia faced by households, distinguishing aggregate risk from idiosyncratic, potentially diversifiable risk. This distinction matters for estimating measures of underlying productivity and has important policy implications.

10.
Econ Inq ; 56(1): 50-80, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31423038

RESUMO

We present a vision for improving household financial surveys by integrating responses from questionnaires more completely with financial statements and combining them with payments data from diaries. Integrated household financial accounts-balance sheet, income statement, and statement of cash flows-are used to assess the degree of integration in leading U.S. household surveys, focusing on inconsistencies in measures of the change in cash. Diaries of consumer payment choice can improve dynamic integration. Using payments data, we construct a statement of liquidity flows: a detailed analysis of currency, checking accounts, prepaid cards, credit cards, and other payment instruments, consistent with conventional cash-flows measures and the other financial accounts.

11.
Lupus Sci Med ; 4(1): e000206, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29214034

RESUMO

Objective: To characterise patients with active SLE based on pretreatment gene expression-defined peripheral immune cell patterns and identify clusters enriched for potential responders to abatacept treatment. Methods: This post hoc analysis used baseline peripheral whole blood transcriptomic data from patients in a phase IIb trial of intravenous abatacept (~10 mg/kg/month). Cell-specific genes were used with a published deconvolution algorithm to identify immune cell proportions in patient samples, and unsupervised consensus clustering was generated. Efficacy data were re-analysed. Results: Patient data (n=144: abatacept: n=98; placebo: n=46) were grouped into four main clusters (C) by predominant characteristic cells: C1-neutrophils; C2-cytotoxic T cells, B-cell receptor-ligated B cells, monocytes, IgG memory B cells, activated T helper cells; C3-plasma cells, activated dendritic cells, activated natural killer cells, neutrophils; C4-activated dendritic cells, cytotoxic T cells. C3 had the highest baseline total British Isles Lupus Assessment Group (BILAG) scores, highest antidouble-stranded DNA autoantibody levels and shortest time to flare (TTF), plus trends in favour of response to abatacept over placebo: adjusted mean difference in BILAG score over 1 year, -4.78 (95% CI -12.49 to 2.92); median TTF, 56 vs 6 days; greater normalisation of complement component 3 and 4 levels. Differential improvements with abatacept were not seen in other clusters, except for median TTF in C1 (201 vs 109 days). Conclusions: Immune cell clustering segmented disease severity and responsiveness to abatacept. Definition of immune response cell types may inform design and interpretation of SLE trials and treatment decisions. Trial registration number: NCT00119678; results.

12.
Nature ; 551(7682): 565, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29189804

Assuntos
Pesquisa , Humanos
13.
Artigo em Inglês | MEDLINE | ID: mdl-28971866

RESUMO

Quantitative whole-body autoradiography was used to assess the distribution and tissue penetration of isavuconazole in rats following single and repeated oral-dose administration of radiolabeled isavuconazonium sulfate, the prodrug of isavuconazole. Following a single-dose administration of radiolabeled isavuconazonium sulfate (labeled on the active moiety), radioactivity was detectable within 1 h postdose in 56 of 65 tissue/fluid specimens. The highest maximum concentrations (Cmax) were observed in bile and liver (66.6 and 24.7 µg eq/g, respectively). The lowest Cmax values were in bone and eye lens (0.070 and 0.077 µg eq/g, respectively). By 144 h postdose, radioactivity was undetectable in all tissues/fluids except liver (undetectable at 336 h) and adrenal gland tissues (undetectable at 672 h). Following daily administration for up to 21 days, 1-h-postdose Cmax values were the highest on or before day 14 in all except seven tissues/fluids, of which only rectum mucosa and small intestine mucosa had Cmax values >25% higher than all other 1-h-postdose values. For 24-h-postdose Cmax values, only large intestine, large intestine mucosa, and urine had the highest Cmax values at day 21. The penetration of single oral doses of unlabeled isavuconazole (25 mg/kg of body weight isavuconazonium sulfate) and voriconazole (50 mg/kg) into rat brain (assessed using liquid chromatography-tandem mass spectrometry) was also compared. Brain concentration/plasma concentration ratios reached approximately 1.8:1 and 2:1, respectively. These data suggest that isavuconazole penetrates most tissues rapidly, reaches a steady state in most or all tissues/fluids within 14 days, does not accumulate in tissues/fluids over time, and achieves potentially efficacious concentrations in the brain.


Assuntos
Encéfalo/metabolismo , Nitrilos/farmacocinética , Piridinas/farmacocinética , Triazóis/farmacocinética , Voriconazol/farmacocinética , Administração Oral , Glândulas Suprarrenais/metabolismo , Animais , Autorradiografia , Bile/metabolismo , Osso e Ossos/metabolismo , Mucosa Intestinal/metabolismo , Infecções Fúngicas Invasivas/tratamento farmacológico , Cristalino/metabolismo , Fígado/metabolismo , Masculino , Nitrilos/metabolismo , Pró-Fármacos/análise , Pró-Fármacos/metabolismo , Piridinas/metabolismo , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Ratos Wistar , Distribuição Tecidual , Triazóis/metabolismo , Voriconazol/metabolismo
14.
Artigo em Inglês | MEDLINE | ID: mdl-28923872

RESUMO

Isavuconazole, the active moiety of the water-soluble prodrug isavuconazonium sulfate, is a triazole antifungal agent for the treatment of invasive fungal infections. The purpose of this analysis was to characterize the isavuconazole exposure-response relationship for measures of efficacy and safety in patients with invasive aspergillosis and infections by other filamentous fungi from the SECURE clinical trial. Two hundred thirty-one patients who received the clinical dosing regimen and had exposure parameters were included in the analysis. The primary drug exposure parameters included were predicted trough steady-state plasma concentrations, predicted trough concentrations after 7 and 14 days of drug administration, and area under the curve estimated at steady state (AUCss). The exposure parameters were analyzed against efficacy endpoints that included all-cause mortality through day 42 in the intent-to-treat (ITT) and modified ITT populations, data review committee (DRC)-adjudicated overall response at end of treatment (EOT), and DRC-adjudicated clinical response at EOT. The safety endpoints analyzed were elevated or abnormal alanine aminotransferase, increased aspartate aminotransferase, and a combination of the two. The endpoints were analyzed using logistic regression models. No statistically significant relationship (P > 0.05) was found between isavuconazole exposure and either efficacy or safety endpoints. The lack of association between exposure and efficacy indicates that the isavuconazole exposures achieved by clinical dosing were appropriate for treating the infecting organisms in the SECURE study and that increases in alanine or aspartate aminotransferase were not related to increase in exposures. Without a clear relationship, there is no current clinical evidence for recommending routine therapeutic drug monitoring for isavuconazole.


Assuntos
Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Infecções Fúngicas Invasivas/tratamento farmacológico , Nitrilos/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Alanina Transaminase/sangue , Antifúngicos/farmacocinética , Aspartato Aminotransferases/sangue , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Humanos , Nitrilos/farmacocinética , Piridinas/farmacocinética , Triazóis/farmacocinética
15.
Transpl Infect Dis ; 19(5)2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28722255

RESUMO

Patients undergoing treatment with immunosuppressant drugs following solid organ or hematopoietic stem cell transplantation are at particular risk for development of serious infections such as invasive aspergillosis. Four triazole antifungal drugs, voriconazole, posaconazole, itraconazole, and isavuconazole, are approved to treat invasive aspergillosis either as first- or second-line therapy. All of these agents are inhibitors of cytochrome P450 3A4, which plays a key role in metabolizing immunosuppressant drugs such as cyclosporine, tacrolimus, and sirolimus. Thus, co-administration of a triazole antifungal drug with these immunosuppressant drugs can potentially increase plasma concentrations of the immunosuppressant drugs, thereby resulting in toxicity, or upon discontinuation, inadvertently decrease the respective concentrations with increased risk of rejection or graft-versus-host disease. In this article, we review the evidence for the extent of inhibition of cytochrome P450 3A4 by each of these triazole antifungal drugs and assess their effects on cyclosporine, tacrolimus, and sirolimus. We also consider other factors affecting interactions of these two classes of drugs. Finally, we examine recommendations and strategies to evaluate and address those potential drug-drug interactions in these patients.


Assuntos
Antifúngicos/farmacocinética , Aspergilose/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/metabolismo , Imunossupressores/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Interações de Medicamentos , Humanos , Imunossupressores/administração & dosagem
16.
Proc Natl Acad Sci U S A ; 114(24): 6176-6184, 2017 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-28592655

RESUMO

We use a variety of different datasets from Thailand to study not only the extremes of micro and macro variables but also within-country flow of funds and labor migration. We develop a general equilibrium model that encompasses regional variation in the type of financial friction and calibrate it to measured variation in regional aggregates. The model predicts substantial capital and labor flows from rural to urban areas even though these differ only in the underlying financial regime. Predictions for micro variables not used directly provide a model validation. Finally, we estimate the impact of a policy of counterfactual, regional isolationism.


Assuntos
Desenvolvimento Econômico , Administração Financeira/economia , Administração Financeira/estatística & dados numéricos , População Rural , População Urbana , Bases de Dados Factuais , Humanos , Fatores Socioeconômicos , Tailândia
17.
J Shoulder Elbow Surg ; 26(9): 1553-1561, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28359693

RESUMO

BACKGROUND: Recent studies have identified the diagnostic challenge of low-grade infections after shoulder arthroplasty surgery. Infections after nonarthroplasty procedures have not been reported. This study assessed patient-related risk factors, outcomes, and clinical presentation of low-grade infection after open and arthroscopic nonarthroplasty shoulder surgery. METHODS: The cases of 35 patients presenting with suspected low-grade infection were reviewed. Biopsy specimens taken at revision surgery were cultured in the sterile environment of a class II laminar flow cabinet and incubated for a minimum of 14 days at a specialist orthopedic microbiology laboratory. Patient-related factors (age, occupation, injection), index surgery, and infection characteristics (onset of symptoms, duration to diagnosis, treatment) were analyzed. RESULTS: Positive cultures were identified in 21 cases (60.0%), of which 15 were male patients (71%). Of all patients with low-grade infection, 47.6% were male patients between 16 and 35 years of age. Propionibacterium acnes and coagulase-negative staphylococcus were the most common organisms isolated (81.1% [n = 17] and 23.8% [n = 5], respectively). Of 14 negative culture cases, 9 were treated with early empirical antibiotics (64.3%); 7 patients reported symptomatic improvement (77.8%). Of 5 patients treated with late empirical antibiotics, 4 stated improvement. Patients presented with symptoms akin to resistant postoperative frozen shoulder (persistent pain and stiffness, unresponsive to usual treatments). CONCLUSION: Young male patients are at greatest risk for low-grade infections after arthroscopic and open nonarthroplasty shoulder surgery. P. acnes was the most prevalent organism. Patients presented with classic postoperative frozen shoulder symptoms, resistant to usual treatments. Interestingly, 78.6% of patients with negative cultures responded positively to empirical treatment.


Assuntos
Artroscopia/efeitos adversos , Infecções por Bactérias Gram-Positivas/microbiologia , Complicações Pós-Operatórias/microbiologia , Propionibacterium acnes/isolamento & purificação , Articulação do Ombro/cirurgia , Infecções Estafilocócicas/microbiologia , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Coagulase/metabolismo , Feminino , Infecções por Bactérias Gram-Positivas/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Reoperação , Estudos Retrospectivos , Fatores de Risco , Articulação do Ombro/microbiologia , Infecções Estafilocócicas/diagnóstico , Staphylococcus/enzimologia , Adulto Jovem
19.
Eur J Clin Pharmacol ; 73(6): 669-678, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28271239

RESUMO

PURPOSE: The purpose of the study is to evaluate the effect of renal impairment (RI) and end-stage renal disease (ESRD) on the pharmacokinetics (PK) of isavuconazole and the inactive cleavage product, BAL8728. METHODS: A single intravenous dose of the prodrug isavuconazonium sulfate (372 mg, equivalent to 200 mg isavuconazole and 75 mg of BAL8728 cleavage product) was administered to healthy controls (parts 1 and 2) and participants with mild, moderate, or severe RI (part 2) or ESRD (part 1); ESRD participants received two doses of 200 mg isavuconazole, 1 h post-dialysis (day 1) and prior to dialysis (day 15). Plasma PK parameters for isavuconazole included maximum concentration (C max), area under the concentration-time curve (AUC) from time of dose to 72 h (AUC72), AUC extrapolated to infinity (AUC∞), AUC to last measurable concentration (AUClast), half-life (t ½ h), volume of distribution (V z), and total clearance (CL), for the healthy control group versus those with mild, moderate, or severe RI or ESRD. RESULTS: Isavuconazole C max values were 4% higher in mild RI and 7, 14, and 21% lower in participants with moderate RI, severe RI, or ESRD versus the healthy control group, respectively. When hemodialysis occurred post-dose (day 15), participants with ESRD had a 30% increase in AUC72 for isavuconazole in parallel with reduction of extracellular volume induced by dialysis. Exposure (AUC∞ and AUClast) was not significantly different for participants with mild, moderate, or severe RI versus healthy controls although there was considerable variability. The t1/2 (day 1) was 125.5 ± 63.6 h (healthy control group), 204.5 ± 82.6 h (ESRD group) in part 1, and 140.5 ± 77.7 h (healthy control group), 117.0 ± 66.2 h (mild RI), 158.5 ± 56.4 h (moderate RI), and 145.8 ± 65.8 L/h (severe RI) in part 2. CL was 2.4 ± 0.8 L/h (healthy control group) and 2.9 ± 1.3 L/h (ESRD group) in part 1 and 2.4 ± 1.2 L/h (healthy control group), 2.5 ± 1.0 L/h (mild RI), 2.2 ± 0.8 L/h (moderate RI), and 2.4 ± 0.8 L/h (severe RI) in part 2. The V z was 382.6 ± 150.6 L in the healthy control group and 735.6 ± 277.3 L in ESRD patients on day 1 in part 1 of the study. In part 2 of the study, V z was 410.8 ± 89.7 L in the healthy control group, 341.6 ± 72.3 L in mild RI, 509.1 ± 262.2 L in moderate RI, and 439.4 L in severe RI. CONCLUSIONS: Based on the findings of this study, dose adjustments of isavuconazole are unlikely to be required in individuals with RI or in those with ESRD who receive hemodialysis.


Assuntos
Falência Renal Crônica/metabolismo , Nitrilos/farmacocinética , Piridinas/farmacocinética , Diálise Renal , Insuficiência Renal/metabolismo , Triazóis/farmacocinética , Administração Intravenosa , Adulto , Idoso , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Área Sob a Curva , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Nitrilos/administração & dosagem , Piridinas/administração & dosagem , Insuficiência Renal/fisiopatologia , Distribuição Tecidual , Triazóis/administração & dosagem , Adulto Jovem
20.
Clin Pharmacol Drug Dev ; 6(1): 86-92, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27278712

RESUMO

This phase 1 trial evaluated pharmacokinetic and pharmacodynamic interactions between the novel triazole antifungal agent isavuconazole and warfarin in healthy adults. Multiple doses of isavuconazole were administered as the oral prodrug, isavuconazonium sulfate (372 mg 3 times a day for 2 days loading dose, then 372 mg once daily thereafter; equivalent to isavuconazole 200 mg), in the presence and absence of single doses of oral warfarin sodium 20 mg. Coadministration with isavuconazole increased the mean area under the plasma concentration-time curves from time 0 to infinity of S- and R-warfarin by 11% and 20%, respectively, but decreased the mean maximum plasma concentrations of S- and R-warfarin by 12% and 7%, respectively, relative to warfarin alone. Mean area under the international normalized ratio curve and maximum international normalized ratio were 4% lower in the presence vs absence of isavuconazole. Mean warfarin area under the prothrombin time curve and maximum prothrombin time were 3% lower in the presence vs absence of isavuconazole. There were no serious treatment-emergent adverse events (TEAEs), and no subjects discontinued the study due to TEAEs. All TEAEs were mild in intensity. These findings indicate that coadministration with isavuconazole has no clinically relevant effects on warfarin pharmacokinetics or pharmacodynamics.


Assuntos
Nitrilos/administração & dosagem , Nitrilos/farmacocinética , Piridinas/administração & dosagem , Piridinas/farmacocinética , Triazóis/administração & dosagem , Triazóis/farmacocinética , Varfarina/administração & dosagem , Varfarina/farmacocinética , Adulto , Área Sob a Curva , Esquema de Medicação , Interações de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Coeficiente Internacional Normatizado , Masculino , Pessoa de Meia-Idade , Tempo de Protrombina , Adulto Jovem
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