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1.
Vasc Med ; 24(5): 414-421, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31277561

RESUMO

Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1ß (IL-1ß) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1ß signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication. Thirty-eight patients (mean age 65 years; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. The mean vessel wall area (by 3.0 T black-blood magnetic resonance imaging (MRI)) of the superficial femoral artery (SFA) was used to measure plaque volume. Mobility was assessed using the 6-minute walk test. Canakinumab was safe and well tolerated. Markers of systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein) fell as early as 1 month after treatment. MRI (32 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA in either placebo-treated or canakinumab-treated patients. Although an exploratory endpoint, placebo-adjusted maximum and pain-free walking distance (58 m) improved as early as 3 months after treatment with canakinumab when compared with placebo. Although canakinumab did not alter plaque progression in the SFA, there is an early signal that it may improve maximum and pain-free walking distance in patients with symptomatic PAD. Larger studies aimed at this endpoint will be required to definitively demonstrate this. ClinicalTrials.gov Identifier: NCT01731990.

4.
Psychiatr Serv ; : appips201800232, 2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30332928

RESUMO

Transgender people who experience serious mental illness represent a uniquely vulnerable population. Because of limited research, however, recommendations for treating this population are scarce. In this article, the authors describe the challenge of recognizing gender dysphoria in people with serious mental illness. They then discuss why existing evidence and clinical experience support provision of gender-affirming medical and surgical treatments for transgender people who have serious mental illness and also demonstrate capacity to make informed medical decisions. More research is needed to develop evidence-based treatments and programs for transgender people with serious mental illness.

7.
N Engl J Med ; 379(4): 352-362, 2018 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-30044938

RESUMO

BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).


Assuntos
Angioedemas Hereditários/prevenção & controle , Inibidores Enzimáticos/administração & dosagem , Calicreína Plasmática/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida
8.
Clin Drug Investig ; 38(8): 703-713, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29949102

RESUMO

BACKGROUND AND OBJECTIVE: Verinurad (RDEA3170) is a high-affinity, selective URAT1 transporter inhibitor in development for treating gout and asymptomatic hyperuricemia. This Phase I, single-dose study investigated the pharmacokinetics, pharmacodynamics, and safety of verinurad in adults with renal impairment and controls with normal renal function. METHODS: Males aged 18-85 years were enrolled with serum urate (sUA) 4.5-10 mg/dl and creatinine clearance 60- < 90, 30- < 60, 15- < 30, or ≥ 90 ml/min (mild, moderate, severe renal impairment and controls, respectively; n = 7/8). Verinurad 15 mg was administered orally under fasted conditions. Serial plasma/serum and urine samplings were 30 min pre-dose to 72 h post-dose. RESULTS: Compared to controls, verinurad maximum observed plasma concentration increased by 53, 73, and 128% and area under the concentration-time curve increased by 24, 148, and 130%, in subjects with mild, moderate, and severe renal impairment, respectively; renal clearance decreased by 5, 42, and 79%. Exposures of major verinurad metabolites also increased with increasing renal impairment. Verinurad decreased sUA in all groups, with greater maximal changes in control and mild renal impairment than moderate and severe impairment groups (- 38.3, - 36.9, - 20.5, - 12.6%, respectively). There were no adverse event-related withdrawals or clinically meaningful changes in laboratory values. CONCLUSION: Exposures of verinurad and metabolites increased with decreasing renal function. Consistent with the renal-dependent mechanism of action of verinurad, increasing severity of renal impairment was associated with decreased sUA lowering. Verinurad safety assessments were similar regardless of renal impairment. Continued investigation of verinurad is warranted in patients with gout and renal impairment. CLINICALTRIALS. GOV IDENTIFIER: NCT02219516.


Assuntos
Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Insuficiência Renal/tratamento farmacológico , Insuficiência Renal/metabolismo , Ácido Úrico/metabolismo , Uricosúricos/metabolismo , Uricosúricos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Masculino , Pessoa de Meia-Idade , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Ácido Úrico/antagonistas & inibidores , Uricosúricos/farmacologia
9.
Aust Prescr ; 41(2): 37-41, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29670309
10.
Artigo em Inglês | MEDLINE | ID: mdl-28947470

RESUMO

Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0-24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.


Assuntos
Antivirais/uso terapêutico , Benzofuranos/uso terapêutico , Hepacivirus/efeitos dos fármacos , Insuficiência Hepática/metabolismo , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Inibidores de Proteases/uso terapêutico , Quinoxalinas/farmacocinética , Quinoxalinas/uso terapêutico , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/farmacocinética , Quimioterapia Combinada , Feminino , Hepacivirus/enzimologia , Humanos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/farmacocinética , Quinoxalinas/efeitos adversos , Adulto Jovem
11.
BMC Nephrol ; 18(1): 273, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28851317

RESUMO

BACKGROUND: In the United States, hemodialysis (HD) is generally performed via a bicarbonate dialysate. It is not known if small amounts of acid used in dialysate to buffer the bicarbonate can meaningfully contribute to overall buffering administered during HD. We aimed to investigate the metabolism of acetate with use of two different acid buffer concentrates and determine if it effects blood bicarbonate concentrations in HD patients. METHODS: The Acid-Base Composition with use of hemoDialysates (ABChD) trial was a Phase IV, prospective, single blind, randomized, cross-over, 2 week investigation of peridialytic dynamics of acetate and bicarbonate associated with use of acid buffer concentrates. Eleven prevalent HD patients participated from November 2014 to February 2015. Patients received two HD treatments, with NaturaLyte® and GranuFlo® acid concentrates containing 4 and 8 mEq/L of acetate, respectively. Dialysate order was chosen in a random fashion. The endpoint was to characterize the dynamics of acetate received and metabolized during hemodialysis, and how it effects overall bicarbonate concentrations in the blood and dialysate. Acetate and bicarbonate concentrations were assessed before, at 8 time points during, and 6 time points after the completion of HD. RESULTS: Data from 20 HD treatments for 11 patients (10 NaturaLyte® and 10 GranuFlo®) was analyzed. Cumulative trajectories of arterialized acetate were unique between NaturaLyte® and GranuFlo® (p = 0.003), yet individual time points demonstrated overlap without remarkable differences. Arterialized and venous blood bicarbonate concentrations were similar at HD initiation, but by 240 min into dialysis, mean arterialized bicarbonate concentrations were 30.2 (SD ± 4.16) mEq/L in GranuFlo® and 28.8 (SD ± 4.26) mEq/L in NaturaLyte®. Regardless of acid buffer concentrate, arterial blood bicarbonate was primarily dictated by the prescribed bicarbonate level. Subjects tolerated HD with both acid buffer concentrates without experiencing any related adverse events. CONCLUSIONS: A small fraction of acetate was delivered to HD patients with use of NaturaLyte® and GranuFlo® acid buffers; the majority of acetate received was observed to be rapidly metabolized and cleared from the circulation. Blood bicarbonate concentrations appear to be determined mainly by the prescribed concentration of bicarbonate. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on 11 Dec 2014 ( NCT02334267 ).


Assuntos
Acetatos/metabolismo , Equilíbrio Ácido-Base/fisiologia , Bicarbonatos/metabolismo , Soluções para Hemodiálise/metabolismo , Falência Renal Crônica/sangue , Diálise Renal , Adulto , Idoso , Bicarbonatos/administração & dosagem , Estudos Cross-Over , Feminino , Soluções para Hemodiálise/administração & dosagem , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Diálise Renal/métodos , Método Simples-Cego
12.
Curr Opin Allergy Clin Immunol ; 17(4): 241-246, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28537933

RESUMO

PURPOSE OF REVIEW: Gadolinium-based contrast agents (GBCAs) have been utilized since the late 1980s to enhance the diagnostic value of MRI studies. They are known to have excellent safety profile and serious adverse reactions are uncommon despite widespread global use. However, immediate hypersensitivity reactions are well described in the literature, with urticaria the most common manifestation. Anaphylaxis can occur, though fatality is extremely rare. This review explores the incidence of GBCA-related hypersensitivity reactions and highlights potential risk factors. RECENT FINDINGS: Emerging evidence suggests that immediate hypersensitivity reactions to GBCAs can be IgE-mediated. Skin testing may be informative in confirmation of causality and revealing cross-reactivity patterns. SUMMARY: GBCA hypersensitivity is infrequent but can be serious. Familiarity with management of acute hypersensitivity reactions may be lifesaving. Appropriate use of diagnostic testing can be used to guide future management of patients who have suffered from such reactions.


Assuntos
Anafilaxia , Meios de Contraste/efeitos adversos , Hipersensibilidade a Drogas , Gadolínio/efeitos adversos , Imunoglobulina E/imunologia , Anafilaxia/induzido quimicamente , Anafilaxia/diagnóstico , Anafilaxia/imunologia , Anafilaxia/prevenção & controle , Meios de Contraste/uso terapêutico , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/imunologia , Hipersensibilidade a Drogas/prevenção & controle , Gadolínio/uso terapêutico , Humanos , Testes Cutâneos/métodos
14.
Knee Surg Sports Traumatol Arthrosc ; 25(3): 924-933, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26520646

RESUMO

PURPOSE: To compare the age-based cost-effectiveness of total knee arthroplasty (TKA), unicompartmental knee arthroplasty (UKA), and high tibial osteotomy (HTO) for the treatment of medial compartment knee osteoarthritis (MCOA). METHODS: A Markov model was used to simulate theoretical cohorts of patients 40, 50, 60, and 70 years of age undergoing primary TKA, UKA, or HTO. Costs and outcomes associated with initial and subsequent interventions were estimated by following these virtual cohorts over a 10-year period. Revision and mortality rates, costs, and functional outcome data were estimated from a systematic review of the literature. Probabilistic analysis was conducted to accommodate these parameters' inherent uncertainty, and both discrete and probabilistic sensitivity analyses were utilized to assess the robustness of the model's outputs to changes in key variables. RESULTS: HTO was most likely to be cost-effective in cohorts under 60, and UKA most likely in those 60 and over. Probabilistic results did not indicate one intervention to be significantly more cost-effective than another. The model was exquisitely sensitive to changes in utility (functional outcome), somewhat sensitive to changes in cost, and least sensitive to changes in 10-year revision risk. CONCLUSIONS: HTO may be the most cost-effective option when treating MCOA in younger patients, while UKA may be preferred in older patients. Functional utility is the primary driver of the cost-effectiveness of these interventions. For the clinician, this study supports HTO as a competitive treatment option in young patient populations. It also validates each one of the three interventions considered as potentially optimal, depending heavily on patient preferences and functional utility derived over time.


Assuntos
Artroplastia do Joelho/economia , Osteoartrite do Joelho/cirurgia , Osteotomia/economia , Tíbia/cirurgia , Adulto , Fatores Etários , Idoso , Artroplastia do Joelho/métodos , Análise Custo-Benefício , Humanos , Articulação do Joelho/cirurgia , Cadeias de Markov , Pessoa de Meia-Idade , Osteotomia/métodos , Resultado do Tratamento
15.
Ther Innov Regul Sci ; 51(3): 285-287, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-30231703

RESUMO

The clinical research industry is changing, and the number of protocols requiring specialty populations for early-phase clinical studies is increasing. In particular, the demand for studies on renal specialty populations has grown, given the prominent role of the renal system in excreting drugs from the body. Understanding the challenges associated with the use of specialty populations is critical to ensure that the study design will allow for the timely and successful completion of the project, while minimizing costs and safety risks.

16.
Ther Innov Regul Sci ; 51(3): 298-302, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-30231705

RESUMO

This paper summarizes a discussion that took place at the 52nd Annual DIA Meeting in Philadelphia, PA, on June 30, 2016, titled "Hot-Button Protocol and Operational Issues between Sponsors and Sites in Clinical Pharmacology Studies." The symposium was a moderated panel of phase 1 clinical research experts representing the sponsor, and investigational sites. Conference attendees of similar experience joined in the discussion after commentary by each panelist. The learning objectives of the symposium were (1) to recognize issues that can provoke sponsor/site conflict or diminish conduct efficiency when they arise in the course of preparing to conduct or execution of phase 1 clinical studies, (2) to discuss how to handle such issues with counterparts when they arise and describe ways to negotiate and formulate a successful resolution. Sponsors and sites both have challenges in executing clinical trials on time and within budget. Both need to set and maintain realistic expectations and communicate with honesty, transparency, and timeliness. Achieving this goal will advance the more important take-away message, that developing new drugs requires sound execution of clinical trials.

17.
Ther Innov Regul Sci ; 51(3): 276-284, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-30231706

RESUMO

A cross-section of clinical research professionals convened at the June 2016 Drug Information Association annual meeting in Philadelphia to discuss and critically analyze the first-in-human (FIH) clinical trial conducted by a French CRO with BIA 10-2474 (BIA) under development for pain relief by Bial-Portela & Ca., S.A., that resulted in 6 healthy volunteers hospitalized with serious adverse events, which resulted in 1 death. This paper summarizes the background, presentations, and discussion points of Symposium no. 107 in an effort to share the learnings of our symposium with others who conduct studies. Novel investigational products studied in phase 1 clinical trials propose a heightened risk of adverse events that may not be foreseeable when relying on animal studies to project outcomes in humans. Novelty of molecular structure, drug class, mechanism of action, proper dose selection, pharmacokinetics, and therapeutic window are all contributing factors that heighten risks when transitioning from animal to human trials. The potential for catastrophic events confronts every sponsor/investigator in clinical trials. Minimizing risks to subjects is an essential ethical and scientific mandate for all those involved in the clinical trials. A complex matrix of planning, conducting, and communicating preclinical and clinical observations need to be considered carefully by the Sponsor, Investigator and others during the planning, execution, and interpretation of FIH studies, in order to promote participant safety and study data integrity. Suggestions may be applied to FIH studies, which may provide a new or improved way to address complex system and prevent or mitigate situations such as what occurred with the Bial FIH trial, where seemingly a number of issues coincided in a "perfect storm" and the system failed to sound a warning or detect an issue before a life was tragically lost.

18.
ACS Med Chem Lett ; 7(10): 929-932, 2016 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-27774131

RESUMO

A novel, isoform-selective inhibitor of histone deacetylase 8 (HDAC8) has been discovered by the repurposing of a diverse compound collection. Medicinal chemistry optimization led to the identification of a highly potent (0.8 nM) and selective inhibitor of HDAC8.

19.
Asia Pac Allergy ; 6(3): 192-4, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27489793

RESUMO

Marking nut Semecarpus anacardium, so-called because it contains a pigment that has been used in the past to mark fabrics, is a known cause of contact hypersensitivity. It may be ingested as an ingredient of some traditional Hindi foods. We describe the first reported case of anaphylaxis to marking nut.

20.
Bioorg Med Chem ; 23(15): 5061-74, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26054247

RESUMO

The formation of a series of analogs containing a pyridine moiety in place of the natural thiazole heterocycle, based on the potent, naturally occurring HDAC inhibitor Largazole has been accomplished. The synthetic strategy was designed modularly to access multiple inhibitors with different aryl functionalities containing both the natural depsipeptide and peptide isostere variant of the macrocycle. The cytotoxicity and biochemical activity of the library of HDAC inhibitors is described herein.


Assuntos
Depsipeptídeos/química , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/química , Tiazóis/química , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Depsipeptídeos/síntese química , Depsipeptídeos/toxicidade , Desenho de Drogas , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/toxicidade , Histona Desacetilases/metabolismo , Humanos , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Piridinas/química , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/toxicidade
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