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1.
Gastroenterology ; 158(1): 111-122.e10, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593702

RESUMO

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease with no approved treatment in the United States. Dupilumab, a VelocImmune-derived human monoclonal antibody against the interleukin (IL) 4 receptor, inhibits IL4 and IL13 signaling. Dupilumab is effective in the treatment of allergic, atopic, and type 2 diseases, so we assessed its efficacy and safety in patients with EoE. METHODS: We performed a phase 2 study of adults with active EoE (2 episodes of dysphagia/week with peak esophageal eosinophil density of 15 or more eosinophils per high-power field), from May 12, 2015, through November 9, 2016, at 14 sites. Participants were randomly assigned to groups that received weekly subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks. The primary endpoint was change from baseline to week 10 in Straumann Dysphagia Instrument (SDI) patient-reported outcome (PRO) score. We also assessed histologic features of EoE (peak esophageal intraepithelial eosinophil count and EoE histologic scores), endoscopically visualized features (endoscopic reference score), esophageal distensibility, and safety. RESULTS: The mean SDI PRO score was 6.4 when the study began. In the dupilumab group, SDI PRO scores were reduced by a mean value of 3.0 at week 10 compared with a mean reduction of 1.3 in the placebo group (P = .0304). At week 12, dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility by 18% vs placebo (P < .0001). Higher proportions of patients in the dupilumab group developed injection-site erythema (35% vs 8% in the placebo group) and nasopharyngitis (17% vs 4% in the placebo group). CONCLUSIONS: In a phase 2 trial of patients with active EoE, dupilumab reduced dysphagia, histologic features of disease (including eosinophilic infiltration and a marker of type 2 inflammation), and abnormal endoscopic features compared with placebo. Dupilumab increased esophageal distensibility and was generally well tolerated. ClinicalTrials.gov, Number: NCT02379052.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Transtornos de Deglutição/tratamento farmacológico , Esofagite Eosinofílica/tratamento farmacológico , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/imunologia , Método Duplo-Cego , Esofagite Eosinofílica/complicações , Esofagite Eosinofílica/imunologia , Mucosa Esofágica/diagnóstico por imagem , Mucosa Esofágica/efeitos dos fármacos , Mucosa Esofágica/imunologia , Esofagoscopia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-4/imunologia , Masculino , Pessoa de Meia-Idade , Medidas de Resultados Relatados pelo Paciente , Placebos/administração & dosagem , Placebos/efeitos adversos , Resultado do Tratamento , Adulto Jovem
2.
BMC Musculoskelet Disord ; 20(1): 389, 2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31470828

RESUMO

BACKGROUND: Lithium, an established psychiatric medication, has recently been shown to enhance new bone formation in preclinical fracture models. Current research is focused on evaluating the efficacy of low-dose, short-term lithium treatment to improve long bone fracture healing through a Phase II randomized clinical trial (LiFT NCT02999022). In working towards future applications of lithium for fracture management, this study aimed to understand the current perceptions of lithium as a psychiatric drug and the potential barriers to its orthopaedic adoption. METHODS: Three questionnaires, evaluating knowledge about lithium and willingness to embrace its use in fracture healing were disseminated among the general population, fracture patients eligible for the LiFT (Lithium for Fracture Treatment) trial and orthopaedic surgeons across Canada. RESULTS: Of the 768 public respondents, 84% were willing to take a medication that would aid fracture healing but only 62.6% if the medication was lithium. Willingness dropped to 44.6% among the 168 respondents who knew about the psychiatric use of lithium. Lack of sufficient knowledge (n = 50) and concerns about side effects including effects on the brain (n = 74) were the main reasons cited by those who were unwilling to use lithium. Of the 29 fracture patients, only 20 patients had previously heard of lithium. Of these, 40% were willing to take lithium for fracture healing with an additional 10% if the dose was low or if the intake duration was short. Only 50% knew that lithium has side effects. Of the 43 orthopaedic surgeons, 38 surgeons knew about clinical use of lithium. Of these, 68% knew that lithium has side effects and 29% knew that it interacts with other drugs. While most agreed that new strategies are needed to improve fracture management, only 68% were willing to prescribe lithium for fractures with an additional 16% if there is scientific evidence and/or a standard dosing protocol. CONCLUSIONS: This study identified a lack of knowledge about uses and side effects of lithium among all three cohorts. A robust educational framework for orthopaedic surgeons, their patients and the members of their clinical care teams will be essential to widespread repurposing of lithium for fracture care.


Assuntos
Competência Clínica/estatística & dados numéricos , Consolidação da Fratura/efeitos dos fármacos , Fraturas Ósseas/terapia , Conhecimentos, Atitudes e Prática em Saúde , Carbonato de Lítio/administração & dosagem , Adolescente , Adulto , Encéfalo/efeitos dos fármacos , Canadá , Relação Dose-Resposta a Droga , Esquema de Medicação , Reposicionamento de Medicamentos , Feminino , Fixação de Fratura , Humanos , Carbonato de Lítio/efeitos adversos , Masculino , Pessoa de Meia-Idade , Cirurgiões Ortopédicos/psicologia , Cirurgiões Ortopédicos/estatística & dados numéricos , Percepção , Placebos/administração & dosagem , Placebos/efeitos adversos , Inquéritos e Questionários/estatística & dados numéricos , Fatores de Tempo , Adulto Jovem
3.
J Drugs Dermatol ; 18(8): 804-813, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31424712

RESUMO

Dupilumab, a monoclonal antibody that blocks the shared receptor subunit for interleukin (IL)-4 and IL-13, is currently approved for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis (AD). The efficacy and safety of dupilumab for AD among racial subgroups is unknown. This post hoc analysis from three phase 3 trials assessed the efficacy and safety of dupilumab vs placebo by racial subgroup (White, Asian, Black/African American). Data from LIBERTY AD SOLO 1 (NCT02277743), SOLO 2 (NCT02277769), and CHRONOS (NCT02260986) were pooled. Outcomes included mean and percent change from baseline to week 16 in the key therapeutic domains Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (NRS), Dermatology Life Quality Index (DLQI), and Patient-Oriented Eczema Measure, as well as Investigator's Global Assessment and pain or discomfort assessed by the European Quality of Life-5 Dimensions 3 level questionnaire. A total of 2,058 patients (White n=1,429, Asian n=501, Black/African American n=128) were included in the current analysis. Baseline demographics and disease characteristics were balanced between treatment groups and racial subgroups. In the three trials, dupilumab significantly (P<0.0001) improved all assessed outcomes compared with placebo in the White and Asian subgroups. In the smaller Black/African American subgroup, dupilumab significantly (P<0.0001) improved EASI endpoints and mean changes in Peak Pruritus NRS and DLQI vs placebo, with positive numeric trends favoring dupilumab in all other endpoints. Dupilumab was generally well tolerated, with an acceptable safety profile in all racial subgroups. Serious adverse events occurred more frequently with placebo; treatment discontinuations due to adverse events were rare in all treatment groups. Significant clinical improvement and a favorable benefit-risk profile can be achieved with dupilumab treatment in patients of White, Asian, and Black/African American racial subgroups with moderate-to-severe AD inadequately controlled with topical medications. ClinicalTrials.gov identifiers: NCT02277743, NCT02277769, NCT02260986


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Adulto , Afro-Americanos/estatística & dados numéricos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Dermatite Atópica/diagnóstico , Método Duplo-Cego , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
4.
J Dermatol ; 46(10): 874-878, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31373068

RESUMO

Hyperhidrosis can seriously impair patients' quality of life. Medical history, including heredity and hyperhidrosis during youth, as well as current age and time elapsed since menopause, is important to consider when distinguishing between postmenopausal hyperhidrosis and vasomotor symptoms to enable adequate treatment. This report concerns a subgroup of eight postmenopausal patients participating in a randomized controlled trial regarding botulinum toxin (Btx) type B treatment in craniofacial hyperhidrosis. Even though the sample size is small and the enrolment is not yet completed, the promising data collected hitherto are interesting to present in advance because this subtype of craniofacial hyperhidrosis is often underrecognized and challenging to treat. Patients were randomized to receive Btx type B or placebo. Measurements were performed before treatment and 3 ± 1 weeks after. The Dermatology Life Quality Index (DLQI) score was improved for all patients after Btx type B treatment (n = 3) with a median decrease of 9 points (90% median improvement). The placebo group (n = 5) had a median increase of 2 points (-18% median decline). When the same group (n = 5) received Btx type B (open) the DLQI score decreased with a median of 7 points compared with baseline (91% median improvement). Treatment-related adverse events were temporary and did not prevent improvement of life quality. Furthermore, background data evaluation uncovered interesting findings regarding vasomotor symptoms in relation to postmenopausal hyperhidrosis. In conclusion, the results indicated that Btx type B seems to be a safe and effective treatment in postmenopausal craniofacial hyperhidrosis. Further research is encouraged.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Hiperidrose/tratamento farmacológico , Pós-Menopausa/fisiologia , Qualidade de Vida , Idoso , Idoso de 80 Anos ou mais , Toxinas Botulínicas Tipo A/efeitos adversos , Face , Feminino , Cabeça , Humanos , Hiperidrose/complicações , Hiperidrose/fisiopatologia , Injeções Intradérmicas , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Resultado do Tratamento
5.
Lancet Psychiatry ; 6(9): 753-765, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31320283

RESUMO

BACKGROUND: Antipsychotic drugs might cause acutely occurring, serious side-effects and thus contribute to the increased physical morbidity and mortality observed in patients with severe mental health disorders. We examined this hypothesis by doing a meta-analysis of International Conference on Harmonisation-Good Clinical Practice-defined serious adverse events occurring in placebo-controlled trials of antipsychotics. METHODS: For this systematic review and meta-analysis, we included randomised controlled trials (RCTs) comparing second-generation antipsychotics with placebo. We searched MEDLINE, Embase, Cochrane CENTRAL, BIOSIS, PsycINFO, PubMed, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform for trials published in any language from database inception up until Jan 27, 2017. Trials were included without limitations in population (diagnostic category, age, sex, ethnicity), dosing regimen, blinding status, duration, or publication year. Only psychological studies lasting less than 1 day and trials done in mainland China were excluded. We contacted pharmaceutical companies, drug regulatory authorities, and study investigators for additional data. The primary outcome was the number of patients with at least one somatic serious adverse event. We estimated minimum and maximum numbers of patients with the outcome in each study group and synthesised the results with odds ratios (ORs) in a common-effects meta-analysis. This study is registered with PROSPERO, number CRD42016033930. FINDINGS: We identified 597 RCTs, comprising 108 664 participants, that met the inclusion criteria. 314 trials (67 642 participants) with details on individual serious adverse events available constituted the main dataset for meta-analysis. 88% of these were 13 weeks (approximately 3 months) or shorter in duration (median 6 weeks, IQR 4-9). At least one somatic serious adverse event occurred in 698 (1·63%) to 862 (2·02%) of 42 600 patients on antipsychotics, and in 343 (1·37%) to 419 (1·67%) of 25 042 patients on placebo. The odds ratios (ORs) were 1·24 (95% CI 1·08-1·42) and 1·24 (1·10-1·41) based on the minimum and maximum estimate, respectively. In predefined subgroup analyses we found evidence suggesting a larger effect in older patients (>65 years; OR 1·56, 95% CI 1·22-1·98; 1·58, 1·25-1·99) as compared with adults (18-65 years; 1·09, 0·91-1·29; 1·10, 0·95-1·28); likewise in children or adolescents (<18 years) although the evidence was more uncertain (1·49, 0·81-2·75; 1·54, 0·85-2·77). Of 597 included RCTs, 30 (5%), 358 (60%), and 209 (35%) were rated at high, moderate, or low risk of bias, respectively. τ2 was zero for both analyses of the primary outcome (minimum estimate, maximum estimate). A Bayesian sensitivity analysis using external information on heterogeneity gave similar results. INTERPRETATION: We found evidence that antipsychotics cause short-term somatic serious adverse events on top of somatic serious adverse events occurring independent of treatment. This effect appears to be mainly driven by results in older patients. Hence, clinicians should be aware that antipsychotics are potentially toxic, particularly when treating patients sharing risk factors with the older population. FUNDING: German Ministry of Education and Research.


Assuntos
Antipsicóticos/efeitos adversos , Transtornos Mentais/tratamento farmacológico , Placebos/efeitos adversos , Distúrbios Somatossensoriais/induzido quimicamente , Adolescente , Adulto , Idoso , Antipsicóticos/classificação , Antipsicóticos/uso terapêutico , China/epidemiologia , Humanos , Incidência , Transtornos Mentais/mortalidade , Pessoa de Meia-Idade , Placebos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Distúrbios Somatossensoriais/epidemiologia , Distúrbios Somatossensoriais/mortalidade , Adulto Jovem
6.
Int J Med Sci ; 16(6): 845-853, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31337958

RESUMO

Background: Knee joint pain is the most common reason for physical disability which associates with age. TamaFlexTM (NXT15906F6) is a synergistic anti-inflammatory formulation which contains ethanol/aqueous extracts of Tamarindus indica seeds and ethanol extract of Curcuma longa rhizome. Methods: In a 90-day randomized, double-blind, placebo-controlled study, we evaluated efficacy of NXT15906F6 in relieving pain and improving joint function in non-arthritic adults. Ninety non-arthritic subjects who experienced knee pain and joint discomfort following a six-minute walk test (SMWT) and Stair climb test (SCT) participated in the present trial. Subjects received either 250 mg (n=30) or 400 mg (n=30) of NXT15906F6 or matched placebo (PL: n=30) daily for 90 days. Improvement from baseline six-minute walk distance (SMWD) in NXT15906F6 groups, compared with placebo (PL) was the primary outcome of the study. Results: At post-intervention, subjects in NXT15906F6-250 (p<0.001) and NXT15906F6-400 (p<0.0001) groups showed substantial improvements in mean changes of SMWD from baseline compared to placebo. The 250 mg and 400 mg NXT15906F6 groups also improved average walking speed from baseline by 0.08±0.07 m/s (p=0.0010) and 0.11±0.08 m/s (p<0.0001), respectively. The NXT15906F6 groups experienced significant improvement in SMWT performances as early as 14 days. NXT15906F6-supplemented participants showed a consistent benefit of pain relief and improved musculoskeletal functions, compared to placebo. Conclusion: NXT15906F6 provided substantial relief from knee pain after physical activity and improved joint function in non-arthritic adults. Study participants did not show any major adverse events, and they tolerated well this novel herbal formulation.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artralgia/tratamento farmacológico , Articulação do Joelho/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Tamarindus/química , Adulto , Anti-Inflamatórios/efeitos adversos , Artralgia/diagnóstico , Artralgia/etiologia , Curcuma/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Exercício/fisiologia , Feminino , Humanos , Articulação do Joelho/fisiopatologia , Masculino , Pessoa de Meia-Idade , Medição da Dor , Placebos/administração & dosagem , Placebos/efeitos adversos , Extratos Vegetais/efeitos adversos , Rizoma/química , Sementes/química , Resultado do Tratamento , Teste de Caminhada
7.
J Dermatol ; 46(8): 686-694, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31237727

RESUMO

Risankizumab, a humanized immunoglobulin G1 monoclonal antibody, selectively inhibits interleukin-23, a key cytokine in the pathogenesis of psoriasis, by binding to its p19 subunit. In SustaIMM (ClinicalTrials.gov/NCT03000075), a phase 2/3, double-blinded, placebo-controlled study, Japanese patients with moderate to severe plaque psoriasis (n = 171) were stratified by bodyweight and concomitant psoriatic arthritis and randomized 2:2:1:1 to 75 mg risankizumab, 150 mg risankizumab, placebo with cross-over to 75 mg risankizumab and placebo with cross-over to 150 mg risankizumab. Dosing was at weeks 0, 4, 16, 28 and 40, with placebo cross-over to risankizumab at week 16. The primary end-point was 90% or more improvement from baseline in Psoriasis Area and Severity Index (PASI-90) at week 16 for risankizumab versus placebo. Missing data were imputed as non-response. All primary and psoriasis-related secondary end-points were met for both risankizumab doses (P < 0.001). At week 16, PASI-90 responses were significantly higher in patients receiving 75 mg (76%) or 150 mg (75%) risankizumab versus placebo (2%). Corresponding response rates were 86%, 93% and 10% for static Physician Global Assessment (sPGA) score of clear/almost clear; 90%, 95% and 9% for PASI-75; and 22%, 33% and 0% for PASI-100, with significantly higher responses for both risankizumab doses versus placebo. Through week 52, PASI and sPGA responses increased or were maintained and treatment-emergent adverse events were comparable across treatment groups. Both doses of risankizumab were superior to placebo in treating patients with moderate to severe plaque psoriasis. The safety profile was consistent with previous risankizumab trials, with no new or unexpected safety findings.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Psoríase/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Subunidade p19 da Interleucina-23/antagonistas & inibidores , Subunidade p19 da Interleucina-23/imunologia , Japão , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Psoríase/diagnóstico , Psoríase/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento
9.
Am J Clin Dermatol ; 20(3): 443-456, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31066001

RESUMO

BACKGROUND: Patients with moderate-to-severe atopic dermatitis (AD) have increased infection risk, including skin infections and systemic infections. Immunomodulators (e.g., anti-tumor necrosis factors, anti-interleukin [anti-IL]-23, anti-IL-17, Janus kinase inhibitors) increase risk of infections. Dupilumab (a monoclonal antibody blocking the shared receptor component for IL-4 and IL-13) is approved for inadequately controlled moderate-to-severe AD and for moderate-to-severe eosinophilic or oral corticosteroid-dependent asthma. OBJECTIVE: The aim was to determine the impact of dupilumab on infection rates in patients with moderate-to-severe AD. METHODS: This analysis pooled data from seven randomized, placebo-controlled dupilumab trials in adults with moderate-to-severe AD. Exposure-adjusted analyses assessed infection rates. RESULTS: Of 2932 patients, 1091 received placebo, 1095 dupilumab 300 mg weekly, and 746 dupilumab 300 mg every 2 weeks. Treatment groups had similar infection rates overall per 100 patient-years (placebo, 155; dupilumab weekly, 150; dupilumab every 2 weeks, 156; dupilumab combined, 152), and similar non-skin infection rates. Serious/severe infections were reduced with dupilumab (risk ratio 0.43; p < 0.05), as were bacterial and other non-herpetic skin infections (risk ratio 0.44; p < 0.001). Although herpesviral infection rates overall were slightly higher with dupilumab than placebo, clinically important herpesviral infections (eczema herpeticum, herpes zoster) were less common with dupilumab (risk ratio 0.31; p < 0.01). Systemic anti-infective medication use was lower with dupilumab. CONCLUSIONS: Dupilumab is associated with reduced risk of serious/severe infections and non-herpetic skin infections and does not increase overall infection rates versus placebo in patients with moderate-to-severe AD. CLINICALTRIALS. GOV IDENTIFIERS: NCT01548404, NCT02210780, NCT01859988, NCT02277743, NCT02277769, NCT02260986, and NCT02755649.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Dermatite Atópica/tratamento farmacológico , Dermatopatias Infecciosas/epidemiologia , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Dermatite Atópica/complicações , Dermatite Atópica/diagnóstico , Método Duplo-Cego , Humanos , Incidência , Injeções Subcutâneas , Placebos/administração & dosagem , Placebos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Dermatopatias Infecciosas/etiologia , Dermatopatias Infecciosas/prevenção & controle , Resultado do Tratamento
10.
J Am Acad Dermatol ; 81(3): 694-701, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31048013

RESUMO

BACKGROUND: Despite widespread use of steroid-sparing agents, particularly cyclosporine, for treatment of alopecia areata (AA), there are no clinical trials investigating the efficacy of these agents. OBJECTIVE: To evaluate the efficacy of cyclosporine compared with placebo at 3 months in patients aged 18 to 65 years with moderate-to-severe AA. METHODS: A double-blind, randomized, placebo-controlled trial was conducted. Adults aged 18 to 65 years of age with moderate-to-severe AA were randomized in a 1:1 ratio to receive 3 months of cyclosporine (4 mg/kg/d) or matching placebo. Blinded assessments included physical examination, blood biochemistry, photography, quality of life measurements, and efficacy evaluation using Severity of Alopecia Tool score and eyelash and eyebrow assessment scales. RESULTS: The results obtained for 32 participants (16 who received cyclosporine and 16 who received placebo) were analyzed. Compared with the placebo group, the cyclosporine group had a greater proportion of participants achieving at least a 50% reduction in Severity of Alopecia Tool score (31.3% vs 6.3% [P = .07]) and greater proportion of participants achieving a 1-grade improvement in eyelash (18.8% vs 0% [P = .07]) and eyebrow (31.3% vs 0% [P = .02]) scale score. LIMITATIONS: Small sample size and single-institution trial may limit interpretation and generalizability of these results. CONCLUSION: Response approached but did not reach a statistically significant difference between cyclosporine and placebo.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Ciclosporina/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Administração Tópica , Adolescente , Adulto , Idoso , Alopecia em Áreas/diagnóstico , Ciclosporina/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Qualidade de Vida , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto Jovem
11.
Dermatol Surg ; 45(12): 1531-1541, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30998531

RESUMO

BACKGROUND: ATX-101 (deoxycholic acid injection) is approved for reduction of moderate or severe submental fat (SMF). OBJECTIVE: To evaluate the efficacy and safety of ATX-101 in subjects with mild or extreme SMF. PATIENTS AND METHODS: Adults with mild or extreme SMF (based on clinician assessment) were randomized to receive ≤6 treatments with ATX-101 or placebo. Efficacy end points, evaluated at 12 weeks after last treatment, included percentage of subjects who achieved ≥1-grade improvement in SMF from baseline based on both clinician and patient assessment (composite CR-1/PR-1 response) as well as multiple subject-reported outcomes. Safety end points included change in skin laxity and incidence of adverse events. RESULTS: Overall, 61.3% of ATX-101-treated subjects versus 6.7% of placebo-treated subjects with mild SMF and 89.3% versus 13.3% of subjects, respectively, with extreme SMF achieved a composite CR-1/PR-1 response (p < .001 for both). ATX-101-treated subjects also reported higher levels of satisfaction and greater reductions in the psychological impact of SMF versus placebo-treated subjects regardless of baseline SMF severity. Skin laxity was unchanged or improved in most of the subjects. Adverse events were mainly mild/moderate, transient, and associated with the injection site. CONCLUSION: ATX-101 was efficacious and well tolerated for reduction of mild or extreme SMF.


Assuntos
Ácido Desoxicólico/administração & dosagem , Satisfação do Paciente , Ritidoplastia/métodos , Gordura Subcutânea/diagnóstico por imagem , Adolescente , Adulto , Idoso , Queixo , Ácido Desoxicólico/efeitos adversos , Método Duplo-Cego , Estética , Feminino , Humanos , Injeções Subcutâneas/efeitos adversos , Lipólise/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Resultado do Tratamento , Adulto Jovem
12.
Future Oncol ; 15(17): 1963-1973, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30977393

RESUMO

Eftilagimod alpha (IMP321), a soluble dimeric recombinant form of LAG-3, is a first-in-class antigen presenting cell activator under clinical development. By stimulating dendritic cells through MHC class II molecules, IMP321 was proven to induce sustained immune responses. Combining active immunotherapy with a standard cytotoxic chemotherapy regimen represents a promising novel strategy that might lead to therapeutic improvements in metastatic breast cancer. Here, we describe the rationale and design of AIPAC (NCT02614833), a double-blind, randomized, multicenter Phase IIb study evaluating IMP321 plus paclitaxel as a first-line chemotherapy compared with paclitaxel plus placebo in hormone receptor-positive metastatic breast cancer patients. The primary end point is progression-free survival and key secondary objectives include overall survival, safety, quality of life and objective response rate.


Assuntos
Antígenos CD/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/administração & dosagem , Adulto , Antígenos CD/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ensaios Clínicos Fase II como Assunto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Estudos Multicêntricos como Assunto , Paclitaxel/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Intervalo Livre de Progressão , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos
13.
Dermatol Surg ; 45(12): 1549-1556, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-30913051

RESUMO

BACKGROUND: Eyebrow hypotrichosis is an important dermatological problem. However, there is no standard treatment. OBJECTIVE: To study the efficacy and safety of bimatoprost 0.01% for the treatment of eyebrow hypotrichosis. MATERIALS AND METHODS: Although bimatoprost 0.03% has been studied previously, this is the first study to evaluate the efficacy and safety of bimatoprost 0.01% for the treatment of eyebrow hypotrichosis. A randomized, double-blinded, vehicle-controlled trial was conducted in 40 patients. All patients were randomized to receive bimatoprost 0.01% or placebo vehicle, once daily, for 6 months. The primary outcome was improvement in eyebrow density and diameter. Additional outcomes were the improvement in clinical assessments and safety evaluation. RESULTS: Compared to the vehicle group, bimatoprost 0.01% significantly increased mean eyebrow hair density, eyebrow hair diameter, and clinical assessments (p < .001) in the drug group. Patients' satisfaction score was higher for the drug group than the vehicle group (p < .05). Adverse effects of the treatment were minimal and similar between the 2 groups. CONCLUSION: Bimatoprost 0.01% was found to be superior to a placebo for eyebrow enhancement. Bimatoprost 0.01% can be considered effective, safe, and well-tolerated for the treatment of eyebrow hypotrichosis.


Assuntos
Bimatoprost/administração & dosagem , Sobrancelhas/efeitos dos fármacos , Hipotricose/tratamento farmacológico , Soluções Oftálmicas/administração & dosagem , Satisfação do Paciente , Administração Tópica , Adolescente , Adulto , Bimatoprost/efeitos adversos , Método Duplo-Cego , Sobrancelhas/crescimento & desenvolvimento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Tailândia , Resultado do Tratamento , Adulto Jovem
14.
Dermatol Surg ; 45(11): 1381-1393, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30893162

RESUMO

BACKGROUND: PrabotulinumtoxinA is a 900-kDa botulinum toxin Type A produced by Clostridium botulinum. OBJECTIVE: To investigate the efficacy and safety of prabotulinumtoxinA for the treatment of glabellar lines. MATERIALS AND METHODS: Adult subjects (n = 330 in EV-001; n = 324 in EV-002) with moderate to severe glabellar lines at maximum frown on the 4-point Glabellar Line Scale (GLS; 0 = no lines, 1 = mild, 2 = moderate, and 3 = severe) were enrolled in 1 of 2 identical 150-day, double-blind, placebo-controlled, single-dose, Phase III studies. Subjects were randomized 3:1 to receive 20-U prabotulinumtoxinA or placebo. The primary efficacy end point was the proportion of responders on Day 30 where the investigator and subject independently agreed that a ≥2-point improvement had occurred on the GLS at maximum frown from Day 0. Adverse events (AEs) were evaluated throughout the study. RESULTS: Responder rates in the prabotulinumtoxinA and placebo groups were 67.5% and 1.2% in EV-001 and 70.4% and 1.3% in EV-002; absolute differences between groups were 66.3% and 69.1% in EV-001 and EV-002, respectively (both p < .001). No serious AE in either study was assessed as study drug related. CONCLUSION: In these studies, a single dose of 20-U prabotulinumtoxinA was safe and effective for the treatment of glabellar lines.


Assuntos
Toxinas Botulínicas Tipo A/administração & dosagem , Técnicas Cosméticas/efeitos adversos , Fármacos Neuromusculares/administração & dosagem , Envelhecimento da Pele/efeitos dos fármacos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Toxinas Botulínicas Tipo A/efeitos adversos , Método Duplo-Cego , Feminino , Testa , Humanos , Injeções Subcutâneas/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fármacos Neuromusculares/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Resultado do Tratamento , Adulto Jovem
15.
Kidney Int ; 95(4): 983-991, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30712923

RESUMO

Mineralocorticoid receptor antagonists have beneficial effects on left ventricular remodeling, cardiac fibrosis, and arrhythmia in heart failure, but efficacy and safety in dialysis patients is less clear. We evaluated the effect of spironolactone on left ventricular mass (LVM), an independent predictor of all-cause and cardiovascular mortality, in hemodialysis patients. In this placebo-controlled, parallel-group trial, 97 hemodialysis patients (23% female; mean age 60.3 years) were randomized to spironolactone 50 mg once daily (n=50) or placebo (n=47). The primary efficacy endpoint was change in LVM index (LVMi) from baseline to 40 weeks as determined by cardiac magnetic resonance imaging. Safety endpoints were development of hyperkalemia and change in residual renal function. There was no significant change in LVMi in participants randomized to spironolactone compared to placebo (-2.86±11.87 vs. 0.41±10.84 g/m2). There was also no difference in the secondary outcomes of mean 24-hour systolic or diastolic ambulatory blood pressure, left ventricular ejection fraction, 6-minute walk test distance, or New York Heart Association functional class. Moderate hyperkalemia (pre-dialysis potassium levels of 6.0-6.5 mmol/L) was more frequent with spironolactone treatment (155 vs. 80 events), but severe hyperkalemia (≥6.5 mmol/L) was not (14 vs. 24 events). Changes in residual urine volume and measured glomerular filtration rate did not differ between groups. There were no deaths in the spironolactone group and 4 deaths in the placebo group. Thus, treatment with 50 mg spironolactone did not change left ventricular mass index, cardiac function, or blood pressure in hemodialysis patients. Spironolactone increased the frequency of moderate hyperkalemia, but did not increase severe hyperkalemia.


Assuntos
Insuficiência Cardíaca/prevenção & controle , Ventrículos do Coração/patologia , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Espironolactona/administração & dosagem , Remodelação Ventricular/efeitos dos fármacos , Idoso , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/etiologia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/efeitos dos fármacos , Humanos , Hiperpotassemia/induzido quimicamente , Hiperpotassemia/epidemiologia , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Placebos/administração & dosagem , Placebos/efeitos adversos , Diálise Renal , Espironolactona/efeitos adversos , Volume Sistólico/efeitos dos fármacos , Resultado do Tratamento
16.
J Surg Res ; 238: 164-174, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30771686

RESUMO

BACKGROUND: N-3 polyunsaturated fatty acid (PUFA) supplementation has been associated with reduced mortality and inflammation in patients with cardiovascular disease. There are limited data on the effects of n-3 PUFA supplementation in patients with peripheral artery disease (PAD). MATERIALS AND METHODS: The OMEGA-PAD II trial was a double-blinded, randomized, placebo-controlled trial to assess the effect of 3 mo of high-dose oral n-3 PUFA supplementation on inflammation, endothelial function, and walking ability in patients with PAD. RESULTS: Twenty-four patients with claudication received 4.4 g/d of fish oil or placebo for 3 mo. Outcomes measured included high-sensitivity C-reactive protein levels, the omega-3 index, endothelial function as measured via flow-mediated vasodilation, walking impairment questionnaire, and a 6-min walk test. Plasma levels of specialized pro-resolving lipid mediators (SPMs) were measured by liquid-chromatography-tandem mass spectrometry. In patients treated with fish oil, the absolute mean omega-3 index significantly increased from baseline (fish oil: 7.2 ± 1.2%, P < 0.001; placebo: -0.4 ± 0.9%, P = 0.31; between-group P < 0.001). Furthermore, there were significant increases in several pathway markers of SPM biosynthesis, including several mono-hydroxyeicosapentaenoic acids and mono-hydroxydocosahexaenoic acids. We also observed significant increases in the SPM lipoxin A5 (fish oil: 0.57 ± 0.70 pg/mL, P = 0.05; placebo: 0.01 ± 0.38 pg/mL, P = 0.93; between-group P = 0.04) and resolvin E3 (fish oil: 154 ± 171 pg/mL, P = 0.04; placebo: 32 ± 54 pg/mL, P = 0.08; between-group P = 0.04). There were no significant changes in high-sensitivity C-reactive protein, flow-mediated vasodilation, walking impairment questionnaire, or 6-min walk test in the fish oil group. CONCLUSIONS: Fish oil increases SPMs in plasma of patients with PAD. Further studies are required to determine whether these early changes translate to clinical improvements in patients with PAD.


Assuntos
Ácidos Docosa-Hexaenoicos/sangue , Ácido Eicosapentaenoico/sangue , Ácidos Graxos Ômega-3/administração & dosagem , Inflamação/dietoterapia , Doença Arterial Periférica/dietoterapia , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/imunologia , Método Duplo-Cego , Ácido Eicosapentaenoico/imunologia , Feminino , Humanos , Inflamação/sangue , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/imunologia , Placebos/administração & dosagem , Placebos/efeitos adversos , Resultado do Tratamento
17.
Clin Microbiol Infect ; 25(6): 673-680, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30616011

RESUMO

BACKGROUND: Sore throat resulting from pharyngotonsillitis is one of the commonest reasons for primary care consultation and inappropriate antibiotic prescription and finding effective alternative treatments is important. OBJECTIVES: To review the evidence for using the probiotic Streptococcus salivarius K12 (SsK12) for the prevention or treatment of pharyngotonsillitis. DATA SOURCES: PubMed, Embase, CINAHL and Cochrane Library. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials (RCTs). PARTICIPANTS: Adults or children. INTERVENTIONS: SsK12 as active treatment or prophylaxis, against pharyngotonsillitis. METHODS: Literature search. RESULTS: Four articles were identified (1846 participants). All were deemed to be of poor quality using the Cochrane risk-of-bias assessment. Two trials studied SsK12 prophylaxis for streptococcal pharyngitis (children without history of recurrence). One compared daily administration of SsK12 to no treatment over 6 months (n = 222, age 33-45 months), reporting significantly lower incidence in the SsK12 group (16.2% vs. 48.6%, p < 0.01), whereas another placebo-controlled RCT over four school terms (n = 1314, 5-14 years) found no significant difference (7.8% vs. 8.8%, p 0.34) with SsK12 (administered on school days). Another trial found daily SsK12 to significantly protect children (n = 250, 6-7 years) against chronic adenoiditis exacerbation over 3 months compared to no treatment (71.7% vs. 100%, p < 0.0001). The one placebo-controlled RCT in adults that studied the use of SsK12 for acute pharyngotonsillitis (concurrently with penicillin) showed no significant benefit. In all trials, SsK12 was safe and well tolerated. CONCLUSIONS: SsK12 appears safe and well tolerated. However, further RCTs are required to establish its role as a prophylactic therapy, particularly among patients experiencing frequent exacerbations of pharyngitis. In the acute setting, SsK12 is unlikely to be effective if given concurrently with antibiotics; however, further RCTs should establish its role as an alternative to antibiotics in nonsevere cases or when prescribed after antibiotic therapy for the prevention of disease recurrence and/or secondary infection.


Assuntos
Faringite/prevenção & controle , Faringite/terapia , Probióticos/administração & dosagem , Streptococcus salivarius/crescimento & desenvolvimento , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
18.
Am J Ther ; 26(5): 583-588, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29509552

RESUMO

BACKGROUND: It is estimated that 1 billion people in the world have a point mutation in the gene encoding the aldehyde dehydrogenase 2 (ALDH2) enzyme, the primary enzyme responsible for the metabolism of acetaldehyde. The presence of this mutation is called ALDH2 deficiency. Because of limited ability to metabolize acetaldehyde, individuals with ALDH2 deficiency experience elevated levels of blood acetaldehyde after exposure to various common sources such as recreational alcohol. Because of higher levels of acetaldehyde, individuals with ALDH2 deficiency are at higher risk for numerous diseases, including liver cirrhosis, esophageal and gastric cancer, osteoporosis, and Alzheimer disease. STUDY QUESTION: The present trial was designed to study the effectiveness, safety, and tolerability of a nutritional supplement (Essential AD2). MEASURES AND OUTCOMES: The primary outcome was change in acetaldehyde levels in the blood after exposure to alcohol in individuals with ALDH2 deficiency before and after the use of study nutritional supplement. STUDY DESIGN: This was a 28-day open-label trial, comparing initial acetaldehyde levels after alcohol ingestion to levels after 28 days of a nutritional supplement (Essential AD2). The study consisted of 12 subjects genotyped to be heterozygous for the ALDH2 gene mutation. RESULTS AND CONCLUSIONS: ALDH2 deficient subjects showed a significant decrease in average blood acetaldehyde level 20 minutes after alcohol consumption (from 0.91 mg/dL to 0.71 mg/dL, P value = 0.02) after receiving 28 days of the nutritional supplement. Acetaldehyde levels taken at 10 minutes and 40 minutes also showed a decrease, although they were not statistically significant. In addition, safety tests looking at liver function tests showed a decrease in aspartate transaminase and alanine transaminase liver proteins from 27.3 to 15.2 and 20.9 to 13.2, respectively, over the 28 days. The treatment was well tolerated and no significant side effects were noted.


Assuntos
Acetaldeído/sangue , Consumo de Bebidas Alcoólicas/sangue , Aldeído-Desidrogenase Mitocondrial/deficiência , Suplementos Nutricionais/efeitos adversos , Etanol/metabolismo , Acetaldeído/metabolismo , Adulto , Consumo de Bebidas Alcoólicas/metabolismo , Aldeído-Desidrogenase Mitocondrial/genética , Grupo com Ancestrais do Continente Asiático/genética , Etanol/administração & dosagem , Etanol/efeitos adversos , Feminino , Voluntários Saudáveis , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Placebos/administração & dosagem , Placebos/efeitos adversos , Mutação Puntual , Resultado do Tratamento , Adulto Jovem
19.
Am J Ther ; 26(3): e350-e357, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-29189311

RESUMO

BACKGROUND: Preemptive use of gabapentin might accelerate recovery by reducing acute post-inguinal herniorrhaphy pain and opioid requirement being an analgesic. STUDY QUESTION: Assessing efficacy of three different doses of oral gabapentin premedication for postoperative pain management after inguinal herniorrhaphy under spinal anesthesia. STUDY DESIGN: This prospective, randomized, placebo controlled study was performed on 120 male patients (ASA I/II) undergoing inguinal herniorrhaphy under subarachnoid block. Patients were divided into 4 groups of 30 patients each to receive placebo (group A) or gabapentin 400 mg (B) or 800 mg (C) or 1200 mg (D), administered orally 2 hours before surgery. Assessment of postoperative pain was made on the basis of the visual analog score (VAS), where 0 cm "no pain" and 10 cm "worst pain imaginable." Patients received IV fentanyl 0.5 µg/kg bolus when VAS >3. MEASURES AND OUTCOMES: VAS score at regular intervals, the first analgesic requirement and total opioid consumption within 24 hours after surgery along with side/adverse effect (s) of study drug in perioperative period. RESULTS: The VAS of the study groups B, C, D were significantly lower than placebo group (A) at 0, 1, 2, 4, 8, 12, 16, 20, and 24-hour intervals after surgery (P < 0.05). The first analgesic need and total opioid consumption within 24 hours after surgery of study groups were significantly lower than placebo group (P < 0.005) while within study groups difference was not significant. Dizziness and somnolence were seen maximally in group D patients (P = 0.01). However, pruritus, nausea and vomiting though maximally reported among group (A) patients but statistically non-significant. CONCLUSION: Preemptive gabapentin is opioid sparing to control postoperative pain with anxiolysis and sedation. We found the optimal dose to be 400 mg for gabapentin. However, increasing dose from 400 to 1200 mg does not increase its efficacy as analgesic but with higher adverse effects.


Assuntos
Analgésicos/administração & dosagem , Gabapentina/administração & dosagem , Herniorrafia/efeitos adversos , Dor Pós-Operatória/prevenção & controle , Pré-Medicação/métodos , Administração Oral , Adulto , Analgésicos/efeitos adversos , Raquianestesia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Gabapentina/efeitos adversos , Hérnia Inguinal/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/diagnóstico , Dor Pós-Operatória/etiologia , Placebos/administração & dosagem , Placebos/efeitos adversos , Período Pré-Operatório , Estudos Prospectivos , Resultado do Tratamento
20.
Br J Dermatol ; 180(2): 297-305, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30171698

RESUMO

BACKGROUND: Topical immune response modifiers are established for actinic keratosis (AK) treatment and efforts are underway to make further improvements to their efficacy and safety. OBJECTIVES: To investigate the optimal dosing regimens of the Toll-like receptor 7/8 agonist resiquimod in terms of efficacy, safety and tolerability. METHODS: In a multicentre, partly placebo-controlled, double-blind clinical trial, we randomized 217 patients with AK lesions to 0·03% resiquimod gel once-daily application three times per week for 4 weeks or seven times within 2 weeks or five times for 1 week (arms 1/2/3) followed by a treatment-free interval of 8 weeks and one repetition of the cycle. In two additional arms (arms 4/5), patients applied either resiquimod gel 0·01% or 0·03% three times per week up to a biological end point defined by skin erosion or for a maximum duration of 8 weeks. Clearance was assessed clinically and histologically. RESULTS: Complete clinical clearance ranged from 56% to 85% with the highest rate observed in arm 2. Resiquimod 0·03% gel was more effective than 0·01% gel. Clearance rates in arms 1/2/3 were comparable and higher than with placebo and were reached with 24, 14 and 10 gel applications, respectively. Overall, 128 patients (59%) experienced treatment-related adverse reactions. CONCLUSIONS: Resiquimod 0·03% gel is more effective than 0·01% gel. From the perspectives of safety and tolerability, the lower concentration and shorter duration are preferable. The clinical response in arms 2/3 was reached with fewer gel applications. The dosing regimens that used the biological end point (arms 4/5) proved equally efficacious as predefined treatment durations and may therefore be suitable for personalized AK treatment.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Imidazóis/administração & dosagem , Ceratose Actínica/tratamento farmacológico , Adjuvantes Imunológicos/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Imidazóis/efeitos adversos , Ceratose Actínica/imunologia , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , Placebos/efeitos adversos , Fatores de Tempo , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/imunologia , Resultado do Tratamento
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