Síndrome DRESS secundária ao uso de alopurinol: um relato de caso / DRESS syndrome secondary to the use of allopurinol: a case report

A Síndrome de DRESS (do inglês, Drug Rash with Eosinophilia and Systemic Symptoms) é uma patologia rara que consiste em uma severa reação medicamentosa mediada por células T. O presente relato de caso retrata uma paciente do sexo feminino, 59 anos, que apresentou icterícia, febre não termometrada, acolia, colúria, mialgia, placas hipercrômicas e lesões pruriginosas. Referiu uso recente de alopurinol, paracetamol e nimesulida, apresentando melhora importante e espontânea após a suspensão das medicações. A extensão do tempo de exposição ao medicamento agressor ocasiona um maior período de internação e risco de mortalidade. Além disso, os dados restritos sobre a Síndrome de DRESS impõe desafios ao seu diagnóstico. Sendo assim, este estudo busca destacar a importância do diagnóstico clínico precoce, a suspensão do medicamento agressor e a instituição da terapêutica adequada para um prognóstico favorável

The Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Syndrome is a rare pathology that consists of a severe drug reaction mediated by T cells. The present case report depicts a female patient, 59 years old, who presented jaundice, non thermometered fever, acholia, choluria, myalgia, hyperchromic plaques and pruritic lesions. She mentioned recent use of allopurinol, paracetamol and nimesulide, showing significant and spontaneous improvement after discontinuation of medications. The extension of time of exposure to the offending drug causes a longer period of hospitalization and risk of mortality. In addition, the restricted data on DRESS Syndrome poses challenges to its diagnosis. Therefore, this study seeks to highlight the importance of early clinical diagnosis, suspension of the offending drug and the institution of appropriate therapy for a favorable prognosis

Apalutamide for patients with metastatic castrationsensitive prostate cancer in East Asia: a subgroup analysis of the TITAN trial / 亚洲男科学杂志(英文版)

Ethnicity might be associated with treatment outcomes in advanced prostate cancer. This study aimed to evaluate the efficacy and safety of androgen deprivation therapy (ADT) combined with apalutamide in East Asians with metastatic castration-sensitive prostate cancer (mCSPC). The original phase 3 Targeted Investigational Treatment Analysis of Novel Anti-androgen (TITAN) trial was conducted at 260 sites in 23 countries. This subgroup analysis included patients enrolled in 62 participating centers in China, Japan, and Korea. Radiographic progression-free survival (PFS), time to prostate-specific antigen (PSA) progression, and PSA changes from baseline were compared between groups in the East Asian population. The intent-to-treat East Asian population included 111 and 110 participants in the apalutamide and placebo groups, respectively. The 24-month radiographic PFS rates were 76.1% and 52.3% in the apalutamide and placebo groups, respectively (apalutamide vs placebo: hazard ratio [HR] = 0.506; 95% confidence interval [CI], 0.302-0.849; P = 0.009). Median time to PSA progression was more favorable with apalutamide than placebo (HR = 0.210; 95% CI, 0.124-0.357; P < 0.001). Median maximum percentages of PSA decline from baseline were 99.0% and 73.9% in the apalutamide and placebo groups, respectively. The most common adverse event (AE) was rash in the apalutamide group, with a higher rate than that in the placebo group (37.3% vs 9.1%). The most common grade 3 or 4 AEs were rash (12 [10.9%]) and hypertension (12 [10.9%]) for apalutamide. The efficacy and safety of apalutamide in the East Asian subgroup of the TITAN trial are consistent with the global results.

Síndrome de DRESS asociado al uso de anticonvulsivantes / DRESS syndrome associated to the use of anti-convulsiveness

Introducción: El síndrome Drug Reaction with Eosinophilia and Systemic Symptoms - DRESS, constituye una grave reacción adversa a medicamentos, principalmente a fármacos anticonvulsivantes. Objetivo: Describir la evolución clínica de un síndrome de DRESS en una paciente atendida en el Hospital Militar Central "Dr. Luis Díaz Soto". Caso Clínico: Paciente femenina de 27 años de edad con antecedentes patológicos personales de epilepsia. Tres meses luego de iniciada terapia con difenilhidantoína aparece fiebre, exantema maculopapular que progresa a eritrodermia exfoliativa, signos de daño hepático, adenopatías cervicales y eosinofilia. Se diagnosticó síndrome de DRESS secundaria al uso de anticonvulsivantes. Conclusiones: La evolución clínica resultó favorable, luego de la retirada del fármaco y la aplicación de esteroides por vía oral(AU)

Introduction: Drug Reaction with Eosinophilia and Systemic Symptoms - DRESS, syndrome constitutes a serious adverse reaction to medications, mainly anticonvulsant drugs. Objective: To describe the clinical evolution of DRESS syndrome in a patient treated at the Hospital Militar Central "Dr. Luis Díaz Soto". Case Report: 27-year-old female patient with a personal pathological history of epilepsy. Three months after initiation of diphenylhydantoin therapy, fever appeared maculopapular rash that progressed to exfoliative erythroderma, signs of liver damage, cervical adenopathies and eosinophilia. DRESS syndrome was diagnosed secondary to the use of anticonvulsants. Conclusions: The clinical evolution was favorable, after the withdrawal of the drug and the application of steroids orally(AU)

Desarrollo de infección tuberculosa latente y efectos adversos de la isoniazida durante tratamiento con biológico por enfermedad de Crohn / Development of latent tuberculosis and adverse effects with isoniazid during biologist therapy´s in Crohn´s disease / Desenvolvimento de tuberculose latente durante e efeitos adversos da isoniazida o tratamento com biológicos para a doença de Crohn

Los fármacos anti factor de necrosis tumoral alfa (TNF-α) bloquean una de las citoquinas implicadas en la patogénesis de la Enfermedad Inflamatoria intestinal (EII). Su uso se relaciona con aumento de tuberculosis (TB), por lo que el despistaje previo es obligatorio. En la infección tuberculosa latente (ITBL) se utiliza isoniazida como quimioprofilaxis, fármaco que no se encuentra libre de reacciones adversas. Se presenta y discute el caso de una paciente con reacción adversa en piel secundaria al uso de isoniazida.

Anti-tumor necrosis factor alfa drugs are responsible for blocking one of the cytoquines implicated on inflammatory bowel disease pathogenesis. Its use has been linked to an increase in tuberculosis cases which is why screening before starting treatment is mandatory. Latent tuberculosis is treated with isoniazid as chemoprophylaxis although its use may provoke adverse effects. A case is presented of a patient with skin adverse reaction due to the use of isoniazid.

Os medicamentos anti factor de necrose tumoral alfa (TNF-α ) bloqueiam uma das citocinas envolvidas na patogénese da doença inflamatória intestinal (DII). A sua utilização está associada com um aumento da tuberculose (TB), de modo que a despistagem anterior dessa doença é necessária. Na TB latente, frequentemente se utiliza a isoniazida é usado como quimioprofilaxia, uma droga que não está livre de reações adversas. Apresentamos e discutimos o caso de uma paciente com reação adversa na pele secundária ao uso da isoniazida.

Síndrome de hipersensibilidad a medicamentos con exantema, eosinofilia y síntomas sistémicos inducido por carbamazepina / Drug rash with eosinophilia and systemic symptoms syndrome induced by carbamazepine: Case report

RESUMEN El síndrome de hipersensibilidad a medicamentos, con exantema, eosinofilia y síntomas sistémicos (Drug Rash Eosinophylia with Systemic Symptoms, DRESS) es una reacción a diferentes medicamentos, principalmente anticonvulsivos, el cual cursa con compromiso sistémico y lesiones eritematosas, al igual que ocurre en diversas dermatosis por reacción a medicamentos. Este síndrome es una condición clínica poco frecuente, cuyo diagnóstico requiere un alto grado de sospecha por parte del personal clínico. Si no se hace un diagnóstico oportuno y se suministra el tratamiento adecuado, puede confundirse con otros tipos de alergias a medicamentos que implican riesgo de muerte. Se presenta el caso de un paciente de 22 años de edad con alteración del neurodesarrollo a quien se le inició tratamiento con carbamazepina. Dos meses después consultó debido a la aparición de síntomas generales y lesiones eritematosas en la piel, inicialmente en el tronco. En la atención ambulatoria se le prescribieron antihistamínicos y antipiréticos, con los cuales no mejoró adecuadamente; su condición empeoró, con la aparición de lesiones en la piel y síntomas sistémicos propios del síndrome DRESS. Al cabo del tratamiento farmacológico administrado durante su hospitalización según los lineamientos recomendados, las manifestaciones y complicaciones asociadas con el síndrome remitieron, la administración de esteroides pudo reducirse gradualmente y, finalmente, el paciente fue dado de alta.

ABSTRACT Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a hypersensitivity reaction associated with a variety of drugs, mainly anticonvulsants, which is characterized by systemic symptoms and erythematous lesions, common to other toxicodermas. It is an uncommon clinical entity that requires a high suspicion by clinical staff given its varied initial presentation, and the fact that symptoms can overlap with those of other adverse cutaneous reactions to drugs. Without early diagnosis and appropriate treatment, mortality increases. We report the case of a 22-year-old patient with impaired neurodevelopment who received treatment with carbamazepine. Two months later he presented with general symptoms and skin erythematous lesions that began on his trunk. The patient received outpatient care with antihistamines and antipyretics without an appropriate response. His case progressed with increased skin lesions and systemic symptoms that met the diagnostic criteria for DRESS syndrome. He was hospitalized and received medical treatment according to recommended guidelines. The patient's condition improved as his symptoms and associated complications resolved. He was discharged with gradual clearing of the steroid therapy.

Identifying the incidence of rash, Stevens-Johnson syndrome and toxic epidermal necrolysis in patients taking lamotrigine: a systematic review of 122 randomized controlled trials

ABSTRACT Lamotrigine is an antiepileptic drug used for the treatment of epilepsy, bipolar disorder and numerous off-label uses. The development of rash significantly affects its use. The most concerning of these adverse reactions is Stevens-Johnson syndrome/toxic epidermal necrolysis. We performed a systematic review of randomized controlled trials using lamotrigine as a monotherapy to quantify the incidence of cutaneous reactions, particularly Stevens-Johnson syndrome/toxic epidermal necrolysis. Of a total of 4,364 papers regarding lamotrigine, 122 studies met our inclusion and exclusion criteria. In total, 18,698 patients were included with 1,570 (8.3%) of patients experiencing an adverse dermatologic reaction. The incidence of Stevens-Johnson syndrome/toxic epidermal necrolysis was 0.04%.

Dermatological adverse reactions to cancer chemotherapy.

The new targeted anticancer drugs as well as the older traditional chemotherapy agents are associated with adverse effects on skin, hair, nails and mucosa. These toxic effects can cause great distress to the patient leading to decreased quality of life and interruption in treatment. Aims: To study the mucocutaneous adverse effects of both single and combined chemotherapy regimens in cancer patients. Materials and Methods: We studied 53 cancer patients attending the oncology outpatient department or those admitted in the oncology ward of Father Muller Medical College Hospital, Mangalore between October 2012 and September 2013. The adverse effects of chemotherapy on skin, hair, nails and mucosa were noted. Results: The most common adverse effects observed in the study were nail changes in 33 (62.2%) patients, followed by hair changes in 20 (37.7%) patients, skin changes in 19 (33.9%) patients, and mucosal changes in 2 (3.7%) patients. The skin changes were acneiform rash in 5 (27.7%) patients, xerosis in 4 (22.2%) patients, hyperpigmentation in 4 (22.2%) patients, and toxic epidermal necrolysis, hand foot syndrome, extravasation, erythema nodosum, and supravenous hyperpigmentation in 1 patient each. The most common nail fi nding was melanonychia seen in 26 (78.7%) patients. Hair changes were in the form of anagen effl uvium seen in 20 (37.7%) patients. Mucosal changes seen were pigmentation of tongue and stomatitis in one case each. Limitations: Sample size is small. Conclusions: While these side effects are generally not life-threatening, they can be a source of signifi cant morbidity. Knowledge about the adverse effects of anti-cancer drugs will help in accurate diagnosis and management, thereby improving the quality of life.

Clinical experience on use of oral EGFR-TKIs as first-line treatment of advanced NSCLC from a tertiary care centre in North India and implications of skin rash.

Background. Limited data are available from India on treatment outcomes with oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in newly diagnosed non-small cell lung cancer (NSCLC). We studied the demographic profile and treatment outcomes of patients with NSCLC, receiving first-line treatment with oral EGFR-TKIs. Methods. Retrospective study of newly diagnosed NSCLC patients treated with oral EGFR-TKIs over a 4-year period at a tertiary care institute in North India. Results. Of 76 patients studied, females and non-smokers constituted 32.9% and 48.7%, respectively. Majority of patients had adenocarcinoma (59.2%), stage IV (64.5%) disease and Karnofsky performance status <70 (74.5%). Gefitinib was the most frequently used EGFR-TKI (92.1%). Most common indication for the use of EGFR-TKIs was poor performance status (65.8%). Among assessable patients, disease control and progressive disease were evident in 66% and 34%, respectively. Most common side effects were skin rash (17%) and diarrhoea (10.6%). Patients with and without skin rash differed significantly in relation to objective response to treatment (100% versus 23.1%) and overall survival (median not reached versus 178 days). On multivariate logistic regression analysis, malignant pleural effusion was associated with occurrence of rash (odds ratio=0.19; 95% confidence interval = 0.04-0.95; p=0.04). Conclusions. Oral EGFR-TKIs appear to be useful for the treatment of clinically selected patients with advanced NSCLC. Occurrence of skin rash was independently associated with treatment response and better survival in the current study.

Comparative analysis of adverse events between infliximab and adalimumab in Crohn's disease management: a Brazilian single-centre experience / Análise comparativa dos eventos adversos entre infliximabe e adalimumabe no tratamento da doença de Crohn: experiência em um centro brasileiro

INTRODUCTION: Data is scarce regarding adverse events (AE) of biological therapy used in the management of Crohn's Disease (CD) among Brazilian patients. OBJECTIVES: To analyse AE prevalence and profile in patients with CD treated with Infliximab (IFX) or Adalimumab (ADA) and to verify whether there are differences between the two drugs. METHOD: Retrospective observational single-centre study of CD patients on biological therapy. Variables analysed: Demographic data, Montreal classification, biological agent administered, treatment duration, presence and type of AE and the need for treatment interruption. RESULTS: Forty-nine patients were analysed, 25 treated with ADA and 24 with IFX. The groups were homogeneous in relation to the variables studied. The average follow-up period for the group treated with ADA was 19.3 months and 21.8 months for the IFX group (p = 0.585). Overall, 40% (n = 10) of patients taking ADA had AE compared with 50% (n = 12) of IFX users (p = 0.571). There was a tendency towards higher incidence of cutaneous and infusion reactions in the IFX group and higher incidence of infections in the ADA treated group, although without significant difference. CONCLUSIONS: No difference was found in the AE prevalence and profile between ADA and IFX CD patients in the population studied. (AU)

INTRODUÇÃO: Há poucos dados sobre os eventos adversos (EA) da terapia biológica usada no tratamento da doença de Crohn (DC) entre os pacientes brasileiros. OBJETIVOS: Analisar a prevalência dos EA e o perfil dos pacientes com DC tratados com Infliximabe (IFX) ou Adalimumabe (ADA) e verificar se há diferenças entre esses dois fármacos. MÉTODO: Estudo observacional e retrospectivo de pacientes com DC em terapia biológica, realizado em centro único. As variáveis analisadas foram: dados demográficos, classificação de Montreal, agente biológico administrado, duração do tratamento, presença e tipo de EA e necessidade de interrupção do tratamento. RESULTADOS: Quarenta e nove pacientes foram analisados, 25 tratados com ADA e 24 com IFX. Os grupos eram homogêneos em relação às variáveis estudadas. O período médio de acompanhamento foi de 19,3 meses para o grupo tratado com ADA e de 21,8 meses para o grupo tratado com IFX (p = 0,585). No total, 40% dos pacientes (n = 10) que receberam ADA tiveram AE, em comparação com 50% dos pacientes (n = 12) que receberam IFX (p = 0,571). Houve uma maior incidência de reação cutânea e à infusão no grupo IFX e de infecções no grupo ADA, embora sem diferença significativa. CONCLUSÃO: Não houve diferença na prevalência de EA e no perfil dos pacientes com DC que receberam ADA e IFX. (AU)

Drug rash with eosinophilia and systemic symptoms syndrome following cholestatic hepatitis A: a case report / 대한간학회지

Hepatitis A virus (HAV) infections occur predominantly in children, and are usually self-limiting. However, 75-95% of the infections in adults are symptomatic (mostly with jaundice), with the illness symptoms usually persisting for a few weeks. Atypical manifestations include relapsing hepatitis, prolonged cholestasis, and complications involving renal injury. Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a severe, drug-induced hypersensitivity reaction characterized by skin rash, fever, lymph-node enlargement, and internal organ involvement. We describe a 22-year-old male who presented with acute kidney injury and was diagnosed with prolonged cholestatic hepatitis A. The patient also developed DRESS syndrome due to antibiotic and/or antiviral treatment. To our knowledge, this is the first report of histopathologically confirmed DRESS syndrome due to antibiotic and/or antiviral treatment following HAV infection with cholestatic features and renal injury.

Rash y anemia aplásica inducidos por fenitoína: caso clínico / Phenytoin-induced rash and aplastic anemia: case report

Rash is a common side effect associated with antiepileptic drugs. The rate of a phenytoin rash is 5.9 percent and increases to 25 percent in those with another antiepileptic drug rash. Aplastic anemia is an adquired hematopoietic stem-cell disorder characterized by pancytopenia of the peripheral blood and hypocellular bone marrow. The use of phenytoin is associated with a 3.5 fold increased risk of aplastic anemia. We report a case of a 70-year-old woman who developed two severe adverse reactions simultaneously with phenytoin: a maculopapular pruritic rash with involvement of mucous and an aplastic anemia. Both conditions normalized after phenytoin withdrawal.

El rash es un efecto secundario común asociado al uso de fármacos antiepilépticos. La frecuencia de rash con fenitoína se ha estimado en un 5,9 por ciento y asciende a un 25 por ciento en pacientes que han presentado rash con otro fármaco antiepiléptico. La anemia aplásica es una anomalía adquirida de las células madre hematopoyéticas caracterizada por pancitopenia de la sangre periférica y médula ósea hipocelular. Los pacientes tratados con fenitoína presentan un riesgo 3,5 veces mayor de desarrollar anemia aplásica. Presentamos el caso de una mujer de 70 años que desarrolló dos reacciones adversas severas y simultáneas a la fenitoína: un exantema maculopapular pruriginoso con compromiso de mucosas y una anemia aplásica. Ambas condiciones se resolvieron completamente con la suspensión del fármaco.

Farmacodermias en la infancia / Childhood cutaneous drug reactions

Las reacciones cutáneas a drogas son frecuentes en la infancia y tienen un alto impacto en la salud de los niños. Desde el punto de vista de sus manifestaciones clínicas, pueden presentarse en forma muy disímil: desde un exantema transitorio sin repercusión sistémica hasta cuadros de necrosis epidérmicas diseminadas con compromiso sistémico, potencialmente fatales. La rápida detección y la instauración del tratamiento adecuado, al igual que la identificación y suspensión del agente causal, son esenciales para prevenir la progresión de la reacción, así como también evitar futuras exposiciones y asegurar el uso adecuado de los fármacos. El objetivo de este artículo es el reconocimiento de las diversas reacciones cutáneas adversas a fármacos, así como el manejo y pronóstico de las mismas.

Functional changes of dendritic cells in hypersensivity reactions to amoxicillin

A better understanding of dendritic cell (DC) involvement in responses to haptenic drugs is needed, because it represents a possible approach to the development of an in vitro test, which could identify patients prone to drug allergies. There are two main DC subsets: plasmacytoid DC (pDC) and myeloid DC (mDC). β-lactams form hapten-carrier conjugates and may provide a suitable model to study DC behavior in drug allergy reactions. It has been demonstrated that drugs interact differently with DC in drug allergic and non-allergic patients, but there are no studies regarding these subsets. Our aim was to assess the functional changes of mDC and pDC harvested from an amoxicillin-hypersensitive 32-year-old woman who experienced a severe maculopapular exanthema as reflected in interleukin-6 (IL-6) production after stimulation with this drug and penicillin. We also aim to demonstrate, for the first time, the feasibility of this method for dendritic cell isolation followed by in vitro stimulation for studies of drug allergy physiopathology. DC were harvested using a double Percoll density gradient, which generates a basophil-depleted cell (BDC) suspension. Further, pDC were isolated by blood DC antigen 4-positive magnetic selection and gravity filtration through magnetized columns. After stimulation with amoxicillin, penicillin and positive and negative controls, IL-6 production was measured by ELISA. A positive dose-response curve for IL-6 after stimulation with amoxicillin and penicillin was observed for pDC, but not for mDC or BDC suspension. These preliminary results demonstrate the feasibility of this methodology to expand the knowledge of the effect of dendritic cell activation by drug allergens.

Síndrome de DRESS: experiencia en un hospital pediátrico / DRESS syndrome: experience in a pediatric hospital

El síndrome de DRESS es una reacción grave de hipersensibilidad a drogas caracterizada por exantema, fiebre adenopatías, afectación de órganos internos y alteraciones hematológicas. Objetivos: 1. Describir las características clínicas y alteraciones de laboratorio de los pacientes con diagnóstico de síndrome de DRESS, evaluados en nuestro Servicio desde enero de 2004 hasta agosto de 2009. 2. Detallar los fármacos responsables del mismo. 3. Describir la evolución de estos pacientes así como también los tratamientos instaurados. Resultados: Se seleccionaron 14 pacientes. El 71% presentó fiebre como primer signo clínico, el exantema se encontró en el 100%, el edema de cara en el 57% y el 71% desarrolló hepatitis durante la internación. La eosinofilia fue hallada en el 79% de los pacientes y un 43% presentó linfocitos atípicos. Los anticonvulsivantes fueron los fármacos responsables más frecuentes. Todos los pacientes recibieron antihistamínicos. El 71% recibió, además, corticoides sistémicos, mientras que la gammaglobulina fue indicada en el 21% de los pacientes en forma concomitante con los corticoides. Conclusiones: Observamos que el rash, la fiebre y el edema de cara constituyen signos clínicos primarios en esta patología, por lo cual ente un paciente con estas características sumado al antecedente de ingesta de un fármaco sospechoso se deberá buscar compromiso de órganos internos para descartar síndrome de DRESS.

Pustulosis exantemática aguda generalizada: a proposito de un caso / Acute generalized exanthematous pustulosis: a report of a case

La pustulosis exantemática aguda generalizada (PEAG) es una patología poco frecuente en la población general y más rara aún en la infancia. Cursa con fiebre y una erupción de pequeñas pústulas estériles, no foliculares, sobre base eritematosa, que comienza en rostro o pliegues para luego generalizarse y resuelve con descamación en 4 a 10 días. El hallazgo histopatológico característico es la presencia de pústulas espongióticas intraepidérmicas. La mayoría de los casos es gatillada por drogas sistémicas, pero también puede ocurrir luego de infecciones. El tratamiento incluye la suspensión de la droga desencadenante si la hubiere y el uso de corticoides tópicos o sistémicos. Presentamos un varón de 12 años de edad que consultó por fiebre, eritema generalizado y pústulas, que aparecieron 48 horas luego de la ingesta de acetaminofén. El diagnóstico clínico presuntivo de PEAG fue confirmado con biopsia de piel. Se indicó suspensión del acetaminofén y se manejó ambulatoriamente con corticoides tópicos, presentando resolución completa del cuadro. Destacamos que la PEAG es una patología rara en la infancia y que en la literatura se describe un único caso asociado a la ingesta de acetaminofén

Acute generalized exanthematous pustulosis (AGEP) is an extremely rare condition in the general population and even more in children. Clinically it consists on an eruption of small, sterile and nonfollicular pustules on an erythematous background, beginning in the face or intertriginous areas that then generalized and resolve with desquamation in 4 to 10 days together with fever. Main histopathological findings are spongiotic intraepidermal pustules. Most cases are triggered by systemic drugs but they can also follow some infections. Treatment includes suspension of the responsible drug and the use of topical or systemic corticosteroids. We describe a 12-year-old boy that presented fever and generalized erythema and pustules that appeared 48 hours after the intake of acetaminophen. Clinical diagnosis of AGEP was confirmed by a skin biopsy. Acetaminophen discontinuation was indicated together with topical corticosteroids and complete resolution was achieved. We highlight that AGEP is uncommon in children and that the literature reports only one case secondary to acetaminophen consumption