RESUMO
We reported the results of three years of house dust mite sublingual immunotherapy with Miticure® tablets. METHODS: Subjects of 115 cases (63 males, median 12.9 years old, 74 children under 15 years old) were evaluated with Japanese Rhino-conjunctivitis Quality of Life Questionnaire No1 (JRQLQ No1) and visual analog scale (VAS) of 100mm length for rhino-ocular and general symptoms. Annual survey was conducted for three years. RESULTS: Symptoms in all items of 1 to 3 years later by JRQLQ No1 and VAS were significantly improved (p<0.01). There was no difference from 1 year to 3 years later. The VAS value for total symptoms decreased from 41 (18-70) mm before treatment to 10 (4-40) mm after 1 year and 10 (3-30) mm after 3 years (median (IQR)). Concomitant medications used in all patients at the start of treatment were not needed in 60.8% after 1 year and 65.2% after 3 years. After 3 years, 16.5% of the patients were completely cured with no concomitant medication and had a symptom score of 0, and 53.0% were in remission with a score of 1 or less. There was no difference in all items between children and adults, and symptoms improved equally. CONCLUSION: The efficacy of house dust mite sublingual immunotherapy from 1 to 3 years was demonstrated.
Assuntos
Pyroglyphidae , Imunoterapia Sublingual , Adulto , Criança , Masculino , Animais , Humanos , Adolescente , Qualidade de Vida , ComprimidosRESUMO
BACKGROUND: We investigated the effect of sublingual immunotherapy (SLIT) on Japanese cedar and cypress pollinosis in a mass scattering year of cedar pollen (total counts: 12353 grains/cm2, approximately four times the average). METHODS: SLIT patients of 84 in the first year, 107 in the second year and 67 in the third year treated with Cedarcure® were included. During the 2023 cedar and cypress pollen dispersal season, nasal and eye symptoms and general symptoms were examined using a visual analog scale (VAS). RESULTS: The VAS during the cedar season significantly decreased to improve with the number of years of SLIT, but the VAS during the cypress period slightly increased. A questionnaire survey before SLIT revealed that only 0.9% to 3.6% of patients had strong cypress symptoms. However, sneezing (pï¼0.01), rhinorrhea, itchy eyes and total symptoms (pï¼0.05) in the third year of SLIT were significantly stronger during the cypress period than during the cedar period. The VAS of total symptoms during the Japanese cedar pollen season were not affected by the pollen count, and the cure rate was affected by SLIT in the third year. CONCLUSION: The clinical efficacy of cedar SLIT on cedar pollinosis was high even in a mass scattering year, and the effect increased with the number of years of treatment. On the other hand, it was shown that the clinical efficacy on cypress pollinosis was insufficient.
Assuntos
Cryptomeria , Cupressus , Rinite Alérgica Sazonal , Imunoterapia Sublingual , Humanos , Rinite Alérgica Sazonal/terapia , Pólen , Resultado do Tratamento , AlérgenosRESUMO
BACKGROUND: Little is known whether sublingual immunotherapy using Japanese cedar pollen extract (cedar SLIT) is effective for not only Japanese cedar pollinosis but also Japanese cypress pollinosis. We investigated the prevalence rate of Japanese cypress pollinosis, efficacy of cedar SLIT on cypress pollinosis and patients' wish to receive cypress SLIT. METHODS: We investigated a multi-center (31 institutions), cross-sectional survey using a self-administrated questionnaire with four questions for patients received cedar SLIT aged from 5 to 69 years old. RESULTS: 2523 subjects were enrolled for analysis. 83.4% of them had pollinosis symptoms during cypress season before cedar SLIT. In such patients, 37.4% experienced lessened efficacy of cedar SLIT during cypress season. Both the prevalence of cypress pollinosis and the lessened efficacy of cedar SLIT on cypress pollinosis were significantly seen in western Japan as compared to eastern Japan. 76.1% of the subject having cypress pollinosis before SLIT wished to receive cypress SLIT if it is available. CONCLUSION: A lessened efficacy of cedar SLIT during cypress season was broadly seen in Japan, and further showed a regional difference. Together with the finding of high wish by patients, these results suggest a development of cypress SLIT is desirable.
Assuntos
Cryptomeria , Cupressus , Rinite Alérgica Sazonal , Imunoterapia Sublingual , Humanos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Rinite Alérgica Sazonal/terapia , Rinite Alérgica Sazonal/tratamento farmacológico , Pólen , Estudos Transversais , Prevalência , Inquéritos e Questionários , AlérgenosRESUMO
BACKGROUND: We examined the clinical effects of Cedarcure® tablets for sublingual immunotherapy (SLIT), and examined the enhancement of the effects over the years of treatment. METHODS: The subjects were 358 patients who treated with SLIT (126 of third year of treatment, 102 of second year, 130 of first year) in a single clinic. The clinical efficacy was evaluated with visual analog scale (VAS) of nose, eye and total symptoms during the peak season of moderate amount of pollen dispersal (2485 grains/cm2/season) in 2022. Concomitant medication scores were calculated by Japanese guidelines. Because many cases of combined use of mite SLIT (dual SLIT) were included in the subjects, we compared cedar SLIT alone and dual SLIT as a secondary analysis. RESULTS: Clinical efficacy improved with the years of treatment, and all assessments of VAS in the 3rd year were significantly better than in the 1st year of treatment (p<0.01). The third year was better with sneezing and nasal discharge than the 2nd year, and the 2nd year was better with itchy eyes than the 1st year (p<0.05). Drug scores were also lower in the 3rd and 2nd years than in the 1st year (p<0.05). Additional mite SLIT did not affect the results. CONCLUSION: Cedarcure® showed enhancement of the effects over the years of treatment by the analysis up to the third year. Both Cedar SLIT alone and Dual SLIT showed similar efficacy on cedar pollinosis.
Assuntos
Cryptomeria , Rinite Alérgica Sazonal , Imunoterapia Sublingual , Humanos , Rinite Alérgica Sazonal/terapia , Administração Sublingual , Resultado do Tratamento , Comprimidos , AlérgenosRESUMO
BACKGROUND: We studied clinical efficacy and safety after 1 year of mite sublingual immunotherapy (SLIT) for perennial allergic rhinitis in children, compared with adults. METHODS: We compared 121 children under 15 yeas old (81 male, aged 5-14 years, a median of 12 years) and 77 adults (36 male, aged 15-65 years, a median of 26 years) treated with mite SLIT tablet (10000 Japanese Allergy Unit). The clinical efficacy before and 1 year after SLIT was evaluated by assessing symptom scores by Japanese rhino-conjunctivitis quality of life questionnaire (JRQLQ No1) and visual analog scale (VAS). Combined medication was also compared. Adverse events of SLIT were checked at every visit. RESULTS: All items of JRQLQ No1 scores and VAS after 1 year of mite SLIT, except eye symptoms in adults by JRQLQ No1, were significantly improved in both children and adults. Comparing children and adults, there were no differences in symptoms before and after 1 year. Combined medication score showed a similar result. Adverse events were observed in 57.9% of children and 58.4% of adults, but there were no serious adverse reactions. CONCLUSION: There was no difference between children and adults in efficacy and safety of mite SLIT, and both group showed significant improvement of symptoms.
Assuntos
Rinite Alérgica Perene , Rinite Alérgica , Imunoterapia Sublingual , Adolescente , Adulto , Idoso , Animais , Antígenos de Dermatophagoides , Criança , Pré-Escolar , Humanos , Masculino , Pessoa de Meia-Idade , Pyroglyphidae , Qualidade de Vida , Rinite Alérgica/terapia , Resultado do Tratamento , Adulto JovemRESUMO
Sublingual immunotherapy (SLIT) with Japanese cedar (JCe) pollinosis was expected to be effective for Japanese cypress (JCy) pollinosis. However, only a half of JCy pollinosis patients clinically improved. Therefore, we examined the immunological effect of SLIT for JCy pollinosis. Peripheral blood mononuclear cells (PBMCs) from patients with JCe and JCy pollinosis who did and did not receive SLIT were incubated with Cry j 1, Cha o 1 and Cha o 3 antigens. Basophil activation test (BAT) were performed. Production of IL-5 and IL-17 induced by antigens was inhibited in the SLIT group. Cry j 1-specific production of IL-10 was increased, and serum Cry j 1-specific IgE and -IgG4 were elevated. However, Cha o 1- or Cha o 3-specific production of IL-10 and specific IgG4 was not increased. Antigens-specific BAT did not decrease after SLIT. New SLIT with JCe and JCy is needed for patients with combined JCe and JCy pollinosis.
Assuntos
Leucócitos Mononucleares/imunologia , Rinite Alérgica Sazonal/terapia , Imunoterapia Sublingual/métodos , Adulto , Antígenos de Plantas/imunologia , Teste de Degranulação de Basófilos , Células Cultivadas , Chamaecyparis/imunologia , Cryptomeria/imunologia , Citocinas/metabolismo , Feminino , Humanos , Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/imunologia , Proteínas de Plantas/imunologia , Pólen/imunologia , Estudos Prospectivos , Rinite Alérgica Sazonal/imunologiaRESUMO
BACKGROUND: There have been no studies of dual administration of sublingual immunotherapy (SLIT) tablets for perennial and seasonal allergic rhinitis. This trial (JapicCTI-184014) was conducted to investigate the safety profile and immunological response during dual therapy with SQ house dust mite (HDM) and Japanese cedar pollen (JCP) SLIT tablets. METHODS: This was a multicenter, open-label, randomized trial of 109 Japanese patients with coexisting HDM and JCP allergic rhinitis who had positive tests for HDM- and JCP specific IgE (≥0.7 kU/L). Patients were allocated to receive HDM (N = 54) or JCP (N = 55) SLIT tablets alone for 4 weeks followed by 8 weeks of dual therapy with both SLIT tablets administered within 5 min of each other. Adverse events (AEs), adverse drug reactions (ADRs), and serum IgE and IgG4 specific for HDM (Dermatophagoides farinae, Dermatophagoides pteronyssinus) and JCP were recorded. RESULTS: The percentage of subjects with AEs and ADRs was similar between the two groups and between the two periods of monotherapy and dual therapy. Most AEs and ADRs were mild in severity, and no serious events were observed. The most common ADRs were local events in the oral cavity. Levels of IgE and IgG4 specific for HDM (D. farinae, D. pteronyssinus) and JCP were increased after treatment with HDM and JCP SLIT tablets, respectively. CONCLUSIONS: Dual therapy with both SLIT tablets administered within 5 min after 4 weeks of monotherapy with HDM or JCP tablet was well tolerated and induced the expected immunological responses.
Assuntos
Rinite Alérgica/tratamento farmacológico , Imunoterapia Sublingual/efeitos adversos , Imunoterapia Sublingual/métodos , Adolescente , Adulto , Animais , Antígenos de Dermatophagoides/administração & dosagem , Criança , Cryptomeria/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pólen/imunologia , Pyroglyphidae/imunologia , Rinite Alérgica/etiologia , Comprimidos , Adulto JovemRESUMO
BACKGROUND: We studied clinical efficacy and safety of pediatric sublingual immunotherapy of cedar pollinosis in the first follow-up year, compared with adult cases or untreated cases. METHODS: We compared 103 pediatrics under 15 yeas old (age, 10.8±2.6 years; male-to-female ratio, 68;35) and 89 adults (age, 38.9±12.5 years; male-to-female ratio, 34;55) treated with Cidarcure®, and untreated 299 patients (age, 31.3±16.0; male-to-female ratio, 144;155). The clinical efficacy was evaluated by assessing symptom scores by Japanese rhino-conjunctivitis quality of life questionnaire and visual analog scale (VAS) during the peak season of moderate amount of pollen dispersal (3582 grains/cm2/season) in 2020. Adverse events of sublingual immunotherapy were also checked at every visits. RESULTS: All patients in both pediatric and adult group successfully maintained the highest dose of 5000JAU as planned. Pediatrics compared with adults showed slightly better effects in all the assessments, but they were not significant. Both pediatrics and adults of sublingual immunotherapy showed significant better effects in all the assessments compared with untreated group. Percentage of total cases of adverse events in pediatric group was low, but it was not significant. Percentage of pruritus of ear and throat was significantly low in pediatric group. CONCLUSION: Pediatric sublingual immunotherapy for cedar pollinosis was treated in safe, and reduced symptoms as well as the effects of adults.
Assuntos
Cryptomeria , Rinite Alérgica Sazonal , Imunoterapia Sublingual , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pediatria , Qualidade de Vida , Rinite Alérgica Sazonal/terapia , Adulto JovemRESUMO
BACKGROUND: The development of methods to predict the clinical effectiveness of sublingual immunotherapy (SLIT) for allergic diseases is a crucial matter. We sought to determine whether whole saliva, which is the first body component that contacts allergen extracts during SLIT, is associated with the clinical effectiveness of SLIT in Japanese cedar pollinosis. METHODS: Blood monocytes or monocytic THP-1 cells were cultured in the presence or absence of either whole saliva or pure saliva with or without treatments including filtration and blockade of TLR2 and/or TLR4 signaling. IL-10 levels in the supernatants were then measured. Whole saliva-induced IL-10 production by THP-1 cells was compared between asymptomatic and disease-onset patients during peak pollen dispersal after SLIT. RESULTS: Both monocytes and THP-1 cells produced substantial amounts of IL-10 in response to whole saliva. IL-10 production was significantly reduced in response to pure saliva and 0.2 µm-filtered saliva. Simultaneous treatment with polymyxin B and TL2.1, a neutralizing antibody against TLR2, also reduced IL-10 production. IL-10 levels produced by THP-1 cells in response to whole saliva collected prior to SLIT were significantly higher in asymptomatic patients determined by symptom-medication scores than disease-onset patients following SLIT. Such differences were not seen in saliva collected 3 months after the initiation of SLIT or saliva collected during peak pollen dispersal. CONCLUSIONS: Our results provide a basis for why the sublingual route is effective and preferable in allergen immunotherapy. Saliva-induced IL-10 levels produced by THP-1 cells may be a predictive marker for clinical remission after SLIT.
Assuntos
Citocinas/imunologia , Rinite Alérgica Sazonal/terapia , Saliva/imunologia , Imunoterapia Sublingual , Adolescente , Adulto , Idoso , Células Cultivadas , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos , Rinite Alérgica Sazonal/imunologia , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Cedarcure® for sublingual immunotherapy of cedar pollinosis was purchased in 2018. We studied clinical efficacy of Cedarcure® in the first year. METHODS: We compared 69 patients treated with Cedarcure® (age, 18.0±13.5 years; male-to-female ratio, 40;29) and a control group of 97 patients treated with Cedartolen® (age, 29.8±16.2 years; male-to-female ratio, 44;53) during the peak season of large amount of pollen dispersal (10933 grains/cm2/season) in 2019. The clinical efficacy was evaluated by assessing symptom scores by Japanese rhino-conjunctivitis quality of life questionnaire and visual analog scale (VAS). RESULTS: All the assessments except nasal congestion were slightly better in Cedarcure® group, but they were not significant. There was no difference of concomitant medication in both groups. Because insurance coverage of Cedartolen® is for patients over 12 years old in Japan, the efficacy in Cedarcure® group enhanced better in all assessments if comparing the patients of over 12 years old. Percentage of adverse events was even in both over and under 12 years old. CONCLUSION: Cedarcure® was treated in safe, and reduced symptoms as well as Cedartolen®.
Assuntos
Cryptomeria/imunologia , Rinite Alérgica Sazonal/terapia , Imunoterapia Sublingual , Administração Sublingual , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: It past 4 years in 2018 after the first treatment of sublingual immunotherapy (SLIT) for Japanese cedar pollinosis. The purpose of this study is to clear the clinical efficacy of SLIT in a large amount of pollen dispersal in 2018 (total 5041 grain). METHODS: The subjects were 270 SLIT (83 forth year of treatment, 72 third year, 48 second year, 67 first year), 320 primary pharmacotherapy that started therapies before pollen dispersal, and 424 untreated. The clinical efficacy was evaluated with symptom scores of Japanese rhinoconjuctivitis quality of life questionnaire No1, medication scores and combined total nasal symptom-medication scores, and visual analog scale of nose, eye and total symptoms. RESULTS: Each SLIT was significantly better than untreated in all assessments, and better than primary pharmacotherapy in assessments of total symptom. SLITs of third and forth year of treatment were also better than primary pharmacotherapy in nasal symptoms. SLIT patients, whose symptom scores of nose and eye were 0 and 1 point without any rescue drugs, accounted for 41.0%, 31.9%, 18.8%, 20.9% in the order from the fourth year to the first year. Of them, patients with score 0 occupied 12.0%, 12.5%, 4.2%, 4.5%, in order. There was no patient who needs treatments for adverse events. CONCLUSION: SLIT was significantly effective compared with primary pharmacotherapy or untreated group in a large amount of pollen dispersal. It was better to treat at least for 4 years.
Assuntos
Hipersensibilidade/terapia , Pólen , Imunoterapia Sublingual , Administração Sublingual , Alérgenos , Humanos , Qualidade de Vida , Resultado do TratamentoAssuntos
Cryptomeria , Imunoterapia Sublingual , Alérgenos , Apoptose , Linfócitos T CD4-Positivos , Humanos , Extratos Vegetais/farmacologia , Pólen , Linfócitos TAssuntos
Dessensibilização Imunológica , Rinite Alérgica , Humanos , Imunidade Adaptativa , Alérgenos , Imunidade Inata , ImunoterapiaRESUMO
It past 3 years in 2017 after the first purchase of the drug for sublingual immunotherapy (SLIT) for Japanese Cedar pollinosis (JCP). We reported the clinical efficacy of SLIT in the first and the second treated year. PURPOSE: The purpose of this study is to clear the clinical efficacy of SLIT in the third treated year by comparing with other therapies, such as subcutaneous immunotherapy (SCIT), or other pharmacotherapy. METHODS: We compared the clinical efficacy in 2017, of 112 SLIT in the third treated year with 38 SCIT, 364 primary pharmacotherapy that started therapies before pollen dispersal, 254 pharmacotherapy that started therapies after pollen disposal, or 333 non-treatment. The clinical efficacy was evaluated with symptom scores, total nasal symptom scores and combined total nasal symptom-medication scores (TNSMS), symptoms of nose and eye by visual analog scale (VAS), quality of life (QOL) scores by Japanese rhino-conjunctivitis QOL questionnaire (JRQLQ No1). RESULTS: Both SCIT and SLIT showed good clinical efficacy without significant difference in every assessment. Both SCIT and SLIT were significantly better than other pharmacotherapy in most assessment. Patients, whose symptom scores of nose and eye were 0 and 1 point without any rescue drugs, accounted for 9 and 24% of total SLIT, respectively. CONCLUSION: SLIT in the third treated year showed good clinical efficacy in reducing symptoms and TNSMS of JCP, and in improving QOL. SLIT was significantly effective compared with other pharmacotherapies.
Assuntos
Cryptomeria/imunologia , Pólen/imunologia , Rinite Alérgica Sazonal/terapia , Imunoterapia Sublingual , Administração Sublingual , Adulto , Feminino , Humanos , Masculino , Rinite Alérgica Sazonal/imunologia , Imunoterapia Sublingual/efeitos adversos , Fatores de TempoRESUMO
Sublingual immunotherapy (SLIT) is thought to have enhanced efficacy in the second year of treatment. We studied treatment efficacy in both the first and the second years of treatment (2015 and 2016, respectively) in patients who began SLIT in 2014. Methods: We compared 132 patients who underwent SLIT (age, 41.8 ± 17.5 years; male-to-female ratio, 75: 57) and a control group of 56 patients who underwent primary pharmacotherapy (age, 44.9 ± 13.5 years; male-to-female ratio, 25: 31). The study was performed during the peak pollen seasons of 2015 and 2016. Pollen dispersal was similar in 2015 and 2016 (2,509 grains/cm2 and 3,505 grains/cm2, respectively). The clinical efficacy of SLIT was evaluated by assessing nasal and eye symptoms and total symptoms with symptom scores and combined symptom-medication scores, visual analog scale scores, and quality of life (QOL) scores according to the Japanese rhino-conjunctivitis QOL questionnaire (JRQLQ No. 1). QOL was also evaluated with JRQLQ No. 1. The first endpoint was enhanced efficacy of SLIT in the second year compared with that in the first year. Results: With respect to nasal and eye symptoms, the assessments in the primary pharmacotherapy group were unchanged in the second year; however, most of these assessments in the SLIT group demonstrated significantly enhanced efficacy of SLIT in the second year. In QOL of SLIT, only 2 of 17 showed significantly enhanced efficacy of SLIT in the second year. Conclusion: SLIT shows enhanced efficacy in the second year.
Assuntos
Cryptomeria/imunologia , Pólen/imunologia , Rinite Alérgica Sazonal/terapia , Imunoterapia Sublingual , Administração Sublingual , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Rinite Alérgica Sazonal/imunologia , Estações do Ano , Inquéritos e Questionários , Adulto JovemRESUMO
It past 2 years in 2016 after the first purchase of the drug for sublingual immunotherapy (SLIT) for Japanese Cedar pollinosis (JCP). PURPOSE: The purpose of this study is to clear the clinical efficacy of SLIT in the second treated year by comparing with other therapies, such as subcutaneous immunotherapy (SCIT), or other pharmacotherapy. METHODS: We started SLIT at our clinic in October-December, 2014. We compared the clinical efficacy in 2016, of 133 SLIT with 46 SCIT, 351 primary pharmacotherapy that started therapies before pollen dispersal, 221 pharmacotherapy that started therapies after pollen disposal, or 337 non-treatment. The clinical efficacy was evaluated with symptom scores and combined symptom-medication scores (SMS), symptoms of nose and eye by visual analog scale (VAS), quality of life (QOL) scores by Japanese rhino-conjunctivitis QOL questionnaire (JRQLQ No1). RESULTS: Fourteen cases by unknown reasons and 3 cases by inevitable reasons were dropped out for 2 years. Both SCIT and SLIT showed good clinical efficacy without significant difference in every assessment. Both SCIT and SLIT were significantly better than other pharmacotherapy in most assessment. Patients, whose symptom scores of nose and eye were 0 or 1 point without any rescue drugs, accounted for 26.3% of total SLIT. CONCLUSION: SLIT in the second treated year showed good clinical efficacy in reducing symptoms and SMS of JCP, and in improving QOL. SLIT was significantly effective compaired with other pharmacotherapies.
Assuntos
Cryptomeria/imunologia , Pólen/imunologia , Rinite Alérgica Sazonal/terapia , Imunoterapia Sublingual , Adulto , Feminino , Humanos , Masculino , Qualidade de Vida , Rinite Alérgica Sazonal/imunologia , Inquéritos e Questionários , Resultado do TratamentoRESUMO
Sublingual immunotherapy (SLIT) for Japanese cedar pollinosis is known to be effective. However, better SLIT adherence is needed to improve its safety and efficacy. ãPurpose: The purpose of this study was to evaluate SLIT adherence and its influence on clinical outcome. ãMethods: We conducted a detailed survey of 132 patients who have been receiving SLIT for 2 years on adherence at each visit using both questionnaires and direct calculation from prescription. Questionnaires on total symptoms using the visual analog scale (VAS), face scale, and total nasal symptom medication score (TNSMS) were obtained at the peak season for Japanese cedar pollinosis. ãResults: Good adherence by prescription for 2 years was observed in 83.1% ± 11.7% of patients. The adherence in the second year (80.8% ± 13.6%) was lower than that in the first year (88.5% ± 9.8%). However, adherence by questionnaire was 13.5% higher than that by prescription. VAS of total symptoms and adherence did not correlate; however, evaluations by VAS, face scale, and TNSMS were significantly improved if the adherence cut-off value was set to 70% or 75%. ãConclusion: Our results suggest that SLIT adherence for Japanese cedar pollinosis is high and adequate adherence is required for better efficacy.