RESUMEN
The dosage of evocalcet required to control serum parathyroid hormone (PTH) levels varies among secondary hyperparathyroidism (SHPT) patients. This post hoc analysis evaluated the dose-dependent efficacy of evocalcet on serum intact PTH (iPTH) levels, corrected calcium (Ca) and phosphate (P) levels, and safety, in an evaluation period (week 28 to week 30) by stratifying the previous phase 3 data with the final evocalcet dosages (low 1-2 mg [131 patients], medium 3-4 mg [90 patients], high 5-8 mg [92 patients]), and identified pre-treatment patient characteristics predicting the use of higher final evocalcet dosages via univariate and multivariate logistic regression models. At the end of the study at week 30, the median serum iPTH level was higher and the achievement ratio for the target range of Japanese Society for Dialysis Therapy (60-240 pg/mL) was lower in the final high-dose subgroup (216 pg/mL and 58%, respectively) than in the other subgroups (low: 149 pg/mL and 79%; medium: 149 pg/mL and 73%, respectively). Among the three subgroups, the mean serum corrected Ca and P levels demonstrated similar trends, and similar ratio of patients achieved the target range (corrected Ca, 8.4-10 mg/dL; P, 3.5-6.0 mg/dL) from week 28 to week 30. No dose-dependent safety concerns were identified. Younger age, prior cinacalcet use, higher serum levels of iPTH and corrected Ca, procollagen type 1 N-terminal propeptide, intact fibroblast growth factor-23, and larger maximum parathyroid gland volume were significantly associated with final high-dose evocalcet (p < 0.05 in all cases). Patients requiring final high-dose evocalcet had pre-treatment characteristics indicating severe SHPT, leading to a lower final achievement rate for the target PTH levels of Japanese Society for Dialysis Therapy. Therefore, the early initiation of evocalcet treatment for SHPT is critical. Trial registration: This trial was registered as follows: ClinicalTrials.gov: NCT02549391 and JAPIC: JapicCTI-153013.
Asunto(s)
Hiperparatiroidismo Secundario , Humanos , Calcio , Cinacalcet/uso terapéutico , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/etiología , Naftalenos/uso terapéutico , Hormona Paratiroidea , Diálisis RenalRESUMEN
This ad hoc analysis of a previously conducted phase 3 head-to-head comparison study of evocalcet and cinacalcet in secondary hyperparathyroidism patients undergoing maintenance hemodialysis evaluated the efficacy and safety of combined once-daily oral evocalcet and intravenous vitamin D receptor activator treatment stratified by weekly vitamin D receptor activator dose (117, 45, and 91 patients in no, low [< 1.5 µg], and high [≥ 1.5 µg] dose groups, respectively). Effects of vitamin D receptor activator were assessed on the basis of intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels; percent changes from baseline; proportions of patients who achieved target intact parathyroid hormone, corrected calcium, and phosphorus at Weeks 28-30; and adverse drug reactions. Intact parathyroid hormone, corrected calcium, phosphorus, and fibroblast growth factor-23 levels decreased in all groups; phosphorus and fibroblast growth factor-23 levels remained high in the high dose group. In the low and high dose groups, greater proportions of patients achieved the corrected calcium target compared with the no dose group (p = 0.043). Ratios of intact-to-C-terminal fibroblast growth factor-23 decreased in all groups. In low and high dose groups, hypocalcemia was less common than in the no dose group (p = 0.014). Evocalcet with concomitant vitamin D receptor activator demonstrated benefits such that more patients achieved the corrected calcium target and exhibited decreased fibroblast growth factor-23 synthesis; the incidence of hypocalcemia also decreased. Clinical trial registration: ClinicalTrials.gov (NCT02549391) and JAPIC (JapicCTI-153013).
Asunto(s)
Calcimiméticos/uso terapéutico , Hiperparatiroidismo Secundario/tratamiento farmacológico , Naftalenos/uso terapéutico , Pirrolidinas/uso terapéutico , Receptores de Calcitriol/agonistas , Método Doble Ciego , Quimioterapia Combinada , Humanos , Hiperparatiroidismo Secundario/patología , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
INTRODUCTION: The calcium-sensing receptor is an important treatment target for secondary hyperparathyroidism (SHPT) in patients undergoing dialysis. In addition to vitamin D receptor activator, cinacalcet has recently been widely used for SHPT management, and the significant suppression of parathyroid hormone (PTH) with better control of serum calcium and phosphorus has been reported. However, low adherence and insufficient dose escalation mainly due to frequent gastrointestinal adverse events, still remain as major issues. To overcome these unmet needs, we have developed a new oral calcimimetic agent evocalcet, which has recently been approved by the Pharmaceutical Affairs Act in Japan. AREAS COVERED: PubMed was searched from inception until April 2020 with the word evocalcet to summarize the development of this new calcimimetic agent, its pharmacokinetics, and the results of clinical trials, along with an overview of the differences among calcimimetic agents. This review also includes the management of SHPT with a focus on calcimimetics. EXPERT OPINION: Evocalcet evoked fewer gastrointestinal-related adverse events while suppressing PTH at a lower dose than cinacalcet. These data suggest evocalcet may contribute to better adherence and sufficient dose escalation in patients with SHPT. Whether or not evocalcet improves clinical outcomes remains to be elucidated.
Asunto(s)
Calcimiméticos/uso terapéutico , Cinacalcet/uso terapéutico , Hiperparatiroidismo Secundario/tratamiento farmacológico , Naftalenos/uso terapéutico , Pirrolidinas/uso terapéutico , Calcimiméticos/efectos adversos , Calcio/sangre , Cinacalcet/efectos adversos , Enfermedades Gastrointestinales/inducido químicamente , Humanos , Hiperparatiroidismo Secundario/sangre , Japón , Naftalenos/efectos adversos , Fósforo/sangre , Pirrolidinas/efectos adversos , Receptores Sensibles al Calcio/efectos de los fármacos , Diálisis Renal , Insuficiencia Renal Crónica/tratamiento farmacológicoRESUMEN
Peanut allergy is severe and persisting from childhood to adulthood. However, there is no effective prophylaxis or treatment for peanut allergy. Little is known to about the molecular process in the pathogenesis of peanuts allergy, especially in innate immunity. Thus we investigated the role of complement activation in murine peanut anaphylaxis. Complement component C3 deposition on peanut extract (PE) was evaluated using sera from wild-type (WT), mannose-binding lectin associated serine protease (MASP)-1/3 deficient, MASP-2 deficient, and C4 deficient mice. Sera from interferon regulatory factor-4 (IRF-4) deficient mice, which lack serum immunoglobulin, were also used. In anaphylaxis study, mice were pretreated with propranolol and a long-acting form of IL-4, and injected with PE. Mice were then assessed for plasma C3a levels and hypothermia shock by ELISA and rectal temperature measurement, respectively. C3 deposition on PE was abolished in immunoglobulin- and C4-deficient sera. No difference in C3 deposition levels were observed among WT, MASP-1/3 deficient and MASP-2 deficient sera. IgM, IgG2b, IgG3, C1q, and ficolin-A deposits were detected on PE. In anaphylaxis study, MASP-1/3 deficient mice showed elevation of plasma C3a levels similar to WT mice. However, they were significantly reduced in C4- and MASP-2-deficient mice compared to WT mice. Consistently, PE-induced anaphylactic shock was prevented in C4 deficient mice and partially in MASP-2 deficient mice. In conclusion, PE activates complement via both the lectin and classical pathways in vivo, and the complement activation contributes to hypothermia shock in mice.
Asunto(s)
Activación de Complemento/inmunología , Proteínas del Sistema Complemento/inmunología , Modelos Animales de Enfermedad , Hipersensibilidad al Cacahuete/inmunología , Animales , Arachis/inmunología , Temperatura Corporal/inmunología , Temperatura Corporal/fisiología , Respuesta al Choque por Frío/inmunología , Activación de Complemento/fisiología , Complemento C1q/inmunología , Complemento C1q/fisiología , Complemento C3/inmunología , Complemento C3/fisiología , Complemento C4/genética , Complemento C4/inmunología , Complemento C4/fisiología , Proteínas del Sistema Complemento/fisiología , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulinas/sangre , Inmunoglobulinas/genética , Inmunoglobulinas/inmunología , Factores Reguladores del Interferón/deficiencia , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/inmunología , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/genética , Serina Proteasas Asociadas a la Proteína de Unión a la Manosa/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Hipersensibilidad al Cacahuete/sangre , Hipersensibilidad al Cacahuete/genética , Extractos Vegetales/inmunologíaRESUMEN
Complement C3 plays an essential role in the opsonization of pathogens in the mammalian complement system, whereas the molecular mechanism underlying C3 activation in invertebrates remains unknown. To understand the molecular mechanism of C3b deposition on microbes, we characterized two types of C2/factor B homologs (designated TtC2/Bf-1 and TtC2/Bf-2) identified from the horseshoe crab Tachypleus tridentatus. Although the domain architectures of TtC2/Bf-1 and TtC2/Bf-2 were identical to those of mammalian homologs, they contained five-repeated and seven-repeated complement control protein domains at their N-terminal regions, respectively. TtC2/Bf-1 and TtC2/Bf-2 were synthesized and glycosylated in hemocytes and secreted to hemolymph plasma, which existed in a complex with C3 (TtC3), and their activation by microbes was absolutely Mg(2+)-dependent. Flow cytometric analysis revealed that TtC3b deposition was Mg(2+)-dependent on Gram-positive bacteria or fungi, but not on Gram-negative bacteria. Moreover, this analysis demonstrated that Ca(2+)-dependent lectins (C-reactive protein-1 and tachylectin-5A) were required for TtC3b deposition on Gram-positive bacteria, and that a Ca(2+)-independent lectin (Tachypleus plasma lectin-1) was definitely indispensable for TtC3b deposition on fungi. In contrast, a horseshoe crab lipopolysaccharide-sensitive protease factor C was necessary and sufficient to deposit TtC3b on Gram-negative bacteria. We conclude that plasma lectins and factor C play key roles in microbe-specific TtC3b deposition in a C2/factor B-dependent or -independent manner.
Asunto(s)
Complemento C2/inmunología , Complemento C3b/inmunología , Factor B del Complemento/inmunología , Cangrejos Herradura/inmunología , Animales , Clonación Molecular , Activación de Complemento/inmunología , Complemento C2/genética , Complemento C2/metabolismo , Complemento C3b/metabolismo , Factor B del Complemento/genética , Factor B del Complemento/metabolismo , ADN Complementario , Factores de Transcripción Forkhead/inmunología , Factores de Transcripción Forkhead/metabolismo , Hongos/inmunología , Bacterias Grampositivas/inmunología , Cangrejos Herradura/microbiología , Magnesio/metabolismo , Modelos Biológicos , Unión Proteica/inmunología , Estructura Terciaria de ProteínaRESUMEN
Hoelen, sclederma of Poria cocos Wolf, has long been used as a sedative and diuretic in traditional medicine. Formerly, we demonstrated that Hoelen in vitro protects red blood cells from AAPH-induced hemolysis. In this study, tests were carried out to identify the main ingredient of Hoelen that has the scavenging effect on free-radicals. Triterpene carboxylic acids isolated from the methanol extract of Hoelen, i.e. pachymic acid, polyporenic acid, 3-epidehydrotumulosic acid, 3beta-hydroxylanosta-7,9(11), 24-trien-21-oic acid and 3-o-acetyl-16 alpha -hydroxytrametenolic acid, were found to have inhibitory activities against AAPH-induced lysis of red blood cells.