RESUMO
ß2-adrenergic receptor (ß2AR) agonists are the clinical gold standard for treatment and prophylaxis of airway constriction in pulmonary obstructive diseases such as asthma and COPD. Inhaled ß2-agonists elicit rapid bronchorelaxation of the airway smooth muscle, yet, clinical tachyphylaxis to this response can occur over repeated and chronic use, which reduces the bronchodilatory effectiveness. Several mechanisms have been proposed to impart ß2-agonist tachyphylaxis, most notably ß2AR desensitization. However, airway tissue is known to be highly oxidative, particularly in obstructive disease states where reactive oxygen species (ROS) generation is upregulated and ROS degradation is suboptimal yielding a large oxidative burden. Recent evidence demonstrates that ß2AR can regulate ROS generation and that ROS can post-translationally alter ß2AR cysteine residues via oxidation, leading to distinct functional receptor outcomes. Herein, we discuss the growing evidence for ß2AR mediated ROS generation in airway cells and the role of ROS in regulating ß2AR via cysteine-oxidation of the receptor. Given the functional consequence of the ß2AR-ROS signaling axis in the airways, we also discuss the potential role of ROS in mediating ß2-agonist tachyphylaxis.
Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Oxirredução , Espécies Reativas de Oxigênio , Receptores Adrenérgicos beta 2 , Taquifilaxia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Oxirredução/efeitos dos fármacos , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Receptores Adrenérgicos beta 2/metabolismo , Animais , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológicoAssuntos
Transtorno Depressivo Resistente a Tratamento , Ketamina , Taquifilaxia , Feminino , Humanos , Pessoa de Meia-Idade , Administração Intravenosa , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/administração & dosagem , Ketamina/farmacologiaRESUMO
Asthma and other airway obstructive disorders are characterized by heightened inflammation and excessive airway epithelial cell reactive oxygen species (ROS), which give rise to a highly oxidative environment. After decades of use, ß2-adrenergic receptor (ß2AR) agonists remain at the forefront of treatment options for asthma, however, chronic use of ß2-agonists leads to tachyphylaxis to the bronchorelaxant effects, a phenomenon that remains mechanistically unexplained. We have previously demonstrated that ß2AR agonism increases ROS generation in airway epithelial cells, which upholds proper receptor function via feedback oxidation of ß2AR cysteine thiolates to Cys-S-sulfenic acids (Cys-SOH). Our previous results also demonstrate that prevention of normal redox cycling of this post-translational oxi-modification back to the thiol prevents proper receptor function. Given that Cys-S-sulfenic acids can be irreversibly overoxidized to Cys-S-sulfinic (Cys-SO2H) or S-sulfonic (Cys-SO3H) acids, which are incapable of further participation in redox reactions, we hypothesized that ß2-agonist tachyphylaxis may be explained by hyperoxidation of ß2AR to S-sulfinic acids. Here, using airway epithelial cell lines and primary small airway epithelial cells from healthy and asthma-diseased donors, we show that ß2AR agonism generates H2O2 in a receptor and NAPDH oxidase-dependent manner. We also demonstrate that acute and chronic receptor agonism can facilitate ß2AR S-sulfination, and that millimolar H2O2 concentrations are deleterious to ß2AR-mediated cAMP formation, an effect that can be rescued to a degree in the presence of the cysteine-donating antioxidant N-acetyl-L-cysteine. Our results reveal that the oxidative state of ß2AR may contribute to receptor functionality and may, at least in part, explain ß2-agonist tachyphylaxis.
Assuntos
Asma , Peróxido de Hidrogênio , Humanos , Peróxido de Hidrogênio/metabolismo , Ácidos Sulfênicos/metabolismo , Cisteína/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Taquifilaxia , Asma/metabolismo , Células Epiteliais/metabolismo , Receptores Adrenérgicos/metabolismoRESUMO
Among the proton-activated channels of the ASIC family, ASIC1a exhibits a specific tachyphylaxis phenomenon in the form of a progressive decrease in the response amplitude during a series of activations. This process is well known, but its mechanism is poorly understood. Here, we demonstrated a partial reversibility of this effect using long-term whole-cell recording of CHO cells transfected with rASIC1a cDNA. Thus, tachyphylaxis represents a slow desensitization of ASIC1a. Prolonged acidifications provided the same recovery from slow desensitization as short acidifications of the same frequency. Slow desensitization and steady-state desensitization are independent processes although the latter attenuates the development of the former. We found that drugs which facilitate ASIC1a activation (e.g., amitriptyline) cause an enhancement of slow desensitization, while inhibition of ASIC1a by 9-aminoacridine attenuates this process. Overall, for a broad variety of exposures, including increased calcium concentration, different pH conditions, and modulating drugs, we found a correlation between their effects on ASIC1a response amplitude and the development of slow desensitization. Thus, our results demonstrate that slow desensitization occurs only when ASIC1a is in the open state.
Assuntos
Canais Iônicos Sensíveis a Ácido , Taquifilaxia , Animais , Cricetinae , Cricetulus , Células CHO , Amitriptilina , Concentração de Íons de HidrogênioRESUMO
PURPOSE: Treatment of choroidal neovascularization due to age-related macular degeneration is a challenging topic since an increasing number of patients show reduced morphological response to conventional treatment with intravitreal injections. The present study tested the hypothesis that the newly introduced anti-VEGF antibody brolucizumab does not only show promising results in pre-treated patients but is also a viable option in cases of tachyphylaxis to aflibercept or bevacizumab. METHODS: Thirty-six eyes of 34 patients with a history of at least 10 anti-VEGF injections as well as persistent retinal fluid following the past 5 monthly injections with aflibercept and bevacizumab prior to first treatment with brolucizumab were included in the study. Morphological and functional treatment response was compared before and after switching to brolucizumab. RESULTS: Mean best-corrected visual acuity did not significantly change after treatment with brolucizumab. In contrast, central retinal thickness significantly decreased 4 weeks after treatment with brolucizumab from 340.36 to 282.22 µm (p < 0.001) as well as pigment epithelial detachment from 346.73 to 280.47 µm (p < 0.001). In 24 eyes (66.67%), complete resolution of intra-and subretinal fluid was observed after a single dose of brolucizumab. No serious adverse events, such as intraocular inflammation and retinal vasculitis, were reported after a single injection of brolucizumab. CONCLUSION: Brolucizumab is not only effective in treatment-naïve patients as shown in the pivotal HAWK and Harrier trials, but also in pre-treated patients as seen in the present study. Our data also suggest that brolucizumab is potent in patients with signs of tachyphylaxis to other anti-VEGF agents and thus a viable treatment option.
Assuntos
Neovascularização de Coroide , Inibidores da Angiogênese , Anticorpos Monoclonais Humanizados , Bevacizumab/uso terapêutico , Neovascularização de Coroide/diagnóstico , Neovascularização de Coroide/tratamento farmacológico , Humanos , Injeções Intravítreas , Receptores de Fatores de Crescimento do Endotélio Vascular , Proteínas Recombinantes de Fusão/uso terapêutico , Taquifilaxia , Acuidade VisualRESUMO
Attenuation of drug response with repeated administration is referred to as tachyphylaxis or tolerance, though the distinction between these two is obscured through both their usage in the literature and imprecise definitions in common pharmacology texts. In this perspective, I propose that these terms be distinguished by the mechanisms underlying the attenuation of drug response. Specifically, tachyphylaxis should be reserved for attenuation that occurs in response to cellular depletion, whereas tolerance should be used to describe attenuation that arises from cellular adaptations. A framework for understanding behavioral tolerance, physiologic tolerance, and dispositional tolerance as distinct phenomena is also discussed. Using this framework, a classification of drugs exhibiting attenuation of drug response with repeated administration is presented. SIGNIFICANCE STATEMENT: Distinction between tachyphylaxis and tolerance is unclear in the literature. Nonetheless, a mechanistic basis for distinguishing these important terms has practical implications for managing or preventing attenuation of drug response with repeated administration.
Assuntos
Taquifilaxia , Tolerância a MedicamentosRESUMO
Several GPCRs (G-protein-coupled receptors) have been reported to exhibit tachyphylaxis, which is an acute loss of functional receptor response after repeated stimuli with an agonist. GPCRs are important clinical targets for a wide range of disorders. Therefore, elucidation of the ligand features that contribute to receptor tachyphylaxis and signaling events underlying this phenomenon is important for drug discovery and development. In this study, we examined the role of ligand-binding kinetics in the tachyphylaxis of AT1R (angiotensin II type 1 receptor) using bioluminescence resonance energy transfer assays to monitor signaling events under both kinetic and equilibrium conditions. We investigated AT1R signal transduction and translocation promoted by the endogenous tachyphylactic agonist Ang II (angiotensin II) and its analogs, described previously for inducing reduced receptor tachyphylaxis. Estimation of binding kinetic parameters of the ligands revealed that the residence time of Ang II was higher than that of the analogs, resulting in more sustained Gq protein activation and recruitment of ß-arrestin than that promoted by the analogs. Furthermore, we observed that Ang II led to more sustained internalization of the receptor, thereby retarding its recycling to the plasma membrane and preventing further receptor responses. These results show that the apparent lack of tachyphylaxis in the studied analogs resulted from their short residence time at the AT1R. In addition, our data highlight the relevance of complete characterization of novel GPCR drug candidates, taking into account their receptor binding kinetics as well.
Assuntos
Angiotensina II/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais/fisiologia , Taquifilaxia/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células HEK293 , Humanos , Losartan/farmacologia , Ligação Proteica , Transdução de Sinais/efeitos dos fármacosRESUMO
Acid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key participant in channel gating. While binding to this region by the venom peptide psalmotoxin modulates channel gating, molecular and structural mechanisms of ASIC gating modulation by small molecules are poorly understood. Here, combining functional, crystallographic, computational and mutational approaches, we show that two structurally distinct small molecules potently and allosterically inhibit channel activation and desensitization by binding at the acidic pocket and stabilizing the closed state of rat/chicken ASIC1. Our work identifies a previously unidentified binding site, elucidates a molecular mechanism of small molecule modulation of ASIC gating, and demonstrates directly the structural basis of such modulation, providing mechanistic and structural insight into ASIC gating, modulation and therapeutic targeting.
Assuntos
Canais Iônicos Sensíveis a Ácido/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , Moduladores de Transporte de Membrana/farmacologia , Canais Iônicos Sensíveis a Ácido/química , Canais Iônicos Sensíveis a Ácido/genética , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Sítios de Ligação , Células CHO , Cricetulus , Cinética , Potenciais da Membrana , Moduladores de Transporte de Membrana/química , Mutação , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , TaquifilaxiaRESUMO
For most G protein-coupled receptors, the third intracellular loop (IL3) and carboxy-terminal tail (CT) are sites for G protein-coupled receptor kinase (GRK)-mediated phosphorylation, leading to ß-arrestin binding and agonist-specific desensitization. These regions of bitter taste receptors (TAS2Rs) are extremely short compared with the superfamily, and their function in desensitization is unknown. TAS2R14 expressed on human airway smooth muscle cells relax the cell, suggesting a novel target for bronchodilators. To assess IL3 and CT in agonist-promoted TAS2R14 desensitization (tachyphylaxis), we generated fusion proteins of both the WT sequence and Ala substituted for Ser/Thr in the IL3 and CT sequences. In vitro, activated GRK2 phosphorylated WT IL3 and WT CT proteins but not Ala-substituted forms. TAS2R14s with mutations in IL3 (IL-5A), CT (CT-5A), and in both regions (IL/CT-10A) were expressed in human embryonic kidney 293T cells. IL/CT-10A and CT-5A failed to undergo desensitization of the intracellular calcium response compared with WT, indicating that functional desensitization by GRK phosphorylation is at residues in the CT. Desensitization of TAS2R14 was blocked by GRK2 knockdown in human airway smooth muscle cells. Receptor:ß-arrestin binding was absent in IL/CT-10A and CT-5A and reduced in IL-5A, indicating a role for IL3 phosphorylation in the ß-arrestin interaction for this function. Agonist-promoted internalization of IL-5A and CT-5A receptors was impaired, and they failed to colocalize with early endosomes. Thus, agonist-promoted functional desensitization of TAS2R14 occurs by GRK phosphorylation of CT residues and ß-arrestin binding. However, ß-arrestin function in the internalization and trafficking of the receptor also requires GRK phosphorylation of IL3 residues.
Assuntos
Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Miócitos de Músculo Liso/metabolismo , Processamento de Proteína Pós-Traducional , RNA Interferente Pequeno/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Substituição de Aminoácidos , Brônquios/citologia , Brônquios/metabolismo , Cálcio/metabolismo , Difenidramina/farmacologia , Endossomos/metabolismo , Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Quinase 2 de Receptor Acoplado a Proteína G/química , Quinase 2 de Receptor Acoplado a Proteína G/genética , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Mutação , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ligação Proteica , RNA Interferente Pequeno/genética , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Taquifilaxia/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , beta-Arrestinas/genética , beta-Arrestinas/metabolismoRESUMO
BACKGROUND: Treprostinil palmitil (TP) is an inhaled long-acting pulmonary vasodilator prodrug of treprostinil (TRE) that has been formulated for delivery as a suspension (treprostinil palmitil inhalation suspension; TPIS) and as a dry powder (treprostinil palmitil inhalation powder; TPIP). In humans, tachyphylaxis is frequently observed with continuous intravenous (IV) or subcutaneous (SC) infusion of TRE and requires dosage escalation to maintain activity. The aim of the present study was to determine whether tachyphylaxis occurs with repeat daily administration of inhaled TPIS. METHODS: Experiments were performed in male Sprague-Dawley rats prepared with a telemetry probe implanted into the right ventricle to measure the change in right ventricular pulse pressure (ΔRVPP) induced by exposure to a 10% oxygen gas mixture. TPIS (6 mL) at concentrations of 0.25, 0.5, and 1 mM was given by nose-only inhalation using an Aeroneb Pro nebulizer, either as a single administration or daily for 16 or 32 consecutive days. In studies involving consecutive daily administrations of TPIS, the delivered TP dosage was 140.3 µg/kg at 1 mM and ranged from 40.2 to 72.2 µg/kg at 0.5 mM. A separate cohort of telemetered rats received continuous IV infusion of TRE via an Alzet mini-pump at a dosage rate of 250 ng/kg/min for 16 days. Blood and lung tissue samples were obtained, and the concentration of TRE in the plasma and TRE and TP in the lungs were measured approximately 1 h after TPIS administration. RESULTS: Dose-response studies with TPIS administered as a single administration inhibited the hypoxia-induced increase in RVPP in both a concentration-dependent (0.25, 0.5, and 1 mM) and time-dependent (1-24 h) manner. TPIS, given QD or BID at inhaled doses ranging from 40.2 to 140.3 µg/kg for 16 or 32 consecutive days, produced statistically significant (P < .05) inhibition of the increase of RVPP due to hypoxia over the full duration of the dosing periods. By contrast, the inhibition of the hypoxia-induced increase in RVPP observed with IV TRE infusion (250 ng/kg/min) disappeared after 16 days of infusion. The plasma concentrations of TRE were significantly higher after IV TRE (range, 2.85-13.35 ng/mL) compared to inhaled TPIS (range, 0.22-0.73 ng/mL) CONCLUSIONS: There was no evidence of tachyphylaxis with repeat daily dosing of TPIS for a period of up to 32 days. The absence of tachyphylaxis with TPIS is likely related to its local vasodilatory effects within the lungs, combined with an absence of sustained high plasma concentrations of TRE.
Assuntos
Taquifilaxia , Vasodilatadores , Animais , Anti-Hipertensivos/uso terapêutico , Epoprostenol/análogos & derivados , Pulmão , Masculino , Ratos , Ratos Sprague-Dawley , Vasodilatadores/farmacologiaRESUMO
BACKGROUND: Pulmonary hypertension is a significant complication for some patients with COVID-19 pneumonia, especially those requiring intensive care. Tachyphylaxis to the current therapy, inhaled nitric oxide (iNO), is also common. In vitro, folic acid directly increases nitric oxide (NO) production and extends its duration of action; effects which could be of benefit in reversing pulmonary hypertension and severe hypoxaemia. Our work has shown that, in the systemic circulation, folic acid in high dose rapidly improves nitric oxide mediated vasodilation, by activating endothelial nitric oxide synthase (eNOS). HYPOTHESIS: A similar effect of high dose folic acid on pulmonary endothelial function would be expected from the same mechanism and would lead to improvement in pulmonary perfusion. We therefore hypothesise that folic acid, 5 mg or greater, is a useful therapeutic option for pulmonary hypertension and/or refractory severe hypoxaemia, in patients with severe COVID-19 associated pneumonia in whom NO therapy is considered, with a very low risk of adverse effects.
Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Ácido Fólico/uso terapêutico , Hipertensão Pulmonar/tratamento farmacológico , Óxido Nítrico/metabolismo , Pandemias , Pneumonia Viral/complicações , Administração por Inalação , Animais , COVID-19 , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ácido Fólico/administração & dosagem , Ácido Fólico/farmacologia , Humanos , Hipertensão Pulmonar/complicações , Hipóxia/tratamento farmacológico , Hipóxia/etiologia , Camundongos , Óxido Nítrico/administração & dosagem , Óxido Nítrico/uso terapêutico , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , SARS-CoV-2 , TaquifilaxiaRESUMO
BACKGROUND, AIMS: In patients with type 2 diabetes, the lost insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP) is more apparent after continuous versus bolus administration. To test whether the difference might be explained by rapid tachyphylaxis in response to elevated concentrations of GIP, and whether patients with type 2 diabetes and their relatives are more susceptible to tachyphylaxis than healthy subjects. PATIENTS AND METHODS: In a two-way crossover design, insulinotropic responses to repeated bolus injection (50â¯pmol/kg body weight at 30 and 120â¯min) and continuous infusion of GIP (2â¯pmol.kg-1.min-1 from 30 to 180â¯min) under hyperglycaemic clamp conditions (8.5â¯mmol/l) was compared in age- gender- and weight-matched patients with type 2 diabetes, first degree relatives of such patients, and healthy subjects. RESULTS: Insulin secretory responses to the first and second GIP bolus were not significantly different in any of the subject groups. Subjects with type 2 diabetes had a significant relative impairment versus healthy subjects with continuous (C-peptide, -13.2 %, pâ¯<â¯0.05), but not with repeated bolus administration of GIP (+11.1 %, n.s.). First-degree relatives tended to hyper-secrete insulin with bolus or continuous administrations of GIP. CONCLUSIONS: Rapid tachyphylaxis in response to continuous exposure to slightly supraphysiological concentrations of GIP does not explain the reduced insulinotropic response to GIP infusions in patients with type 2 diabetes or their first-degree relatives.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Secreção de Insulina , Receptores dos Hormônios Gastrointestinais/metabolismo , Taquifilaxia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Polipeptídeo Inibidor Gástrico/sangue , Fármacos Gastrointestinais/sangue , Humanos , Masculino , Pessoa de Meia-IdadeAssuntos
Humanos , Inibidores da Angiogênese/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular/tratamento farmacológico , Doenças Retinianas/tratamento farmacológico , Taquifilaxia , Proteínas Recombinantes de Fusão/uso terapêutico , Angiofluoresceinografia , Acuidade Visual , Protocolos Clínicos , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/economia , Receptores de Fatores de Crescimento do Endotélio Vascular , Tomografia de Coerência Óptica , Aptâmeros de Nucleotídeos/uso terapêutico , Uso Off-Label , Injeções Intravítreas , Bevacizumab/uso terapêutico , Ranibizumab/uso terapêutico , Degeneração Macular/economiaRESUMO
Toll-like receptors 7 and 8 (TLR7 and TLR8) are endosomal pattern recognition receptors that detect a variety of single-stranded RNA species. While TLR7/8 agonists have robust therapeutic potential, clinical utility of these agents is limited by sickness responses associated with treatment induction. To understand the kinetics and mechanism of these responses, we characterized the acute and chronic effects of TLR7 stimulation. Single-cell RNA-sequencing studies, RNAscope, and radiolabeled in situ hybridization demonstrate that central nervous system gene expression of TLR7 is exclusive to microglia. In vitro studies demonstrate that microglia are highly sensitive to TLR7 stimulation, and respond in a dose-dependent manner to the imidazoquinoline R848. In vivo, both intraperitoneal (IP) and intracerebroventricular (ICV) R848 induce acute sickness responses including hypophagia, weight loss, and decreased voluntary locomotor activity, associated with increased CNS pro-inflammatory gene expression and changes to glial morphology. However, chronic daily IP R848 resulted in rapid tachyphylaxis of behavioral and molecular manifestations of illness. In microglial in vitro assays, pro-inflammatory transcriptional responses rapidly diminished in the context of repeated R848. In addition to TLR7 desensitization, we found that microglia become partially refractory to lipopolysaccharide (LPS) following R848 pretreatment, associated with induction of negative regulators A20 and Irak3. Similarly, mice pre-treated with R848 demonstrate reduced sickness responses, hypothalamic inflammation, and hepatic inflammation in response to LPS. These data combined demonstrate that TLR7 stimulation induces acute behavioral and molecular evidence of sickness responses. Following prolonged dosing, R848 induces a refractory state to both TLR7 and TLR4 activation, consistent with induced immune tolerance.
Assuntos
Glicoproteínas de Membrana/agonistas , Glicoproteínas de Membrana/imunologia , Microglia/imunologia , Receptor 7 Toll-Like/agonistas , Receptor 7 Toll-Like/imunologia , Animais , Comportamento Animal , Células Cultivadas , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/imunologia , Citocinas/imunologia , Feminino , Imidazóis/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Masculino , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Taquifilaxia/imunologia , Receptor 7 Toll-Like/genética , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/genética , Receptor 8 Toll-Like/imunologiaRESUMO
PURPOSE: At present, the standard treatment of neovascular age-related macular degeneration (AMD) is the repeated administration of antivascular endothelial growth factor (VEGF) agents. However, we often encounter patients who develop tachyphylaxis for anti-VEGF agents. In this study, we investigated the characteristics of patients who developed tachyphylaxis on repeated intravitreal aflibercept (IVA) injections for neovascular AMD and the frequency of tachyphylaxis. METHODS: Three hundred thirteen eyes (313 patients) with treatment-naïve AMD who achieved resolution soon after starting IVA and were followed up for ≥ 12 months were enrolled in this retrospective, interventional, consecutive case series. The eyes were investigated for tachyphylaxis to aflibercept. Tachyphylaxis was defined as absence of any improvement (more than 100 µm) in or worsening of CRT within 1 month after more than two repeated monthly IVA injections when the exudative change remained. RESULTS: Twenty-eight (8.9%) of the 313 eyes developed tachyphylaxis (occult with no classic, n = 14; polypoidal choroidal vasculopathy, n = 14) at an annual rate of about 3%. The mean number of IVA injections was 10.5 ± 7.8, and the mean interval until tachyphylaxis was 20.9 ± 14.0 months. There was a significant difference in the AMD subtypes between the group with tachyphylaxis and the group without it (p = 0.0029). Occult with no classic type and polypoidal choroidal vasculopathy were the only AMD subtypes in the eyes with tachyphylaxis. In the analysis of the eyes that had occult with no classic or polypoidal choroidal vasculopathy, only intraretinal edema was significantly less common (p = 0.042). A combination of photodynamic therapy and aflibercept was effective in 13 (87%) of 15 eyes with tachyphylaxis, and switching to intravitreal ranibizumab was effective in 5 (56%) of 9 eyes. CONCLUSIONS: Tachyphylaxis occurs after repeated IVA injections in a minority of patients with AMD for a long term and is more likely to occur in eyes with lesions beneath the retinal pigment epithelium and no intraretinal edema. Treatment of AMD should be performed keeping this fact in mind, while considering the consecutive treatment.