RESUMEN
Podocytes are specialized epithelial cells that maintain the glomerular filtration barrier. These cells are susceptible to lipotoxicity in the obese state and irreversibly lost during kidney disease leading to proteinuria and renal injury. PPARγ is a nuclear receptor whose activation can be renoprotective. This study examined the role of PPARγ in the lipotoxic podocyte using a PPARγ knockout (PPARγKO) cell line and since the activation of PPARγ by Thiazolidinediones (TZD) is limited by their side effects, it explored other alternative therapies to prevent podocyte lipotoxic damage. Wild-type and PPARγKO podocytes were exposed to the fatty acid palmitic acid (PA) and treated with the TZD (Pioglitazone) and/or the Retinoid X receptor (RXR) agonist Bexarotene (BX). It revealed that podocyte PPARγ is essential for podocyte function. PPARγ deletion reduced key podocyte proteins including podocin and nephrin while increasing basal levels of oxidative and ER stress causing apoptosis and cell death. A combination therapy of low-dose TZD and BX activated both the PPARγ and RXR receptors reducing PA-induced podocyte damage. This study confirms the crucial role of PPARγ in podocyte biology and that their activation in combination therapy of TZD and BX may be beneficial in the treatment of obesity-related kidney disease.
Asunto(s)
Enfermedades Renales , Podocitos , Tiazolidinedionas , Humanos , PPAR gamma/metabolismo , Pioglitazona/farmacología , Tiazolidinedionas/metabolismo , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Enfermedades Renales/tratamiento farmacológico , Bexaroteno/farmacologíaRESUMEN
Bexarotene is an effective oral drug for the treatment of cutaneous T-cell lymphoma, but careful management is required due to its various side effects. In particular, hypertriglyceridemia often requires a reduction or even suspension of bexarotene therapy. The risk factors of bexarotene-associated severe hypertriglyceridemia are not clear. Here, we conducted a post hoc analysis of the data from our previous clinical trial, which confirmed the efficacy and safety of combined bexarotene and phototherapy, to evaluate the effect of body mass index on bexarotene-associated hypertriglyceridemia. Twenty-five subjects were divided into two subgroups: normal and underweight (body mass index [BMI] <25 kg/m2 group) and overweight and obese (BMI ≥25 kg/m2 group) patients. The overall incidence of hypertriglyceridemia was 81.3% (13/16) in the BMI <25 kg/m2 group and 88.9% (8/9) in the BMI ≥25 kg/m2 group. The incidence of grade ≥3 hypertriglyceridemia (≥500 mg/dL) was 7.7% (1/13) in the BMI <25 kg/m2 group and 7/8 (87.5%) in the BMI ≥25 kg/m2 group (P < 0.001). Consequently, dose reduction in the BMI ≥25 kg/m2 group was larger than that in the BMI <25 kg/m2 group. The bexarotene-induced change in the serum triglyceride concentration was significantly increased in cutaneous T-cell lymphoma patients with a higher body mass index (ρ = 0.508, P = 0.009). The area under the curve was 0.886 (95% confidence interval 0.748-1.000, P = 0.002). With a body mass index cut-off of 24.85 kg/m2 , the sensitivity and specificity for identifying grade ≥3 hypertriglyceridemia were 0.875 and 0.882, respectively. The present findings suggest that BMI ≥25 kg/m2 is a risk factor for bexarotene-associated severe hypertriglyceridemia, therefore overweight and obese patients treated with bexarotene should receive lipid-lowering drugs prophylactically. Further studies for optimizing the initial bexarotene dose in such patients are required.
Asunto(s)
Hipertrigliceridemia , Linfoma Cutáneo de Células T , Neoplasias Cutáneas , Humanos , Bexaroteno/efectos adversos , Índice de Masa Corporal , Tetrahidronaftalenos/efectos adversos , Pueblos del Este de Asia , Sobrepeso/inducido químicamente , Sobrepeso/tratamiento farmacológico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Hipertrigliceridemia/inducido químicamente , Hipertrigliceridemia/epidemiología , Neoplasias Cutáneas/patología , Fototerapia/efectos adversos , Obesidad/epidemiología , Obesidad/tratamiento farmacológicoRESUMEN
Multiple sulfatase deficiency (MSD, MIM #272200) results from pathogenic variants in the SUMF1 gene that impair proper function of the formylglycine-generating enzyme (FGE). FGE is essential for the posttranslational activation of cellular sulfatases. MSD patients display reduced or absent sulfatase activities and, as a result, clinical signs of single sulfatase disorders in a unique combination. Up to date therapeutic options for MSD are limited and mostly palliative. We performed a screen of FDA-approved drugs using immortalized MSD patient fibroblasts. Recovery of arylsulfatase A activity served as the primary readout. Subsequent analysis confirmed that treatment of primary MSD fibroblasts with tazarotene and bexarotene, two retinoids, led to a correction of MSD pathophysiology. Upon treatment, sulfatase activities increased in a dose- and time-dependent manner, reduced glycosaminoglycan content decreased and lysosomal position and size normalized. Treatment of MSD patient derived induced pluripotent stem cells (iPSC) differentiated into neuronal progenitor cells (NPC) resulted in a positive treatment response. Tazarotene and bexarotene act to ultimately increase the stability of FGE variants. The results lay the basis for future research on the development of a first therapeutic option for MSD patients.
Asunto(s)
Enfermedad por Deficiencia de Múltiples Sulfatasas , Humanos , Enfermedad por Deficiencia de Múltiples Sulfatasas/diagnóstico , Enfermedad por Deficiencia de Múltiples Sulfatasas/genética , Enfermedad por Deficiencia de Múltiples Sulfatasas/patología , Bexaroteno , Evaluación Preclínica de Medicamentos , Sulfatasas/genética , Oxidorreductasas actuantes sobre Donantes de Grupos SulfuroRESUMEN
We previously synthesized two retinoid X receptor (RXR) agonists, 4'-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid ethyl ester (4'OHE) and 6-hydroxy-3'-propyl-[1,1'-biphenyl]-3-propanoic acid ethyl ester (6OHE), based on the structure of magnaldehyde B, a natural product obtained from Magnolia obovata. 4'OHE and 6OHE exhibited different selectivities for peroxisome proliferator-activated receptor (PPAR)/RXR heterodimers. To examine the regulatory effects of these compounds in adipogenesis, 3T3-L1 mouse preadipocytes were treated with a differentiation cocktail with or without test compounds to induce differentiation, and subsequently treated with test compounds in insulin-containing medium every alternate day. Lipid droplets were stained with Oil Red O to examine lipid accumulation. In addition, adipogenesis-related gene expression was measured using RT-qPCR and immunoblotting. The results showed that a PPARγ agonist, 4'OHE, which exerts agonistic effects on PPARγ and RXRα, enhanced adipogenesis similar to rosiglitazone. However, unlike GW501516, a PPARδ agonist, 6OHE and its hydrolysis product (6OHA), which exert agonistic effects on PPARδ and RXRα, suppressed adipogenesis. In a manner similar to 6OHE and 6OHA, bexarotene, an RXR agonist, suppressed adipocyte differentiation, and its anti-adipogenic effect was reversed by an RXR antagonist. Furthermore, 6OHA and bexarotene inhibited the increase in Pparγ2 and Cebpa mRNA levels 2 days after the induction of differentiation. We demonstrated the adipogenic effect of 4'OHE and anti-adipogenic effects of 6OHE and 6OHA in 3T3-L1 cells. Previously, RXR agonists have been reported to positively regulate the differentiation of mesenchymal stem cells into adipocytes, but our current data showed that they inhibited the differentiation of preadipocytes, at least 3T3-L1 cells, into adipocytes.
Asunto(s)
Lignanos , PPAR delta , Animales , Ratones , Adipogénesis , PPAR gamma/farmacología , Receptores X Retinoide/farmacología , Células 3T3-L1 , Propionatos/farmacología , Bexaroteno/farmacología , PPAR delta/farmacología , Diferenciación Celular , Lignanos/farmacologíaRESUMEN
Bexarotene is a specific retinoid X receptor agonist that has been used for the treatment of cutaneous T-cell lymphoma (CTCL). Because bexarotene causes hypothyroidism, it requires the administration of levothyroxine. However, levothyroxine, in addition to its ubiquitous nuclear receptors, can activate the αVß3 integrin that is overexpressed in CTCL, potentially interfering the antineoplastic effect of bexarotene. We thus investigated the biological effect of levothyroxine in relation to bexarotene treatment. Although in isolated CTCL cells levothyroxine decreased, in an αVß3-dependent manner, the antineoplastic effect of bexarotene, levothyroxine supplementation in preclinical models was necessary to avoid suppression of lymphoma immunity. Accordingly, selective genetic and pharmacologic inhibition of integrin αVß3 improved the antineoplastic effect of bexarotene plus levothyroxine replacement while maintaining lymphoma immunity. Our results provide a mechanistic rationale for clinical testing of integrin αVß3 inhibitors as part of CTCL regimens based on bexarotene administration. TEASER: Inhibiting αVß3 integrin improves the antineoplastic effect of bexarotene while maintaining lymphoma immunity.
Asunto(s)
Anticarcinógenos , Antineoplásicos , Linfoma Cutáneo de Células T , Neoplasias Cutáneas , Anticarcinógenos/farmacología , Anticarcinógenos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bexaroteno/farmacología , Bexaroteno/uso terapéutico , Humanos , Integrina alfaVbeta3 , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Neoplasias Cutáneas/patología , Tetrahidronaftalenos/farmacología , Tetrahidronaftalenos/uso terapéutico , Tiroxina/uso terapéuticoRESUMEN
Mycosis fungoides (MF) is a rare subtype of non-Hodgkin lymphoma, for which no standard treatment exists. The objective of this study is to provide evidence-based recommendations for adult patients with early-stage MF treated with oral bexarotene and phototherapy. A systematic review and meta-analysis was conducted utilizing studies identified via Embase, Pubmed, Web of Science, and the Cochrane Library from inception to April 2020 to evaluate the clinical efficacy and adverse events of oral bexarotene and phototherapy. Of 645 abstracts retrieved, 17 full-text articles with 143 subjects were included for analysis. There were nine case reports, five retrospective cohort studies, two prospective cohort studies, and one randomized controlled trial. Most subjects were men (24.48%) with stage IB disease (54.4%), and the mean age at presentation was 63. One patient had folliculotropic disease. The retrospective studies' analysis included 67 subjects and indicated that the partial response was 40.36% (95% CI 18.24-64.92), complete response was 34.06% (95% CI 10.73-62.56), and overall response was 64.48% (95% CI 48.56-78.89). Side effects from bexarotene were hypertriglyceridemia (54%), hypothyroidism (50%), and hypercholesterolemia (46%). Similar results were noted in the prospective studies. The literature consists mostly of uncontrolled studies, which suggest that combination therapy with oral bexarotene and phototherapy is a therapeutic option. Future randomized control studies with longer follow-up and standardized definitions of treatment responses and dosages are needed to support the development of evidence-based approaches for the treatment of early-stage MF.
Asunto(s)
Micosis Fungoide , Neoplasias Cutáneas , Adulto , Bexaroteno/efectos adversos , Femenino , Humanos , Masculino , Micosis Fungoide/tratamiento farmacológico , Micosis Fungoide/patología , Fototerapia/efectos adversos , Fototerapia/métodos , Estudios Prospectivos , Estudios Retrospectivos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
INTRODUCTION: In this survey, we analyzed data from patients suffering from the most common cutaneous T-cell lymphomas (CTCLs) subtypes mycosis fungoides (MF) and Sézary syndrome (SS), treated with the retinoid alitretinoin during a 7-year period at our outpatient department between 2015 and 2020. MATERIALS AND METHODS: We analyzed patient medical records including TNMB stage, side effects under therapy with alitretinoin, time to next treatment (TTNT), and previous photo documentation. RESULTS: A total of 35 patients with MF (n = 28) and SS (n = 7) were included in the study, of whom 69% were male and 31% were female. The mean age of onset was 56 ± 15 years in MF and 65.4 ± 10.8 years in SS with 51.4% having early stage (IA-IIA) and 48.6% having advanced stage (IIB-IVA) CTCL. Of these patients 37.2% responded to alitretinoin, 28.6% had a stable course, and 34.3% experienced progression. Alitretinoin was administered as a monotherapy (25.7%) or combined with five concomitant therapies (74.2%), most frequently with ECP (31.4%) and PUVA (11.4%). 63% did not report any side effects, most often hypertriglyceridemia (20%) was described. CONCLUSION: Considering that nearly two thirds of the CTCL patients treated with alitretinoin showed a response or stable disease, together with a low number of side effects and low cost compared to bexarotene, alitretinoin may be a potential alternative in the treatment of less advanced CTCLs. This survey represents the largest number of recorded therapies with the retinoid alitretinoin in CTCLs in a European patient collective.
Asunto(s)
Alitretinoína/uso terapéutico , Antineoplásicos/uso terapéutico , Micosis Fungoide/tratamiento farmacológico , Síndrome de Sézary/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Alitretinoína/efectos adversos , Antineoplásicos/efectos adversos , Bexaroteno/uso terapéutico , Terapia Combinada/métodos , Progresión de la Enfermedad , Femenino , Humanos , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Masculino , Persona de Mediana Edad , Micosis Fungoide/patología , Terapia PUVA , Síndrome de Sézary/patología , Neoplasias Cutáneas/patologíaRESUMEN
T-cell lymphomas (TCLs) constitute a rare subset of non-Hodgkin lymphomas, with mycosis fungoides/Sézary syndrome (MF/SS) being the most common subtype of cutaneous TCLs (CTCLs). Considered an incurable but treatable disease, MF/SS management presents several challenges including diagnostic delays, debilitating effect on patients' quality of life, need for several lines of therapies, multidisciplinary care and cumulative drug toxicities limiting duration of use. The present review intends to provide an overview of the recent advances in our understanding of the biology of CTCL and how these are being leveraged to provide additional treatment options for management of advanced and recurrent disease. In addition, the discussion of the different modalities of treatment is summarised to further outline the importance of multidisciplinary care and early referral to CTCL centres.
Asunto(s)
Micosis Fungoide/terapia , Síndrome de Sézary/terapia , Neoplasias Cutáneas/terapia , Corticoesteroides/uso terapéutico , Anciano , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Bexaroteno/uso terapéutico , Biomarcadores de Tumor/sangre , Ensayos Clínicos como Asunto , Terapia Combinada , Diagnóstico Tardío , Diagnóstico Diferencial , Electrones/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Interferón-alfa/uso terapéutico , Masculino , Micosis Fungoide/diagnóstico , Micosis Fungoide/patología , Micosis Fungoide/fisiopatología , Estadificación de Neoplasias , Células Madre Neoplásicas/química , Células Madre Neoplásicas/patología , Terapia PUVA , Fotoféresis , Pronóstico , Retinoides/uso terapéutico , Síndrome de Sézary/diagnóstico , Síndrome de Sézary/patología , Síndrome de Sézary/fisiopatología , Transducción de Señal , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/fisiopatología , Subgrupos de Linfocitos T/química , Subgrupos de Linfocitos T/patologíaRESUMEN
BACKGROUND: Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, a malignant, chronic disease initially affecting the skin. Several therapies are available, which may induce clinical remission for a time. This is an update of a Cochrane Review first published in 2012: we wanted to assess new trials, some of which investigated new interventions. OBJECTIVES: To assess the effects of interventions for MF in all stages of the disease. SEARCH METHODS: We updated our searches of the following databases to May 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We searched 2 trials registries for additional references. For adverse event outcomes, we undertook separate searches in MEDLINE in April, July and November 2017. SELECTION CRITERIA: Randomised controlled trials (RCTs) of local or systemic interventions for MF in adults with any stage of the disease compared with either another local or systemic intervention or with placebo. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. The primary outcomes were improvement in health-related quality of life as defined by participants, and common adverse effects of the treatments. Key secondary outcomes were complete response (CR), defined as complete disappearance of all clinical evidence of disease, and objective response rate (ORR), defined as proportion of patients with a partial or complete response. We used GRADE to assess the certainty of evidence and considered comparisons of psoralen plus ultraviolet A (PUVA) light treatment as most important because this is first-line treatment for MF in most guidelines. MAIN RESULTS: This review includes 20 RCTs (1369 participants) covering a wide range of interventions. The following were assessed as either treatments or comparators: imiquimod, peldesine, hypericin, mechlorethamine, nitrogen mustard and intralesional injections of interferon-α (IFN-α) (topical applications); PUVA, extracorporeal photopheresis (ECP: photochemotherapy), and visible light (light applications); acitretin, bexarotene, lenalidomide, methotrexate and vorinostat (oral agents); brentuximab vedotin; denileukin diftitox; mogamulizumab; chemotherapy with cyclophosphamide, doxorubicin, etoposide, and vincristine; a combination of chemotherapy with electron beam radiation; subcutaneous injection of IFN-α; and intramuscular injections of active transfer factor (parenteral systemics). Thirteen trials used an active comparator, five were placebo-controlled, and two compared an active operator to observation only. In 14 trials, participants had MF in clinical stages IA to IIB. All participants were treated in secondary and tertiary care settings, mainly in Europe, North America or Australia. Trials recruited both men and women, with more male participants overall. Trial duration varied from four weeks to 12 months, with one longer-term study lasting more than six years. We judged 16 trials as at high risk of bias in at least one domain, most commonly performance bias (blinding of participants and investigators), attrition bias and reporting bias. None of our key comparisons measured quality of life, and the two studies that did presented no usable data. Eighteen studies reported common adverse effects of the treatments. Adverse effects ranged from mild symptoms to lethal complications depending upon the treatment type. More aggressive treatments like systemic chemotherapy generally resulted in more severe adverse effects. In the included studies, CR rates ranged from 0% to 83% (median 31%), and ORR ranged from 0% to 88% (median 47%). Five trials assessed PUVA treatment, alone or combined, summarised below. There may be little to no difference between intralesional IFN-α and PUVA compared with PUVA alone for 24 to 52 weeks in CR (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.87 to 1.31; 2 trials; 122 participants; low-certainty evidence). Common adverse events and ORR were not measured. One small cross-over trial found once-monthly ECP for six months may be less effective than twice-weekly PUVA for three months, reporting CR in two of eight participants and ORR in six of eight participants after PUVA, compared with no CR or ORR after ECP (very low-certainty evidence). Some participants reported mild nausea after PUVA but no numerical data were given. One participant in the ECP group withdrew due to hypotension. However, we are unsure of the results due to very low-certainty evidence. One trial comparing bexarotene plus PUVA versus PUVA alone for up to 16 weeks reported one case of photosensitivity in the bexarotene plus PUVA group compared to none in the PUVA-alone group (87 participants; low-certainty evidence). There may be little to no difference between bexarotene plus PUVA and PUVA alone in CR (RR 1.41, 95% CI 0.71 to 2.80) and ORR (RR 0.94, 95% CI 0.61 to 1.44) (93 participants; low-certainty evidence). One trial comparing subcutaneous IFN-α injections combined with either acitretin or PUVA for up to 48 weeks or until CR indicated there may be little to no difference in the common IFN-α adverse effect of flu-like symptoms (RR 1.32, 95% CI 0.92 to 1.88; 82 participants). There may be lower CR with IFN-α and acitretin compared with IFN-α and PUVA (RR 0.54, 95% CI 0.35 to 0.84; 82 participants) (both outcomes: low-certainty evidence). This trial did not measure ORR. One trial comparing PUVA maintenance treatment to no maintenance treatment, in participants who had already had CR, did report common adverse effects. However, the distribution was not evaluable. CR and OR were not assessable. The range of treatment options meant that rare adverse effects consequently occurred in a variety of organs. AUTHORS' CONCLUSIONS: ââThere is a lack of high-certainty evidence to support decision making in the treatment of MF. Because of substantial heterogeneity in design, missing data, small sample sizes, and low methodological quality, the comparative safety and efficacy of these interventions cannot be reliably established on the basis of the included RCTs. PUVA is commonly recommended as first-line treatment for MF, and we did not find evidence to challenge this recommendation. There was an absence of evidence to support the use of intralesional IFN-α or bexarotene in people receiving PUVA and an absence of evidence to support the use of acitretin or ECP for treating MF. Future trials should compare the safety and efficacy of treatments to PUVA, as the current standard of care, and should measure quality of life and common adverse effects.
Asunto(s)
Micosis Fungoide/terapia , Neoplasias Cutáneas/terapia , Acitretina/efectos adversos , Acitretina/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Bexaroteno/uso terapéutico , Terapia Combinada/métodos , Humanos , Factores Inmunológicos/uso terapéutico , Interferón-alfa/uso terapéutico , Micosis Fungoide/patología , Estadificación de Neoplasias/métodos , Terapia PUVA/métodos , Fotoquimioterapia/métodos , Fotoféresis/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Cutáneas/patologíaRESUMEN
Coronavirus Disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a crude case fatality rate of about 0.5-10 % depending on locality. A few clinically approved drugs, such as remdesivir, chloroquine, hydroxychloroquine, nafamostat, camostat, and ivermectin, exhibited anti-SARS-CoV-2 activity in vitro and/or in a small number of patients. However, their clinical use may be limited by anti-SARS-CoV-2 50 % maximal effective concentrations (EC50) that exceeded their achievable peak serum concentrations (Cmax), side effects, and/or availability. To find more immediately available COVID-19 antivirals, we established a two-tier drug screening system that combines SARS-CoV-2 enzyme-linked immunosorbent assay and cell viability assay, and applied it to screen a library consisting 1528 FDA-approved drugs. Cetilistat (anti-pancreatic lipase), diiodohydroxyquinoline (anti-parasitic), abiraterone acetate (synthetic androstane steroid), and bexarotene (antineoplastic retinoid) exhibited potent in vitro anti-SARS-CoV-2 activity (EC50 1.13-2.01 µM). Bexarotene demonstrated the highest Cmax:EC50 ratio (1.69) which was higher than those of chloroquine, hydroxychloroquine, and ivermectin. These results demonstrated the efficacy of the two-tier screening system and identified potential COVID-19 treatments which can achieve effective levels if given by inhalation or systemically depending on their pharmacokinetics.
Asunto(s)
Antivirales/farmacología , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Evaluación Preclínica de Medicamentos/métodos , Neumonía Viral/tratamiento farmacológico , Androstenos/farmacología , Animales , Benzoxazinas/farmacología , Betacoronavirus/efectos de los fármacos , Betacoronavirus/fisiología , Bexaroteno/farmacología , COVID-19 , Células CACO-2 , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Infecciones por Coronavirus/virología , Efecto Citopatogénico Viral/efectos de los fármacos , Bases de Datos Farmacéuticas , Aprobación de Drogas , Reposicionamiento de Medicamentos , Ensayo de Inmunoadsorción Enzimática , Humanos , Yodoquinol/farmacología , Pandemias , Neumonía Viral/virología , SARS-CoV-2 , Estados Unidos , United States Food and Drug Administration , Células Vero , Carga Viral/efectos de los fármacos , Replicación Viral/efectos de los fármacos , Tratamiento Farmacológico de COVID-19RESUMEN
Cutaneous T-cell lymphoma (CTCL) is a chronic condition with low malignancy. International treatment guidelines for CTCL are widely followed in Europe and the USA. Combination therapy with therapeutic agents for CTCL and phototherapy is effective on the basis of European data. The efficacy and safety of combination therapy for Japanese CTCL patients are not established. We investigated the efficacy and safety of combination therapy with photo(chemo)therapy and bexarotene in Japanese CTCL patients. Twenty-five patients received daily oral bexarotene (300 mg/m2 body surface), followed by bath-psoralen plus ultraviolet (UV)-A (PUVA) or narrowband UV-B. Treatment results were evaluated using the modified Severity-Weighted Assessment Tool (mSWAT) and the Physician Global Assessment of Clinical Condition (PGA) up to week 24. Safety was also assessed. Twenty-four weeks after initiating treatment, the total response rate was 80.0% (mSWAT) and 84.0% (PGA). Response rates did not differ when stratified by disease stage. Number of days (mean ± standard deviation) for time to response, duration of response and time to progression determined by the mSWAT were 20.7 ± 9.62, 117.0 ± 43.0 and 163.6 ± 28.8, respectively. T-helper 2 chemokine levels in patients at stage IIA or more decreased significantly at weeks 12 and 24. All patients experienced adverse events and adverse drug reactions. Serious adverse drug reactions included sepsis, anemia and congestive cardiac insufficiency (n = 1 each). Other adverse drug reactions were of mild to moderate severity. Combination therapy with bexarotene and PUVA was safe and effective in Japanese CTCL patients.
Asunto(s)
Antineoplásicos/administración & dosificación , Bexaroteno/administración & dosificación , Linfoma Cutáneo de Células T/tratamiento farmacológico , Terapia PUVA/métodos , Neoplasias Cutáneas/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Anemia/diagnóstico , Anemia/epidemiología , Antineoplásicos/efectos adversos , Bexaroteno/efectos adversos , Progresión de la Enfermedad , Femenino , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Humanos , Japón , Linfoma Cutáneo de Células T/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Terapia PUVA/efectos adversos , Sepsis/inducido químicamente , Sepsis/diagnóstico , Sepsis/epidemiología , Índice de Severidad de la Enfermedad , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Bexarotene is useful for both early and advanced cutaneous T-cell lymphoma (CTCL), and is sometimes applied to ultraviolet-tolerant early CTCL patients as one of the first-line therapies in the real world. However, continuous administration of bexarotene is sometimes difficult because of its adverse events (AE). Development of an appropriate protocol for bexarotene that can induce a consistent response for CTCL without severe AE (SAE) is needed. We retrospectively investigated 29 Japanese cases of CTCL and evaluated the efficacy of treatment and incident ratios of all AE and SAE. Objective response rate (ORR) for the overall cohort was 65.5%. ORR of the 300 mg/m2 cohort (conventional dose) was 76.2%, while that of the 150-300 mg/body (low dose) with narrowband ultraviolet B light (NBUVB) cohort was 37.5%. Mean event-free survival was 10.0 months for all patients, 6.7 months for the bexarotene conventional-dose cohort and 19.1 months for the low-dose with NBUVB cohort. The incident ratio of total SAE for all patients was 20.7%. The incident ratio of total SAE was 23.8% for the conventional-dose cohort and 12.5% for the low-dose with NBUVB cohort. Our present study suggests that low-dose bexarotene plus NBUVB therapy is well-tolerated and could be one of the optimal therapies for advanced CTCL.
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Bexaroteno/administración & dosificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Linfoma Cutáneo de Células T/terapia , Neoplasias Cutáneas/terapia , Terapia Ultravioleta/métodos , Adulto , Anciano , Anciano de 80 o más Años , Bexaroteno/efectos adversos , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Humanos , Incidencia , Japón , Linfoma Cutáneo de Células T/mortalidad , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Neoplasias Cutáneas/mortalidad , Terapia Ultravioleta/efectos adversosRESUMEN
Primary cutaneous B-cell lymphomas are a group of diseases with indolent and aggressive behavior. The goal of the initial workup is to evaluate for systemic involvement, provide adequate staging, and guide therapy. Histopathological studies are a critical part of the workup for classification of these lymphomas because they are similar to their nodal counterparts. There are limited data for treatment guidelines, and thus, therapy differs among institutions. Overall, localized therapies are preferred for indolent types and chemotherapy or immunotherapy for the aggressive forms.
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Antineoplásicos/uso terapéutico , Procedimientos Quirúrgicos Dermatologicos , Linfoma de Células B/terapia , Neoplasias Cutáneas/terapia , Administración Cutánea , Corticoesteroides/uso terapéutico , Antibacterianos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bexaroteno/uso terapéutico , Borrelia burgdorferi , Ciclofosfamida/uso terapéutico , Procedimientos Quirúrgicos de Citorreducción , Manejo de la Enfermedad , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapéutico , Humanos , Inyecciones Intralesiones , Enfermedad de Lyme/tratamiento farmacológico , Linfoma de Células B/diagnóstico , Linfoma de Células B/patología , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/microbiología , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B de la Zona Marginal/terapia , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/terapia , Mecloretamina/uso terapéutico , Polietilenglicoles/uso terapéutico , Prednisona/uso terapéutico , Rituximab/uso terapéutico , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patología , Vincristina/uso terapéuticoRESUMEN
Protein aggregation has been implicated in many medical disorders, including Alzheimer's and Parkinson's diseases. Potential therapeutic strategies for these diseases propose the use of drugs to inhibit specific molecular events during the aggregation process. However, viable treatment protocols require balancing the efficacy of the drug with its toxicity, while accounting for the underlying events of aggregation and inhibition at the molecular level. To address this key problem, we combine here protein aggregation kinetics and control theory to determine optimal protocols that prevent protein aggregation via specific reaction pathways. We find that the optimal inhibition of primary and fibril-dependent secondary nucleation require fundamentally different drug administration protocols. We test the efficacy of our approach on experimental data for the aggregation of the amyloid-ß(1-42) peptide of Alzheimer's disease in the model organism Caenorhabditis elegans Our results pose and answer the question of the link between the molecular basis of protein aggregation and optimal strategies for inhibiting it, opening up avenues for the design of rational therapies to control pathological protein aggregation.
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Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/antagonistas & inhibidores , Bexaroteno/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Fragmentos de Péptidos/antagonistas & inhibidores , Agregación Patológica de Proteínas/prevención & control , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/metabolismo , Animales , Caenorhabditis elegans , Modelos Animales de Enfermedad , Esquema de Medicación , Evaluación Preclínica de Medicamentos , Humanos , Cinética , Fragmentos de Péptidos/metabolismo , Agregado de Proteínas/efectos de los fármacos , Agregación Patológica de Proteínas/patología , Factores de TiempoAsunto(s)
Micosis Fungoide/diagnóstico por imagen , Neoplasias Cutáneas/diagnóstico por imagen , Bexaroteno/uso terapéutico , Biopsia , Dermoscopía , Diagnóstico Diferencial , Extremidades , Humanos , Linfoma/diagnóstico , Masculino , Persona de Mediana Edad , Micosis Fungoide/patología , Micosis Fungoide/terapia , Terapia PUVA , Piel/diagnóstico por imagen , Piel/patología , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/terapia , Torso , Resultado del TratamientoRESUMEN
For performance assessment of the lipid-based drug delivery systems (LBDDSs), in vitro lipolysis is commonly applied because traditional dissolution tests do not reflect the complicated in vivo micellar formation and solubilization processes. Much of previous research on in vitro lipolysis has mostly focused on rank-ordering formulations for their predicted performances. In this study, we have incorporated in vitro lipolysis with microsomal stability to quantitatively predict the oral bioavailability of a lipophilic antineoplastic drug bexarotene (BEX) administered in LBDDS. Two types of LBDDS were applied: lipid solution and lipid suspension. The predicted oral bioavailability values of BEX from linking in vitro lipolysis with microsomal stability for lipid solution and lipid suspension were 34.2 ± 1.6% and 36.2 ± 2.6%, respectively, whereas the in vivo oral bioavailability of BEX was tested as 31.5 ± 13.4% and 31.4 ± 5.2%, respectively. The predicted oral bioavailability corresponded well with the oral bioavailability for both formulations, demonstrating that the combination of in vitro lipolysis and microsomal stability can quantitatively predict oral bioavailability of BEX. In vivo intestinal lymphatic uptake was also assessed for the formulations and resulted in <1% of the dose, which confirmed that liver microsomal stability was necessary for correct prediction of the bioavailability.
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Antineoplásicos/farmacocinética , Bexaroteno/farmacocinética , Portadores de Fármacos/metabolismo , Ácido Linoleico/metabolismo , Aceite de Girasol/metabolismo , Administración Oral , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/sangre , Bexaroteno/administración & dosificación , Bexaroteno/sangre , Disponibilidad Biológica , Lipólisis , Masculino , Microsomas Hepáticos/metabolismo , Modelos Biológicos , Ratas , Ratas Sprague-Dawley , SolubilidadRESUMEN
BACKGROUND: Bexarotene (Targretin®) is currently the only FDA approved retinoid X receptor (RXR) -selective agonist for the treatment of cutaneous T-cell lymphomas (CTCLs). The main side effects of bexarotene are hypothyroidism and elevation of serum triglycerides (TGs). The novel RXR ligand, 9-cis UAB30 (UAB30) does not elevate serum TGs or induce hypothyroidism in normal subjects. OBJECTIVES: To assess preclinical efficacy and mechanism of action of UAB30 in the treatment of CTCLs and compare its action with bexarotene. METHODS: With patient-derived CTCL cell lines, we evaluated UAB30 function in regulating growth, apoptosis, cell cycle check points, and cell cycle-related markers. RESULTS: Compared to bexarotene, UAB30 had lower half maximal inhibitory concentration (IC50) values and was more effective in inhibiting the G1 cell cycle checkpoint. Both rexinoids increased the stability of the cell cycle inhibitor, p27kip1 protein, in part, through targeting components involved in the ubiquitination-proteasome system: 1) decreasing SKP2, a F-box protein that binds and targets p27kip1 for degradation by 26S proteasome and 2) suppressing 20S proteasome activity (cell line-dependent) through downregulation of PSMA7, a component of the 20S proteolytic complex in 26S proteasome. CONCLUSIONS: UAB30 and bexarotene induce both early cell apoptosis and suppress cell proliferation. Inhibition of the G1 to S cell cycle transition by rexinoids is mediated, in part, through downregulation of SKP2 and/or 20S proteasome activity, leading to increased p27kip1 protein stability. Because UAB30 has minimal effect in elevating serum TGs and inducing hypothyroidism, it is potentially a better alternative to bexarotene for the treatment of CTCLs.
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Antineoplásicos/farmacología , Ácidos Grasos Insaturados/farmacología , Linfoma Cutáneo de Células T/tratamiento farmacológico , Naftalenos/farmacología , Receptores X Retinoide/agonistas , Transducción de Señal/efectos de los fármacos , Adolescente , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Bexaroteno , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Regulación hacia Abajo , Evaluación Preclínica de Medicamentos , Ácidos Grasos Insaturados/uso terapéutico , Humanos , Concentración 50 Inhibidora , Linfoma Cutáneo de Células T/patología , Masculino , Persona de Mediana Edad , Naftalenos/uso terapéutico , Complejo de la Endopetidasa Proteasomal/efectos de los fármacos , Complejo de la Endopetidasa Proteasomal/metabolismo , Receptores X Retinoide/metabolismo , Proteínas Quinasas Asociadas a Fase-S/metabolismo , Tetrahidronaftalenos/farmacologíaAsunto(s)
Antineoplásicos/uso terapéutico , Bexaroteno/uso terapéutico , Papulosis Linfomatoide/terapia , Fototerapia , Neoplasias Cutáneas/terapia , Femenino , Humanos , Papulosis Linfomatoide/patología , Persona de Mediana Edad , Piel/patología , Neoplasias Cutáneas/patología , Resultado del TratamientoRESUMEN
Neurons must maintain protein and mitochondrial quality control for optimal function, an energetically expensive process. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that promote mitochondrial biogenesis and oxidative metabolism. We recently determined that transcriptional dysregulation of PPARδ contributes to Huntington's disease (HD), a progressive neurodegenerative disorder resulting from a CAG-polyglutamine repeat expansion in the huntingtin gene. We documented that the PPARδ agonist KD3010 is an effective therapy for HD in a mouse model. PPARδ forms a heterodimer with the retinoid X receptor (RXR), and RXR agonists are capable of promoting PPARδ activation. One compound with potent RXR agonist activity is the U.S. Food and Drug Administration-approved drug bexarotene. We tested the therapeutic potential of bexarotene in HD and found that bexarotene was neuroprotective in cellular models of HD, including medium spiny-like neurons generated from induced pluripotent stem cells (iPSCs) derived from patients with HD. To evaluate bexarotene as a treatment for HD, we treated the N171-82Q mouse model with the drug and found that bexarotene improved motor function, reduced neurodegeneration, and increased survival. To determine the basis for PPARδ neuroprotection, we evaluated metabolic function and noted markedly impaired oxidative metabolism in HD neurons, which was rescued by bexarotene or KD3010. We examined mitochondrial and protein quality control in cellular models of HD and observed that treatment with a PPARδ agonist promoted cellular quality control. By boosting cellular activities that are dysfunctional in HD, PPARδ activation may have therapeutic applications in HD and potentially other neurodegenerative diseases.