RESUMEN
In response to genotoxic stress, the tumor suppressor p53 acts as a transcription factor by regulating the expression of genes critical for cancer prevention. Mutations in the gene encoding p53 are associated with cancer development. PRIMA-1 and eprenetapopt (APR-246/PRIMA-1MET) are small molecules that are converted into the biologically active compound, methylene quinuclidinone (MQ), shown to reactivate mutant p53 by binding covalently to cysteine residues. Here, we investigate the structural basis of mutant p53 reactivation by MQ based on a series of high-resolution crystal structures of cancer-related and wild-type p53 core domains bound to MQ in their free state and in complexes with their DNA response elements. Our data demonstrate that MQ binds to several cysteine residues located at the surface of the core domain. The structures reveal a large diversity in MQ interaction modes that stabilize p53 and its complexes with DNA, leading to a common global effect that is pertinent to the restoration of non-functional p53 proteins.
Asunto(s)
Antineoplásicos/farmacología , Compuestos Aza/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Neoplasias/tratamiento farmacológico , Quinuclidinas/farmacología , Proteína p53 Supresora de Tumor/agonistas , Antineoplásicos/uso terapéutico , Compuestos Aza/química , Compuestos Aza/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Cristalografía por Rayos X , Humanos , Mutación con Pérdida de Función/efectos de los fármacos , Neoplasias/genética , Dominios Proteicos/efectos de los fármacos , Quinuclidinas/química , Quinuclidinas/uso terapéutico , Proteínas Recombinantes/genética , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/ultraestructura , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/aislamiento & purificación , Proteína p53 Supresora de Tumor/ultraestructuraRESUMEN
NTRK gene fusions are found in <1% of all cancers but are uniformly present in mammary analog secretory carcinomas (MASC) of the salivary glands. Two selective histology-agnostic tropomyosin receptor kinase (TRK) inhibitors are currently approved for malignancies with these oncogenic fusions. Resistance to TRK inhibition has been recognized, and the mediating mechanisms are presently being studied. This report describes a patient diagnosed with an MASC of the parotid gland who after undergoing multiple lines of treatment was found to have an ETV6-NTRK3 fusion and initiated TRK-targeted therapy using entrectinib. Upon disease progression, we performed tumor genetic sequencing that showed a secondary resistance mutation. The patient subsequently responded to selitrectinib, a next-generation TRK inhibitor.
Asunto(s)
Compuestos Aza/uso terapéutico , Carcinoma Secretor Análogo al Mamario , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Benzamidas , Resistencia a Antineoplásicos , Humanos , Indazoles , Carcinoma Secretor Análogo al Mamario/tratamiento farmacológico , Carcinoma Secretor Análogo al Mamario/genética , Proteínas de Fusión Oncogénica/genética , Glándula Parótida/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de las Glándulas Salivales/genéticaRESUMEN
OBJECTIVE: Glucocorticoid levels rise rapidly following status epilepticus and remain elevated for weeks after the injury. To determine whether glucocorticoid receptor activation contributes to the pathological sequelae of status epilepticus, mice were treated with a novel glucocorticoid receptor modulator, C108297. METHODS: Mice were treated with either C108297 or vehicle for 10 days beginning one day after pilocarpine-induced status epilepticus. Baseline and stress-induced glucocorticoid secretion were assessed to determine whether hypothalamic-pituitary-adrenal axis hyperreactivity could be controlled. Status epilepticus-induced pathology was assessed by quantifying ectopic hippocampal granule cell density, microglial density, astrocyte density and mossy cell loss. Neuronal network function was examined indirectly by determining the density of Fos immunoreactive neurons following restraint stress. RESULTS: Treatment with C108297 attenuated corticosterone hypersecretion after status epilepticus. Treatment also decreased the density of hilar ectopic granule cells and reduced microglial proliferation. Mossy cell loss, on the other hand, was not prevented in treated mice. C108297 altered the cellular distribution of Fos protein but did not restore the normal pattern of expression. INTERPRETATION: Results demonstrate that baseline corticosterone levels can be normalized with C108297, and implicate glucocorticoid signaling in the development of structural changes following status epilepticus. These findings support the further development of glucocorticoid receptor modulators as novel therapeutics for the prevention of brain pathology following status epilepticus.
Asunto(s)
Compuestos Aza/uso terapéutico , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Receptores de Glucocorticoides/metabolismo , Estado Epiléptico/metabolismo , Estado Epiléptico/patología , Animales , Compuestos Aza/farmacología , Relación Dosis-Respuesta a Droga , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Ratones , Pilocarpina/toxicidad , Receptores de Glucocorticoides/agonistas , Receptores de Glucocorticoides/antagonistas & inhibidores , Estado Epiléptico/inducido químicamente , Estado Epiléptico/tratamiento farmacológicoRESUMEN
INTRODUCTION: Neurotrophic receptor tyrosine kinase fusions cause overexpression or activation of kinase and are believed to confer oncogenic potential in some non-rhabdomyosarcoma soft tissue sarcomas. TRK inhibitors have recently been shown to induce responses in these tumours though current experience with these agents is still limited. CASE REPORT: We report a case of an adolescent with treatment-refractory non-rhabdomyosarcoma soft tissue sarcomas, carrying a novel DCTN1-NTRK1 gene fusion whose progressive disease was treated with multi-kinase and TRK inhibitors.Management and outcome: Our patient was started on pan-TRK inhibitor larotrectinib, as his disease progressed after chemotherapy, radiation therapy and surgery, based on next-generation sequencing test showing DCTN1-NTRK1 gene fusion. He responded quickly to larotrectinib with the improvement of symptoms and reduction of masses. However, this response was short-lived due to the development of acquired solvent front resistance mutation. This patient did not respond to next-generation TRK inhibitor selitrectinib and eventually succumbed to his disease. DISCUSSION: The initial rapid and drastic response of our patient to larotrectinib was not sustained due to the development of acquired resistance. This case emphasizes the need for upfront and periodic next-generation sequencing testing to guide treatment of patients with refractory non-rhabdomyosarcoma soft tissue sarcomas.
Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos Aza/uso terapéutico , Complejo Dinactina/genética , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptor trkA/genética , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Adolescente , Terapia Combinada , Resistencia a Antineoplásicos/genética , Resultado Fatal , Humanos , Imagen por Resonancia Magnética , Masculino , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Resultado del TratamientoRESUMEN
Dendrimers are nanosized, arborescent macromolecules synthesized in a stepwise fashion with attractive degrees of functionality and structure definition. This is one of the reasons why they are widely used for biomedical applications. Previously, we have shown that a poly(phosphorhydrazone) (PPH) dendrimer capped with anionic azabisphosphonate groups (so-called ABP dendrimer) has immuno-modulatory and anti-inflammatory properties towards human immune cells in vitro. Thereafter, we have shown that the ABP dendrimer has a promising therapeutic efficacy to treat models of acute and chronic inflammatory disorders in animal models. In these models, the active pharmaceutical ingredient was administered systematically (intravenous and oral administrations), but also loco-regionally in the vitreous tissue. Herein, we assessed the therapeutic efficacy of the ABP dendrimer in the preclinical mouse model of psoriasis induced by imiquimod. The ABP dendrimer was administered in phosphate-buffered saline solution via either systemic injection or topical application. We show that the topical application enabled the control of both the clinical and histopathological scores, and the control of the infiltration of macrophages in the skin of treated mice.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Dendrímeros/uso terapéutico , Hidrazonas/uso terapéutico , Polímeros/uso terapéutico , Psoriasis/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Compuestos Aza/química , Compuestos Aza/uso terapéutico , Dendrímeros/síntesis química , Dendrímeros/química , Difosfonatos/química , Difosfonatos/uso terapéutico , Modelos Animales de Enfermedad , Hidrazonas/síntesis química , Hidrazonas/química , Imiquimod , Masculino , Ratones , Ratones Endogámicos BALB C , Estructura Molecular , Polímeros/síntesis química , Polímeros/química , Psoriasis/inducido químicamente , Psoriasis/patologíaRESUMEN
High dose intake of docosahexaenoic acid showed beneficial effects on atopic dermatitis in patients and was found to increase regulatory T cells in mice, but its molecular target has not been identified. Free fatty acid receptor 4 (FFA4, also known as GPR120) is a receptor sensing polyunsaturated long-chain fatty acids including docosahexaenoic acid. In the present study, we examined whether FFA4 acted as a therapeutic target of docosahexaenoic acid for treating atopic dermatitis. Experimental atopic dermatitis was induced in mice by 2,4-dinitrochlorobenzene (DNCB) sensitization on day 0, followed by repeated DNCB challenges from D7 to D48. The mice were treated with a selective agonist compound A (30 mg· kg-1· d-1, ip) from D19 to D48, and sacrificed on D49. We found that DNCB-induced atopic dermatitis-like skin lesions, i.e. hypertrophy and mast cell infiltration in skin tissues, as well as markedly elevated serum IgE levels. Administration of compound A significantly suppressed the atopic responses in ears and lymph nodes, such as hypertrophy and mast cell infiltration in the ears, enlarged sizes of lymph nodes, and elevated serum IgE and levels of cytokines IL-4, IL-13, IL-17, and IFN-γ in ear tissue. The therapeutic effects of compound A were abolished by FFA4 knockout. Similarly, increased CD4+Foxp3+ regulatory T-cell population in lymph nodes was observed in wide-type mice treated with compound A, but not seen in FFA4-deficient mice. In conclusion, we demonstrate that activation of FFA4 ameliorates atopic dermatitis by increasing CD4+Foxp3+ regulatory T cells, suggesting FFA4 as a therapeutic target for atopic dermatitis.
Asunto(s)
Ácido Acético/uso terapéutico , Compuestos Aza/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Receptores Acoplados a Proteínas G/agonistas , Linfocitos T Reguladores/metabolismo , Animales , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/patología , Dinitroclorobenceno , Oído/patología , Técnicas de Inactivación de Genes , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/patología , Masculino , Ratones Endogámicos BALB C , Ratones Noqueados , Receptores Acoplados a Proteínas G/genéticaRESUMEN
RATIONALE: A variety of neural systems are involved in drug addiction, and some of these systems are shared across different addictive drugs. We have found several different types of drug treatments that successfully reduce nicotine self-administration. OBJECTIVES: The current set of studies is the first in a series to determine if drug treatments that have been found to significantly reduce nicotine self-administration would reduce opiate self-administration. METHODS: Amitifadine, a triple reuptake inhibitor of dopamine, norepinephrine, and serotonin, was assessed in female Sprague-Dawley rats to determine whether it significantly reduces remifentanil self-administration with either acute or chronic treatment. RESULTS: Acutely, amitifadine doses of 5, 10, and 20 mg/kg each significantly reduced remifentanil self-administration. In a chronic study, repeated treatment with 10 mg/kg of amitifadine continued to reduce remifentanil self-administration, even after the cessation of treatment. However, amitifadine was not found to attenuate the rise in remifentanil self-administration with continued access. This study and our earlier one showed that the 10 mg/kg amitifadine dose did not significantly affect food motivated responding. Amitifadine did not attenuate remifentanil-induced antinociception as measured on the hot plate test but extended and maintained antinociceptive effects. CONCLUSIONS: These studies show the promise of amitifadine as a treatment for countering opiate self-administration for adjunctive use with opioids for analgesia. Further studies are needed to determine the possible efficacy of amitifadine for combating opiate addiction or preventing it in humans during adjunctive use with opioids for chronic pain.
Asunto(s)
Analgésicos Opioides/administración & dosificación , Compuestos Aza/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Inhibidores de Captación de Dopamina/uso terapéutico , Norepinefrina/antagonistas & inhibidores , Remifentanilo/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Animales , Compuestos Aza/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Dopamina/metabolismo , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Motivación/efectos de los fármacos , Motivación/fisiología , Nicotina/administración & dosificación , Norepinefrina/metabolismo , Dolor/tratamiento farmacológico , Dolor/metabolismo , Ratas , Ratas Sprague-Dawley , Autoadministración , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , EstereoisomerismoRESUMEN
Peptide mimicry employing a combination of aza-amino acyl proline and indolizidinone residues has been used to develop allosteric modulators of the prostaglandin F2α receptor. The systematic study of the N-terminal phenylacetyl moiety and the conformation and side chain functions of the central turn dipeptide residue has demonstrated the sensitive relationships between modulator activity and topology. Examination of aza-Gly-Pro and aza-Phe-Pro analogs 2a and 2b in a murine preterm labor model featuring treatment with lipopolysaccharide demonstrated their capacity to extend significantly (>20 h) the average time of delivery offering new prototypes for delaying premature birth.
Asunto(s)
Compuestos Aza/uso terapéutico , Indolicidinas/química , Péptidos/uso terapéutico , Nacimiento Prematuro/prevención & control , Prolina/análogos & derivados , Receptores de Prostaglandina/metabolismo , Tocolíticos/uso terapéutico , Regulación Alostérica , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Escherichia coli/química , Femenino , Lipopolisacáridos , Ratones , Imitación Molecular , Péptidos/síntesis química , Péptidos/química , Embarazo , Nacimiento Prematuro/inducido químicamente , Estereoisomerismo , Relación Estructura-Actividad , Tocolíticos/síntesis química , Tocolíticos/química , Contracción Uterina/efectos de los fármacos , Útero/efectos de los fármacosRESUMEN
To compare and evaluate the differences of stereoselective activity, the binding affinity, metabolism, transport and molecular docking of phencynonate isomers to muscarinic acetylcholine receptor (mAChR) were investigated in this study. The rotation stimulation and locomotor experiments were used to evaluate anti-motion sickness effects. The competitive affinity with [3H]-QNB and molecular docking were used for studying the interactions between the two isomers and mAChR. The stereoselective mechanism of isomers was investigated by incubation with rat liver microsomes, a protein binding assay and membrane permeability assay across a Caco-2 cell monolayer using a chiral column HPLC method. The results indicated that S-isomer was more effective against motion sickness and had not anxiogenic action at therapeutic doses. S-isomer has the higher affinity and activity for mAChR in cerebral cortex and acted as a competitive mAChR antagonist. The stereoselective elimination of S-isomer was primarily affected by CYP1B1 and 17A1 enzymes, resulting in a higher metabolic stability and slower elimination. Phencynonate S isomer, as a eutomer and central anticholinergic chiral drug, is a novel anti-motion sickness drug with higher efficacy and lower central side effect. Our data assisted the development of a novel drug and eventual use of S-isomer in clinical practice.
Asunto(s)
Compuestos Aza/uso terapéutico , Antagonistas Colinérgicos/uso terapéutico , Glicolatos/uso terapéutico , Mareo por Movimiento/tratamiento farmacológico , Mareo por Movimiento/prevención & control , Receptores Muscarínicos/efectos de los fármacos , Animales , Compuestos Aza/química , Células CACO-2 , Línea Celular Tumoral , Antagonistas Colinérgicos/química , Citocromo P-450 CYP1B1/metabolismo , Glicolatos/química , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Ratas , Ratas Sprague-DawleyRESUMEN
Azepane-based compounds showed a variety of pharmacological properties, and its derivatives possess a high degree of structural diversity, and it is useful for the discovery of new therapeutic agents. The development of new less toxic, low-cost and highly active azepane-containing analogs is a hot research topic in medicinal chemistry. Now, more than 20 azepane-based drugs have been approved by FDA, and widely used to treat various types of diseases. This review highlights the recent developments of azepane-based compounds in a wide range of therapeutic applications, such as anti-cancer, anti-tubercular, anti-Alzheimer's disease, and antimicrobial agents, as well as, histamine H3 receptor inhibitors, α-glucosidase inhibitors, anticonvulsant drugs and other miscellaneous applications. We here briefly describe the structure-activity relationship (SAR) and molecular docking studies of potential bioactive compounds for future discovery of suitable drug candidates. It can serve as an inspiration for new ideas for design and development of less toxic and more powerful azepane-based drugs against numerous devastating diseases.
Asunto(s)
Compuestos Aza/uso terapéutico , Química Farmacéutica , Descubrimiento de Drogas , Animales , Humanos , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
ω3-polyunsaturated free fatty acids (ω3-PUFAs), particularly docosahexaenoic (DHA) and eicosapentaenoic acid (EPA), are thought to exert health promoting effects in metabolic and in inflammatory diseases. The molecular mechanisms of these beneficial effects are only partially understood. DHA and EPA activate Free Fatty Acid receptor 4 (GPR120/FFA4). Recently, the first orally available, synthetic ligand of FFA4, 3-[2-chloro-5-(trifluoromethoxy)phenyl]-3-azaspiro[5.5]undecane-9-acetic acid ("compound A"; cpd A) has been developed. Cpd A exhibits distinctly higher potency, efficiency, and selectivity at FFA4 than ω3-PUFAs and ameliorates insulin resistance and adipose tissue inflammation in the mouse. With GPR120/FFA4 activation believed to also attenuate tissue inflammation in autoimmune diseases, cpd A may also have a beneficial effect in these diseases. We have therefore addressed the therapeutic potential of cpd A in mouse models of three prototypical autoimmune diseases, specifically psoriasis, rheumatoid arthritis, and bullous pemphigoid. The effect of cpd A on the course of Aldara™-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, and antibody transfer pemphigoid disease-like dermatitis was scrutinized. Cpd A did not alter the course of Aldara-induced psoriasis-like dermatitis, K/BxN serum transfer arthritis, or antibody transfer pemphigoid disease-like dermatitis. Our results suggest that therapeutic regimens solely relying on FFA4 activation do not bear the potential to treat inflammatory diseases. With cpd A distinctly more potent in activating GPR120/FFA4 than ω3-PUFAs, this also suggests that GPR120/FFA4 activation by ω3-PUFAs does not significantly contribute to the health-promoting effects of ω3-PUFAs in autoimmune diseases.
Asunto(s)
Ácido Acético/administración & dosificación , Antiinflamatorios no Esteroideos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Compuestos Aza/administración & dosificación , Penfigoide Ampolloso/tratamiento farmacológico , Psoriasis/tratamiento farmacológico , Receptores Acoplados a Proteínas G/agonistas , Ácido Acético/uso terapéutico , Administración Oral , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Reumatoide/inmunología , Compuestos Aza/uso terapéutico , Modelos Animales de Enfermedad , Ácidos Grasos Omega-3/metabolismo , Humanos , Imiquimod/inmunología , Ratones , Ratones Endogámicos C57BL , Penfigoide Ampolloso/inmunología , Psoriasis/inmunología , Receptores Acoplados a Proteínas G/inmunología , Receptores Acoplados a Proteínas G/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND: There has been renewal of interest in the use of prophylactic antibiotics to reduce the frequency of exacerbations and improve quality of life in chronic obstructive pulmonary disease (COPD). OBJECTIVES: To determine whether or not regular (continuous, intermittent or pulsed) treatment of COPD patients with prophylactic antibiotics reduces exacerbations or affects quality of life. SEARCH METHODS: We searched the Cochrane Airways Group Trials Register and bibliographies of relevant studies. The latest literature search was performed on 27 July 2018. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared prophylactic antibiotics with placebo in patients with COPD. DATA COLLECTION AND ANALYSIS: We used the standard Cochrane methods. Two independent review authors selected studies for inclusion, extracted data, and assessed risk of bias. We resolved discrepancies by involving a third review author. MAIN RESULTS: We included 14 studies involving 3932 participants in this review. We identified two further studies meeting inclusion criteria but both were terminated early without providing results. All studies were published between 2001 and 2015. Nine studies were of continuous macrolide antibiotics, two studies were of intermittent antibiotic prophylaxis (three times per week) and two were of pulsed antibiotic regimens (e.g. five days every eight weeks). The final study included one continuous, one intermittent and one pulsed arm. The antibiotics investigated were azithromycin, erythromycin, clarithromycin, doxycyline, roxithromycin and moxifloxacin. The study duration varied from three months to 36 months and all used intention-to-treat analysis. Most of the pooled results were of moderate quality. The risk of bias of the included studies was generally low.The studies recruited participants with a mean age between 65 and 72 years and mostly at least moderate-severity COPD. Five studies only included participants with frequent exacerbations and two studies recruited participants requiring systemic steroids or antibiotics or both, or who were at the end stage of their disease and required oxygen. One study recruited participants with pulmonary hypertension secondary to COPD and a further study was specifically designed to asses whether eradication of Chlamydia pneumoniae reduced exacerbation rates.The co-primary outcomes for this review were the number of exacerbations and quality of life.With use of prophylactic antibiotics, the number of participants experiencing one or more exacerbations was reduced (odds ratio (OR) 0.57, 95% CI 0.42 to 0.78; participants = 2716; studies = 8; moderate-quality evidence). This represented a reduction from 61% of participants in the control group compared to 47% in the treatment group (95% CI 39% to 55%). The number needed to treat for an additional beneficial outcome with prophylactic antibiotics given for three to 12 months to prevent one person from experiencing an exacerbation (NNTB) was 8 (95% CI 5 to 17). The test for subgroup difference suggested that continuous and intermittent antibiotics may be more effective than pulsed antibiotics (P = 0.02, I² = 73.3%).The frequency of exacerbations per patient per year was also reduced with prophylactic antibiotic treatment (rate ratio 0.67; 95% CI 0.54 to 0.83; participants = 1384; studies = 5; moderate-quality evidence). Although we were unable to pool the result, six of the seven studies reporting time to first exacerbation identified an increase (i.e. benefit) with antibiotics, which was reported as statistically significant in four studies.There was a statistically significant improvement in quality of life as measured by the St George's Respiratory Questionnaire (SGRQ) with prophylactic antibiotic treatment, but this was smaller than the four unit improvement that is regarded as being clinically significant (mean difference (MD) -1.94, 95% CI -3.13 to -0.75; participants = 2237; studies = 7, high-quality evidence).Prophylactic antibiotics showed no significant effect on the secondary outcomes of frequency of hospital admissions, change in forced expiratory volume in one second (FEV1), serious adverse events or all-cause mortality (moderate-quality evidence). There was some evidence of benefit in exercise tolerance, but this was driven by a single study of lower methodological quality.The adverse events that were recorded varied among the studies depending on the antibiotics used. Azithromycin was associated with significant hearing loss in the treatment group, which was in many cases reversible or partially reversible. The moxifloxacin pulsed study reported a significantly higher number of adverse events in the treatment arm due to the marked increase in gastrointestinal adverse events (P < 0.001). Some adverse events that led to drug discontinuation, such as development of long QTc or tinnitus, were not significantly more frequent in the treatment group than the placebo group but pose important considerations in clinical practice.The development of antibiotic resistance in the community is of major concern. Six studies reported on this, but we were unable to combine results. One study found newly colonised participants to have higher rates of antibiotic resistance. Participants colonised with moxifloxacin-sensitive pseudomonas at initiation of therapy rapidly became resistant with the quinolone treatment. A further study with three active treatment arms found an increase in the degree of antibiotic resistance of isolates in all three arms after 13 weeks treatment. AUTHORS' CONCLUSIONS: Use of continuous and intermittent prophylactic antibiotics results in a clinically significant benefit in reducing exacerbations in COPD patients. All studies of continuous and intermittent antibiotics used macrolides, hence the noted benefit applies only to the use of macrolide antibiotics prescribed at least three times per week. The impact of pulsed antibiotics remains uncertain and requires further research.The studies in this review included mostly participants who were frequent exacerbators with at least moderate-severity COPD. There were also older individuals with a mean age over 65 years. The results of these studies apply only to the group of participants who were studied in these studies and may not be generalisable to other groups.Because of concerns about antibiotic resistance and specific adverse effects, consideration of prophylactic antibiotic use should be mindful of the balance between benefits to individual patients and the potential harms to society created by antibiotic overuse. Monitoring of significant side effects including hearing loss, tinnitus, and long QTc in the community in this elderly patient group may require extra health resources.
Asunto(s)
Antibacterianos/uso terapéutico , Profilaxis Antibiótica/métodos , Progresión de la Enfermedad , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Calidad de Vida , Anciano , Amoxicilina/efectos adversos , Amoxicilina/uso terapéutico , Antibacterianos/efectos adversos , Compuestos Aza/uso terapéutico , Azitromicina/efectos adversos , Azitromicina/uso terapéutico , Claritromicina/uso terapéutico , Ácido Clavulánico/efectos adversos , Ácido Clavulánico/uso terapéutico , Esquema de Medicación , Eritromicina/uso terapéutico , Fluoroquinolonas , Humanos , Moxifloxacino/uso terapéutico , Quinolinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Roxitromicina/efectos adversos , Roxitromicina/uso terapéutico , Combinación Trimetoprim y Sulfametoxazol/efectos adversos , Combinación Trimetoprim y Sulfametoxazol/uso terapéuticoRESUMEN
NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be mediated by the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005 that are being explored in clinical trials. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.
Asunto(s)
Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Compuestos Aza/uso terapéutico , Niño , ADN Tumoral Circulante/sangre , Humanos , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/genética , Neoplasias/sangre , Neoplasias/epidemiología , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/sangre , Pediatría , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Receptor trkA/antagonistas & inhibidores , Receptor trkA/genética , Receptor trkB/antagonistas & inhibidores , Receptor trkB/genética , Receptor trkC/antagonistas & inhibidores , Receptor trkC/genética , Análisis de Secuencia de ARNRESUMEN
Major depression is a highly prevalent disorder with no effective medical treatments available. Recent evidence has shown that sirtuins (SIRTs) signaling has been implicated to play an essential in the pathogenesis of depression. Here in this study, we aimed to investigate the potential role of the phencynonate hydrochloride (PHH) in rat models of chronic unpredictable mild stress (CUMS)-induced depression. SIRT6 expression was up-regulated by PHH via increasing NAD+/NADH ratio in the prefrontal cortex. PHH was able to suppress CUMS-induced oxidative stress and enhance the antioxidant capacity and antioxidant proteins activity, such as superoxide dismutase 2 (SOD2) and peroxiredoxin 6 (Prdx6). In vitro study, we found that SIRT6 directly bound to SOD2 and Prdx6 and deacetylated them at Lys68/122 and Lys63/209, which were acetylated by p300/CBP-associated factor (PCAF). Finally, we showed that PHH ameliorated CUMS-induced depressive phenotypes by up-regulating SIRT6 deacetylation activity. In summary, PHH-mediating SIRT6 pathway is required for antidepressant response and PHH can be used as a novel therapeutic to effectively treat depression.
Asunto(s)
Compuestos Aza/farmacología , Glicolatos/farmacología , Peroxiredoxina VI/metabolismo , Sirtuinas/metabolismo , Superóxido Dismutasa/metabolismo , Acetilación , Animales , Antidepresivos/farmacología , Compuestos Aza/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/etiología , Glicolatos/uso terapéutico , Ratas , Estrés Psicológico/complicaciones , Estrés Psicológico/tratamiento farmacológicoRESUMEN
Amitifadine, the only drug ever clinically tested in Phase 3 for treating depression, is a triple reuptake inhibitor (TRI) that simultaneously interacts with human monoamine transporters (MATs) including hSERT, hNET and hDAT. This novel multi-target strategy improves drug efficacy and reduces the toxic side effects of drugs. However, the binding modes accounting for amitifadine's polypharmacological mode of action are still elusive, and extensive exploration of the amitifadine-target interactions between amitifadine and MATs is urgently needed. In this study, a total of 0.63 µs molecular dynamics (MD) simulations with an explicit solvent as well as endpoint binding free energy (BFE) calculation were carried out. MD simulation results identified a shared binding mode involving eleven key residues at the S1 site of MATs for the binding of amitifadine, and the results of the BFE calculations were in good agreement with experimental reports. Moreover, by analyzing the per-residue energy contribution variation at the S1 site of three MATs and additional cross-mutagenesis simulations, the variation in the inhibition ratio of amitifadine between hSERT and two other MATs was discovered to mainly come from non-conserved residues (Y95, I172 and T439 in hNET and Y95, I172, A169 and T439 in hDAT). As the rational inhibition ratio of multi-target drugs among various therapeutic targets was found to be the key to their safety and tolerance, the findings of this study may further facilitate the rational design of more potent but less toxic multi-target antidepressant drugs.
Asunto(s)
Antidepresivos/metabolismo , Compuestos Aza/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Antidepresivos/química , Antidepresivos/uso terapéutico , Compuestos Aza/química , Compuestos Aza/uso terapéutico , Sitios de Unión , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Análisis por Conglomerados , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/patología , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/antagonistas & inhibidores , Humanos , Simulación de Dinámica Molecular , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Unión Proteica , Estructura Terciaria de Proteína , Proteínas de Transporte de Serotonina en la Membrana Plasmática/química , TermodinámicaRESUMEN
BACKGROUND: p53 is the most mutated protein in cancer and the reactivation of its inactive mutated form represents one possibility for antitumor therapy. Reactivation leads to the initiation of apoptosis followed by the suppression of the malignant phenotype. Prima-1 and its methylated form Prima-1Met (also called APR-246) are compounds capable of reactivating mutated p53. Both are low-molecular substances that have been tested in a number of tumor cell lines and tumors bearing mutated p53. AIM: This article summarizes what is currently known about both compounds, describes the possibilities of their use in anti-tumor therapy, and outlines the results of currently undergoing clinical trials of APR-246. CONCLUSION: The results show that the mechanism of action of both compounds is still not clear. The mechanism is only known clearly in the case of Prima-1, and APR-246 is only known to induce apoptosis. The specificity of both substances for mutated p53 differs considerably and depends mainly on the cell model employed and the type of mutation. In addition to p53 reactivation itself, these compounds likely influence other mechanisms that also affect cytotoxic activity. Key words: Prima-1Met - APR-246 - Prima-1 - reactivation of p53 - apoptosis NPU I - LO1413. This work was supported by the project MEYS - NPS I - LO1413. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Accepted: 16. 07. 2018.
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Compuestos Aza/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Neoplasias/tratamiento farmacológico , Quinuclidinas/uso terapéutico , Apoptosis/efectos de los fármacos , Humanos , Proteína p53 Supresora de Tumor/metabolismoAsunto(s)
Antineoplásicos/uso terapéutico , Compuestos Aza/uso terapéutico , Resistencia a Antineoplásicos/genética , Mutación , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Progresión de la Enfermedad , Humanos , Neoplasias/genética , Neoplasias/patologíaRESUMEN
Acute lung injury, characterized by inflammation, is a main cause of respiratory failure that affects patients worldwide. Antidesmone is one compound mainly isolated from Ajugade cumbens Thunb (Labiatae), an herb agent of Labiatae family. In this research, we investigated the anti-inflammation effect of antidesmone in vitro and in vivo. Antidesmone exerted none apparently cytotoxicity in vitro and toxic in vivo. In vitro results demonstrated that antidesmone suppressed the excess inflammatory cytokines production, including tumor necrosis factor-α, interleukin-6 and interleukin-1ß in lipopolysaccharide (LPS)-exposed RAW264.7 cells. In vivo results suggested that antidesmone inhibited inflammatory cytokines in the bronchoalveolar lavage fluid and lung tissue after LPS stimulation. Moreover, antidesmone attenuated the nuclear translocation of p65. Mechanism study revealed that mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways play important roles in antidesmone's action. Taken together, our data uncover a relative toxic anti-inflammatory drug, antidesmone, can inhibit inflammation on stimulated macrophages and thereby prevents acute lung injury by regulating MAPK and NF-κB signaling pathways.
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Lesión Pulmonar Aguda/tratamiento farmacológico , Antiinflamatorios/uso terapéutico , Compuestos Aza/uso terapéutico , Inflamación/tratamiento farmacológico , Lamiaceae/inmunología , Macrófagos/efectos de los fármacos , Animales , Citocinas/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Lipopolisacáridos/inmunología , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Células RAW 264.7 , Transducción de Señal/efectos de los fármacosAsunto(s)
Compuestos Aza/efectos adversos , Inmunosupresores/efectos adversos , Linfopenia/diagnóstico , Mercaptopurina/efectos adversos , Efectos Tardíos de la Exposición Prenatal/diagnóstico , Purinas/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T/genética , Inmunodeficiencia Combinada Grave/diagnóstico , Linfocitos T/fisiología , Compuestos Aza/uso terapéutico , Femenino , Humanos , Inmunosupresores/uso terapéutico , Lactante , Recién Nacido , Recuento de Linfocitos , Linfopenia/genética , Linfopoyesis/efectos de los fármacos , Masculino , Mercaptopurina/uso terapéutico , Tamizaje Neonatal , Patología Molecular , Embarazo , Estados UnidosRESUMEN
OBJECTIVES: To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80). METHODS: Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI). RESULTS: In the first study (n = 44), the maximum upper bounds of the 90% confidence interval (CI) for mean placebo-corrected change from baseline in QTcI across 13 time points over 24 h were: 10.0 msec for BTDS 10 (Day 6) and 13.3 msec for BTDS 40 (Day 13); and 17.0 msec (Day 6) and 15.5 msec (Day 13) for moxifloxacin, respectively. Similarly, in the second study (n = 66), the upper bound of the 90% CI for mean placebo-corrected change from baseline for QTcI was under 10 msec at all time points for BTDS 10 (maximum upper bound, 5.63 msec), over 10 msec at 5 time points for BTDS 40 (maximum 11.81 msec) and over 10 msec at all 13 time points for BTDS 80 (maximum, 14.14 msec). Naltrexone administered with BTDS eliminated the QTcI prolongation seen with supratherapeutic BTDS doses (BTDS 40, BTDS 80) administered without naltrexone. CONCLUSIONS: At the therapeutic dose of 10 mcg/h, BTDS has no clinically significant effect on QTc. At supratherapeutic doses of 40 and 80 mcg/h, BTDS treatment produces prolongation of QTcI similar in magnitude to that produced by a 400 mg dose of moxifloxacin. Despite the modest, dose-dependent increase in QTcI noted in these studies, transdermal buprenorphine has not been associated with proarrhythmic effects.