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1.
Zhonghua Zhong Liu Za Zhi ; 42(2): 133-138, 2020 Feb 23.
Artigo em Chinês | MEDLINE | ID: mdl-32135648

RESUMO

Objective: To evaluate the long-term effect and safety of chrono-chemotherapy combined with intensity modulated radiotherapy (IMRT) in locally advanced nasopharyngeal carcinoma (NPC). Methods: 160 patients with locally advanced NPC were randomly divided into a chrono group and conventional group according to random number table. In the first stage, all patients underwent two cycles of induced chemotherapy, consisting of docetaxel, cisplatin and 5-Fu every 21 days. Notably, patients received chrono-moduated chemotherapy according to circadian rhythm in the chrono group, and conventional chemotherapy in the conventional group. Then, 21 days after the completion of first stage, three cycles of concurrent cisplatin chemotherapy every 21 days were given to all patients during IMRT. The median follow-up after the completion of radiotherapy was 31 months. Long-term side effects and the survival of patients were observed. Results: Patients in the chrono group had significantly lower rates of hearing loss (22.72%), dysphagia (0) and neck fibrosis (4.54%) compared with those in the conventional group (39.13%、8.69%, 15.94%, respectively, all P<0.05). Meanwhile, the 1- year overall survival rates (97.0% vs 92.8%), 3-year overall survival rates (80.3% vs 81.2%), 1-year progression free survival rates (95.5% vs 87.0%), 3-year progression free survival rates (71.2% vs 73.9%), 1-year locoregional relapse-free survival rates (97.0% vs 95.7%), 1-year locoregional relapse-free survival rates (92.4% vs 92.8%), 1-year distant metastasis-free survival rates (97.0% vs 98.6%) and 3-year distant metastasis-free survival rates (90.9% vs 91.3%) between the chrono group and the conventional group were not statistically significant (all P>0.05). Conclusions: Compared with conventional chemotherapy, chrono-chemotherapy combined with IMRT didn't affect long-term survival, but reducing the incidence of adverse events in patients with locally advanced NPC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Nasofaríngeo/tratamento farmacológico , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/radioterapia , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimiorradioterapia/métodos , Cisplatino/administração & dosagem , Terapia Combinada , Docetaxel/administração & dosagem , Cronoterapia Farmacológica , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/patologia , Radioterapia de Intensidade Modulada/métodos , Resultado do Tratamento
2.
PLoS Comput Biol ; 16(1): e1007218, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31986133

RESUMO

Precision medicine requires accurate technologies for drug administration and proper systems pharmacology approaches for patient data analysis. Here, plasma pharmacokinetics (PK) data of the OPTILIV trial in which cancer patients received oxaliplatin, 5-fluorouracil and irinotecan via chronomodulated schedules delivered by an infusion pump into the hepatic artery were mathematically investigated. A pump-to-patient model was designed in order to accurately represent the drug solution dynamics from the pump to the patient blood. It was connected to semi-mechanistic PK models to analyse inter-patient variability in PK parameters. Large time delays of up to 1h41 between the actual pump start and the time of drug detection in patient blood was predicted by the model and confirmed by PK data. Sudden delivery spike in the patient artery due to glucose rinse after drug administration accounted for up to 10.7% of the total drug dose. New model-guided delivery profiles were designed to precisely lead to the drug exposure intended by clinicians. Next, the complete mathematical framework achieved a very good fit to individual time-concentration PK profiles and concluded that inter-subject differences in PK parameters was the lowest for irinotecan, intermediate for oxaliplatin and the largest for 5-fluorouracil. Clustering patients according to their PK parameter values revealed patient subgroups for each drug in which inter-patient variability was largely decreased compared to that in the total population. This study provides a complete mathematical framework to optimize drug infusion pumps and inform on inter-patient PK variability, a step towards precise and personalized cancer chronotherapy.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Cronoterapia Farmacológica , Medicina de Precisão/métodos , Antineoplásicos/uso terapêutico , Feminino , Humanos , Bombas de Infusão/normas , Masculino , Modelos Teóricos , Neoplasias/tratamento farmacológico
3.
Biol Pharm Bull ; 42(9): 1562-1568, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31474716

RESUMO

Chronopharmacology is the study of the varying responses of drugs to changes in biological timing and endogenous periodicities. The dipeptidyl peptidase-4 inhibitor sitagliptin is a globally prescribed anti-hyperglycemic drug. Although dipeptidyl peptidase-4 inhibitors are usually administered once, the specific intake time is generally not mentioned. Therefore, this study aimed at investigating the diurnal effects of sitagliptin-induced anti-hyperglycemia in high-fat diet (HFD)-induced obesity in mice. Five-week-old male C57BL/6J mice were fed normal (control) diet or HFD for 10 weeks. During the last 2 weeks, the mice were administered saline or sitagliptin (10 mg/kg, per os) in the light or dark phase, respectively. At the end of the experiment, the mice were euthanized after an 18 h fasting period, and plasma and tissue samples (liver, kidney, and epididymal white adipose tissues) were collected, or the oral glucose tolerance test was performed. Sitagliptin administration in the light phase significantly decreased plasma glucose levels, insulin levels, hepatic steatosis, and restored the glucose tolerance compared with the HFD group. In contrast, these parameters remained unchanged in the dark phase-treated mice. Our data therefore suggests that sitagliptin portrays definite chronopharmacology, which may provide valuable information on the importance of drug administration timing for maximum pharmacological effects.


Assuntos
Cronoterapia Farmacológica , Hiperglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Obesidade/tratamento farmacológico , Fosfato de Sitagliptina/administração & dosagem , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Glicemia/análise , Dieta Hiperlipídica , Modelos Animais de Doenças , Glucose/metabolismo , Hiperglicemia/metabolismo , Hipoglicemiantes/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Obesidade/sangue , Tamanho do Órgão/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico
4.
Toxicol Lett ; 313: 188-195, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31284022

RESUMO

Brucine is one of the main bioactive and toxic constituents of the herb drug Semen Strychni. Here we aimed to determine dosing time-dependent hepatotoxicity of brucine, and to investigate the role of metabolism in generation of brucine chronotoxicity. Brucine was administered to wild-type or Npas2-/- (a clock disrupted model) mice at different circadian time points for toxicity and pharmacokinetic characterization. The hepatotoxicity was evaluated by plasma alanine aminotransferase and aspartate aminotransferase measurements and histopathological analysis. The role of Cyp3a11 in brucine metabolism was determined by chemical inhibition assays and Cyp3a11-overexpressing HEK293 cells. Hepatic circadian Cyp3a11 mRNA and protein levels were determined by qPCR and Western blotting, respectively. The toxicity of brucine was more severe in the light phase [Zeitgeber time (ZT) 2 and ZT8] than in the dark phase (ZT14 and ZT20). Chemical inhibition and substrate metabolism assays suggested Cyp3a11 as a significant contributor to brucine metabolism. The Cyp3a11 mRNA, protein and activity in the livers of wild-type mice displayed significant circadian fluctuations. Npas2 ablation markedly down-regulated Cyp3a11 mRNA, protein and activity, and abrogated their circadian rhythms. The circadian time differences in brucine pharmacokinetics and liver distribution were lost in Npas2-/- mice, so were the time differences in brucine hepatotoxicity. In conclusion, chronotoxicity of brucine was determined by circadian variations in Cyp3a11 metabolism. The findings have implications in improving brucine (and possibly Semen Strychni) efficacy via dosing time optimization.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia , Ritmo Circadiano , Citocromo P-450 CYP3A/metabolismo , Fígado/efeitos dos fármacos , Fígado/enzimologia , Proteínas de Membrana/metabolismo , Fotoperíodo , Estricnina/análogos & derivados , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Ritmo Circadiano/genética , Cronoterapia Farmacológica , Células HEK293 , Humanos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Estricnina/administração & dosagem , Estricnina/metabolismo , Estricnina/farmacocinética , Estricnina/toxicidade
5.
Rev Cardiovasc Med ; 20(2): 91-98, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31345001

RESUMO

A meta-analysis was performed to compare the antihypertensive efficacy of morning and evening dosing. Database of Pubmed, Embase, Cochrane, Web of Science CNKI, VIP, and Wanfang were searched up to December 2018. A total of 19 randomized control trials and 1215 participants were included in this meta-analysis. Administration time of amlodipine did not affect the office blood pressure (RR = -0.03, 95% CI -0.93-0.88, P = 0.96), daytime blood pressure (RR = -0.30, 95% CI -1.05-0.46, P = 0.44), 24 h mean blood pressure (RR = 1.15, 95% CI -0.39-2.70, P = 0.14), or heart rate (RR = 0.11, 95% CI -1.22-1.45, P = 0.87). Administration of amlodipine in the evening could significantly reduce the nighttime blood pressure (RR = 2.04, 95% CI 1.27-2.81, P < 0.00001), increased non-dipper alteration (RR = 0.51, 95% CI 0.41-0.63, P < 0.00001), and contained better anti-hypertension efficacy (RR = 0.64, 95% CI 0.55-0.74, P < 0.00001). For patients with hypertension, especially for non-dipper hypertension, taking amlodipine in the evening will be more beneficial. Better quality trials conducted in different regions and with larger sample size are necessary to verify the conclusion of this study.


Assuntos
Anlodipino/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/administração & dosagem , Hipertensão/tratamento farmacológico , Anlodipino/efeitos adversos , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Cronoterapia Farmacológica , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
6.
Am J Obstet Gynecol ; 221(3): 255.e1-255.e9, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31051121

RESUMO

BACKGROUND: The benefit of aspirin in preventing preeclampsia is well established; however, studies over the years have demonstrated variability in outcomes with its use. Potential contributing factors to this variation in efficacy include dosing, time of dosing, and preparation of aspirin. OBJECTIVE: We aimed to compare the difference in pharmacokinetics of aspirin, through its major active metabolite, salicylic acid, in pregnant women and nonpregnant women, and to examine the effect of dose (100 mg vs 150 mg), preparation (enteric coated vs non-enteric-coated), and chronotherapy of aspirin (morning vs evening) between the 2 groups. MATERIALS AND METHODS: Twelve high-risk pregnant women and 3 nonpregnant women were enrolled in this study. Pregnant women were in 1 of 4 groups (100 mg enteric coated, 100 mg non-enteric-coated, 150 mg non-enteric-coated morning dosing, and 150 mg non-enteric-coated evening dosing), whereas nonpregnant women undertook each of the 4 dosing schedules with at least a 30-day washout period. Blood samples were collected at baseline (before ingestion) and at 1, 2, 4, 6, 12, and 24 hours after ingestion of aspirin. Plasma obtained was analyzed for salicylic acid levels by means of liquid chromatography-mass spectrometry. Pharmacokinetic values of area under the curve from time point 0 to 24 hours point of maximum concentration, time of maximum concentration, volume of distribution, clearance, and elimination half-life were analyzed for statistical significance with SPSS v25 software. RESULTS: Pregnant women had a 40% ± 4% reduction in area under the curve from time point 0 to 24 hours (P < .01) and 29% ± 3% reduction in point of maximum concentration (P < .01) with a 44% ± 8% increase in clearance (P < .01) in comparison to that in nonpregnant women when 100 mg aspirin was administered. The reduction in the area under the curve from time point 0 to 24 hours, however, was minimized with the use of 150 mg aspirin in pregnant women, with which the area under the curve from time point 0 to 24 hours was closer to that achieved with the use of 100 mg aspirin in nonpregnant women. There was a 4-hour delay (P < .01) in the time of maximum concentration, a 47% ± 3% reduction in point of maximum concentration (P < .01) and a 48% ± 1% increase in volume of distribution (P < .01) with the use of 100 mg enteric-coated aspirin compared to non-enteric-coated aspirin, with no difference in the overall area under the curve. There was no difference in the pharmacokinetics of aspirin between morning and evening dosing. CONCLUSION: There is a reduction in the total drug metabolite concentration of aspirin in pregnancy, and therefore a dose adjustment is potentially required in pregnant women. This is likely due to the altered pharmacokinetics of aspirin in pregnancy, with an increase in clearance. There was no difference in the total drug metabolite concentration of aspirin between enteric-coated and non-enteric-coated aspirin and between morning and evening dosing of aspirin. Further pharmacodynamic and clinical studies are required to examine the clinical relevance of these pharmacokinetic findings.


Assuntos
Aspirina/farmacocinética , Cronoterapia Farmacológica , Inibidores da Agregação de Plaquetas/farmacocinética , Gravidez/fisiologia , Adulto , Área Sob a Curva , Aspirina/administração & dosagem , Aspirina/uso terapêutico , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Feminino , Humanos , Inibidores da Agregação de Plaquetas/administração & dosagem , Inibidores da Agregação de Plaquetas/uso terapêutico , Pré-Eclâmpsia/prevenção & controle , Comprimidos com Revestimento Entérico
7.
Clin Neuropharmacol ; 42(3): 80-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31082833

RESUMO

This review describes the characteristics of a number of pathologies, which are considered from the point of view of chronobiology, that is, the way in which biological processes are expressed throughout the 24-hour day. This perspective is a relatively new way of thinking about disease and additionally about how to treat diseases. It has called attention to the importance of not only the quantity of a drug that is administered but also when it is administered. In addition, the review presents an overview of the emerging clinical strategies known as chronotherapeutics, that is, the effects of the daily scheduling of drug administration and the consequences of the activity and efficacy of therapies that are applied in this manner. This article also reviews innovative ways in which physicians are applying time-specified drug treatment (chronopharmacology) for sleep disorders. Here, we present a systematic description of chronopharmacology as well as definitions of key terms that, we believe, will be helpful for newcomers to the field. It is hoped that greater awareness of this new perspective on pharmacology will promote its adoption by researchers and clinicians.


Assuntos
Fenômenos Cronobiológicos/efeitos dos fármacos , Ritmo Circadiano/efeitos dos fármacos , Cronoterapia Farmacológica , Transtornos do Sono-Vigília/tratamento farmacológico , Humanos
8.
Neurobiol Aging ; 79: 110-118, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31035036

RESUMO

Numerous aspects of mammalian physiology exhibit cyclic daily patterns known as circadian rhythms. However, studies in aged humans and animals indicate that these physiological rhythms are not consistent throughout the life span. The simultaneous development of disrupted circadian rhythms and age-related impairments suggests a shared mechanism, which may be amenable to therapeutic intervention. Recently, the endocannabinoid system has emerged as a complex signaling network, which regulates numerous aspects of circadian physiology relevant to the neurobiology of aging. Agonists of cannabinoid receptor-1 (CB1) have consistently been shown to decrease neuronal activity, core body temperature, locomotion, and cognitive function. Paradoxically, several lines of evidence now suggest that very low doses of cannabinoids are beneficial in advanced age. One potential explanation for this phenomenon is that these drugs exhibit hormesis-a biphasic dose-response wherein low doses produce the opposite effects of higher doses. Therefore, it is important to determine the dose-, age-, and time-dependent effects of these substances on the regulation of circadian rhythms and other processes dysregulated in aging. This review highlights 3 fields-biological aging, circadian rhythms, and endocannabinoid signaling-to critically assess the therapeutic potential of endocannabinoid modulation in aged individuals. If the hormetic properties of exogenous cannabinoids are confirmed, we conclude that precise administration of these compounds may bidirectionally entrain central and peripheral circadian clocks and benefit multiple aspects of aging physiology.


Assuntos
Envelhecimento/fisiologia , Canabinoides/farmacologia , Ritmo Circadiano , Animais , Ritmo Circadiano/efeitos dos fármacos , Relação Dose-Resposta a Droga , Cronoterapia Farmacológica , Endocanabinoides/metabolismo , Endocanabinoides/fisiologia , Hormese/efeitos dos fármacos , Humanos , Camundongos , Receptor CB1 de Canabinoide/agonistas , Transdução de Sinais/efeitos dos fármacos
9.
Recent Pat Drug Deliv Formul ; 13(2): 74-82, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30827275

RESUMO

BACKGROUND: Asthma is a common ailment with a larger circadian difference. Nocturnal Asthma (NA) is an inconstant exacerbation of asthmatic condition related to the rise in warning sign during the night time and there is a need for its treatment addressing air route alertness and decline in lung functions. These symptoms are linked to sleep or known as circadian events. Chronotherapeutics is a management system based on an in-vivo drug accessibility programmed to check the rhythms of ailment in a direction to improve the therapeutic outcomes by suppressing the side effects. This review aims to provide an overview of NA, chronotherapeutics for the treatment of NA, bilayer tablets, and advanced techniques involved in the fabrication of bilayer tablets. The review also discusses some of the related patents. METHODS: Relevant literature about the latest developments and updated information related to NA, chronotherapeutics and bilayer tablets has been very widely searched on different biomedical literature programs such as Google, Web of Science, PubMed portals, etc. Bilayer tablet mediated chronotherapy has gained significant attention and consideration as it is developed and fabricated based on the body's circadian rhythm. Bilayer tablets can deliver the bioactive compounds at an appropriate time, place as well as amount and site. RESULTS: Available literature advocated that the bilayer matrix tablet containing a single drug in the sustained release film and fast releasing film, may be beneficial for the chronic diseases like asthma, migraine, diabetes, hypertension and inflammation which usually require immediate as well as maintained therapeutic effect. CONCLUSION: The application of nanotechnology in the arena of medicine will transform the diagnosis and treatment strategies of a wide range of diseases in the upcoming years. The findings of this review confirm the importance of bilayer tablet based chronotherapy in nocturnal asthma.


Assuntos
Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Cronoterapia Farmacológica , Asma/fisiopatologia , Química Farmacêutica/métodos , Ritmo Circadiano/fisiologia , Preparações de Ação Retardada , Humanos , Patentes como Assunto , Comprimidos
10.
Joint Bone Spine ; 86(3): 327-333, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30227223

RESUMO

Circadian rhythms (Nobel prize for Medicine 2017) regulate, under action of biological clocks located both at the level of central nervous system and inside peripheral cells, several daily activities, embracing sleep, feeding times, energy metabolism, endocrine and immune functions with related pathological conditions, including rheumatoid arthritis (RA). In RA the circadian rhythms impact on cellular functions, involving night synthesis and release of pro-inflammatory cytokines and chemokines, cell migration to inflamed tissues, phagocytosis, proliferative cell response and all are peaking at late night. In chronic inflammatory conditions such as RA, the amplitude of the circadian rhythm of the anti-inflammatory endogenous cortisol availability is not increased as expected and requested, which indicate a reduced night cortisol secretion under the adrenal chronic stress induced by the disease. Therefore, the prevention/treatment of the immune cell night hyperactivity, with related flare of cytokine synthesis and morning RA clinical symptoms, has been shown more effective when the availability of the exogenous glucocorticoids is obtained in the middle of the night (night release). The impressive positive results observed in RA patients treated with modified-night release prednisone with a low-dose chronotherapy, seem applicable even for other agents such as conventional NSAIDs and DMARDs, including the positive experimental and clinical results obtained by the night time daily administration of methotrexate. Interestingly, a very recent study showed that methotrexate upregulates important cell circadian genes, resulting in induction of apoptosis in synovial fibroblasts. The link between the circadian rhythms of the disease and the chronotherapy of RA is promising.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Ritmo Circadiano/efeitos dos fármacos , Cronoterapia Farmacológica , Glucocorticoides/administração & dosagem , Idoso , Artrite Reumatoide/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Medição de Risco , Índice de Gravidade de Doença , Resultado do Tratamento
12.
Arterioscler Thromb Vasc Biol ; 38(12): 2819-2826, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30571171

RESUMO

Objective- Evening but not morning administration of low-dose aspirin has been reported to lower blood pressure in hypertensive patients. The present study was designed to determine whether this phenomenon could be replicated in mice, and if so, whether a time-dependent effect of aspirin on blood pressure was because of alteration of circadian clock function. Approach and Results- We recapitulated the protective effect of aspirin (50 µg/d for 7 days) at zeitgeber time 0 (active-to-rest transit), but not at zeitgeber time 12, on a high-salt diet-induced increase of blood pressure. However, the time of aspirin administration did not influence expression of canonical clock genes or their acetylation. We used mouse Bmal1 and Per2-luciferase reporters expressed in U2OS cells to determine the real-time effect of aspirin on circadian function but found that the oscillation of bioluminescence was unaltered. Timing of aspirin administration also failed to alter urinary prostaglandin metabolites or catecholamines, or the acetylation of its COX-1 (cyclooxygenase-1) target in platelets. Conclusions- The time-dependent hypotensive effect of aspirin in humans has been recapitulated in hypertensive mice. However, this does not seem to reflect a direct impact of aspirin on circadian clocks or on acetylation of platelet COX-1.


Assuntos
Anti-Hipertensivos/administração & dosagem , Aspirina/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Ritmo Circadiano , Hipertensão/prevenção & controle , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Linhagem Celular Tumoral , Relógios Circadianos/efeitos dos fármacos , Relógios Circadianos/genética , Ritmo Circadiano/efeitos dos fármacos , Ciclo-Oxigenase 1/sangue , Modelos Animais de Doenças , Cronoterapia Farmacológica , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Proteínas de Membrana/sangue , Camundongos Endogâmicos C57BL , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Cloreto de Sódio na Dieta , Fatores de Tempo
13.
Postgrad Med J ; 94(1117): 653-658, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30523071

RESUMO

Circadian rhythms are endogenously generated recurring patterns of around 24 hours with well-established roles in physiology and behaviour. These circadian clocks are important in both the aetiology and treatment of various psychiatric and metabolic diseases. To maintain physiological homeostasis and optimal functioning, living life synchronised to these clocks is desirable; modern society, however, promotes a '24/7' lifestyle where activity often occurs during the body's 'biological night', resulting in mistimed sleep and circadian misalignment. This circadian desynchrony can increase the risk of disease and can also influence treatment response. Clinicians should be aware of the influence that circadian desynchrony can have on health and disease, in order to potentially develop new therapeutic strategies and to incorporate chronotherapeutics into current treatment strategies to enhance their utility.


Assuntos
Ritmo Circadiano/fisiologia , Doenças Metabólicas/etiologia , Doenças Metabólicas/fisiopatologia , Estresse Psicológico/fisiopatologia , Relógios Circadianos/fisiologia , Cronoterapia Farmacológica , Humanos , Sono , Vigília
15.
Hear Res ; 370: 16-21, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30253329

RESUMO

Cisplatin is a potent chemotherapeutic compound for which ototoxicity is a significant side effect. Cisplatin has shown sensitivity to circadian time, in that cisplatin is most effective as an anti-tumor compound, and least nephrotoxic, when given in the active (dark) period of the light-dark cycle in rodents. The objective of the study was to determine the sensitivity of cisplatin ototoxicity to circadian time. Fifty-seven Fischer 344/NHsd rats were exposed to 12 mg/kg cisplatin by intra-peritoneal injection at one of six time points on a 12 h light-12 h dark cycle: 2, 6, or 10 h after light onset or 2, 6, or 10 h after light offset. Cochlear injury was evaluated using auditory brainstem response threshold shifts and postmortem outer hair cell counts. All animals experienced threshold shift in the highest frequencies tested (30 and 40 kHz). The animals exposed to cisplatin at 6 h after light onset (the inactive period) had significantly higher mid-frequency threshold shifts and outer hair cell losses than the groups exposed during the dark hours. The results indicate that cisplatin is less likely to cause ototoxicity in the Fischer 344/NHsd rat when given during the active period. This finding is consistent with the lower nephrotoxicity that has been detected in cisplatin-exposed animals treated during the dark hours, and the magnitude of differences in threshold shifts between the light and dark exposure indicates that circadian timing has a significant impact on susceptibility to cisplatin ototoxicity.


Assuntos
Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Cóclea/efeitos dos fármacos , Doenças Cocleares/prevenção & controle , Cronoterapia Farmacológica , Animais , Antineoplásicos/toxicidade , Fadiga Auditiva/efeitos dos fármacos , Cisplatino/toxicidade , Cóclea/patologia , Cóclea/fisiopatologia , Doenças Cocleares/induzido quimicamente , Doenças Cocleares/patologia , Doenças Cocleares/fisiopatologia , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Feminino , Células Ciliadas Auditivas Externas/efeitos dos fármacos , Células Ciliadas Auditivas Externas/patologia , Masculino , Fotoperíodo , Ratos Endogâmicos F344 , Fatores de Tempo
16.
Curr Hypertens Rep ; 20(11): 97, 2018 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-30267334

RESUMO

PURPOSE OF REVIEW: Given the emerging knowledge that circadian rhythmicity exists in every cell and all organ systems, there is increasing interest in the possible benefits of chronotherapy for many diseases. There is a well-documented 24-h pattern of blood pressure with a morning surge that may contribute to the observed morning increase in adverse cardiovascular events. Historically, antihypertensive therapy involves morning doses, usually aimed at reducing daytime blood pressure surges, but an absence of nocturnal dipping blood pressure is also associated with increased cardiovascular risk. RECENT FINDINGS: To more effectively reduce nocturnal blood pressure and still counteract the morning surge in blood pressure, a number of studies have examined moving one or more antihypertensives from morning to bedtime dosing. More recently, such studies of chronotherapy have studied comorbid populations including obstructive sleep apnea, chronic kidney disease, or diabetes. Here, we summarize major findings from recent research in this area (2013-2017). In general, nighttime administration of antihypertensives improved overall 24-h blood pressure profiles regardless of disease comorbidity. However, inconsistencies between studies suggest a need for more prospective randomized controlled trials with sufficient statistical power. In addition, experimental studies to ascertain mechanisms by which chronotherapy is beneficial could aid drug design and guidelines for timed administration.


Assuntos
Anti-Hipertensivos/administração & dosagem , Cronoterapia Farmacológica , Hipertensão/tratamento farmacológico , Complicações do Diabetes , Humanos , Hipertensão/complicações , Insuficiência Renal Crônica/complicações , Apneia Obstrutiva do Sono/complicações
17.
Trends Pharmacol Sci ; 39(9): 812-827, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30060890

RESUMO

Daily rhythms in behavior, physiology, and metabolism are an integral part of homeostasis. These rhythms emerge from interactions between endogenous circadian clocks and ambient light-dark cycles, sleep-activity cycles, and eating-fasting cycles. Nearly the entire primate genome shows daily rhythms in expression in tissue- and locus-specific manners. These molecular rhythms modulate several key aspects of cellular and tissue function with profound implications in public health, disease prevention, and disease management. In modern societies light at night disrupts circadian rhythms, leading to further disruption of sleep-activity and eating-fasting cycles. While acute circadian disruption may cause transient discomfort or exacerbate chronic diseases, chronic circadian disruption can enhance risks for numerous diseases. The molecular understanding of circadian rhythms is opening new therapeutic frontiers placing the circadian clock in a central role. Here, we review recent advancements on how to enhance our circadian clock through behavioral interventions, timing of drug administration, and pharmacological targeting of circadian clock components that are already providing new preventive and therapeutic strategies for several diseases, including metabolic syndrome and cancer.


Assuntos
Doença Crônica/terapia , Relógios Circadianos/efeitos dos fármacos , Relógios Circadianos/fisiologia , Cronoterapia Farmacológica , Animais , Esquema de Medicação , Humanos
18.
Eur J Pharm Sci ; 123: 452-458, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30077713

RESUMO

Uracil-tegafur (UFT) is an oral anticancer drug containing uracil and 5­fluorouracil prodrug tegafur and is widely used for adjuvant chemotherapy of colorectal cancer. Although clinical data show circadian variations in plasma 5­fluorouracil concentrations during its long-term infusion, and feasibility studies of chronomodulated administration have been previously reported, the circadian pattern in plasma 5­fluorouracil concentration after UFT administrations remains unclear. The aim of this study was to identify factors causing circadian variations in UFT pharmacokinetics and estimate circadian patterns of plasma 5­fluorouracil concentration corresponding to UFT dosing time in rats. Rats were orally administered UFT (15 mg/kg as tegafur) at three different times of the day: 07:00 (23 h after light onset, HALO), 13:00 (5 HALO), or 19:00 (11 HALO), and then plasma concentrations of tegafur, 5­fluorouracil, and uracil were measured after UFT administration. We found that the area under the plasma concentration-time curves (AUC0-∞) of 5­fluorouracil depended on the UFT dosing time of day with a 2.4-fold difference between the peak (at 19:00: 13.7 ±â€¯1.4 µmol·h/L) and trough (at 13:00: 5.6 ±â€¯1.3 µmol·h/L). The simulated population mean clearance of 5­fluorouracil followed a 24-h cosine circadian curve, with the highest value in the early light phase being 2.2-fold higher than the lowest value in the early dark phase, which was an inverse circadian pattern compared to the plasma 5­fluorouracil concentration. The plasma tegafur levels suggested that circadian variation in tegafur absorption and conversion to 5­fluorouracil are factors causing variations in plasma 5­fluorouracil levels following UFT administration. In conclusion, the circadian pattern of 5­fluorouracil clearance and circadian variations in tegafur pharmacokinetics are important determinants of plasma 5­fluorouracil concentrations following UFT administration. This knowledge could help in developing a chronomodulated administration strategy of UFT for improving clinical outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ritmo Circadiano , Tegafur/administração & dosagem , Tegafur/farmacocinética , Uracila/administração & dosagem , Uracila/farmacocinética , Administração Oral , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Biotransformação , Esquema de Medicação , Cronoterapia Farmacológica , Combinação de Medicamentos , Masculino , Modelos Biológicos , Ratos Wistar , Tegafur/análogos & derivados , Tegafur/sangue , Uracila/análogos & derivados , Uracila/sangue
19.
AAPS PharmSciTech ; 19(6): 2700-2709, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29968041

RESUMO

This work developed a chronotherapeutic drug delivery system (CTDDS) utilizing a potential continuous hot-melt extrusion (HME) technique. Ketoprofen (KTP) and ibuprofen (IBU) were used as two separate model drugs. Eudragit S100 (ES100) was the matrix-forming agent, and ethyl cellulose (EC) (2.5 and 5%) was the release-retarding agent. A 16-mm extruder was used to develop the CTDDS to pilot scale. The obtained extrudate strands were transparent, indicating that the drugs were homogeneously dispersed in the matrix in an amorphous form, confirmed by both differential scanning calorimetry and powder X-ray diffraction. The strands were pelletized into 1, 2, and 3 mm size pellets. A 100% drug release from 1, 2, and 3 mm pellets with 2.5% EC was observed at 12, 14, and 16 h, whereas the drug release was sustained for 14, 16, and 22 h from 5% EC pellets, respectively, for KTP. The release characteristics of IBU were similar to those of KTP with modest variations in release at lag time. The in vitro drug release study conducted in three-stage dissolution media showed a desired lag time of 6 h. The percent drug release from 1, 2, and 3 mm pellets with 40% drug load showed < 20% release from all formulations at 6 h. The amount of ethyl cellulose and pellet size significantly affected drug release. Formulations of both KTP and IBU were stable for 4 months at accelerated stability conditions of 40°C/75% RH. In summary, HME is a novel technique for developing CTDDS.


Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Artrite , Cronoterapia Farmacológica , Sistemas de Liberação de Medicamentos/métodos , Ibuprofeno/síntese química , Cetoprofeno/síntese química , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/metabolismo , Artrite/tratamento farmacológico , Artrite/metabolismo , Varredura Diferencial de Calorimetria/métodos , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Preparações de Ação Retardada/metabolismo , Composição de Medicamentos/métodos , Implantes de Medicamento , Ibuprofeno/administração & dosagem , Ibuprofeno/metabolismo , Cetoprofeno/administração & dosagem , Cetoprofeno/metabolismo , Solubilidade , Difração de Raios X/métodos
20.
Drug Discov Today ; 23(11): 1883-1888, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29964181

RESUMO

Genome-wide association studies have been increasingly used to map and characterize genes that contribute to interindividual variation in drug response. Some studies have integrated the pharmacokinetic (PK) and pharmacodynamic (PD) processes of drug reactions into association mapping, gleaning new insight into how genes determine the dynamic relationship of drug effect and drug dose. Here, we present an evolutionary framework by which two distinct concepts, chronopharmacodynamics and heterochrony (describing variation in the timing and rate of developmental events), are married to comprehend the pharmacogenetic architecture of drug response. The resulting new concept, heterochronopharmacodynamics (HCPD), can better interpret how genes influence drug efficacy and drug toxicity according to the circadian rhythm of the body and changes in drug concentration.


Assuntos
Mapeamento Cromossômico , Cronoterapia Farmacológica , Animais , Estudo de Associação Genômica Ampla , Humanos , Modelos Biológicos
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