RESUMEN
Interstitial lung disease (ILD) is a well-known adverse effect of mammalian target of rapamycin (mTOR) inhibitors. However, it remains unknown how lung toxicities are induced by mTOR inhibitors. Here, we constructed a mouse model of mTOR inhibitor-induced ILD using temsirolimus and examined the pathogenesis of the disease. Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus (3 or 30 mg·kg(-1)·wk(-1)) or vehicle. Temsirolimus treatment increased capillary-alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space, indicating alveolar epithelial and/or endothelial injury. It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols. Alveolar macrophage depletion is thought to cause surfactant lipid accumulation. To further examine whether temsirolimus has cytotoxic and/or cytostatic effects on alveolar macrophages and alveolar epithelial cells, we performed in vitro experiments. Temsirolimus inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells. Temsirolimus treatment caused some signs of pulmonary inflammation, including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates, and an increase in lymphocytes in the bronchoalveolar lavage fluid. These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation, resulting in pulmonary inflammation. This is the first study to focus on the pathogenesis of mTOR inhibitor-induced ILD using an animal model.
Asunto(s)
Metabolismo de los Lípidos/efectos de los fármacos , Macrófagos Alveolares/metabolismo , Neumonía/metabolismo , Surfactantes Pulmonares/metabolismo , Sirolimus/análogos & derivados , Animales , Citocinas/metabolismo , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos ICR , Fosfolípidos/metabolismo , Neumonía/inducido químicamente , Neumonía/patología , Alveolos Pulmonares/metabolismo , Alveolos Pulmonares/patología , Sirolimus/farmacologíaRESUMEN
AIM: To investigate whether (i) angiotensin receptor occupying profiles of angiotensin II receptor blockers (ARBs) vary among the drugs and (ii) such differences contribute to the degree of their pleiotropic effects. METHODS: In a randomized, three phase crossover study, nine hypertensive patients received repeated doses (each recommended starting dose for 7 days and then each maximum recommended dose for 20 days) of irbesartan, valsartan and candesartan. The time course profiles and trough level of receptor occupancy were determined on days 7 and 28, respectively. The pleiotropic effect related parameters were measured on days 0 and 28 in each trial. RESULTS: Of the pleiotropic effect related parameters investigated, urinary 8-isoprostane, fasting serum insulin and homeostasis model assessment of insulin resistance index were more suppressed after 4 weeks treatment with irbesartan than after candesartan and valsartan therapy, respectively. The maximum, area under the curve and trough values of receptor occupancy significantly differed between the ARBs [geometric mean (and 95% CI) of trough value 18.1 (12.9, 25.3) for irbesartan, 9.6 (6.0, 15.3) for valsartan and 5.5 (2.8, 10.8) for candesartan, respectively] and were negatively correlated with the change in urinary 8-isoprostane (r = -0.46 - -0.55, P < 0.05), but not the markers of insulin resistance (r = 0.02-0.15, P = 0.46-0.94). CONCLUSIONS: Our results demonstrate that the receptor occupying profiles are different among the ARBs. This class of drugs might have both receptor occupancy dependent and independent pleiotropic effects.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antihipertensivos/farmacología , Hipertensión/tratamiento farmacológico , Adulto , Antihipertensivos/farmacocinética , Área Bajo la Curva , Bencimidazoles/farmacología , Compuestos de Bifenilo/farmacología , Presión Sanguínea/efectos de los fármacos , Estudios Cruzados , Dinoprost/análogos & derivados , Dinoprost/orina , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Humanos , Insulina/sangre , Resistencia a la Insulina , Irbesartán , Mediciones Luminiscentes , Masculino , Persona de Mediana Edad , Estrés Oxidativo , Ensayo de Unión Radioligante , Receptores de Angiotensina/metabolismo , Tetrazoles/farmacología , Factores de Tiempo , Valina/análogos & derivados , Valina/farmacología , Valsartán , Adulto JovenRESUMEN
Raloxifene, a selective oestrogen receptor modulator commonly used for the treatment of post-menopausal osteoporosis, affects the coagulation and fibrinolytic systems and consequently increases the risk of venous thromboembolism. Because both the coagulation and fibrinolytic systems exhibit circadian rhythms, the aim of the present study was to investigate the effects of dosing time of raloxifene on markers of coagulation and fibrinolysis, as well as on markers of bone metabolism. Thirty-nine post-menopausal patients with osteoporosis were randomly allocated to two groups: one received 60 mg raloxifene once daily in the morning, whereas the other received 60 mg raloxifene once daily in the evening, for 12 months. In both groups, the activity of coagulation Factors IX and XII was increased significantly after 12 months treatment compared with baseline. The activity of coagulation Factors II and V and levels of markers of bone metabolism (i.e. bone alkaline phosphatase and tartrate-resistant acid phosphatase 5b) decreased in both groups. The changes in these markers did not differ between the two groups. In contrast, the plasma concentration of plasminogen activator inhibitor (PAI)-1 increased in the group receiving the morning dose (mean change 40.9%; 95% confidence interval (CI) 9.4, 72.5), but not in the groups receiving the evening dose (mean change -0.3%; 95% CI -31.5, 30.9); these percentage changes differed significantly (P < 0.05). Because an elevated concentration of PAI-1 is known to be associated with the risk of venous thromboembolism, the findings of the present study suggest that the dosing time of raloxifene influences its safety. Further larger-scale studies are needed to determine the clinical usefulness of chronotherapy with raloxifene.
Asunto(s)
Esquema de Medicación , Fibrinólisis/efectos de los fármacos , Osteoporosis Posmenopáusica/tratamiento farmacológico , Inhibidor 1 de Activador Plasminogénico/sangre , Clorhidrato de Raloxifeno/administración & dosificación , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Anciano , Anciano de 80 o más Años , Factores Biológicos/sangre , Ritmo Circadiano/fisiología , Femenino , Fibrinólisis/fisiología , Humanos , Osteoporosis Posmenopáusica/sangre , Clorhidrato de Raloxifeno/efectos adversos , Clorhidrato de Raloxifeno/uso terapéutico , Moduladores Selectivos de los Receptores de Estrógeno/efectos adversos , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Resultado del Tratamiento , Trombosis de la Vena/etiología , Trombosis de la Vena/prevención & controlRESUMEN
Serotonin (5-HT) transporter (5-HTT) plays a key role in the control of 5-HT neuronal activity by reuptaking extracellular 5-HT from the synapse cleft. We have previously demonstrated that 5-HTT mRNA expression levels and its uptake activity in the mouse midbrain are significantly higher in the dark phase than those in the light phase. However, the molecular mechanisms of time-dependent expression of 5-HTT have not been clarified. In this study, expression of 5-HTT mRNA in the mouse midbrain showed a significant 24-h rhythm and was higher in the dark phase. Although such an oscillation was eliminated by a Clock gene mutation, CLOCK and BMAL1 did not activate 5-HTT transcription in the luciferase reporter assay. Activating transcription factor-4 (ATF4), a member of the ATF/cAMP response element (CRE)-binding protein family, is a component responsible for sustaining circadian oscillations of CRE-mediated gene expression. ATF4 significantly activated 5-HTT transcription in vitro and time dependently bound to the CRE site in the 5-HTT promoter in the mouse midbrain. In addition, mutation of the Clock gene disrupted temporal binding of ATF4 to the CRE site in the 5-HTT promoter. These results indicated that the circuit of circadian-basis molecular regulation between the clockwork system and mouse 5-HTT gene was connected by the ATF4 signaling pathway.
Asunto(s)
Factor de Transcripción Activador 4/fisiología , Proteínas CLOCK/biosíntesis , Ritmo Circadiano/fisiología , Regulación de la Expresión Génica/fisiología , Mesencéfalo/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/biosíntesis , Factor de Transcripción Activador 4/genética , Factor de Transcripción Activador 4/metabolismo , Animales , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Masculino , Ratones , Ratones Endogámicos ICR , Mutación , Regiones Promotoras Genéticas , Unión Proteica/genética , Unión Proteica/fisiología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Transducción de Señal/fisiologíaRESUMEN
Adverse events in tocolytic therapy with ß2-adrenergic agents compromise cardiovascular and non-cardiovascular functions, including blood glucose regulation and liver function. Here, we have examined the effects of the ß2 agonist ritodrine on glucose metabolism and liver injury in mice. Under fasting conditions, ritodrine significantly increased serum insulin levels and decreased glucose concentrations. This contrasts with the ß2 agonist-induced hyperglycemia observed in previous studies on humans and other animals. After 14 days of ritodrine treatment, the mice showed a decrease in the total mass of epididymal fat pads, whereas their body weights increased significantly. Chronic ritodrine treatment attenuated the glucose-lowering effect observed during acute administration. Ritodrine also significantly increased serum levels of liver enzymes, which returned to control levels after 14 days of treatment. Thus, ritodrine responsiveness changes between acute and chronic treatment, indicating that close monitoring of blood glucose and serum liver enzymes is necessary in patients with reduced glucose tolerance. The findings reported here of glucose homeostasis in mice provide a unique opportunity to understand refractoriness of ß2-adrenoceptor signaling in response to ß2 agonists during the course of treatment.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Glucemia/efectos de los fármacos , Receptores Adrenérgicos beta 2/fisiología , Ritodrina/administración & dosificación , Transducción de Señal/efectos de los fármacos , Animales , Glucemia/metabolismo , Femenino , Insulina/sangre , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/fisiología , Resultado del TratamientoRESUMEN
Finasteride (FIN), a widely used medication for the treatment of androgen-dependent diseases, blocks the conversion of testosterone to a more potent androgen, dihydrotestosterone (DHT). In this study, we investigated a dosing time-dependent effect and safety of FIN in rats. Androgen receptor (AR) mRNA and nuclear protein levels exhibited clear daily rhythms with the peak during the dark period in the prostate and during the light period in the liver. Repeated oral administration of FIN (5 or 100 mg/kg) at 3 h after lights on (HALO) for 2 weeks decreased serum DHT concentration throughout a 24-h period, whereas the dosing of the agent at 15 HALO decreased its level only transiently even in the higher dose group. FIN caused laboratory abnormalities in the 3 HALO group but not in the 15 HALO group. However, the effect of FIN on the prostate weight was not influenced by the dosing time. These results suggest that the safety, but not effect, of FIN depends on its dosing time in rats. The dosing of FIN in the active period might be a rational dosage regimen, which is needed to be confirmed in human subjects.
Asunto(s)
Finasterida/efectos adversos , Finasterida/uso terapéutico , Animales , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Finasterida/sangre , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Próstata/efectos de los fármacos , Próstata/metabolismo , Ratas , Ratas Wistar , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/sangre , Receptores Androgénicos/genética , Resultado del TratamientoRESUMEN
Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antagonistas de Receptores de Angiotensina/farmacología , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Accidente Cerebrovascular/complicaciones , Bloqueadores del Receptor Tipo 1 de Angiotensina II/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Antagonistas de Receptores de Angiotensina/sangre , Antagonistas de Receptores de Angiotensina/farmacocinética , Animales , Antihipertensivos/sangre , Antihipertensivos/farmacocinética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Distribución Aleatoria , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Receptores de Angiotensina/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Factores de TiempoRESUMEN
Protective effect of valsartan (Val), an angiotensin II (AII)-receptor blocker (ARB), against organ damage is reported to depend on the dosing time in hypertensive patients. Dosing-time-dependent effect of Val on survival of stroke-prone spontaneously hypertensive rats (SHRSP) under a 12-h lighting cycle was examined. Val (4 mg/kg per day) and olmesartan medoxomil (OM) (1 mg/kg per day), another ARB with a slower dissociation from the AII receptor, were given once daily at 2, 8, 14, or 20 HALO (hours after lights on). Dosing-time-dependent differences in plasma drug concentrations and effect on blood pressure (BP) were also evaluated. Survival of SHRSP showed a dosing-time-dependent change during Val therapy, with a peak at 2 HALO and a trough at 14 HALO. OM equally prolonged survival in all groups. The BP-lowering effect persisted for more than 24 h after dosing of Val at 2 HALO and of OM at 2 and 14 HALO, but disappeared at 5.5-h after Val dosing at 14 HALO. Plasma concentrations of Val and OM were higher after dosing at 2 HALO than at 14 HALO. These results suggest that the chronopharmacological phenomenon of Val was partly due to the dosing-time-dependent difference in plasma concentration and subsequent duration of the antihypertensive effect. Slower dissociation of OM from AII receptors might have blunted a potential dosing-time-dependent event.
RESUMEN
The clinical use of arsenic trioxide (ATO) is often limited because of its adverse effects. We examined whether α-lipoic acid (LA) protects against the ATO-induced cardiac toxicity. In the chronic study, two of four rats suddenly died by the repeated dosing of ATO, whereas no deaths were observed in combination with LA. In the acute study, continuous ECG recording revealed that intravenous injection of ATO caused transient ST-T change, whereas pretreatment with LA abolished the ATO-induced ECG abnormality in all animals. These results suggest that LA protects against the ATO-induced acute cardiac toxicity and subsequent sudden death in rats.
Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Electrocardiografía/efectos de los fármacos , Corazón/efectos de los fármacos , Óxidos/toxicidad , Ácido Tióctico/farmacología , Transaminasas/sangre , 8-Hidroxi-2'-Desoxicoguanosina , Fosfatasa Alcalina/sangre , Animales , Antineoplásicos/toxicidad , Antioxidantes/toxicidad , Trióxido de Arsénico , Arsenicales , Creatinina/sangre , Muerte Súbita Cardíaca/etiología , Muerte Súbita Cardíaca/prevención & control , Desoxiguanosina/análogos & derivados , Desoxiguanosina/orina , Relación Dosis-Respuesta a Droga , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología , Sustancias Protectoras/toxicidad , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
The clinical use of arsenic trioxide (ATO) is often limited because of its adverse effects. We examined whether α-lipoic acid (LA) protects against the ATO-induced cardiac toxicity. In the chronic study, two of four rats suddenly died by the repeated dosing of ATO, whereas no deaths were observed in combination with LA. In the acute study, continuous ECG recording revealed that intravenous injection of ATO caused transient ST-T change, whereas pretreatment with LA abolished the ATO-induced ECG abnormality in all animals. These results suggest that LA protects against the ATO-induced acute cardiac toxicity and subsequent sudden death in rats.
RESUMEN
P-glycoprotein (P-gp) is one of the ATP-binding cassette transporters and acts as an efflux pump for cytotoxic substances. P-gp mRNA expression and transporting activity show the daily rhythm and contribute to the chrono-pharmacokinetic profiles of many drugs. It is reported that the daily rhythm of abcb1a mRNA is regulated by a circadian clock-controlled output pathway. Time-restricted feeding is well known to shift the peripheral circadian phase of clock gene expression without changing the central clock function. This study was undertaken to examine the influence of a time-restricted feeding procedure during the light phase on the daily rhythms of abcb1a mRNA expression and P-gp activity. The abcb1a mRNA and P-gp activity showed a daily rhythm with a peak early in the dark phase in rat intestine under ad libitum feeding. Time-restricted feeding during the light phase shifted these rhythms to 12-h advance. The mRNA expression of clock genes (DBP and HLF, the transcript activators of abcb1a) also showed daily rhythms, and their phases were shifted by the time-restricted feeding procedure. The peak time of DBP mRNA expression was similar to that of abcb1a mRNA expression under ad libitum feeding and time-restricted feeding conditions. These results indicate that a time-restricted feeding procedure changes DBP mRNA expression, which in turn influences abcb1a mRNA expression and P-gp activity.
Asunto(s)
Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Ritmo Circadiano/genética , Ingestión de Alimentos/genética , Expresión Génica , Yeyuno/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/fisiología , Animales , Transporte Biológico , Corticosterona/sangre , Digoxina/farmacocinética , Masculino , Perfusión , ARN Mensajero/genética , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Especificidad por SustratoRESUMEN
AIM: To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9. METHODS: The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics. RESULTS: Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects. CONCLUSIONS: Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations.
Asunto(s)
Hidrocarburo de Aril Hidroxilasas/metabolismo , Inhibidores de la Ciclooxigenasa/farmacocinética , Diclofenaco/farmacocinética , Microsomas Hepáticos/metabolismo , Extractos Vegetales/metabolismo , Vaccinium macrocarpon/metabolismo , Administración Oral , Adulto , Bebidas , Inhibidores de la Ciclooxigenasa/administración & dosificación , Citocromo P-450 CYP2C9 , Diclofenaco/administración & dosificación , Monitoreo de Drogas , Métodos Epidemiológicos , Femenino , Interacciones Alimento-Droga/fisiología , Humanos , Masculino , Adulto JovenRESUMEN
Oseltamivir phosphate, which is available in oral formulation, is effective for type A/B influenza virus infection. In Japan, drug-induced adverse reactions such as central nervous system symptoms are a concern, especially in children. In this survey, we implemented a questionnaire regarding the administration period described on prescriptions and the duration for which patients took the drug, to investigate compliance with oseltamivir phosphate therapy. The results showed that therapy with oseltamivir phosphate was discontinued by 21.1%. The main reasons for discontinuation were the relief of symptoms and appearance of adverse reactions. This survey revealed that some patients taking oseltamivir phosphate would like to be prescribed medication for as short a term as possible. Although it is recommended that oseltamivir phosphate be administered for 5 days to treat influenza symptoms, 3- or 4-day administration was frequently prescribed for young patients (aged <20 years) and children. Because the appropriate administration period for influenza treatment is unclear, further epidemiological data are needed to determine the most rational use of neuraminidase inhibitors for influenza treatment.
Asunto(s)
Antivirales/administración & dosificación , Gripe Humana/tratamiento farmacológico , Cumplimiento de la Medicación , Oseltamivir/administración & dosificación , Adolescente , Adulto , Factores de Edad , Anciano , Antivirales/efectos adversos , Antivirales/uso terapéutico , Niño , Preescolar , Esquema de Medicación , Humanos , Lactante , Japón , Persona de Mediana Edad , Oseltamivir/efectos adversos , Oseltamivir/uso terapéutico , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Recent studies have revealed a close relationship between the pathophysiology of metabolic syndrome, which is characterized by obesity and hyperglycemia, and the functioning of internal molecular clocks. In this study, we show that the rhythmic mRNA expression of clock genes (Clock, Bmal1, Cry1, and Dbp) is not attenuated in the liver and visceral adipose tissues of Goto-Kakizaki rats, a model of nonobese, type 2 diabetes, as compared to control Wistar rats. Our results suggest that molecular clock impairment in peripheral tissues of obese diabetic animals may be either caused by obesity-related factor(s), but not hyperglycemia, or be a cause, but not a consequence, of hyperglycemia.
Asunto(s)
Tejido Adiposo/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Flavoproteínas/metabolismo , Hígado/metabolismo , Transactivadores/metabolismo , Factores de Transcripción ARNTL , Animales , Glucemia/metabolismo , Proteínas CLOCK , Ritmo Circadiano , Criptocromos , Proteínas de Unión al ADN , Modelos Animales de Enfermedad , Insulina/sangre , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas Mutantes , Ratas Wistar , Factores de TranscripciónRESUMEN
Chronic morphine exposure upregulates adenylate cyclase signaling and reduces analgesic efficacy, a condition known as opioid tolerance. Nonopioid neurotransmitters can enhance morphine tolerance, but the mechanism for this is poorly understood. We show that morphine tolerance was delayed in mice lacking vasopressin 1b receptors (V1bRs) or after administration of V1bR antagonist into the rostral ventromedial medulla, where transcripts for V1bRs and µ-opioid receptors are co-localized. Vasopressin increased morphine-binding affinity in cells expressing both V1bR and µ-opioid receptors. Complex formation among V1bR, ß-arrestin-2, and µ-opioid receptor resulted in vasopressin-mediated upregulation of ERK phosphorylation and adenylate cyclase sensitization. A leucine-rich segment in the V1bR C-terminus was necessary for the association with ß-arrestin-2. Deletion of this leucine-rich segment increased morphine analgesia and reduced vasopressin-mediated adenylate cyclase sensitization. These findings indicate that inhibition of µ-opioid-receptor-associated V1bR provides an approach for enhancing morphine analgesia without increasing analgesic tolerance.
Asunto(s)
Tolerancia a Medicamentos/genética , Morfina/farmacología , Narcóticos/farmacología , Receptores Opioides mu/metabolismo , Receptores de Vasopresinas/metabolismo , Arrestina beta 2/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/genética , Inyecciones , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Bulbo Raquídeo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Morfina/farmacocinética , Dependencia de Morfina/psicología , Narcóticos/farmacocinética , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Fosforilación , Receptores Opioides mu/genética , Receptores de Vasopresinas/genética , Arrestina beta 2/genéticaRESUMEN
Although altered homeostatic regulation, including disturbance of 24-h rhythms, is often observed in the patients undergoing glucocorticoid therapy, the mechanisms underlying the disturbance remains poorly understood. We report here that chronic treatment with a synthetic glucocorticoid, prednisolone (PSL), can cause alteration of circadian clock function at molecular level. Treatment of cultured hepatic cells (HepG2) with PSL induced expression of Period1 (Per1), and the PSL treatment also attenuated the serum-induced oscillations in the expression of Period2 (Per2), Rev-erbalpha, and Bmal1 mRNA in HepG2 cells. Because the attenuation of clock gene oscillations was blocked by pretreating the cells with a Per1 antisense phosphothioate oligodeoxynucleotide, the extensive expression of Per1 induced by PSL may have resulted in the reduced amplitude of other clock gene oscillations. Continuous administration of PSL into mice constitutively increased the Per1 mRNA levels in liver and skeletal muscle, which seems to attenuate the oscillation in the expressions of Per2, Rev-erbalpha, and Bmal1. However, a single daily administration of PSL at the time of day corresponding to acrophase of endogenous glucocorticoid levels had little effect on the rhythmic expression of clock genes. These results suggest a possible pharmacological action by PSL on the core circadian oscillation mechanism and indicate the possibility that the alteration of clock function induced by PSL can be avoided by optimizing the dosing schedule.
Asunto(s)
Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/genética , Regulación de la Expresión Génica/efectos de los fármacos , Prednisolona/efectos adversos , Factores de Transcripción ARNTL , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/efectos de los fármacos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Proteínas de Ciclo Celular , Células Cultivadas , Esquema de Medicación , Humanos , Hígado/efectos de los fármacos , Hígado/fisiología , Masculino , Ratones , Ratones Endogámicos ICR , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Proteínas Nucleares/efectos de los fármacos , Proteínas Nucleares/genética , Proteínas Circadianas Period , Prednisolona/administración & dosificación , Pruebas de Toxicidad Crónica , Factores de Transcripción/efectos de los fármacos , Factores de Transcripción/genéticaRESUMEN
The chronic mild stress (CMS) model has been established as a realistic model of depressive disorder as it simulates anhedonia. In the present study, the consumption of sucrose solution was decreased in the rats exposed to CMS, which coincided with many published studies. Since depression is a multifaceted disorder, and a number of symptoms may be present, including circadian rhythm disturbances, we attempted to find the chronobiological abnormalities in CMS rats. After 4-week of the stress procedure, the rhythmic pattern of rectal temperature in the CMS group was extinguished. In particular, the temperature in the CMS group in the light phase was significantly higher than that in the control group. The plasma corticosterone levels in the CMS group were remarkably increased in the light phase compared to the control group, but not in the dark phase. It was concluded that the CMS procedure caused the disturbance of circadian rhythms with hyperthermia and hypercortisolism.
Asunto(s)
Trastornos Cronobiológicos/etiología , Síndrome de Cushing/etiología , Fiebre/etiología , Estrés Psicológico/complicaciones , Análisis de Varianza , Animales , Temperatura Corporal/fisiología , Trastornos Cronobiológicos/sangre , Ritmo Circadiano/fisiología , Corticosterona/sangre , Síndrome de Cushing/sangre , Depresión , Modelos Animales de Enfermedad , Fiebre/sangre , Preferencias Alimentarias/fisiología , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/sangre , Sacarosa/administración & dosificación , Edulcorantes/administración & dosificaciónRESUMEN
PURPOSE: The anti-prostate cancer drug flutamide occasionally causes hepatotoxicity, and predictive biomarkers of flutamide-induced liver injury (FILI) are needed to improve safety of this drug. The aim of this prospective study was to identify such a biomarker by analyzing peripheral blood samples from patients before flutamide therapy. METHODS: Blood samples were obtained from 52 patients with prostate cancer before flutamide therapy. FILI was defined as treatment-related elevation of the serum concentration of aspartate or alanine aminotransferase to more than twice the upper limit of the reference range. The patients were monitored for at least 6 months regarding FILI. Microarray and quantitative real-time PCR analyses were conducted to compare gene expression profiles between the groups with and without FILI. RESULTS: Seventeen patients developed FILI. Microarray analysis of the training set in 15 patients detected 11 annotated genes showing >twofold expression changes between the groups (p < 0.005). Quantitative PCR analysis of both the training set and validation set confirmed that mRNA levels of multidrug and toxin extrusion protein 1 (MATE1 or SLC47A1, encoded by 1 of the 11 genes) were significantly lower in patients with FILI. A small experiment on mice (three per group) showed that Mate1 knockout mice had an elevated serum concentration of 4-nitro-3-(trifluoromethyl)phenylamine, a major metabolite of flutamide, 2 h after administration of the drug, suggesting that Mate1 could affect the pharmacokinetics of flutamide. CONCLUSIONS: The MATE1 mRNA level in peripheral blood is a possible negative predictive biomarker of FILI.
Asunto(s)
Antineoplásicos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Flutamida/efectos adversos , Proteínas de Transporte de Catión Orgánico/genética , ARN Mensajero/genética , Anciano , Alanina Transaminasa/metabolismo , Antagonistas de Andrógenos/efectos adversos , Antagonistas de Andrógenos/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Flutamida/uso terapéutico , Humanos , Masculino , Ratones , Ratones Noqueados , Estudios Prospectivos , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
Circadian clocks in peripheral tissues are powerfully entrained by feeding. The mechanisms underlying this food entrainment remain unclear, although various humoral and neural factors have been reported to affect peripheral clocks. Because glucagon-like peptide-1 (GLP-1), which is rapidly secreted in response to food ingestion, influences multiple humoral and neural signaling pathways, we suggest that GLP-1 plays a role in the food entrainment of peripheral clocks. To test this, we compared the effects of exendin-4, a GLP-1 receptor agonist, on mRNA expression of the clock genes (Clock, Bmal1, Nr1d1, Per1, Per2, and Cry1) with those of refeeding. In addition, we investigated whether exendin-4 could affect the rhythms of the peripheral clocks. In male C57BL/6J mice, although refeeding rapidly (within 2 h) altered mRNA levels of Per1 and Per2 in the liver and that of Per1 in adipose tissue, a single i.p. injection of exendin-4 did not cause such changes. However, unlike the GLP-1 receptor antagonist exendin-(9-39), exendin-4 significantly influenced Per1 mRNA levels in the liver at 12 h after injection. Moreover, pretreatment with exendin-4 affected the rapid-feeding-induced change in Per1 not only in the liver, but also in adipose tissue, without effect on food intake. Furthermore, during light-phase restricted feeding, repeated dosing of exendin-4 at the beginning of the dark phase profoundly influenced both the food intake and daily rhythms of clock gene expression in peripheral tissues. Thus, these results suggest that exendin-4 modulates peripheral clocks via multiple mechanisms different from those of refeeding.
Asunto(s)
Proteínas CLOCK/genética , Relojes Circadianos/efectos de los fármacos , Ritmo Circadiano/efectos de los fármacos , Péptido 1 Similar al Glucagón/genética , Incretinas/farmacología , Péptidos/farmacología , Ponzoñas/farmacología , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/metabolismo , Animales , Proteínas CLOCK/metabolismo , Relojes Circadianos/genética , Ritmo Circadiano/genética , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Exenatida , Regulación de la Expresión Génica , Péptido 1 Similar al Glucagón/agonistas , Péptido 1 Similar al Glucagón/antagonistas & inhibidores , Péptido 1 Similar al Glucagón/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Fragmentos de Péptidos/farmacología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de SeñalRESUMEN
Recent clinical data suggest that the efficacy of statin treatment in patients with heart failure varies depending on the drugs administered. The present study was undertaken to compare murine cardiac gene expression profiles following treatment with four different statins. In normal male C57BL/6J mice, 4 weeks of treatment with or without a statin (pitavastatin, pravastatin, rosuvastatin, or atorvastatin) did not affect any biochemical parameters, including the lipid profile. However, cardiac gene expression profiling by microarray analysis revealed distinct patterns among the five groups. Several genes that might be involved in cardiac function, including Ccnd2, Klf7 and Timp3, were differentially regulated by treatment with a specific statin. In the primary cultured neonatal mouse cardiomyocytes, statin-induced changes in the expression of these genes were largely unaffected by supplementation with mevalonic acid. These data indicate that statins directly regulate cardiac gene expression in a drug-specific manner in normal mice. Additional studies are needed to determine whether these differences influence the clinical efficacy in particular patients, such as those with heart failure.