ABSTRACT
INTRODUCTION: Circadian rhythm influences the pharmacokinetics and pharmacodynamics of a number of drugs and affects their therapeutic efficacy and toxicity depending on the time of day they are administered. Chronopharmacology is a method for incorporating knowledge about circadian rhythm into pharmacotherapy. Chronotherapy, which is the clinical application of chronopharmacology, is particularly relevant when the risk and/or severity of symptoms of a disease change in a predictable manner over time. Chronotherapy has potential benefits in the treatment of many diseases. AREAS COVERED: Although a considerable amount of knowledge about chronopharmacology and chronotherapy has been accumulated, its therapeutic application in clinical practice remains limited in terms of therapy optimization. Resolution of these issues will improve our ability to deliver adequate drug treatment. EXPERT OPINION: We propose four approaches for promoting chronotherapy-based drug treatment in clinical practice: targeting drug development and regulatory authorities; education about chronotherapy; drug information for both health professionals and consumers; and a chronotherapy network.
Subject(s)
Chronotherapy , Circadian Rhythm , Humans , Chronotherapy/methodsABSTRACT
Eating during a rest phase disrupts the biological clock system and leads to obesity and metabolic diseases. Although a rest phase restricted feeding (RF) is reported to enhance hepatic lipid accumulation, the mechanism(s) of the phenomenon is still unknown. This study evaluated the potential involvement of the CD36-related transport of lipids into the liver in mice with the RF procedure. This study showed that hepatic lipid accumulation was more significant in the RF group compared with mice under an active phase restricted feeding (AF). The RF procedure also elevated the expression of CD36 mRNA and its protein on the cellular membrane throughout the day. The transcription factor profiling array revealed that the RF activated the proliferator-activated receptor-γ (PPARγ), one of the CD36 transcript enhancers. In the liver of RF mice, the expression of miR-27b-3p, which is known to interfere with PPARγ gene expression, significantly decreased. These results suggest that the RF procedure inhibits the expression of miR-27b-3p in the liver and subsequently elevates PPARγ activity. Activated PPARγ might lead to CD36 upregulation, which, in turn, stimulates the transport of lipids into the liver.
Subject(s)
MicroRNAs , PPAR gamma , Animals , Circadian Rhythm , Lipids , Liver/metabolism , Mice , MicroRNAs/genetics , PPAR gamma/metabolismABSTRACT
Background and Objectives: The antidiabetic agent metformin is known to activate AMP-activated protein kinase (AMPK) in various tissues. Because AMPK can modulate intracellular circadian clocks through regulating the stability of clock components, a single dose of metformin has been reported to affect circadian clocks in the peripheral tissues. In this study, therefore, we investigated whether chronic treatment with metformin causes the impairment of circadian clocks, especially if given at an inappropriate time. Materials and Methods: Non-diabetic C57BL/6J mice were allowed access to food only during 4 h at the beginning of the dark period, and repeatedly i.p. injected with a nearly maximum non-toxic dose of metformin, once daily either at 4 h after the beginning of the dark period or at the beginning of the light period. Diabetic ob/ob mice were given free access to food and treated with metformin in drinking water. Results: Under the controlled feeding regimen, 8-day treatment with metformin did not alter the mRNA expression rhythms of clock genes in both liver and adipose tissue of C57BL/6J mice, regardless of dosing time. In addition, chronic treatment with metformin for 2 weeks affected hepatic AMPK activation rhythm but did not disrupt the circadian clocks in the liver and adipose tissues of the ob/ob mice. Conclusions: These results mitigate concerns that treatment with metformin impairs peripheral circadian clocks, although confirmation is needed in humans.
Subject(s)
Circadian Clocks , Metformin , Animals , Circadian Clocks/genetics , Circadian Rhythm/physiology , Liver , Mice , Mice, Inbred C57BLABSTRACT
Coagulation-fibrinolytic system activity shows daily rhythmicity, with hypercoagulability in the morning and hypocoagulability in the evening. Consequently, the efficacy of anticoagulants may be influenced by their dosing time. Edoxaban, a selective inhibitor of the active form of coagulation factor X (FXa), is taken orally once daily, but the optimal dosing time is unknown. This study evaluated the dosing time-dependent effects of edoxaban on coagulation activity and thrombus formation in rats. Edoxaban (10 mg/kg) or vehicle was administered to Wistar rats at zeitgeber time (ZT)-2 (beginning of the light phase) or ZT14 (beginning of the dark phase), followed by blood collection at ZT4, ZT10, ZT16, or ZT22, to measure the activity of coagulation factors and edoxaban concentrations, or followed by inferior vena cava ligations at ZT4 or ZT16, to assess the efficacy of edoxaban against thrombus formation. Coagulation FX activity was high during the light phase, and a single dose of edoxaban administered at ZT2 inhibited FX activity and thrombus formation more potently compared with the same dose administered at ZT14. The inhibitory effects during the light phase could be attributed, at least in part, to the high blood concentration of edoxaban achieved by dosing at ZT2. Morning dosing of edoxaban leads to a high blood concentration of the drug during the morning hours and thus may better counteract the hypercoagulability and hypofibrinolytic activity characteristic of the morning hours. Optimizing the dosing time may contribute to improving the efficacy of edoxaban.
ABSTRACT
OBJECTIVE: Impaired circadian clocks can cause obesity, but their pathophysiological role in brown adipose tissue (BAT), a major tissue regulating energy metabolism, remains unclear. To address this issue, we investigated the effects of complete disruption of the BAT clock on thermogenesis and energy expenditure. METHODS: Mice with brown adipocyte-specific knockout of the core clock gene Bmal1 (BA-Bmal1 KO) were generated and analyzed. RESULTS: The BA-Bmal1 KO mice maintained normal core body temperatures by increasing shivering and locomotor activity despite the elevated expression of thermogenic uncoupling protein 1 in BAT. BA-Bmal1 KO disrupted 24 h rhythmicity of fatty acid utilization in BAT and mildly reduced both BAT thermogenesis and whole-body energy expenditure. The impact of BA-Bmal1 KO on the development of obesity became obvious when the mice were fed a high-fat diet. CONCLUSIONS: These results reveal the importance of the BAT clock for maintaining energy homeostasis and preventing obesity.
Subject(s)
ARNTL Transcription Factors/genetics , ARNTL Transcription Factors/metabolism , Adipocytes, Brown/metabolism , Thermogenesis/genetics , Thermogenesis/physiology , Adipose Tissue, Brown/metabolism , Animals , Body Weight , Circadian Rhythm , Cold Temperature , Diet, High-Fat , Energy Metabolism , Fatty Acids , Homeostasis , Male , Metabolome , Mice , Mice, Knockout , Obesity/metabolism , Uncoupling Protein 1/metabolismSubject(s)
Aldehyde Dehydrogenase, Mitochondrial/genetics , Nitroglycerin/pharmacokinetics , Pharmacogenomic Variants , Polymorphism, Genetic , Vasodilation/drug effects , Vasodilator Agents/pharmacokinetics , Aldehyde Dehydrogenase, Mitochondrial/metabolism , Biological Variation, Population , Dose-Response Relationship, Drug , Humans , Nitroglycerin/administration & dosage , Pharmacogenetics , Vasodilator Agents/administration & dosageABSTRACT
Current hypertension guidelines fail to provide a recommendation on when-to-treat, thus disregarding relevant circadian rhythms that regulate blood pressure (BP) level and 24 h patterning and medication pharmacokinetics and pharmacodynamics. The ideal purpose of ingestion-time (chronopharmacology, i.e. biological rhythm-dependent effects on the kinetics and dynamics of medications, and chronotherapy, i.e. the timing of pharmaceutical and other treatments to optimize efficacy and safety) trials should be to explore the potential impact of endogenous circadian rhythms on the effects of medications. Such investigations and outcome trials mandate adherence to the basic standards of human chronobiology research. In-depth review of the more than 150 human hypertension pharmacology and therapeutic trials published since 1974 that address the differential impact of upon-waking/morning versus at-bedtime/evening schedule of treatment reveals diverse protocols of sometimes suboptimal or defective design and conduct. Many have been "time-of-day," i.e. morning versus evening, rather than circadian-time-based, and some relied on wake-time office BP rather than around-the-clock ambulatory BP measurements (ABPM). Additionally, most past studies have been of too small sample size and thus statistically underpowered. As of yet, there has been no consensual agreement on the proper design, methods and conduct of such trials. This Position Statement recommends ingestion-time hypertension trials to follow minimum guidelines: (i) Recruitment of participants should be restricted to hypertensive individuals diagnosed according to ABPM diagnostic thresholds and of a comparable activity/sleep routine. (ii) Tested treatment-times should be selected according to internal biological time, expressed by the awakening and bed times of the sleep/wake cycle. (iii) ABPM should be the primary or sole method of BP assessment. (iv) The minimum-required features for analysis of the ABPM-determined 24 h BP pattern ought to be the asleep (not "nighttime") BP mean and sleep-time relative BP decline, calculated in reference to the activity/rest cycle per individual. (v) ABPM-obtained BP means should be derived by the so-called adjusted calculation procedure, not by inaccurate arithmetic averages. (vi) ABPM should be performed with validated and calibrated devices at least hourly throughout two or more consecutive 24 h periods (48 h in total) to achieve the highest reproducibility of mean wake-time, sleep-time and 48 h BP values plus the reliable classification of dipping status. (vii) Calculation of minimum required sample size in adherence with proper statistical methods must be provided. (viii) Hypertension chronopharmacology and chronotherapy trials should preferably be randomized double-blind, randomized open-label with blinded-endpoint, or crossover in design, the latter with sufficient washout period between tested treatment-time regimens.
Subject(s)
Blood Pressure Monitoring, Ambulatory , Hypertension , Antihypertensive Agents/therapeutic use , Blood Pressure , Chronotherapy , Circadian Rhythm , Eating , Humans , Hypertension/drug therapy , Reproducibility of Results , Risk Factors , Time FactorsABSTRACT
INTRODUCTION: We previously reported in ob/ob mice, one of animal models of human type 2 diabetes mellitus (DM2), that (i) acetylation of histone H3 lysine 9 (H3K9) at the promoter region of clock gene Dbp and DBP mRNA expression are reduced in epididymal adipose tissue, (ii) binding of DBP to the promoter region of peroxisome proliferator-activated receptor (Ppar)-γ and mRNA expression of PPAR-γ1sv were decreased in preadipocytes and (iii) adiponectin secretion was decreased, leading to the impaired insulin sensitivity. RESEARCH DESIGN AND METHODS: The present study was undertaken to evaluate whether such the changes in visceral adipose tissue were detected in patients with DM2. We obtained omental and mesenteric adipose tissue during surgery of lymph node dissection for gastric and colorectal cancers, and investigated these variables in adipose tissue (omental from gastric cancer; 13 non-DM, 12 DM2: mesenteric from colorectal cancer; 12 non-DM, 11 DM2). RESULTS: Acetylation of histone H3K9 at the promoter region of Dbp and DBP mRNA expression in omental, but not in mesenteric adipose tissue were significantly lower in DM2 than in patients without DM. PPAR-γ mRNA expression in omental adipose tissue was also lower in patients with DM2, but not in mesenteric adipose tissue. CONCLUSIONS: The changes in DBP-PPAR-γ axis observed in mice with diabetes were also detected in patients with DM2. Because adiponectin secretion is reported to be enhanced through the PPAR-γ-related mechanism, this study supports the hypothesis that omental adipose tissue is involved in the mechanism of DM2.
Subject(s)
Diabetes Mellitus, Type 2 , Adipose Tissue/metabolism , DNA-Binding Proteins , Diabetes Mellitus, Type 2/genetics , Gene Expression Regulation , Humans , PPAR gamma/genetics , PPAR gamma/metabolism , RNA, Messenger , Transcription FactorsABSTRACT
The neutrophil gelatinase-associated lipocalin (NGAL) receptor (24p3R) is expressed in distal nephron and contributes to the endocytosis of NGAL in urine. This study was undertaken to evaluate an influence of renal ischaemia-reperfusion injury on 24p3R. Unilateral renal pedicle was clamped for 0, 10, 20, 30, or 45 minutes in male Wistar rats. Urine was collected for 24 hours after reperfusion, and ischaemic kidney and blood sample were obtained. Apparent histological injury in the ischaemic kidney was detected in the 30 and 45 minutes-treated groups. Urinary NGAL excretion elevated in rats with renal ischaemia for more than 20 minutes, while serum creatinine increased in rats for more than 30 minutes of ischaemia. Renal protein expression of NGAL did not significantly change. Renal mRNA expressions of megalin and cubilin, which are expressed at renal proximal tubules and uptake NGAL, decreased in animals with renal ischaemia for more than 20 minutes. Renal protein expression of 24p3R, which is expressed at renal distal tubules and uptake NGAL, decreased in rats with renal ischaemia for 45 min. This study showed for the first time that renal 24p3R decreased in response to renal ischaemia. As relatively longer renal ischaemia (45 minutes) decreased renal 24p3R protein and increased urinary NGAL excretion, the down-regulation of 24p3R protein might contribute to the elevated urinary excretion of NGAL in rats with unilateral ischaemia-reperfusion injury.
Subject(s)
Acute Kidney Injury/genetics , Kidney/metabolism , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Reperfusion Injury/genetics , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Animals , Biomarkers/metabolism , Cells, Cultured , Gene Expression Regulation , Kidney Tubules, Proximal/metabolism , Lipocalin-2/metabolism , Lipocalin-2/urine , Male , Nephrons/metabolism , Rats , Rats, Wistar , Reperfusion Injury/metabolism , Reperfusion Injury/pathologyABSTRACT
PURPOSE: The influence of the aldehyde dehydrogenase 2 (ALDH2) gene polymorphism on the pharmacokinetics and haemodynamics of nitroglycerin (GTN) was determined in human subjects. METHODS: Eighteen infants (nine each with and without ALDH2 gene polymorphism) with congenital heart disease and pulmonary arterial hypertension participated in this study. GTN treatment started at a dose of 2 µg/kg/min, and the dose was escalated by 1-2 µg/kg/min until pulmonary vascular resistance (PVR) was reduced by more than 30%. The plasma GTN concentration and PVR were measured at the end of each infusion period. RESULTS: Plasma GTN concentrations were significantly higher in patients with the ALDH2 gene polymorphism than in those without the polymorphism. Conversely, the reduction in PVR was smaller in patients with the ALDH2 gene polymorphism than in those without. CONCLUSIONS: These data suggest that the ALDH2 gene polymorphism influences the pharmacokinetics and haemodynamics of GTN in human subjects.
Subject(s)
Aldehyde Dehydrogenase, Mitochondrial/genetics , Heart Diseases/genetics , Heart Diseases/metabolism , Nitroglycerin/pharmacokinetics , Pulmonary Arterial Hypertension/genetics , Pulmonary Arterial Hypertension/metabolism , Vasodilator Agents/pharmacokinetics , Female , Genotype , Heart Diseases/drug therapy , Humans , Infant , Male , Nitroglycerin/blood , Nitroglycerin/therapeutic use , Polymorphism, Genetic , Pulmonary Arterial Hypertension/drug therapy , Vasodilation/drug effects , Vasodilator Agents/blood , Vasodilator Agents/therapeutic useABSTRACT
We previously reported that a histone deacetylase inhibitor (HDACi) increases D-site binding protein (Dbp) mRNA expression in adipose tissue and subsequently improved insulin sensitivity of obese (ob/ob) mice. However, the potential mechanism of this phenomenon was unclear. Thus, the aim of this study was to clarify the molecular mechanism involved in enhanced Dbp mRNA expression and improvement of insulin sensitivity in mice. Ob/ob mice were treated with HDACi every second day for 3 weeks. At the end of treatment, an insulin tolerance test was performed and epididymal adipose tissue obtained for fractionation into adipocytes and preadipocytes. HDACi improved insulin sensitivity in ob/ob mice and significantly increased Dbp mRNA in epididymal adipose tissue. Further, epididymal adipocytes of ob/ob mice showed a tendency towards a larger size distribution, while HDACi increased the proportion of smaller sized cells in fractionated preadipocytes. Dbp knocked-down 3T3-L1 cells down-regulated peroxisome proliferator-activated receptor-γ (PPAR-γ1) protein expression during adipogenesis, which suppressed adipocyte differentiation. These data indicate that DBP promotes adipocyte differentiation via direct up-regulation of PPAR-γ1 production in preadipocytes. In fractionated preadipocytes of ob/ob mice, DBP binding to the promoter region of the Ppar-γ gene and splicing variant of Ppar-γ (Ppar-γ1sv) mRNA expression were suppressed. HDACi significantly increased DBP binding to the Ppar-γ gene and Ppar-γ1sv transcription. Altogether, this indicates a modification in genetic regulation downstream from the circadian clock that can ameliorate an environmental function of adipose tissue, leading to improved insulin sensitivity in ob/ob mice.
Subject(s)
Adipocytes/cytology , DNA-Binding Proteins/metabolism , Histone Deacetylase Inhibitors/pharmacology , Insulin Resistance , Transcription Factors/metabolism , 3T3-L1 Cells , Adipose Tissue/metabolism , Alternative Splicing , Animals , Benzamides/pharmacology , Cell Differentiation , Chromatin/metabolism , Circadian Rhythm , DNA-Binding Proteins/genetics , Gene Expression Regulation , Gene Silencing , Glucose Tolerance Test , Insulin/physiology , Mice , Mice, Inbred C57BL , Mice, Obese , PPAR gamma/metabolism , Protein Binding , Pyridines/pharmacology , RNA, Messenger/metabolism , Transcription Factors/genetics , Up-RegulationABSTRACT
PURPOSE: The ability of predicting severe adverse reactions caused by regorafenib is important. We evaluated regorafenib concentrations for adverse reaction risks and assessed the relevance of laboratory values and gene polymorphisms. METHODS: A total of 28 Japanese cancer patients who were treated with regorafenib were evaluated for the steady state of serum regorafenib concentrations and adverse reactions for 28 days. In addition, we determined the association of regorafenib concentrations with ABCG2 and OATP1B1 polymorphisms, which are regorafenib transporters. RESULTS: Regorafenib concentrations were significantly higher in the group with Grade 2 or higher total bilirubin elevation and thrombocytopenia compared with the group with grades 0 or 1 [3.45 (2.18-7.31) vs. 1.76 (0.26-2.77) µg/mL, P = 0.01 and 3.45 (2.12-7.31) vs. 1.76 (0.26-2.77) µg/mL, P = 0.02, respectively]. A strong association was noted between serum regorafenib concentrations and total bilirubin levels, but the physical and genetic factors predicting regorafenib pharmacokinetics could not be clarified. CONCLUSIONS: Regorafenib concentrations were associated with total bilirubin elevation and thrombocytopenia. Total serum bilirubin could be a useful marker when estimating regorafenib pharmacokinetics.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics , Colonic Neoplasms/drug therapy , Gastrointestinal Stromal Tumors/drug therapy , Liver-Specific Organic Anion Transporter 1/genetics , Neoplasm Proteins/genetics , Phenylurea Compounds/adverse effects , Phenylurea Compounds/blood , Polymorphism, Genetic , Pyridines/adverse effects , Pyridines/blood , Adult , Aged , Aged, 80 and over , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Female , Follow-Up Studies , Gastrointestinal Neoplasms/drug therapy , Gastrointestinal Neoplasms/genetics , Gastrointestinal Neoplasms/pathology , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/pathology , Genotype , Humans , Male , Middle Aged , Prognosis , Prospective StudiesABSTRACT
ADVERSE EVENT: A drug interaction leading to greater exposure to tacrolimus. DRUG IMPLICATED: Tacrolimus and Beni-Madonna (a new cultivar citrus categorized as 'Tangor'). THE PATIENT: A 9-month-old girl with biliary atresia (body weight, 7.5 kg) taking tacrolimus after liver transplantation. EVIDENCE THAT LINKS THE DRUG TO THE EVENT: The time course was consistent with the appearance of the interaction, which was confirmed by an increase in the blood concentration of tacrolimus. Dihydroxybergamottin was detected in peel of Beni-Madonna and in peel and fruit pulp of grapefruit. MANAGEMENT: Avoiding Beni-Madonna intake. MECHANISM: Inhibition of activity of CYP3A4, P-glycoprotein, or both, by Beni-Madonna. IMPLICATION FOR THERAPY: Clinicians should be aware of this potential interaction, and patients taking drugs such as tacrolimus (the kinetics of which are affected by grapefruit juice) should avoid Beni-Madonna intake. HYPOTHESIS TO BE TESTED: Further study is required to determine if other Citrus species categorized as Tangor contain furanocoumarins.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , Citrus , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Food-Drug Interactions , Furocoumarins/pharmacology , Immunosuppressive Agents/blood , Liver Transplantation , Tacrolimus/blood , Citrus paradisi , Cytochrome P-450 CYP3A , Female , Humans , InfantABSTRACT
PURPOSE: Curcumin is expected to have beneficial effects including an anti-cancer effect. However, its lower bioavailability is a critical concern and limits the utility of curcumin in clinical practice. In this study, we investigated whether transpulmonary delivery of curcumin is pharmacologically effective along with improving its bioavailability in mice with lung metastasis. METHODS: C57BL/6J mice were injected with B16F10 melanoma cells via their tail vein and given curcumin by pulmonary administration every other day. The lung tissue of the vehicle-treated mice on day 17 was covered by nodules of metastatic melanoma. RESULTS: Pulmonary curcumin administration significantly and dose-dependently protected the lung metastasis of melanoma. The phosphorylation of JNK (c-Jun NH2 terminal kinase) and HLJ1 expression levels in the lung metastatic nodules of the melanoma were significantly increased by pulmonary curcumin administration. The anti-metastatic effect of curcumin was blunted in mice injected with HLJ1 knocked-down B16F10 melanoma. Systemic bioavailability after pulmonary administration was 61-times higher than after oral administration. Additionally, the curcumin concentration in the lung tissue was sustained to a high level until 24 h after pulmonary administration. CONCLUSIONS: This study showed the usefulness of curcumin to suppress lung metastasis of melanoma by pulmonary administration, a method that may overcome the low-bioavailability of curcumin.
Subject(s)
Curcumin/administration & dosage , Lung Neoplasms/prevention & control , Lung Neoplasms/secondary , Melanoma, Experimental/drug therapy , Melanoma, Experimental/pathology , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Curcumin/pharmacokinetics , HSP40 Heat-Shock Proteins/metabolism , MAP Kinase Kinase 4/metabolism , Male , Melanoma, Experimental/metabolism , Mice , Mice, Inbred C57BL , PhosphorylationABSTRACT
In general, chronotherapy is desirable for a more effective and/or safe dosage regimen. In this study, a daily rhythm of skin vitamin D receptor (VDR) and chronotherapeutic profiles of maxacalcitol, a vitamin D analogue, were evaluated using mice with skin inflammation induced by topical 12-O-tetradecanoylphorbol-13-acetate (TPA). This study showed that skin nuclear VDR expression in TPA-treated mice has a daily rhythm with the peak at the middle of active period. The effects of maxacalcitol were greater after dosing during early to middle of active period than those after dosing during early to middle of inactive period. These data suggest that chronotherapeutic profiles of maxacalcitol partly depend on the daily rhythm of skin nuclear VDR in TPA-treated mice. Because TPA-treated mice are considered as one of animal models of psoriasis, these animal data might be helpful for establishing chronotherapeutic approach of maxacalcitol in clinical practice.
Subject(s)
Calcitriol/analogs & derivatives , Chronotherapy , Circadian Rhythm/drug effects , Skin/drug effects , Tetradecanoylphorbol Acetate/pharmacology , Animals , Calcitriol/pharmacology , Chronotherapy/methods , Inflammation/drug therapy , Inflammation/metabolism , Male , Mice , Mice, Inbred C57BL , Psoriasis , Receptors, Calcitriol/drug effectsABSTRACT
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.
Subject(s)
Drug Tolerance/genetics , Morphine/pharmacology , Narcotics/pharmacology , Receptors, Opioid, mu/metabolism , Receptors, Vasopressin/metabolism , beta-Arrestin 2/metabolism , Adenylyl Cyclases/metabolism , Animals , Calcium Signaling/drug effects , Calcium Signaling/genetics , Injections , MAP Kinase Signaling System/drug effects , Male , Medulla Oblongata , Mice , Mice, Inbred C57BL , Mice, Knockout , Morphine/pharmacokinetics , Morphine Dependence/psychology , Narcotics/pharmacokinetics , Pain Measurement/drug effects , Pain Threshold/drug effects , Phosphorylation , Receptors, Opioid, mu/genetics , Receptors, Vasopressin/genetics , beta-Arrestin 2/geneticsABSTRACT
Docetaxel, cisplatin plus fluorouracil (DCF) regimen is a useful chemotherapy, but is sometimes withdrawn due to severe adverse effects (AE). In this study, we examined whether the chronotherapy of DCF regimen could reduce the drugs-induced toxicities in clinical practice. Patients with oral squamous cell carcinoma were enrolled. Chemotherapy started at 10:30 (Morning-dosing) or 18:30 (Evening-dosing) for 5 days by a cross-over design. AE were assessed for 14 days after an initiation of each dosing. The grades of nausea, vomiting and neutropenia were smaller during Evening-dosing than during Morning-dosing. These data suggest that the chrono-chemotherapy might provide a merit for reducing the DCF regimen-related severe AE.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Squamous Cell/drug therapy , Cisplatin/therapeutic use , Drug Administration Schedule , Mouth Neoplasms/drug therapy , Adult , Aged , Circadian Rhythm/drug effects , Cisplatin/administration & dosage , Cross-Over Studies , Docetaxel/administration & dosage , Female , Fluorouracil/administration & dosage , Humans , Male , Middle Aged , Mouth Neoplasms/pathology , Pilot Projects , Time Factors , Treatment Outcome , Young AdultABSTRACT
BACKGROUND/AIM: We investigated whether measuring the excretion of each acute kidney injury (AKI) biomarker after cisplatin (CDDP) administration is useful for predicting AKI and evaluated the most appropriate AKI marker in patients treated with CDDP. PATIENTS AND METHODS: We measured NAG, Kim-1, and NGAL in urinary samples of 40 cancer patients treated with chemotherapy on day 1 (before chemotherapy), day 2, and day 5 after treatment; serum creatinine (sCr) was compared on days 7 and 28 after CDDP administration vs. baseline. RESULTS: NAG, Kim-1, and NGAL excretion (creatinine corrected) were not significantly elevated 5 days after receiving chemotherapy in the non-CDDP chemotherapy group. Conversely, all markers were significantly higher 5 days after receiving chemotherapy in the CDDP group when compared to baseline. CONCLUSION: Urinary NAG, Kim-1, and NGAL can detect renal injury more sensitively than sCr.
Subject(s)
Acute Kidney Injury/chemically induced , Biomarkers/urine , Cisplatin/adverse effects , Neoplasms/drug therapy , Acute Kidney Injury/blood , Analysis of Variance , Biomarkers/blood , Cisplatin/administration & dosage , Creatinine/blood , Female , Humans , Male , Middle Aged , Neoplasms/blood , Time FactorsABSTRACT
The anticoagulant effect of rivaroxaban, a direct inhibitor of activated factor X (FX), might be influenced by its dosing time because the activity of the coagulofibrinolytic system exhibits daily rhythmicity. In rats, FX activity follows a 24-h rhythm with a peak in the middle of the light phase and a trough at the beginning of the dark phase. Consistent with these findings, a single dose of rivaroxaban had a stronger inhibitory effect on FX activity after dosing at the beginning of the light phase than after dosing at the beginning of the dark phase. A similar chronopharmacological effect was seen in a quantitative model of venous stasis thrombosis. In comparison, the dosing time had minimal influence on the pharmacokinetics of rivaroxaban. These data indicate that the anticoagulant effect of rivaroxaban is influenced by the dosing time. Further studies should confirm this finding in a clinical setting.