Further studies on the chronotherapy of asthma with inhaled steroids: The effect of dosage timing on drug efficacy

Background: Chronotherapy studies with inhaled corticosteroids have shown optimal therapeutic benefit when steroids are administered four times per day (QID) or once daily at 3 PM.Objective: This study evaluated whether more convenient once-daily dosage times (8 AM and 5:30 PM) produce improvement in asthma equivalent to QID.Methods: Efficacy outcome measures included FEV₁, peak expiratory flow rates, bronchial responsiveness, use of β₂-agonists, nocturnal awakenings, and responses to a quality of life questionnaire. Systemic effects were blood eosinophil count, cortisol level, 24-hour urinary cortisol, and evaluation for oral candidiasis and dysphonia.Results: Baseline measurements for all three treatment groups were similar. For morning peak expiratory flow rate, significant improvement was seen for the QID group (p = 0.001) and the 5:30 PM group (p = 0.003), but not the 8 AM group (p = 0.75). For evening peak expiratory flow rate, significant improvement was seen for the QID group (p = 0.005) and the 5:30 PM group (p = 0.01), but not for the 8 AM group (p = 0.47). There were significant improvements in all other outcome variables for each group except PC₂₀. There was a significant improvement in PC₂₀ only in the QID group. The systemic effects of the three regimens were comparable.Conclusion: Dosing of inhaled steroid at 5:30 PM had no increased systemic effects and produced efficacy similar to QID dosing. Dosing at 8 AM did not produce results consistently comparable to QID dosing. Optimal once-daily dosing of inhaled steroid is between 3 PM and 5:30 PM.     

Circadian disruption and human health: A bidirectional relationship

Circadian rhythm disorders have been classically associated with disorders of abnormal timing of the sleep–wake cycle, however circadian dysfunction can play a role in a wide range of pathology, ranging from the increased risk for cardiometabolic disease and malignancy in shift workers, prompting the need for a new field focused on the larger concept of circadian medicine. The relationship between circadian disruption and human health is bidirectional, with changes in circadian amplitude often preceding the classical symptoms of neurodegenerative disorders. As our understanding of the importance of circadian dysfunction in disease grows, we need to develop better clinical techniques for identifying circadian rhythms and also develop circadian based strategies for disease management. Overall this review highlights the need to bring the concept of time to all aspects of medicine, emphasizing circadian medicine as a prime example of both personalized and precision medicine.     

Temporal regulation of the human immune system

Under the model of spatial or tissue-specific immune compartmentalization, the site of immunogen exposure (oral, mucosal and dermal) shapes the consequent immune response. Thus, spatial compartmentalization provides a mechanism whereby different immune responses may evolve in different tissue compartments. Many immune cytokines are subject to circadian variation, for example, interleukin-1, -6, -10 and -12, macrophage migration inhibitory factor, tumor necrosis factor-α and interferon-γ. These cytokine rhythms reflect the influence of regulatory hormones including cortisol and melatonin that exhibit circadian rhythmicity. This raises the question of what role, if any, circadian rhythms play in immune function. The hypothesis put forward is that circadian cytokine rhythms indicate the existence of temporal immune compartments. Temporal immune compartments include a daytime compartment characterized by high plasma cortisol and a regulatory cytokine environment, and a nocturnal compartment characterized by low cortisol, high melatonin and heightened inflammatory cytokine levels. Thus, time itself is a critical factor when measuring or interpreting immune response. This highlights the potential of immune chronotherapy where time-dependency principles guide the design of more effective and better tolerated immunotherapies and vaccines.     

Nocturnal asthma

Nocturnal symptoms and overnight decrements in lung function are a common part of the asthma clinical syndrome. As many as 75% of asthmatic subjects are awakened by asthma symptoms at least once per week, with approximately 40% experiencing nocturnal symptoms on a nightly basis. An extensive body of research has demonstrated that nocturnal symptoms of cough and dyspnea are accompanied by circadian variations in airway inflammation and physiologic variables, including airflow limitation and airways hyperresponsiveness. Alterations in beta2-adrenergic and glucocorticoid receptors and hypothalamic-pituitary-adrenal axis function might play a role in modulating the nocturnal asthma phenotype, and recent studies have suggested that melatonin, a neurohormonal controller of circadian rhythms, might be important as well. Treatment strategies in nocturnal asthma are similar to those used in persistent asthma, although dosing of medications to target optimum effect during periods of nocturnal worsening is beneficial.     

应用时间治疗学指导高血压病人护理的研究进展

对时间治疗学的概念及其控制高血压的理论依据和护理进行阐述,指出根据病人24h的血压变化来指导病人用药和进行护理干预,可以提高治疗和护理效果,减少药物的不良反应,减少心脑血管意外的发生,从而提高高血压病人的生活质量。     

Sirtuins, melatonin and circadian rhythms: building a bridge between aging and cancer

Abstract:  Histone deacetylases (HDAC) have been under intense scientific investigation for a number of years. However, only recently the unique class III HDAC, sirtuins, have gained increasing investigational momentum. Originally linked to longevity in yeast, sirtuins and more specifically, SIRT1 have been implicated in numerous biological processes having both protective and/or detrimental effects. SIRT1 appears to play a critical role in the process of carcinogenesis, especially in age-related neoplasms. Similarly, alterations in circadian rhythms as well as production of the pineal hormone melatonin have been linked to aging and cancer risk. Melatonin has been found act as a differentiating agent in some cancer cells and to lower their invasive and metastatic status. In addition, melatonin synthesis and release occurs in a circadian rhythm fashion and it has been linked to the core circadian machinery genes ( Clock , Bmal1 , Periods , and Cryptochromes ). Melatonin has also been associated with chronotherapy, the timely administration of chemotherapy agents to optimize trends in biological cycles. Interestingly, a recent set of studies have linked SIRT1 to the circadian rhythm machinery through direct deacetylation activity as well as through the nicotinamide adenine dinucleotide (NAD⁺) salvage pathway. In this review, we provide evidence for a possible connection between sirtuins, melatonin, and the circadian rhythm circuitry and their implications in aging, chronomodulation, and cancer.     

Colonic treatments and targets: issues and opportunities

The colon provides a plethora of therapeutic opportunities. There are multiple disease targets, drug molecules, and colon-specific delivery systems to be explored. Clinical studies highlight the potential for systemic delivery via the colon, and the emerging data on the levels of cell membrane transporters and metabolic enzymes along the gut could prove advantageous for this. Often efflux transporters and metabolic enzyme levels are lower in the colon, suggesting a potential for improved bioavailability of drug substrates at this site. The locoregional distribution of multiple metabolic enzymes (including cytochromes), efflux transporters (including P-glycoprotein and breast cancer resistance proteins), and influx transporters (including the solute carrier family) along the intestine is summarized. Local delivery to the colonic mucosa remains a valuable therapeutic option. New therapies that target inflammatory mediators could improve the treatment of inflammatory bowel disease, and old and new anticancer molecules could, when delivered topically, prove to be beneficial adjuncts to the current systemic or surgical treatments. New issues such as pharmacogenomics, chronotherapeutics, and the delivery of prebiotics and probiotics are also discussed in this review. Targeting drugs to the colon utilizes various strategies, each with their advantages and flaws. The most promising systems are considered in the light of the physiological data which influence their in vivo behavior.     

5-FLUOROURACIL: A PHARMACOLOGICAL PARADIGM IN THE USE OF CYTOTOXICS

1. Painstaking progress in drug development is well illustrated by 5-fluorouracil (5FU), originally designed 40 years ago as a fluorinated analogue of the naturally occurring base uracil. Innovative pharmacokinetic and pharmacodynamic strategies have seen significant clinical improvements for cancer patients over the past decade. 2. 5-Fluorouracil acts by three main mechanisms. Principally, the intermediate metabolite fluorodeoxj uridine monophosphate inhibits a key enzyme in pyrimidine biosynthesis, namely thymidylate synthase (TS). Additionally, 5FU is metabolized to ribo- and deoxy-ribonucleotides, which act as false bases for incorporation into RNA and DNA. 3. Biomodulation of 5FU has been attempted with methotrexate (MTX), folinic acid, interferons, cisplatin and radiotherapy. Methotrexate augments the actions of 5FU by inhibiting dihy-drofolate reductase and decreasing the folate pool required for pyrimidine biosynthesis, inhibiting TS via MTX-polyglutamate and directly inhibiting purine biosynthesis. Interferons increase steady state concentrations of 5FU. 5-Fluorouracil enhances the cytotoxicity of cisplatin and radiotherapy by inhibiting DNA repair. Folinic acid enhances TS inhibition by increasing the intracellular pool of folates that stabilize the 5FU-TS complex. 4. S-Fluorouracil has a short plasma half-life. Thymidylate synthase inhibition is limited to the S-phase of the cell cycle and only a small fraction of most cancer cells are in S-phase at any one time. Increased response rates seen with infusional protocols may reflect the effective recruitment of additional mechanisms of cytotoxicity, not dependent on cell cycle, including effects on RNA synthesis. 5. Patients with localized metastatic disease may benefit from locoregional treatments. These include hepatic intra-arterial therapy with related compounds, such as floxuridine, which reach high concentrations at sites of tumour, while systemic toxicities are minimized by efficient hepatic clearance. 6. Recent developments include orally bioavailable formulations, such as ftorafur, capecitabine and the combination of 5FU with the dihydropyrimidine phosphate dehydrogenase inhibitor ethynyluracil. Recognition of diurnal variation in the activity of such key enzymes as DPD has led to the administration of 5FU at regulated, variable infusion rates (chronomodu-lation). These promising pharmacological approaches may further improve clinical outcomes in common cancers.     

Circadian heart rate response to chronotherapy versus conventional therapy in patients with hypertension and myocardial ischemia

BACKGROUND: Changes in heart rate (HR) may contribute to the higher incidence of cardiovascular events in the morning. HYPOTHESIS: The objectives of this analysis were to assess HR patterns in two populations (patients with chronic stable angina or stage I to III hypertension) and to compare the effects of various antianginal and antihypertensive treatments on HR. METHODS: This was a retrospective analysis of HR data from two clinical trials evaluating the efficacy of controlled-onset, extended-release (COER)-verapamil. The effects of COER-verapamil were compared with placebo, nifedipine gastrointestinal therapeutic system (GITS), amlodipine, and the combination of amlodipine and atenolol. RESULTS: In patients with angina (n = 498), the change from baseline in HR following 4 weeks of treatment was -6.7 +/- 10.5 beats/min in the COER-verapamil group, -10.8 +/- 10.8 beats/min in the amlodipine/atenolol group, + 2.5 +/- 9.1 beats/ min in the amlodipine monotherapy group, and -1.3 +/- 10.5 beats/min in the placebo group (p<0.001). Data were stratified based on whether patients experienced asymptomatic ischemia during baseline ambulatory electrocardiographic monitoring. The circadian HR pattern was morphologically similar in all groups; however, differences in the magnitude of HR response were evident. In the subset of patients with asymptomatic ischemia (n = 101), treatment with amlodipine monotherapy increased HR compared with placebo. In this same subset of patients, HR reductions were achieved with COER-verapamil and amlodipine/atenolol. In patients with hypertension (n = 557), the change in HR following 10 weeks of treatment was -3.3 beats/min for patients treated with COER-verapamil compared with + 2.0 beats/min for patients treated with nifedipine GITS (p < 0.0001, between-group differences). CONCLUSION: This analysis demonstrates that morphologically similar circadian patterns of HR occur in both hypertensive patients and those with angina. In addition, significant variation exists among antianginal and antihypertensive agents regarding HR effects.