Pharmacogenomics and circadian rhythms as mediators of cardiovascular drug-drug interactions.

This article summarizes the current literature and documents new evidence concerning drug-drug interactions (DDI) stemming from pharmacogenomic and circadian rhythm determinants of therapies used to treat common cardiovascular diseases (CVD), such as atherosclerosis and hypertension. Patients with CVD often have more than one pathophysiologic condition, namely metabolic syndromes, hypertension, hyperlipidemia, and hyperglycemia, among others, which necessitate polytherapeutic or polypharmaceutic management. Interactions between drugs, drugs and food/food supplements, or drugs and genetic/epigenetic factors may have adverse impacts on the cardiovascular and other systems of the body. The mechanisms underlying cardiovascular DDI may involve the formation of a complex pharmacointeractome, including the absorption, distribution, metabolism, and elimination of drugs, which affect their respective bioavailability, efficacy, and/or harmful metabolites. The pharmacointeractome of cardiovascular drugs is likely operated with endogenous rhythms controlled by circadian clock genes. Basic and clinical investigations have improved the knowledge and understanding of cardiovascular pharmacogenomics and pharmacointeractomes, and additionally they have presented new evidence that the staging of deterministic circadian rhythms, according to the dosing time of drugs, e.g., upon awakening vs. at bedtime, cannot only differentially impact their pharmacokinetics and pharmacodynamics but also mediate agonistic/synergetic or antagonistic DDI. To properly manage CVD patients and avoid DDI, it is important that clinicians have sufficient knowledge of their multiple risk factors, i.e., age, gender, and life style elements (like diet, smoking, psychological stress, and alcohol consumption), and comorbidities, such as diabetes, hypertension, dyslipidemia, and depression, and the potential interactions between genetic or epigenetic background of their prescribed therapeutics.

Cardiovascular disease risk stratification by the Framigham score is markedly improved by ambulatory compared with office blood pressure.

INTRODUCTION AND OBJECTIVES: Ambulatory blood pressure (BP) better predicts cardiovascular disease (CVD) outcomes than office BP measurements (OBPM). Nonetheless, current CVD risk stratification models continue to rely on exclusively daytime OBPM along with traditional factors, eg, age, sex, smoking, dyslipidemia, and/or diabetes. METHODS: Data from 19 949 participants of the primary care-based Hygia Project assessed by 48-hour ambulatory BP monitoring (ABPM) and without prior CVD events were used to compare the diagnostic accuracy, discrimination, and performance of the original Framingham risk score (RSOFG) and its adjusted version to the Hygia Project study population (RSAFG) with that of a novel CVD risk stratification model constructed by replacing OBPM with ABPM-derived prognostic parameters (RSABPM). RESULTS: During the follow-up, lasting up to 12.7 years, 1854 participants experienced a primary CVD outcome of CVD death, myocardial infarction, coronary revascularization, heart failure, stroke, transient ischemic attack, angina pectoris, or peripheral artery disease. Asleep systolic BP (SBP) mean and sleep-time relative SBP decline were the only joint significant ABPM-derived predictive factors of CVD risk and were therefore used to substitute for in-clinic SBP in the RSABPM model. The RSABPM model, in comparison with the RSOFG and RSAFG models, showed significantly improved calibration, diagnostic accuracy, discrimination, and performance (always P<.001). The RSAFG-derived event-probabilities of 57.3% of the participants were outside the 95% confidence limits of the event probability determined by the RSABPM model. CONCLUSIONS: These collective findings reveal important limitations of CVD risk stratification when based upon OBPM, as in the Framingham score, and corroborate the clinical value of around-the-clock ABPM to properly diagnose true hypertension and reliably stratify CVD vulnerability.

Daily, weekly and annual patterns in children's accidental sport injuries.

Details of serious injuries to children ≤16 yrs. of age that necessitated urgent surgical intervention by the Department of Pediatric Surgery of the University Hospital of Lausanne, Switzerland were recorded into a database registry. Some 15 110 entries listed the precise time of injury, and 3114 (20.6%) of these resulted from participating in sport-associated activities. Time-of-day, day-of-week and month-of-year differences in the total number of children's accidental sport injuries (CASI) were validated. Time-of-day patterns were substantiated for "All Sports", for both boys and girls 5-16 yrs. of age, with more boys than girls experiencing incidents at almost every clock hour. Moreover, they were substantiated for this age group for each of the six different considered individual and team CASI categories - Physical Exercises at School; Bicycle Riding; Roller Skating and Skateboarding; Snow Skiing, Sledding, and Tobogganing; Soccer; and Basketball - for which sample sizes were sufficiently large (n > 230) to perform statistical assessment by ANOVA, t-test and/or cosinor analyses. CASI happened primarily between 06:00 and 17:00 h and rarely evening or overnight. Features - specific clock-time and number of peaks and troughs - of the CASI daily curve pattern of the individual six sport categories differed somewhat; nonetheless, excess or greatest number of CASI typically happened between 12:00 and 14:00 h, even when summertime and other scheduled school and family vacation periods were taken into account. Time-of-day and day-of-week patterns in the boy/girl sex ratio were also validated, with midday and Friday/Saturday peaks, respectively. We hypothesize the prominent 24 h patterns of CASI of 5-16 yr. olds, in particular, are representative of a combination of several determinants. These include exogenous periodic and cyclic environmental and sociocultural phenomena, genetic sex-related traits, plus endogenous circadian cognitive and physiologic rhythms, with the common midday injury excess of many sport categories, at least in part, the consequence of the well-documented midday dip in attention and vigilance of children.

Circadian disruption: New clinical perspective of disease pathology and basis for chronotherapeutic intervention.

Biological processes are organized in time as innate rhythms defined by the period (τ), phase (peak [Φ] and trough time), amplitude (A, peak-trough difference) and mean level. The human time structure in its entirety is comprised of ultradian (τ < 20 h), circadian (20 h > τ < 28 h) and infradian (τ > 28 h) bioperiodicities. The circadian time structure (CTS) of human beings, which is more complicated than in lower animals, is orchestrated and staged by a brain central multioscillator system that includes a prominent pacemaker - the suprachiasmatic nuclei of the hypothalamus. Additional pacemaker activities are provided by the pineal hormone melatonin, which circulates during the nighttime, and the left and right cerebral cortices. Under ordinary circumstances this system coordinates the τ and Φ of rhythms driven by subservient peripheral cell, tissue and organ clock networks. Cyclic environmental, feeding and social time cues synchronize the endogenous 24 h clocks and rhythms. Accordingly, processes and functions of the internal environment are integrated in time for maximum biological efficiency, and they are also organized and synchronized in time to the external environment to ensure optimal performance and response to challenge. Artificial light at night (ALAN) exposure can alter the CTS as can night work, which, like rapid transmeridian displacement by air travel, necessitates realignment of the Φ of the multitude of 24 h rhythms. In 2001, Stevens and Rea coined the phrase "circadian disruption" (CD) to label the CTS misalignment induced by ALAN and shift work (SW) as a potential pathologic mechanism of the increased risk for cancer and other medical conditions. Current concerns relating to the effects of ALAN exposure on the CTS motivated us to renew our long-standing interest in the possible role of CD in the etiopathology of common human diseases and patient care. A surprisingly large number of medical conditions involve CD: adrenal insufficiency; nocturia; sleep-time non-dipping and rising blood pressure 24 h patterns (nocturnal hypertension); delayed sleep phase syndrome, non-24 h sleep/wake disorder; recurrent hypersomnia; SW intolerance; delirium; peptic ulcer disease; kidney failure; depression; mania; bipolar disorder; Parkinson's disease; Smith-Magenis syndrome; fatal familial insomnia syndrome; autism spectrum disorder; asthma; byssinosis; cancers; hand, foot and mouth disease; post-operative state; and ICU outcome. Poorly conceived medical interventions, for example nighttime dosing of synthetic corticosteroids and certain ß-antagonists and cyclic nocturnal enteral or parenteral nutrition, plus lifestyle habits, including atypical eating times and chronic alcohol consumption, also can be causal of CD. Just as surprisingly are the many proven chronotherapeutic strategies available today to manage the CD of several of these medical conditions. In clinical medicine, CD seems to be a common, yet mostly unrecognized, pathologic mechanism of human disease as are the many effective chronotherapeutic interventions to remedy it.

Nocturnal light pollution and underexposure to daytime sunlight: Complementary mechanisms of circadian disruption and related diseases.

Routine exposure to artificial light at night (ALAN) in work, home, and community settings is linked with increased risk of breast and prostate cancer (BC, PC) in normally sighted women and men, the hypothesized biological rhythm mechanisms being frequent nocturnal melatonin synthesis suppression, circadian time structure (CTS) desynchronization, and sleep/wake cycle disruption with sleep deprivation. ALAN-induced perturbation of the CTS melatonin synchronizer signal is communicated maternally at the very onset of life and after birth via breast or artificial formula feedings. Nighttime use of personal computers, mobile phones, electronic tablets, televisions, and the like--now epidemic in adolescents and adults and highly prevalent in pre-school and school-aged children--is a new source of ALAN. However, ALAN exposure occurs concomitantly with almost complete absence of daytime sunlight, whose blue-violet (446-484 nm λ) spectrum synchronizes the CTS and whose UV-B (290-315 nm λ) spectrum stimulates vitamin D synthesis. Under natural conditions and clear skies, day/night and annual cycles of UV-B irradiation drive corresponding periodicities in vitamin D synthesis and numerous bioprocesses regulated by active metabolites augment and strengthen the biological time structure. Vitamin D insufficiency and deficiency are widespread in children and adults in developed and developing countries as a consequence of inadequate sunlight exposure. Past epidemiologic studies have focused either on exposure to too little daytime UV-B or too much ALAN, respectively, on vitamin D deficiency/insufficiency or melatonin suppression in relation to risk of cancer and other, e.g., psychiatric, hypertensive, cardiac, and vascular, so-called, diseases of civilization. The observed elevated incidence of medical conditions the two are alleged to influence through many complementary bioprocesses of cells, tissues, and organs led us to examine effects of the totality of the artificial light environment in which humans reside today. Never have chronobiologic or epidemiologic investigations comprehensively researched the potentially deleterious consequences of the combination of suppressed vitamin D plus melatonin synthesis due to life in today's man-made artificial light environment, which in our opinion is long overdue.

Diurnal and twenty-four hour patterning of human diseases: cardiac, vascular, and respiratory diseases, conditions, and syndromes.

Various medical conditions, disorders, and syndromes exhibit predictable-in-time diurnal and 24 h patterning in the signs, symptoms, and grave nonfatal and fatal events, e.g., respiratory ones of viral and allergic rhinorrhea, reversible (asthma) and non-reversible (bronchitis and emphysema) chronic obstructive pulmonary disease, cystic fibrosis, high altitude pulmonary edema, and decompression sickness; cardiac ones of atrial premature beats and tachycardia, paroxysmal atrial fibrillation, 3rd degree atrial-ventricular block, paroxysmal supraventricular tachycardia, ventricular premature beats, ventricular tachyarrhythmia, symptomatic and non-symptomatic angina pectoris, Prinzmetal vasospastic variant angina, acute (non-fatal and fatal) incidents of myocardial infarction, sudden cardiac arrest, in-bed sudden death syndrome of type-1 diabetes, acute cardiogenic pulmonary edema, and heart failure; vascular and circulatory system ones of hypertension, acute orthostatic postprandial, micturition, and defecation hypotension/syncope, intermittent claudication, venous insufficiency, standing occupation leg edema, arterial and venous branch occlusion of the eye, menopausal hot flash, sickle cell syndrome, abdominal, aortic, and thoracic dissections, pulmonary thromboembolism, and deep venous thrombosis, and cerebrovascular transient ischemic attack and hemorrhagic and ischemic stroke. Knowledge of these temporal patterns not only helps guide patient care but research of their underlying endogenous mechanisms, i.e., circadian and others, and external triggers plus informs the development and application of effective chronopreventive and chronotherapeutic strategies.

Diurnal and twenty-four hour patterning of human diseases: acute and chronic common and uncommon medical conditions.

The symptom intensity and mortality of human diseases, conditions, and syndromes exhibit diurnal or 24 h patterning, e.g., skin: atopic dermatitis, urticaria, psoriasis, and palmar hyperhidrosis; gastrointestinal: esophageal reflux, peptic ulcer (including perforation and hemorrhage), cyclic vomiting syndrome, biliary colic, hepatic variceal hemorrhage, and proctalgia fugax; infection: susceptibility, fever, and mortality; neural: frontal, parietal, temporal, and occipital lobe seizures, Parkinson's and Alzheimer's disease, hereditary progressive dystonia, and pain (cancer, post-surgical, diabetic neuropathic and foot ulcer, tooth caries, burning mouth and temporomandibular syndromes, fibromyalgia, sciatica, intervertebral vacuum phenomenon, multiple sclerosis muscle spasm, and migraine, tension, cluster, hypnic, and paroxysmal hemicranial headache); renal: colic and nocturnal enuresis and polyuria; ocular: bulbar conjunctival redness, keratoconjunctivitis sicca, intraocular pressure and anterior ischemic optic neuropathy, and recurrent corneal erosion syndrome; psychiatric/behavioral: major and seasonal affective depressive disorders, bipolar disorder, parasuicide and suicide, dementia-associated agitation, and addictive alcohol, tobacco, and heroin cravings and withdrawal phenomena; plus autoimmune and musculoskeletal: rheumatoid arthritis, osteoarthritis, axial spondylarthritis, gout, Sjögren's syndrome, and systemic lupus erythematosus. Knowledge of these and other 24 h patterns of human pathophysiology informs research of their underlying circadian and other endogenous mechanisms, external temporal triggers, and more effective patient care entailing clinical chronopreventive and chronotherapeutic strategies.

Shift work and cancer risk: potential mechanistic roles of circadian disruption, light at night, and sleep deprivation.

Shift work that includes a nighttime rotation has become an unavoidable attribute of today's 24-h society. The related disruption of the human circadian time organization leads in the short-term to an array of jet-lag-like symptoms, and in the long-run it may contribute to weight gain/obesity, metabolic syndrome/type II diabetes, and cardiovascular disease. Epidemiologic studies also suggest increased cancer risk, especially for breast cancer, in night and rotating female shift workers. If confirmed in more controlled and detailed studies, the carcinogenic effect of night and shift work will constitute additional serious medical, economic, and social problems for a substantial proportion of the working population. Here, we examine the possible multiple and interconnected cancer-promoting mechanisms as a consequence of shift work, i.e., repeated disruption of the circadian system, pineal hormone melatonin suppression by exposure to light at night, sleep-deprivation-caused impairment of the immune system, plus metabolic changes favoring obesity and generation of proinflammatory reactive oxygen species.

Optimal frequency of imiquimod (aldara) 5% cream for the treatment of external genital warts in immunocompetent adults: a meta-analysis.

BACKGROUND: Postmarketing research has explored the optimal application schedule of imiquimod 5% cream for treatment of external anogenital warts. OBJECTIVES: We systemically reviewed the published literature on the efficacy and safety of the medication when applied either by a three times per week or once-daily regimen for 16 weeks. METHODS: MEDLINE (1966 to Feb 10, 2007), Scopus (1996 to Feb 10, 2007), and Cochrane Library (Issue 1, 2007) databases were searched for randomized trials on the medication. Primary efficacy outcome was the proportion of patients completely cleared of warts by end of treatment. Two primary safety outcomes were as follows: (a) proportion of patients who withdrew and (b) proportion of patients who required at least one rest period from treatment because of drug-related adverse events. RESULTS: Six studies were selected for subgroup analysis of circumcised men, uncircumcised men, and women. The once-daily compared to three times per week regimen did not improve treatment efficacy in any of the 3 subgroups (P <0.05), but resulted in greater incidence and severity of local skin reactions. There was no difference in medication-related withdrawals between the 2 regimens, although significantly more women and uncircumcised men required at least one rest period with the once-daily than the three times per week treatment schedule (P <0.05). CONCLUSIONS: The optimal application schedule of imiquimod 5% cream for external anogenital warts is three times per week.

Chronobiology, drug delivery, and chronotherapeutics.

Biological processes and functions are organized in space, as a physical anatomy, and time, as a biological time structure. The latter is expressed by short-, intermediate-, and long-period oscillations, i.e., biological rhythms. The circadian (24-h) time structure has been most studied and shows great importance to the practice of medicine and pharmacotherapy of patients. The phase and amplitude of key physiological and biochemical circadian rhythms contribute to the known predictable-in-time patterns in the occurrence of serious and life-threatening medical events, like myocardial infraction and stroke, and the manifestation and severity of symptoms of chronic diseases, like allergic rhinitis, asthma, and arthritis. Moreover, body rhythms can significantly affect responses of patients to diagnostic tests and, most important to the theme of this special issue, medications. Rhythmicity in the pathophysiology of disease is one basis for chronotherapeutics--purposeful variation in time of the concentration of medicines in synchrony with biological rhythm determinants of disease activity--to optimize treatment outcomes. A second basis is the control of undesired effects of medications, especially when the therapeutic range is narrow and the potential for adverse effects high, which is the case for cancer drugs. A third basis is to meet the biological requirements for frequency-modulated drug delivery, which is the case for certain neuroendocrine peptide analogues. Great progress has been realized with hydrogels, and they offer many advantages and opportunities in the design of chronotherapeutic systems for drug delivery via the oral, buccal, nasal, subcutaneous, transdermal, rectal, and vaginal routes. Nonetheless, innovative delivery systems will be necessary to ensure optimal application of chronotherapeutic interventions. Next generation drug-delivery systems must be configurable so they (i) require minimal volitional adherence, (ii) respond to sensitive biomarkers of disease activity that often vary in time as periodic (circadian rhythmic) and non-periodic (random) patterns to release medication to targeted tissue(s) on a real time as needed basis, and (iii) are cost-effective.

A pilot home study of temporal variations of symptoms in chronic obstructive lung disease.

The purposes of this pilot study are to describe the 24-hr patterns of dyspnea, fatigue, and peak expiratory flow rate (PEFR) in patients with chronic obstructive pulmonary disease (COPD) and examine their interrelationships. The repeated-measures design protocol involved 10 patients with moderate to severe COPD who self-assessed dyspnea, fatigue, and PEFR five times a day for 8 days. Circadian rhythms were documented by single cosinor analysis in 40% of the participants for dyspnea, 60% for fatigue, and 60% for PEFR. The 8-day, 24-hr means of dyspnea and fatigue were moderately correlated; 70% of the sample displayed significant correlations. The means of PEFR and both dyspnea and fatigue were weakly negatively correlated. The findings suggest that circadian rhythm in lung function may not be temporally coupled with the circadian rhythm in dyspnea and fatigue in all patients and that the mean self-perceived levels of dyspnea and fatigue are moderately related.

Seasonal variation in occurrence of pulmonary embolism: analysis of the database of the Emilia-Romagna region, Italy.

Seasonal variation in the occurrence of cardiovascular and cerebrovascular events, including pulmonary embolism (PE), has been reported; however, recent large-scale, population-based studies conducted in the United States did not confirm such seasonality. The aim of this large-scale population study was to determine whether a temporal pattern in the occurrence of PE exists. The analysis considered all consecutive cases of PE in the database of all hospital admissions of the Emilia Romagna region in Italy at the Center for Health Statistics between January 1998 and December 2005. PE cases were first grouped according to season of occurrence, and the data were analyzed by the chi(2) test for goodness of fit. Then, inferential chronobiologic (cosinor and partial Fourier) analysis was applied to monthly data, and the best-fitting curve for the annual variation was derived. The total sample consisted of 19,245 patients (8,143 male, mean age 71.6+/-14.1 yrs; 11,102 female, mean age 76.1+/-13.7 yrs). Of these, 2,484 were <65 yrs, 5,443 were between 65 and 74, and 11,318 were > or = 75 yrs. There were 4,486 (23.3%) fatal-case outcomes. PE occurred least frequently in spring (n=4,442 or 23.1%) and most frequent in winter (n=5,236 or 27.2%, goodness of fit chi(2)=75.75, p<0.001). Similar results were obtained for subgroups formed by gender, age, fatal/non-fatal outcome, presence/absence of major underlying co-morbid conditions, and specific risk factors. Inferential chronobiological analysis identified a significant annual pattern in PE, with the peak between November and December for the total sample of cases (p<0.001), males (p<0.001), females (p=0.002), fatal and non-fatal cases (p<0.001 for both), and subgroups formed by age (<65 yrs, p=0.012; 65-74 yrs, p<0.001; > or = 75 yrs, p=0.012). This pattern was independent of the presence/absence of hypertension (p=0.003 and p<0.001, respectively), pulmonary disease (p<0.001 and p<0.001, respectively), stroke (p<0.001 and p=0.004, respectively), neoplasms (p=0.005 and p=0.001, respectively), heart failure (p=0.022 and p<0.001, respectively), and deep vein thrombosis (p=0.002 and p<0.001, respectively). However, only a non-statistically significant trend was found for subgroups formed by cases of diabetes mellitus, infections, renal failure, and trauma.

Glutathione S-transferase gene polymorphisms and risk and survival of pancreatic cancer.

BACKGROUND: Pancreatic cancer is a multifactorial disease with metastasis-prone and therapy-resistant nature. The authors hypothesized that genetic variants of glutathione S-transferase (GST) affect detoxification of carcinogens and anticancer agents in the human pancreas and, thus, the risk and survival of pancreatic cancer. METHODS: Genotypes of GSTM1, GSTT1, and GSTP1 were determined in 352 patients with pancreatic ductal adenocarcinoma and in a control group of 315 healthy, non-Hispanic whites (frequency-matched by age and sex). Survival analysis was performed in a subset of 290 patients. Epidemiological and clinical information was obtained. A multiple unconditional logistic regression model, a Cox proportional hazards model, and log-rank tests were used for statistical analysis. RESULTS: No significant main effects of any of 3 GST genes on the risk of pancreatic cancer were observed. Subgroup analysis showed that older individuals (aged >or=62 years) who carried the GSTP1*C ((105)Val-(114)Val) containing genotype tended to have a reduced risk compared with younger individuals who carried the non-*C genotype (for sex and pack-years of smoking, the adjusted odd ratio was 0.54; 95% confidence interval [95% CI], 0.29-1.02). In a survival analysis of 138 patients who received 5-flurorouracil, patients who carried the GSTP1*C containing genotype had a significantly longer survival than patients who carried the non-*C genotype (multivariate hazard ratio, 0.45; 95% CI, 0.22-0.94). CONCLUSIONS: The GSTP1*C variant conferred a possible protective effect against pancreatic cancer in older individuals and a significant survival advantage in patients who received 5-florouracil. The current findings must be confirmed before further inferences can be made.