Chronopharmacology and Therapeutic Drug Regulations: Commentary

A quiet, little-publicized development has taken place in the biomedical sciences in recent years. The new terms chronobiology, chronopharmacology, chronopharma-codynamics, chronopharmacokineties, and even chronotoxicology very gently have entered our language and our science. Chronobiologic considerations have been proved to increase or decrease therapeutic drug effectiveness or modify their toxicology. Many authors have pointed out that cues to these advantages or disadvantages may be obtained from animal studies that show that normal changes of cellular rhythms take place at prescribed intervals for many biologic parameters. We are observing replacement of the traditional unidimensional reference intervals by timing drug administration most effectively according to the rhythms having phase, frequency, and amplitude. Oncologists have utilized these concepts most successfully to increase the therapeutic effectiveness and decrease toxicity of antineoplastic agents. In addition, asthma has received great attention as a circadian rhythm-related disorder; angina and myocardial infarction, hypertension, peptic ulcer, and epilepsy are other disease conditions that have been treated successfully by understanding how biological rhythms influence diagnosis and therapy.     

Chronopharmacology and Therapeutic Drug Regulations: Commentary

A quiet, little-publicized development has taken place in the biomedical sciences in recent years. The new terms chronobiology, chronopharmacology, chronopharma-codynamics, chronopharmacokineties, and even chronotoxicology very gently have entered our language and our science. Chronobiologic considerations have been proved to increase or decrease therapeutic drug effectiveness or modify their toxicology. Many authors have pointed out that cues to these advantages or disadvantages may be obtained from animal studies that show that normal changes of cellular rhythms take place at prescribed intervals for many biologic parameters. We are observing replacement of the traditional unidimensional reference intervals by timing drug administration most effectively according to the rhythms having phase, frequency, and amplitude. Oncologists have utilized these concepts most successfully to increase the therapeutic effectiveness and decrease toxicity of antineoplastic agents. In addition, asthma has received great attention as a circadian rhythm-related disorder; angina and myocardial infarction, hypertension, peptic ulcer, and epilepsy are other disease conditions that have been treated successfully by understanding how biological rhythms influence diagnosis and therapy.     

Circadian chronobiology of epilepsy: murine models of seizure susceptibility and theoretical perspectives for neurology

As an integrative discipline in physiology and medical research, chronobiology renders possible the discovery of new regulation processes regarding the central mechanisms of epilepsy. In this context, the temporal fluctuations of seizure susceptibility rhythmometrically detected tend to demonstrate 1. that tonic-clonic events are circadian stage-dependent processes whose temporal characteristics (i.e. MESOR, amplitude, acrophase) and clinical parameters (e.g. neurological components, severity of motor discharges) are predictable on the basis of mathematical models, and 2. that the generalized epileptic onsets may respond to telencephalic integrations modulated by centrencephalic circadian processes of vigilance. Considering the data model assumed for our rhythmometric analyses, the circadian psychophysiological patterns of epilepsy also express dynamic biologic systems which reveal some intermodulating endogenous processes between vigilance and seizure susceptibility. The new chronophysiology investigations considered at a rhythmometric level of resolution suggest several heuristic perspectives regarding 1. the central pathophysiology of epilepsy and 2. the behavioral classification of convulsive events. Such circadian studies also show that chronobiology raises some working hypotheses in psychophysiology and permits the development of new theoretical concepts in the field of neurological science.     

Circadian patterns of basic emotional reactivity and stress related events revisited in mice treated with lithium: behavioral rhythmometric analyses

This research dealt with rhythmometric methods for estimating and comparing the main temporal parameters characterizing the circadian structure of behavioral events in mice with and without lithium treatment. Such comparative chronobiologic studies would tend to demonstrate in psychophysiology that this drug does not displace the circadian patterns of basic emotionality, but does displace some behavioral circadian rhythms associated with more corticalized integrations. The present behavioral observations would tend to support the hypothesis that lithium salts modify the circadian structure of emotionality by cortical modulation rather than only by physiological subcortical integrations. Such circadian studies show also that behavioral chronobiology raises some working hypotheses in comparative ethology and permits the development of new heuristic concepts in the field of biological psychiatry.     

中西医观解读时间生物学

时间生物学是一门研究生命活动节律的科学。在西方医学中,研究时间生物学是利用分子生物学实验来阐释其机制,以西医的思维方法解释时间生物学的生理及病理过程;中医对时间生物学的记载有两千多年的历史,阴阳理论、子午流注学说以及五运六气学说一直以来都在指导中医的诊断和治疗。中西医观的不同对时间生物学的研究提供了新的研究思路,同时时间生物学也为研究中西医结合提供了广阔的前景。     

Chronobiology in mental retardation research: progress and prospects.

The premise of this review is that chronobiology, the science of biologic time structure and rhythms, is important in investigations concerning the etiology, mechanisms and effects of deficient mental adaptive development. Chronobiology is also shown to have potential importance in therapeutics and rehabilitation. Most of the information available now and supporting this wide-spread relevance of chronobiology relates to circadian rhythms, but physiological and behavioral rhythms having other cycle lengths also contribute. Recent findings in seven topic areas of chronobiology are reviewed with emphasis on facts and relationships actually or potentially important for consideration in mental retardation research. These are: 1) development of sleep and EEG patterns; 2) rhythmic susceptibility to seizures; 3) adrenocortical and dependent rhythms; 4) circadian rhythms in amino acids and biogenic amines; 5) rhythmic behaviors; 6) circadian rhythms in susceptibility and responses to drugs; and 7) circadian rhythms in human perception and performance.     

Chronobiological aspects of obesity and metabolic syndrome

Circadian rhythms (approximately 24h) are widely characterized at molecular level and their generation is acknowledged to originate from oscillations in expression of several clock genes and from regulation of their protein products. While general entrainment of organisms to environmental light-dark cycles is mainly achieved through the master clock of the suprachiasmatic nucleus in mammals, this molecular clockwork is functional in several organs and tissues. Some studies have suggested that disruption of the circadian system (chronodisruption (CD)) may be causal for manifestations of the metabolic syndrome. This review summarizes (1) how molecular clocks coordinate metabolism and their specific role in the adipocyte; (2) the genetic aspects of and scientific evidence for obesity as a chronobiological illness; and (3) CD and its causes and pathological consequences. Finally, ideas about use of chronobiology for the treatment of obesity are discussed.     

International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 15/2. Metabolism and metabolic effects of ethanol, including interaction with drugs, carcinogens and nutrition

Different pathways of alcohol metabolism, the alcohol dehydrogenase pathway, the microsomal ethanol-oxidizing system and the catalase pathway are discussed. Alcohol consumption leads to accelerated ethanol metabolism by different mechanisms including an increased microsomal function. Microsomal induction leads to interactions of ethanol with drugs, hepatotoxic agents, steroids, vitamins and to an increased activation of mutagens/carcinogens. A number of ethanol-related complications may be explained by the production of its first metabolite, acetaldehyde, such as alterations of mitochondria, increased lipid peroxidation and microtubular alterations with its adverse effects on various cellular activities, including disturbances of cell division. Nutritional factors in alcoholics such as malnutrition are discussed especially with respect to its possible relation to cancer.     

Chronic alcohol consumption potentiates the development of diabetes through pancreatic β-cell dysfunction

Chronic ethanol consumption is well established as a major risk factor for type-2 diabetes(T2D), which is evidenced by impaired glucose metabolism and insulin resistance. However, the relationships between alcoholconsumption and the development of T2 D remain controversial. In particular, the direct effects of ethanol consumption on proliferation of pancreatic β-cell and the exact mechanisms associated with ethanolmediated β-cell dysfunction and apoptosis remain elusive. Although alcoholism and alcohol consumption are prevalent and represent crucial public health problems worldwide, many people believe that low-tomoderate ethanol consumption may protect against T2 D and cardiovascular diseases. However, the J- or U-shaped curves obtained from cross-sectional and large prospective studies have not fully explained the relationship between alcohol consumption and T2 D. This review provides evidence for the harmful effects of chronic ethanol consumption on the progressive development of T2 D, particularly with respect to pancreatic β-cell mass and function in association with insulin synthesis and secretion. This review also discusses a conceptual framework for how ethanolproduced peroxynitrite contributes to pancreatic β-cell dysfunction and metabolic syndrome.     

Larval ethanol exposure alters adult circadian free-running locomotor activity rhythm in Drosophila melanogaster

Alcohol consumption causes disruptions in a variety of daily rhythms, including the sleep-wake cycle. Few studies have explored the effect of alcohol exposure only during developmental stages preceding maturation of the adult circadian clock, and none have examined the effects of alcohol on clock function in Drosophila. This study investigates developmental and behavioral correlates between larval ethanol exposure and the adult circadian clock in Drosophila melanogaster, a well-established model for studying circadian rhythms and effects of ethanol exposure. We reared Drosophila larvae on 0%, 10%, or 20% ethanol-supplemented food and assessed effects upon eclosion and the free-running period of the circadian rhythm of locomotor activity. We observed a dose-dependent effect of ethanol on period, with higher doses resulting in shorter periods. We also identified the third larval instar stage as a critical time for the developmental effects of 10% ethanol on circadian period. These results demonstrate that developmental ethanol exposure causes sustainable shortening of the adult free-running period in Drosophila melanogaster, even after adult exposure to ethanol is terminated, and suggests that the third instar is a sensitive time for this effect.     

Alcohol dependence and polymorphisms of serotonin-related genes

Genetic factors have a non-specific but significant impact on the risk of alcohol-dependence. Molecular genetic analyses are now less devoted to the genes involved in the metabolism of ethanol, focusing on core concepts of addiction, such as arousal, pleasure, reward, craving, and impulsivity. Indeed, the neuro-cognitive functions, temperament traits and psycho-behavioral specificities of patients with alcohol abuse or dependence led to select new sets of candidate genes. One of them are related to serotonin transmission, as serotonin modulates dopaminergic pathways, and is also stimulated by many addictive susbtances. The genetic analyses of serotonin in alcohol-dependence are mainly focused on the serotonin transporter gene (5-HTT), as one polymorphism within the promoter has a functional impact. From the 16 case-control association studies yet performed, many are positive, and one family-based study showed a large excess of transmission of the short allele. We performed a meta-analysis of the case-control studies showing that the S allele could be a risk factor for a phenotype related to alcohol-dependence (OR=1.31), with still unknown boundaries. Other genes coding for serotonin receptors were analysed with mainly negative results, for example the 5-HT2A, 5-HT2C, 5-HT5A and 5-HT7 receptors. The 5-HT1B could be more interesting as being located in a locus linked to alcohol preference in rodents, and associated with antisocial alcoholism in two human studies. Genetics may thus provide new insights about the different mechanisms which explain why some subjects are more at risk for the development of alcohol abuse or dependence. Genes involved in the transmission, reuptake and metabolism of serotonin constitute a set of candidate genes that could be involved in core aspects of alcoholism, such as the tendency to prefer immediate reward, despite negative consequences.     

Nonoxidative ethanol metabolism in human leukocytes: detection of fatty acid ethyl ester synthase activity

Oxidative pathways of alcohol metabolism such as alcohol dehydrogenase usually are not present in human blood and therefore clinical studies correlating ethanol metabolism with alcohol abuse syndromes have not been performed. To assess the activity of nonoxidative ethanol metabolism in blood, we assayed for the activity of fatty acid ethyl ester synthase, a pathway recently described as abundant in the human organs most commonly damaged by alcohol. Indeed, peripheral human leukocytes contain detectable fatty acid ethyl ester synthase activity: 1.2 X 10(6) leukocytes from 10 ml blood catalyze the synthesis of ethyl oleate at 1.4 nmol/4 hr. The reaction is linear with respect to cell number and expended time; Km oleate = 600 microM, Km ethanol = 600 mM. DEAE cellulose chromatography partially purifies synthase activity into a minor and major form (activity ratio = 10/1). Thus, gene products exist in human blood that recognize ethanol and whose biological activity is conveniently assayable for clinical investigations of alcohol metabolism and abuse.     

Kinetic studies of lipoprotein metabolism in the metabolic syndrome including effects of nutritional interventions

Nutritional interventions may favourably regulate dyslipoproteinemia and, hence, decrease cardiovascular disease risk. Lipoprotein kinetic studies afford a powerful approach to understanding and defining the mechanisms by which such interventions modulate lipoprotein metabolism. Stable isotope tracers and compartment models are now commonly employed for such studies. We review the recent application of tracer methodologies to the study of dyslipoproteinemia in the metabolic syndrome. We also focus on the effects of nutritional intervention studies that have addressed the effects of weight loss, n-3 fatty acids, plant sterols and alcohol on very low density lipoprotein, LDL and HDL metabolism. The potential for statin treatment as an adjunct to dietary modification is also discussed. New tracer methodologies are discussed, specifically those referring to reverse cholesterol transport. The nutritional interventions discussed in this review are readily transferable into clinical preventive practice. The potential benefits to be gained by weight loss and fish oil supplementation in the metabolic syndrome extend beyond their specific and positive effects on lipoprotein metabolism. Furthermore, recent developments in tracer methodologies afford new tools for probing the in-vivo pathways of lipoprotein metabolism in future studies.     

Hepatic alcohol oxidation and its metabolic liability.

The pathways responsible for ethanol oxidation and the toxic results of its metabolism are reviewed. The predominant pathway for ethanol oxidation at low ethanol concentrations involves alcohol dehydrogenase. However, at high alcohol concentrations, up to 50% of ethanol uptake is 4-methylpyrazole-intensitive. Oxidation of ethanol under these conditions is associated with a change in the steady-stage concentration of catalase-H2O2. Based on recent evidence, we conclude that it is unnecessary to postulate that ethanol is oxidized directly via cytochrome P-450. Acetaldehyde production from ethanol via the microsomal subfraction can be accounted for by the combined activities of catalase-H2O2 and alcohol dehydrogenase. The metabolism of ehtanol via alcohol dehydrogenase produces a marked reduction in the hepatocellular NAD-NADH sytems. This reduction is indirectly responsible for the inhibition of glycolysis, gluconeogenesis, citric acid cycle activity, and fatty acid oxidation and may be related to some of the pathological effects observed following chronic consumption of alcohol. Attempts in inhibit alcohol dehydrogenase with alkylpyrazoles and activate catalase with substrates for peroxisomal H2O2-generating flavoproteins, while successful, may have limited applicability because of the native toxicity of the substrates themselves...     

Chronic ethanol intake alters circadian period-responses to brief light pulses in rats

Although chronic alcohol intake is associated with widespread disruptions of sleep-wake cycles and other daily biological rhythms in both human alcoholics and experimental animals, the extent to which the chronobiological effects of alcohol are mediated by effects on the underlying circadian pacemaker remains unknown. Nevertheless, recent studies indicate that both adult and perinatal ethanol treatments may alter the free-running period and photic responsiveness of the circadian pacemaker. The present experiment was designed to further characterize the effects of chronic ethanol intake on the response of the rat circadian pacemaker to brief light pulses. Ethanol-treated and control animals were exposed to 15-min light pulses during either early or late subjective night on the first day of constant darkness following entrainment to a 12:12 light-dark cycle. Relative to pulses delivered during early subjective night and to “no-pulse” conditions, light pulses delivered during late subjective night resulted in period-shortening after-effects under constant darkness, but only in control animals, not in ethanol-treated animals. These results indicate that chronic ethanol intake reduces the responsiveness of the circadian pacemaker to acute photic stimulation, and suggest that the chronobiological disruptions seen in human alcoholics are due in part to alterations in circadian pacemaker function.     

Lipid metabolism around the body clocks

Lipids play important roles in energy metabolism along with diverse aspects of biological membrane structure, signaling and other functions. Perturbations of lipid metabolism are responsible for the development of various pathologies comprising metabolic syndrome, obesity, and type 2 diabetes. Accumulating evidence suggests that circadian oscillators, operative in most cells of our body, coordinate temporal aspects of lipid homeostasis. In this review we summarize current knowledge on the circadian regulation of lipid digestion, absorption, transportation, biosynthesis, catabolism, and storage. Specifically, we focus on the molecular interactions between functional clockwork and biosynthetic pathways of major lipid classes comprising cholesterol, fatty acids, triacylglycerols, glycerophospholipids, glycosphingolipids, and sphingomyelins. A growing body of epidemiological studies associate a socially imposed circadian misalignment common in modern society with growing incidence of metabolic disorders, however the disruption of lipid metabolism rhythms in this connection has only been recently revealed. Here, we highlight recent studies that unravel the mechanistic link between intracellular molecular clocks, lipid homeostasis and development of metabolic diseases based on animal models of clock disruption and on innovative translational studies in humans. We also discuss the perspectives of manipulating circadian oscillators as a potentially powerful approach for preventing and managing metabolic disorders in human patients.     

Evening Alcohol Consumption Alters the Circadian Rhythm of Body Temperature

To the Editor: Recordings of body temperature rhythms are used as a marker of the circadian system in many fields of study, including shift work, jet lag, affective disorders, gerontology, and sleep disorders. In our studies of circadian rhythms, we routinely prohibit subjects from drinking alcohol because of findings published in 1933 (1). That study found that after alcohol consumption the nocturnal temperature minimum during sleep occurred earlier, and was higher, than on control nights. In the years since that report, there have been no other studies of how alcohol changes the temperature waveform during sleep, despite other studies of the dose- and time-dependent effects of ethanol in humans (2). We decided to investigate whether the results of the 1933 report would generalize to other subjects and to women.     

Clinical Chronobiology and Chronotherapeutics with Applications to Asthma

The concept of homeostasis (i.e., constancy of the milieu interne) has long dominated the teaching and practice of medicine. Concepts and findings from chronobiology, the scientific study of biological rhythms, challenge this construct. Biological processes and functions are not at all constant; rather, they are organized in time as rhythms with period lengths that range in duration from as short as a second or less to as long as a year. It is the body's circadian (24h) rhythms that have been researched most intensely. The peak and trough of these rhythms are ordered rather precisely in time to support the biological requirements of activity during the day and sleep at night. The timing of the peak and trough plus the magnitude of variation (amplitude) of physiological and biochemical functions during the 24h give rise to predictable-in-time, day-night patterns in the manifestation and exacerbation of many common medical conditions. Circadian rhythms also can influence the response of patients to diagnostic tests and therapeutic interventions according to their timing with reference to body rhythms. Rhythms in the pathophysiology of medical conditions and patient tolerance to medications constitute the basis for chronotherapeutics, the timing of treatment in relation to biological rhythm determinants as a means of optimizing beneficial effects and safety. The article discusses recent advances in medical chronobiology and chronotherapeutics and their relevance to clinical medicine in general and the management of asthma in particular. Indeed, since asthma is a disease that exhibits rather profound circadian rhythmicity, investigation of its pathophysiology and therapy necessitates a chronobiologic approach.