Current Pharmaceutical Design - Volume 21, Issue 24, 2015

The circadian clock is a biological system that allows organisms to adapt to temporal constraints of the environment. It governs all body functions. The circadian clock has an endogenous period and entrains to the external day by the means of timing cues, also called “zeitgebers”. A discrepancy between internal and external day or internal day and certain body functions results in circadian desynchrony, most prominently represented in jet lag. Circadian desynchrony may be a factor in many diseases. This review presents literature in which the impact of circadian desynchrony on disease development - with a special focus on critical illness - has been addressed. The treatment options that have so far been investigated are also presented.

A robust circadian timekeeping system is important for human health and well-being. Inappropriately timed light exposure can cause circadian and sleep disruption, which has been shown to have negative health consequences. Lighting in medical care facilities, such as the NICU, ICU, and nursing homes, is not typically controlled and may be associated with circadian disruption observed in such settings. Cycled lighting and increased exposure to sunlight in medical care facilities have been shown to have positive effects on patient recovery and well-being, and expedite hospital discharge. Additional clinical research is needed to determine the optimal light exposure timing, duration, intensity, and spectrum to best promote recovery, health and well-being in the context of medical care.

Purpose: This article reviews our current understanding of the relationships between critical illness, circadian disruption, and delirium. Summary: Delirium is a common and morbid complication of hospitalization, particularly in the setting of critical illness and intensive care unit (ICU) admission. Critical illness involves a host of acute metabolic, hormonal and inflammatory responses that appear to disrupt normal sleep architecture and precipitate cerebral dysfunction. The intervention-heavy environment of the ICU further disrupts normal circadian rhythms and increases delirium risk. Despite strong evidence for correlation of sleep disruption, critical illness and delirium, causal relationships remain difficult to prove. Delirium is almost certainly a multifactorial condition. This article reviews proposed pathophysiologic mechanisms and potential therapeutic targets. In the absence of definitive pharmacologic therapy, interventions prioritizing maintenance of normal circadian, sleep, and behavioral patterns have shown promise in delirium risk reduction.

The confinement of critically ill patients in intensive care units (ICU) imposes environmental constancy throughout both day and night (continuous light, noise, caring activities medications, etc.), which has a negative impact on human health by inducing a new syndrome known as circadian misalignment, circadian disruption or chronodisruption (CD). This syndrome contributes to poor sleep quality and delirium, and may impair septic states frequently observed in critically ill patients. However, and although the bidirectional crosstalk between CD with sleep impairment, delirium and inflammation in animal models has been known for years and has been suspected in ICU patients, few changes have been introduced in the environment and management of ICU patients to improve their circadian rhythmicity. Delirium, the most serious condition because it has a severe effect on prognosis and increases mortality, as well as sleep impairment and sepsis, all three of them linked to disorganization of the circadian system in critically ill patients, will be revised considering the functional organization of the circadian system, the main input and output signals that synchronize the clock, including a brief description of the molecular circadian clock machinery, the non-visual effects of light, and the ICU light environment. Finally, the potential usefulness of increased light/dark contrast and melatonin treatment in this context will be analyzed, including some practical countermeasures to minimize circadian disruption and improve circadian system chronoenhancement, helping to make these units optimal healing environments for patients.

The earth rotates on its axis around the sun, creating a day and night cycle, that caused the development of circadian rhythms. The circadian rhythm is primarily entrained by light, which is detected by the retina. Retinal ganglion cells project to a part of the hypothalamus termed suprachiasmatic nucleus. Here, we find the master molecular clock, composed of a transcription-translation-loop at its core. The master clock indirectly influences the innate immune system via different biological systems. Also, the master clock controls the peripheral clocks, which are present in innate immune cells. Here, circadian rhythm proteins influence the response of immune cells to pathogens. Furthermore, the master clock influences our sleep-pattern, the most important restorative physiological function. In critically ill patients the circadian rhythm is substantially altered, supporting a dysfunctional innate immune response. This review discusses recent basic science findings on the interaction of the circadian rhythm and the innate immune system. Furthermore we give an outlook on potential future therapeutic strategies.

The adaptation of species to the environment in which they live is accomplished by so-called “clocks” that allow the biological, physiological, metabolic and behavioral system to correct any development during the day. The alteration of those ‘clocks’ (circadian rhythms) shows a strong relationship with organic disorders such as neurodegenerative diseases. Many studies show that oxidative stress combined with pro-inflammatory mechanisms, play a key role in the development of neurodegenerative diseases and psychiatric disorders. Oxidative stress is fought by many antioxidant molecules. Melatonin, a hallmark of circadian rhythm functionality, is a natural antioxidant with a circadian secretion pattern. The mechanisms involved in the antioxidant properties of melatonin are complex but its depletion or lack unequivocally leads to cell damage. This process is also linked to the disruption of the circadian rhythm. A disrupted circadian rhythm followed by oxidative stress and inflammatory processes could be the pathophysiological basis for several disorders of the central nervous system. In the current review we will analyze those interactions. We will focus on the relationship between melatonin and its light/dark rhythms of secretion and how the antioxidant properties of melatonin opens a new therapeutic hope against central nervous system disorders.

With the current high rates of associated morbidity and mortality, proper management of critical illness is vital in the treatment of severely ill patients. Disruptions of key body systems stemming from these illnesses may be attributed to their severity and limited treatment options. Disruption in circadian rhythms caused by critical illnesses may lead to a decreased patient prognosis, as the biological clocks stemming from circadian rhythms play several key roles in regulating our internal pathways. This review will highlight how the occurrence of hyperoxic injury during the progression of critical illness may severely damage circadian rhymicity, and lead to an increased risk of infection, development of disease, severity of symptoms, morbidity and mortality, and dysregulation of multiple body systems. Overall, there is strong evidence suggesting that the disruption of circadian rhythms may be caused by critical illness. Studies performed on several animal models have shown alterations of key genes associated with circadian clock function may heavily contribute to the increased severity of critical illness linked to circadian disruption. This review will aid in further understanding the link between circadian disruption and critical illness.

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of partial (hypopnea) or complete interruption (apnea) in breathing during sleep due to airway collapse in the oral or pharyngeal region. Prospective studies have established the adverse cardiovascular consequences of OSA, including an increased risk for developing hypertension, coronary artery disease, stroke, and heart failure. However, more studies are needed to better assess the impact of OSA, and possible benefit of treatment with continuous positive airway pressure (CPAP) on cardiovascular mortality. The leading pathophysiological mechanisms involved in the changes triggered by OSA include intermittent hypoxemia and re-oxygenation, arousals and changes in intrathoracic pressure. Hypertension is strongly related with activation of the sympathetic nervous system, stimulation of the renin-angiotensin-aldosterone system and endothelial dysfunction. OSA should be suspected in hypertensive individuals, particularly in patients with resistant hypertension. CPAP treatment reduces blood pressure, and its effects are more pronounced in patients with high baseline blood pressure and elevated treatment compliance. At present, no clear evidence supports CPAP treatment for primary or secondary cardiovascular disease prevention.

The cardiovascular system exhibits significant daily rhythms in physiologic processes (heart rate, blood pressure, cardiac contractility and function), and molecular gene and protein expression. An increasing number of clinical and experimental studies demonstrate the circadian system is an important underlying mechanism that coordinates these rhythmic processes for the health of the cardiovascular system. However, what happens when rhythms are disturbed has been generally clinically unappreciated. Here we describe the profound adverse impact of disturbed circadian rhythms and sleep on the cardiovascular system, including recovery from myocardial infarction in acute care settings, shift work and heart disease, sleep disorders including obstructive sleep apnea, and cardiovascular pathophysiology associated with disturbed nocturnal blood pressure profiles. We also discuss therapeutic applications of circadian rhythms for the cardiovascular system. Cardiovascular disease is a leading cause of death worldwide, and applying circadian biology to cardiology (and indeed medicine in general) provides a new translational approach to benefit patients clinically.

There exist circadian patterns in the occurrence of sudden cardiac death. The suprachiasmatic nuclei is the ‘master clock’ in mammalian bodies. Furthermore, several circadian genes have been successfully isolated in basic studies and a huge variety of key players form the human circadian rhythm. Obvious circadian patterns are present in the occurrence of critical events, but those characteristics differ greatly according to each disease. In this review we summarized the current understanding of the basic mechanism and association with specific cardiovascular diseases that demonstrate a circadian onset of fatal events. We also summarized the recent deep understanding of sleep-disordered breathing. The close relationship between sleep-disordered breathing and cardiovascular diseases may provide us with the possibility of a novel intervention against sudden cardiac death.

Angiogenesis plays an important role in the treatment of acute myocardial infarction (MI). Formation of micro-vessels has the potential to prevent apoptosis of the ischemic myocardium and to improve cardiac function after MI. Delivery of growth factors or administration of stem/progenitor cells (mainly from bone marrow) are the dominant therapies to induce angiogenesis after MI. Nevertheless, clinical trials have shown that delivery of a single growth factor or single type of cell does not provide sufficient angiogenesis to promote cardiac repair. Circadian rhythms control many physiological and pathological processes in mammals. Many studies show a close relationship between circadian rhythms and MI. Disruption of the circadian rhythms in humans leads to increased incidence of MI. The onset and infarct area of MI are markedly elevated at certain time points. Determining the mechanisms of angiogenesis and vessel maturation in the ischemic heart under the control of circadian rhythms could help in the development of novel and angiogenesis- targeted therapeutics for the treatment of MI.

The phospholipid derivative lysophosphatidic acid (LPA) serves as a signalling molecule through the activation of LPA receptors, which belong to the G-protein-coupled receptors. From a pharmacological point of view, the (‘EDG-like’) LPA1-3 receptors have attracted much attention, therefore we have also been focusing in our study on these subtypes. The LPA1receptors are widely expressed in the human body; interestingly, LPA1 might have a role in the pathomechanism of obesity. In order to recognize key structural features of the molecular interactions of human LPA1with its agonists, we built up the 3D structure of the LPA1 through homology modeling. Next, LPA1 agonists and antagonists were docked into the model. The mode of binding and the interactions between ligands and key amino acids (R3.28 and Q3.29) were consistent with mutagenesis assays and previously published models, indicating that this model is able to discriminate high-affinity compounds and may be useful for the development of novel agonists of LPA1. Homology models were also constructed for LPA2 and LPA3. All available agonists with published EC50 values, antagonists with IC50 values and compounds with Ki values for either of LPA1, LPA2 or LPA3 were collected from the ChEMBL database and were docked into the corresponding model.Ourmodels for the LPA1-3 receptors can discriminate high-affinity compounds identified in silico HTS studies and may be useful for the development of novel agonistsof LPA receptors. With a better understanding of the differences between LPA1-3 receptors new, selective agonists and antagonist could be designed, which could be used in the therapy of various diseases with a better side-effect profile.

Vascular endothelial growth factor (VEGF) is one of the main endogenous pro-angiogenic cytokines. Inhibition of the VEGF signaling pathways is an effective treatment for cancer patients. In addition, local anti- VEGF therapy was developed and established to treat proliferative diabetic retinopathy, age-related macular degeneration and retinal vein occlusion. For systemic administration of anti-VEGF drugs, serious side effects including hypertension or renal disorders have been observed. Evidence suggests that systemic effects might occur or develop in long-term treatment, despite limited resorption and minimal local side effects. Here, only limited data from clinical studies are available. The VEGF system is delicately balanced, and changes might result in deleterious effects. This review provides a brief overview of the VEGF-system, and summarizes its relevance in proliferative eye diseases. The anti-VEGF drugs locally used to treat different disease conditions are discussed with their local and systemic side effects.

Background: Alcoholism affects bone repair and this study evaluated the recombinant human BMP-2 (rhBMP-2)/collagen sponge association aiming to improve the bone healing process. The aim of this study was to investigate the action of alcoholism and its effect on the repair of bone defects (BD) performed on rat calvaria after the application of rhBMP-2, either pure or combined with a collagen matrix, using radiographic, histological and immunohistochemical methods. Methods: We used 80 rats divided into two groups and these into 4 subgroups, each with a waiting period for sacrifice of four and six weeks after the BD (5mm). The groups were divided into: Veh-X) vehicle+BD, Veh-BMP) water+BD+5µg rhBMP-2, Veh-ACS) water+ BD+absorbable collagen sponge, Veh-BMP/ACS) water+BD+5µg rhBMP-2/absorbable collagen sponge, EtOH-X) ethanol+BD, EtOH-BMP) ethanol+BD+5µgrhBMP-2, EtOH-ACS) ethanol+BD+absorbable collagen sponge, and EtOH-BMP/ACS) ethanol+ BD+5µg of rhBMP-2/ absorbable collagen sponge. Results: Radiographically, it was found that after six weeks, for the groups treated with rhBMP-2, independent of the carrier use and ethanol administration, there was more new bone formation (p<0.05). For immunohistochemical analysis, osteocalcin and bone sialoprotein were found to be predominant in groups treated with rhBMP-2. For quantitative stereology, which aims to calculate the volume of new bone, higher values for the groups treated with rhBMP-2 pure or combined with the carrier were found; but for the groups treated with ethanol, a higher bone formation in the groups treated with rhBMP-2 associated with the carrier in the periods of four and six weeks (p<0.001) was found. Conclusion: It was concluded that the carrier was effective for rhBMP-2 delivery, even in the presence of ethanol.