Editorial
Chronotherapeutics: A Hype or future of chronopharmacology? Chronotherapeutics refers to treating a patient according to a person’s daily, monthly, seasonal, or yearly biological clock, in order to maximize the health benefits and minimize adverse effects.[1] A hypothetical cycle in physiological, emotional, or intellectual well-being is referred as biorhythm. These are self-sustaining oscillation of endogenous origin. Bio means life and rhythm is flow with regular movement. Biorhythms are reregulated by sunlight. There are different types of biorhythms namely, circadian, ultradian, infradian, circaseptan, circalunar, and circannual. A daily cycle or periodicity affects biochemical, physiological, or behavioral process of living being is known as circadian rhythm. It was coined by Franz Halberg from latin words ‘circa’ = about and ‘diem’ = day. Genetic function of human body programmed to function on roughly a daily cycle of 24 h. Circadian rhythm is important in determining sleep and feeding. Daily cycle can alter body temperature, neuronal activity, hormone synthesis, cell regeneration, and other biological activities. Circadian rhythms are maintained by endogenous pacemakers whose activity is modulated by environmental cues. The rhythms that have period shorter than 24 h are known as ultradian rhythm, for example eye blink, heartbeat, sleep pattern, every 4th hourly rhythm of awakening of babies for feeding. A rhythm of 7 days period is circaseptan rhythm, for example road traffic accidents peak at weekends. Synchronized rhythms to waxing and waning of moon that forms a lunar month are referred as circalunar rhythm. They last approximately 29.5 days, for example menstrual cycle. Chronopharmacology is the investigative science concerned with the effects of drugs upon the timing of biological events and rhythms. It also links effects of drugs on biological timing to get the dynamic activity. Chronopharmacokinetics is subdivision of chronopharmacology which deals with the study of the temporal changes in the pharmacokinetics of the drugs with respective time. It is clear that daily synchrony between day and night cycles and circadian rhythms is essential for the optimization of metabolism and energy utilization for sustaining of life processes. Biological processes, including the sleep-wake cycle controlled by pacemaker which is present in the suprachiasmatic nuclei (SCN) in mammals. Due to alterations in biological activities With respect to time, the pathophysiology of many diseases like allergic rhinitis, arthritis, asthma, cardiovascular diseases, peptic ulcer disease, Access this article online Website: www.ijp-online.com DOI: 10.4103/0253-7613.121265
Quick Response Code:
etc., results in exacerbation of symptoms.[2] Circadian rhythms, physiology, and behavior of mammalian bodies are controlled by clock genes namely Per1, Per2 and Per3, which are rhythmically expressed in the SCN.[3] The clock genes are present in peripheral tissue also. Recent experiment has revealed that there are many genes expressing a circadian rhythm in the liver.[4] The liver is a biological clock capable of creating its own circadian rhythms[5] and governs daily biochemical and physiological processes.[3] Many drugs are still given without regard to the time of day. To increase the therapeutic benefit and reduce the side effects of pharmaceuticals, monitoring of markers such as clock genes may be useful to choose the most appropriate time of day for administration of drugs. Food and Drug Administration (FDA ) has suggested additional parameters for chronotherapeutics clinical studies such as: 1. Drug administration time of the day. 2. Patient’s normal habits and sleep patterns. 3. Biological factors which are time-related, like seasonal disorders. The influence of circadian rhythms on pharmacological effects of drugs have become a big challenge for drug-discovery and drug-delivery scientists. Pharmaceutical industries have come up with various technologies such as time-controlled, pulsed, triggered, and programmed drug delivery devices in recent years for delivery of synchronized drug concentrations to rhythms in disease activity. Some of the diseases where chronotherapeutics is employed currently are cardiovascular diseases, bronchial asthma, peptic ulcer, cancer, chemotherapy, etc. A 40% increase in risk of myocardial infarction occurs between 6 am and noon. A 29% of increase in sudden cardiac death in early morning hours and 49% increase in stroke risk between 6 am and noon have been noted. Few examples of drug effect related to circadian rhythm are: faster reduction in BP with morning dose of enalapril, maximum vasodilatation occurs with morning dose of nitrates, 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor being more effective when administered in the evening with exception of atorvastatin. Bronchial asthma is a most common disorder with largest circadian variation. Several types of chronotherapy are tried like timed-release theophylline: 3 pm dose; therapeutic drug concentrations during the night and avoiding toxic levels during the day. Inhaled corticosteroids: single daily dose at 5:30 pm (vs 8 am) nearly as effective as four doses a day. Oral prednisone (3 pm) is much more effective in improving nocturnal asthma rather than 8 am and 8 pm dose barely better than placebo. In peptic ulcer patients, there will be a maximum acid secretion, ulcer pain, and exacerbation during night. Administration of H2 antagonists drugs at bedtime is more effective in reducing acid secretion and promoting ulcer healing. Indian Journal of Pharmacology | December 2013 | Vol 45 | Issue 6 545
Bairy: Chronotherapeutics
There is a clear circadian rhythm in cell cycle phase distribution in healthy or malignant mammalian tissues. Residual malignant lymphoblasts are more susceptible to antimetabolites in evening than in morning. Similarly circadiantimed maintenance therapy is currently a consensus treatment for childhood acute lymphoblastic leukemia. Identification of rhythmic markers for selecting dosing time and further research in the field of chronopharmaceuticals will lead to improved progress and diffusion of chronotherapeutics. This area offers a further dimension for research for safer and efficient disease therapy in future. Laxminarayana K. Bairy Department of Pharmacology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India E-mail: [email protected]
References 1. Erkekoglu P, Baydar T. Chronopharmacokinetics of drugs in toxicological aspects: A short review for pharmacy practitioners. J Res Pharm Pract 2012;1:3-9. 2. Satwara RS, Patel PK, Shaikh F. Chronotherapeutical approach: Circadian rhythm in human and its role in occurrence and severity of diseases. Int J PharmTech Res 2012;4:765-77. 3. Ohdo S. Chronopharmacology focused on biological clock. Drug Metab Pharmacokinet 2007;22:3-14. 4. Desai VG, Moland CL, Branham WS, Delongchamp RR, Fang H, Duffy PH, et al. Changes in expression level of genes as a function of time of day in the liver of rats. Mutat Res 2004;549:115-29. 5. Turek FW, Allanda R. Liver has rhythm. Hepatology 2002;35:743-45.
Cite this article as: Bairy LK. Chronotherapeutics: A hype or future of chronopharmacology?. Indian J Pharmacol 2013;45:545-6.
Source of Support: Nil. Conflict of Interest: None declared.
Indian Pharmacological Society
(Registered under the Societies Registration Act XXI of Patna. R.No.03/17.04.1968) www.indianpharmacology.org
Executive Committee-2013 President Vice President General Secretary Finance Secretary Chief Editor Secretary (Clinical) Secretary (International) Executive Committee Members
Organizing Secretary Immediate Past President General Secretary Past 546 Indian Journal of Pharmacology | December 2013 | Vol 45 | Issue 6
Dr. Prakash V. Diwan Dr. Kumari Indu Singh Dr. Anil Balapure Dr. Tapan Kumar Mandal Dr. B. Kalakumar Ph.D., Dr. Chetna Desai Dr. Bikash Medhi Dr. Gautam Palit Dr. Balaram Ghosh, Kolkata (East) Dr. M. Umekar Prof. D.C.Roy Dr. R. K. Goel Dr. Trupti Rekha Swian Dr. Reginald Paul Sequeira Baherin - EC overseas Dr. Raju Koneri Prof. S. K. Bandopadhyaya Dr. B. Dinesh Kumar
Copyright of Indian Journal of Pharmacology is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Chronotherapeutics: A Hype or future of chronopharmacology? Chronotherapeutics refers to treating a patient according to a person’s daily, monthly, seasonal, or yearly biological clock, in order to maximize the health benefits and minimize adverse effects.[1] A hypothetical cycle in physiological, emotional, or intellectual well-being is referred as biorhythm. These are self-sustaining oscillation of endogenous origin. Bio means life and rhythm is flow with regular movement. Biorhythms are reregulated by sunlight. There are different types of biorhythms namely, circadian, ultradian, infradian, circaseptan, circalunar, and circannual. A daily cycle or periodicity affects biochemical, physiological, or behavioral process of living being is known as circadian rhythm. It was coined by Franz Halberg from latin words ‘circa’ = about and ‘diem’ = day. Genetic function of human body programmed to function on roughly a daily cycle of 24 h. Circadian rhythm is important in determining sleep and feeding. Daily cycle can alter body temperature, neuronal activity, hormone synthesis, cell regeneration, and other biological activities. Circadian rhythms are maintained by endogenous pacemakers whose activity is modulated by environmental cues. The rhythms that have period shorter than 24 h are known as ultradian rhythm, for example eye blink, heartbeat, sleep pattern, every 4th hourly rhythm of awakening of babies for feeding. A rhythm of 7 days period is circaseptan rhythm, for example road traffic accidents peak at weekends. Synchronized rhythms to waxing and waning of moon that forms a lunar month are referred as circalunar rhythm. They last approximately 29.5 days, for example menstrual cycle. Chronopharmacology is the investigative science concerned with the effects of drugs upon the timing of biological events and rhythms. It also links effects of drugs on biological timing to get the dynamic activity. Chronopharmacokinetics is subdivision of chronopharmacology which deals with the study of the temporal changes in the pharmacokinetics of the drugs with respective time. It is clear that daily synchrony between day and night cycles and circadian rhythms is essential for the optimization of metabolism and energy utilization for sustaining of life processes. Biological processes, including the sleep-wake cycle controlled by pacemaker which is present in the suprachiasmatic nuclei (SCN) in mammals. Due to alterations in biological activities With respect to time, the pathophysiology of many diseases like allergic rhinitis, arthritis, asthma, cardiovascular diseases, peptic ulcer disease, Access this article online Website: www.ijp-online.com DOI: 10.4103/0253-7613.121265
Quick Response Code:
etc., results in exacerbation of symptoms.[2] Circadian rhythms, physiology, and behavior of mammalian bodies are controlled by clock genes namely Per1, Per2 and Per3, which are rhythmically expressed in the SCN.[3] The clock genes are present in peripheral tissue also. Recent experiment has revealed that there are many genes expressing a circadian rhythm in the liver.[4] The liver is a biological clock capable of creating its own circadian rhythms[5] and governs daily biochemical and physiological processes.[3] Many drugs are still given without regard to the time of day. To increase the therapeutic benefit and reduce the side effects of pharmaceuticals, monitoring of markers such as clock genes may be useful to choose the most appropriate time of day for administration of drugs. Food and Drug Administration (FDA ) has suggested additional parameters for chronotherapeutics clinical studies such as: 1. Drug administration time of the day. 2. Patient’s normal habits and sleep patterns. 3. Biological factors which are time-related, like seasonal disorders. The influence of circadian rhythms on pharmacological effects of drugs have become a big challenge for drug-discovery and drug-delivery scientists. Pharmaceutical industries have come up with various technologies such as time-controlled, pulsed, triggered, and programmed drug delivery devices in recent years for delivery of synchronized drug concentrations to rhythms in disease activity. Some of the diseases where chronotherapeutics is employed currently are cardiovascular diseases, bronchial asthma, peptic ulcer, cancer, chemotherapy, etc. A 40% increase in risk of myocardial infarction occurs between 6 am and noon. A 29% of increase in sudden cardiac death in early morning hours and 49% increase in stroke risk between 6 am and noon have been noted. Few examples of drug effect related to circadian rhythm are: faster reduction in BP with morning dose of enalapril, maximum vasodilatation occurs with morning dose of nitrates, 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) reductase inhibitor being more effective when administered in the evening with exception of atorvastatin. Bronchial asthma is a most common disorder with largest circadian variation. Several types of chronotherapy are tried like timed-release theophylline: 3 pm dose; therapeutic drug concentrations during the night and avoiding toxic levels during the day. Inhaled corticosteroids: single daily dose at 5:30 pm (vs 8 am) nearly as effective as four doses a day. Oral prednisone (3 pm) is much more effective in improving nocturnal asthma rather than 8 am and 8 pm dose barely better than placebo. In peptic ulcer patients, there will be a maximum acid secretion, ulcer pain, and exacerbation during night. Administration of H2 antagonists drugs at bedtime is more effective in reducing acid secretion and promoting ulcer healing. Indian Journal of Pharmacology | December 2013 | Vol 45 | Issue 6 545
Bairy: Chronotherapeutics
There is a clear circadian rhythm in cell cycle phase distribution in healthy or malignant mammalian tissues. Residual malignant lymphoblasts are more susceptible to antimetabolites in evening than in morning. Similarly circadiantimed maintenance therapy is currently a consensus treatment for childhood acute lymphoblastic leukemia. Identification of rhythmic markers for selecting dosing time and further research in the field of chronopharmaceuticals will lead to improved progress and diffusion of chronotherapeutics. This area offers a further dimension for research for safer and efficient disease therapy in future. Laxminarayana K. Bairy Department of Pharmacology, Kasturba Medical College, Manipal University, Manipal, Karnataka, India E-mail: [email protected]
References 1. Erkekoglu P, Baydar T. Chronopharmacokinetics of drugs in toxicological aspects: A short review for pharmacy practitioners. J Res Pharm Pract 2012;1:3-9. 2. Satwara RS, Patel PK, Shaikh F. Chronotherapeutical approach: Circadian rhythm in human and its role in occurrence and severity of diseases. Int J PharmTech Res 2012;4:765-77. 3. Ohdo S. Chronopharmacology focused on biological clock. Drug Metab Pharmacokinet 2007;22:3-14. 4. Desai VG, Moland CL, Branham WS, Delongchamp RR, Fang H, Duffy PH, et al. Changes in expression level of genes as a function of time of day in the liver of rats. Mutat Res 2004;549:115-29. 5. Turek FW, Allanda R. Liver has rhythm. Hepatology 2002;35:743-45.
Cite this article as: Bairy LK. Chronotherapeutics: A hype or future of chronopharmacology?. Indian J Pharmacol 2013;45:545-6.
Source of Support: Nil. Conflict of Interest: None declared.
Indian Pharmacological Society
(Registered under the Societies Registration Act XXI of Patna. R.No.03/17.04.1968) www.indianpharmacology.org
Executive Committee-2013 President Vice President General Secretary Finance Secretary Chief Editor Secretary (Clinical) Secretary (International) Executive Committee Members
Organizing Secretary Immediate Past President General Secretary Past 546 Indian Journal of Pharmacology | December 2013 | Vol 45 | Issue 6
Dr. Prakash V. Diwan Dr. Kumari Indu Singh Dr. Anil Balapure Dr. Tapan Kumar Mandal Dr. B. Kalakumar Ph.D., Dr. Chetna Desai Dr. Bikash Medhi Dr. Gautam Palit Dr. Balaram Ghosh, Kolkata (East) Dr. M. Umekar Prof. D.C.Roy Dr. R. K. Goel Dr. Trupti Rekha Swian Dr. Reginald Paul Sequeira Baherin - EC overseas Dr. Raju Koneri Prof. S. K. Bandopadhyaya Dr. B. Dinesh Kumar
Copyright of Indian Journal of Pharmacology is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
