Chronotherapeutics in Ayurveda

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REVIEW ARTICLE Mar-Apr 2021 Journal of Ayurveda and Integrated Medical Sciences | Mar - Apr 2021 | Vol. 6 | Issue 2 105 Chronotherapeutics in Ayurveda Dr. Anishma AS 1 , Dr. Harita Chandran 2 , Dr. Leena P. Nair 3 , Dr. C. Usha Kumari 4 , Dr. Haroon Irshad 5 1 Post Graduate Scholar, 2 Assistant Professor, 3,5 Associate Professor, 4 Professor & HOD, Department of Moulika Siddhanta (Basic principles of Ayurveda), Amrita School of Ayurveda, Amrita Vishwa Vidyapeetham, Amritapuri, INDIA. I NTRODUCTION Biological rhythms are sequences of events that are repeated over time in the same manner and with the same interval such as circadian, ultradian, infradian, circannual regulates many body functions in humans. Many diseases like hypertension, asthma, peptic ulcer, cancer follow these rhythms. Blood pressure and heart rate are highest during the hours of 6 am- 12 pm. Human synchronizers can be knowledge of the time of day, light-dark cycle, sleep-wake cycle, time of Address for correspondence: Dr. Haroon Irshad Associate Professor, Department of Moulika Siddhanta (Basic Principles of Ayurveda), Amrita School of Ayurveda, Amrita Vishwa Vidyapeetham, Amritapuri, INDIA. E-mail: haroon 84 irshad@gmail.com Submission Date: 09/03/2021 Accepted Date: 14/04/2021 Access this article online Quick Response Code Website: www.jaims.in Published by Maharshi Charaka Ayurveda Organization, Vijayapur, Karnataka (Regd) under the license CCby-NC-SA eating. Use of these rhythmic cycles for the application of therapy is chronotherapy, the science of time related medication. It is administered to maximize the desired effects and to minimize the undesired effects of a treatment. Chronotherapy can be classified in to time controlled systems where in the drug release is controlled primarily by the delivery system, stimuli induced pulsative drug delivery system in which release is controlled by the stimuli, such as P H or enzymes present in the intestinal tract [1] The safety and efficacy of the drug is achieved by coordinating the peak plasma concentration of the drug with circadian rhythm of the body [2] Some of the examples for circadian time-dependent changes in the pharmacokinetics of medications are the cardiovascular active drugs such as beta-blockers, calcium channel blockers, ACE-inhibitors, organic nitrates etc , anti-asthmatics drugs like theophyline, beta agonists, leukotriene antagonists, glucocorticoids etc, anticancer agents such as 5-FU, methotrexate, 6- mercaptopurine, platinum analogues etc, NSAIDs, local anaesthetics, H 1 and H 2-histamine antagonists, A B S T R A C T In order to maximize health benefits and minimize adverse effects of a treatment, chronotherapeutics is administered to patients according to his/her daily, monthly, seasonal or yearly biological clock. According to Ayurveda observation of the specific features of disease corresponding to season, day and night, age and meal is known as Kaala Aveksha. The Dasha Bheshaja Kaala (ten different time period for the administration of medicine) is one among the Shadaveksha Kaala (Six observatory aspects of time). It is defined according to the biological clock. The medicines at proper Bheshaja Kaala help to attain the equilibrium of Doshas and Dhatus . Here chronotherapeutics can be correlated with Bheshaja Kaala. As it gives importance to the time of administration which can be responsible for variations of drug kinetics. Objective: To conduct an in-depth analysis of the literature in order to identify and evaluate the evidence base for chronotherapy. Data source: A literature search was conducted in classics of Ayurveda and electronic databases. Result: Review shows that the drug administered according to the Bheshaja kaala has more beneficial outcomes than the other methods. Conclusion: The review presents the scope of chronotherapy in drug administration. Key words: Aushadhakaala, Bhaishajya Kaala, Bheshaja Kala, chronobiology, chronotherapy.

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Dr. Anishma AS et al. Chronotherapeutics in Ayurveda ISSN: 2456-3110 REVIEW ARTICLE Mar-Apr 2021 Journal of Ayurveda and Integrated Medical Sciences | Mar - Apr 2021 | Vol. 6 | Issue 2 106 protein pump inhibitors, antidepressants and such other central nervous system acting drugs [3] Ancient scholars of Ayurveda have documented environmental influence on human physiology as the functioning of Tridosha (3 humours) as which are responsible for the normal functioning of the body. The physiological variation of Tridosha depends on the factors like Vaya (age), Ahas (day), Ratri (night), Bhukta (intake of food) [4] which all are related to time. The pathological vitiation of the Dosha leads to disease and its intensity will be more during the physiological dominant time of each Dosha . So, the administration of the medicine at the dominant phase will leads to the pacification more effectively. Observation of the specific features of disease corresponding to season, day and night, age and meal is known as Kaala Aveksha. [5] The concept of Bheshaja Kaala mentioned by Ayurvedic scholars is one among the Shad Aveksha Kaala (Six observatory aspects of time) like 1) Dina (day) 2) Rogi (patient) 3) Aushadha (medicine) 4) Vyadhi (disease) 5) Jeerna Lakshana and 6) Rutu (seasons) [6] The administration of Bheshaja (medicine) is mainly related to the day, afternoon, evening and night time with relation to timing of food. Because the rhythm of Tridosha varies according to this time as Vatika disorders aggravate at the end of day, end of night and after digestion. Pittaja disorders in the middle of the day, middle of night, and during digestion and Kaphaja disorders in the beginning of the day, beginning of the night, and just after meals [7- 8] Similarly the rate of metabolism of drug with the help of Agni (digestive fire) is also affected by the factors like food, type of drug, time of drug administration. Agni (digestive fire) present in the Jathara (stomach) which digests the food and drug is served by Prana, Apana and Samana Vata by blowing/increasing, protecting and preserving. Hence success of treatment depends on proper administration of drugs which includes appropriate dosage and timing [9] M ATERIALS AND M ETHODS The review data was collected from Ayurvedic classics like Charaka Samhita, Sushruta Samhita, Ashtanga Sangraha, Kashyapa Samhita, Sharangadhara Samhita, and the electronic databases like Google scholar, pub med, Scopus and Google for relevant studies. Search revealed total 5243 articles of which 83 articles were selected. Among 83 articles, references from abstracts and full-text articles which are freely downloadable and relevant for this were only included. R EVIEW OF L ITERATURE According to Ayurveda, Chikitsa Kaala (treatment time) depends up on 1) Dina (day) 2) Rogi (patient) 3) Aushadha (medicine) 4) Vyadhi (disease) 5) Jeerna Lakshana and 6) Rutu (seasons) together called as Shad Aveksha Kaala . Dina (different parts of the day): It indicates particular part of the day, for example, Vamana Dravya (emetics) is to be given in the early morning, that is Purvahna (morning) [10] Rogi (patient): After assessing the strength of the patient, time of administration for medicine should be selected. If a patient has good strength, then medicine can be given in empty stomach early in the morning and if the patient is weak, medicine should be administered after Laghu Bhojana (light food) [11] Vyadhi (disease): Based on the Vyadhi (disease) also Kaala is classified. For example: In Jwara (fever) - every 6 th day the medicine has to be changed like Peya (liquids), Kasaya (decoctions), Kshira (milk preparation) , Sarpi (ghee preparation) and Virechana (purgation) respectively depending on the condition [12] Jeernalinga (stage of the digestion of the food): The Jeerna Lakshanas (digested signs) like proper appetite, timely discharge of urges (flatus, faeces, urine etc.), lightness of the body and feeling of purity of eructation should be assessed before administering the medicine. If the Bheshaja (medicine) is administered in Amavastha (undigested stage) and Jiryamana Avastha (during digestion) it produces the aggravation of symptoms. Ritu (nature of the season): Based on the Ritu, Kaala should be assessed by Chaya (increase of Dosha on site), Prakopa (excessive increase of Dosha ) Lakshanas

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Dr. Anishma AS et al. Chronotherapeutics in Ayurveda ISSN: 2456-3110 REVIEW ARTICLE Mar-Apr 2021 Journal of Ayurveda and Integrated Medical Sciences | Mar - Apr 2021 | Vol. 6 | Issue 2 107 told for each Dosha and administer medicine accordingly [13] Aushadha (medicine): Based on the type of medicine, Kaala have been told. The time of administration and the type of medicine must be decided as per the condition and diseased status of the patient. Appropriate timing of drug administration in relation to Kaala Aveksha is a complex process . But the administration of the medicine at the dominant phase of Dosha will leads to the pacification more effectively. Classical references of some diseases that shows the rhythmicity described in table 1. Table 1: Examples for disease which shows rhythmicity Diseases Rhythmicity Vataja Shopha (inflammatory edema due to Vata Dosha ) [14] Aggravates during day time Kaphaja Shopha (inflammatory edema due to Kapha Dosha ) [15] Aggravates at night Sangraha Grahani (colitis) [16] Aggravates during day and relieves at night. Vataja Shiroroga (headache due to Vata Dosha). [17] Intensity of head ache maximum at night Pittaja Shiroroga (headache due to Pitta Dosha [18] Intensity of headache is alleviated at night Sooryavarta (headache at supra orbital region) [19] Headache starts with the sunrise, its intensity gradually increases with and maximum in mid noon, then its intensity diminishes gradually. According to Ashtanga Sangraha the time of administration of medicine are 11 in number. In Samhitas like Charaka, Susrutha, Ashtanga Hrudaya and Kashyapa 10 types of Bheshajakaala are explained. Sarangadhara included this under five Bheshaja Kaala . Types of Bheshaja Kaala are described in table 2. Table 2: Bheshaja Kaala according to different Acharyas SN Charaka Samhita [20] Susruta Samhita [21] Ashtanga Sangraha [22] Kasyapa Samhita [23] Sharangadara Samhita [24] 1 Niranna Abhakta Abhaktam Poorvebhaktasya Prabhate 2. Bhuktadau Pragbhaktm Pragbhaktam Madyebhaktam Divasabhojane 3. Bhuktamadye Madyebhaktm Madyebhaktam Adhobhaktam Saayantanebhojane 4. Praatabhakta Adhobhaktam Adhobhaktam Saamudgam Muhurmuhu 5. Paschat Muhurmuhu Sabhaktam Muhurmuhu Nisi 6. Sayambhaktapaschat Samudgam Antarabhaktam Sabhaktam - 7. Muhurmuhu Sabhaktam Samudgam Bhaktayormadyam - 8. Samudgam Grasantaram Muhurmuhu Graasa - 9. Bhakta Samyuktam Antarabhaktam Sagrasam Grasaantara - 10. Grase Grase Grasantare Abhakta -

[Find the meaning and references behind the names: Ways, Leha, Mild, Indu, Tender, Thin, Cure, Loss, Prior, Diet, Person, Fixed, Kampa, Gone, Take, Kasa, Case, Lower, Antara, Half, Property]

Dr. Anishma AS et al. Chronotherapeutics in Ayurveda ISSN: 2456-3110 REVIEW ARTICLE Mar-Apr 2021 Journal of Ayurveda and Integrated Medical Sciences | Mar - Apr 2021 | Vol. 6 | Issue 2 108 11. Grasantaram - Nisi - - Aushadha Sevana Kaala explained by different Acharyas can be incorporated as per Ashtanga Sangrahakara Abhakta (Without giving any food) - In persons who are strong, drugs should be given in the morning after the increased Kapha has moved out of the Koshta . In case of others, it should be before food (of the morning or breakfast) as the person will not suffer from fatigue by the support of food This is very potent; it eradicates all the disease immediately as the strong person defeats the weak, [25] however if it is used by children, aged, women and weak person it causes languor and loss of strength [26] Pratah Niranna Kaala is specified by Charaka. Chakrapani considered it as Bhuktadau Kaala . Pragbhakta (Just prior to the meal) - Hemadri states that in this Kaala the Bheshaja intake is immediately followed by food. It is useful in the treatment of disease caused by Apana Vata , in diseases of the lower extremities, for strengthening the body and for making the body thin. The medicine used before food does not cause loss of strength, it destroys the Doshas located in stomach, it gets digested immediately due to being fixed in the body by food. The emesis, eructation like troubles do not develop. So, it can be used in weak persons [27] Madhyabhakta (In the middle of the meal) - It is useful in diseases caused by Samaana Vata , in diseases of the Koshta and diseases of Pitta origin. Chakrapani and Indu states that half of the food is taken first then followed by the intake of Aushadha then the remaining half of food. The medicine taken in middle of meals getting obstructed in both the ways by diet extracts the Doshas situated in internal organs very easily [28] It is desired in mild diseases [29] Adhobhakta (After the meal drug is taken) - Hemadri and Indu states that Bheshaja is to be administered immediately after meals. In diseases due to Vyanavata , it should be after the morning meal and in diseases due to Udanavata it should be after the evening meal. This method is useful for strengthening the upper part of the body, cure of their diseases and for diseases caused by Kapha, to cause stoutness of the body. Sabhakta (Mixing the drug with the food during preparation, after preparation or eating immediately after the drug administration) - This type of Kaala indicated for children, persons who are of tender constitution, those who hate medicines, in loss of appetite and diseases affecting the whole body. Antara bhakta (intake medicine in midday after the digestion of the forenoon meal. Then meal can take at the evening after the digestion of medicine). It is for those who have strong digestion and in disorders caused by Vyanavata. Samudga (Intake of medicine twice, once just before meals and once again immediately after meals). Drug should be having digestive property and be in the form of Leha (confection), Choorna (powder) are taken in this Kaala. It is advised in Hidma (hiccup), Kampa (tremors), Aakshepa (convulsions), and when the Dosas are localized at both upper and lower parts of the body. Antara Bhaktam Kaala is also same as Samudga It is advised to take the medicine in event of Doshas having gone upward and downward, in opposite way (before and after meals) [30] Muhurmuhu (Use frequently with or without food) - In Swasa (dyspnoea), Kasa (cough), Hidma (hiccup), Trut (thirst), Chardi (vomiting), and in Vishavikara (diseases caused by poisons). Sagrasa (Only once with morsel of food). In this Kaala drugs should be in the form of Choorna (powder), Leha (confection), Vataka (granules) and having the Agni-deepana (digestive fire stimulating) property. It is advised in Prana Vata disorders, and Vajeekarana (aphrodisiacs) medicines are used as Sagrasa. Grasantara (After every morsel)- In Prana Vata disorders. Drugs which cure diseases like Hrudroga ( disease related to heart ) , Drugs to produce vomiting,

[Find the meaning and references behind the names: Bala, Netra, Ideal, Less, Stones, Asmari, Act, Asa, Gata, Deepika, Bed, Nishi, Madhu, Jala, State, Target, Chi, Pana]

Dr. Anishma AS et al. Chronotherapeutics in Ayurveda ISSN: 2456-3110 REVIEW ARTICLE Mar-Apr 2021 Journal of Ayurveda and Integrated Medical Sciences | Mar - Apr 2021 | Vol. 6 | Issue 2 109 Dhoomapanadravyas (smoking drugs) are advised to take in this Kaala . Nisi (Bed time) - In Jatrurdharogas (diseases above the shoulder). This time is ideal for Lekhana (curetting), Brumhana (strengthening and nourishing), Pachana (digestive action) and Shamana (palliative action) purpose [31] Medicines should be given on empty stomach at night. In Deepika commentary it is mentioned that the timing of administration of medicine is 1 Yaama (3 hr) after evening meals. References from classics for the intake of medicine according to Bheshaja Kaala are listed in Table number 3. Table: 3 References from classics for Bheshaja Kaala Adhikarana Yogam Reference Prameha-Pratah Niranna Haridra+Madhu+Amalakiswar asa A.S.Ci 14/5 Vishamajwara- Pragbhakta Kalyanaka Ghrita,Shatpalaghrita A.H.Ci 1/154 Grahani-Madhya Bakta Yavagu+Ghrita A.H.Ci 10/75 Rajayakshma- Adhobakta Rasnaghritam Ch.Ci 8/94 Gulmam- Sagrasa Ashtachoornam+Ghrita A.H.Chi 14/3 5 Udara- Muhurmuhu Ghrita Prayogam A.H.Ci 15/36 Arshorogaadhikar a-Samudga Praanada Gutika B.R/58-59 Netra Balyam- Nishi Triphala+Madhu+Sarpi A.S.Su 10 Likewise, the Triphala Modaka is given before the meal in between the meal and after the meal in diseases of lower extremities, abdomen and head & neck respectively [32] This also shows the endogenous effect of circadian rhythm. Moreover, it has been also described that the diseases occurring due to effect of time should be treated even before the onset of symptoms of diseases. Not only the drugs but the food articles given at different times also have different effect like: intake of milk at morning is Balya (strengthening), Brimhana (nourishing) and Agni vardaka (appetizing). If it is in noon, it enhances Bala (strength), cures Mootrakrucha (dysuria) and Asmari (stones). The same taken at night become pacifier for many disorders [33] Similarly sugarcane if taken before meal alleviates Pitta while taken after meal aggravates Pitta and in between meals delays its digestion [34] Effect of Jala Pana (water intake) with respect the Annakala (food intake time) also shows difference like Jala at Bhukthadau Kaala (before meals) it causes weakness of the digestion and emaciation of the body. In Bhukthamadhya Kaala (in between meals) it maintains the normalcy of the tissues and helps for easy digestion. And at the end of the meals, it cause obesity and accumulation of Kapha in the parts above the stomach [35] DISCUSSION For the proper metabolism of Aushadha and Ahara proper Agni should be there. Drug metabolism is one among the pharmacokinetics processes. As per Ayurveda in Abhakta Kaala Agni and Aushadha interaction is unobstructed because of absence of food and Agni will be in Pradeeptha Avastha. Hemadri clarifies that medicine should be administered in the Kapha Udreka Gata Kaala [36] In Kapha Kaala, Agni (digestive fire) will be in Mandavastha (less powerful state). Kapha Kaala is one ‑ third part of the day, and later half of this one ‑ third part is Kapha Udreka Gata Kaala. As per Indu Bheshaja should be given 3 hours after sunrise in Abhakta kaala [37] This shows the importance of time for the administration of drug. Praagbhakta is administration of the drug just prior to the meal. Thus, it is the first target of Agni and not the food. In this Kaala the Bheshaja digests immediately. This Kaala is advised mainly for Apana Vata vitiation. So, in case of Mootravaha, Malavaha, Shukravaha Srotovikara, Arsas (hemorrhoids), Gudabramsha (rectal prolapse) this type of Kaala can be adopted. Madhyabhakta is administration of the drug in the middle of the meal. So, the medicine can’t spread and is forced to act locally and eradicate the Sthanika

[Find the meaning and references behind the names: Par, Level, Faster, Kara, Anna, Round, Dose, Adha, Gati, Main, Steady, Rest, Sun, Rasa, Moon, Reason, Factor]

Dr. Anishma AS et al. Chronotherapeutics in Ayurveda ISSN: 2456-3110 REVIEW ARTICLE Mar-Apr 2021 Journal of Ayurveda and Integrated Medical Sciences | Mar - Apr 2021 | Vol. 6 | Issue 2 110 Doshas . As Samana Vayu and Pachaka Pitta are in Koshta this type of Kaala helps to control the Paithika and Koshtagata Vyadis . Adhobhakta is use of the drug after the meal. In Vyana Vikruti the drug administered after the lunch and in Udana Vikruti after dinner can stimulate these Vata and can corrects its dysfunctions. By the action of Udanavayu , the Urdhvagati of Bheshaja becomes easier, there by strengthening the upper parts of body. In this prolonged effect of Agni, Bheshaja interaction is expected. pH of the stomach is one dependent factor for the action of Bheshaja . It might be one of the reasons behind before and after administration of food. According to Indu Sabhakta is partaking food prepared by mixing the drug like some Yavagu (porridge) preparations or mixing the drug to the prepared food and eating immediately. The expected activity of Bheshaja in this type is to potentiate the Agnibala and the drug mixes with Rasa Dhatu and spread all over the body through Urdhva, Adha and Tiryakgati . So, this type of Kaala can be used in Sarvanga samsrita vyadhis . In this type of Kaala and in Grasa Kaala maximum availability of the rasa of the Bheshaja is expected. According to Ayurveda mainly two Annakala is described [38] So in Antarabhakta Kaala (in between food), after the digestion of morning meal the drug is administered in midday so in this Madyahna (midday) the Agni (digestive fire) is in stimulated condition and after the drug metabolism again food is taken in evening. This type can be given in the night also. In this type of Kaala, Agni (digestive fire) and Bheshaja interaction occurs. It is mainly used in Vyana Vatajanya Vikaras . Vitiation of Vyana Vata hampers its functions as well as nutrition and movements of the body. It can circulate the whole body. The main site of Vyana is Hridaya (heart). Ayurveda explains the functions of Hridaya (heart) in relation to sun-moon cycle. Samudga provides the localized action of the Bheshaja on Anna . The medicines which having the Utklesha Kara property, which cause Glani (languor) like Vikaras should not be used in this Kaala . It promotes Urdhva (upward) and Adhogati (downward movement) of the drug and helps in correcting Gati Vikruti (disturbance in normal movement) of Vata Dosha by promoting Anulomana (downward movement) of Vata dosha , eg: in Hikka (hiccup) both Vata and Kapha dosha are involved [39] The Sthana (site) of Kapha is Urdhwashareera (upper part of body) and of Vata is Adhashareera (lower part of the body). Bheshaja (medicine) administered in this Kaala can pacify both the Doshas in both parts of the body. Muhurmuhu is the use of medicine, frequently with or without food. In this type prolonged effect of Agni-Bheshaja interaction is expected and treats the vitiated Doshas in their Sanchaya and Vegavastha and the blood level concentration of medicines is to be maintained at par round the clock. This is adopted in conditions where Pranavaha Srotodushti, Udakavaha Srotodushti, Annavaha Srotodushti Vikaras occurs. In repeated administration, accumulation of drug occurs when it is administered before the previous dose is completely eliminated. Then the amount of drug in the body progressively increases. When the rate of drug elimination compensates the rate of drug administration, the average drug concentration reaches steady state. Sagrasa is taking medicine only once with morsel of food so that it facilitates absorption of drug from buccal mucosa. Grasaantara is taking it after every morsel and having the property of kindling digestion. According to Arunadatta and Hemadri in this Kaala, Bheshaja is mixed with every morsel of food. So, the concentration of medicine will be more and causes the faster actions in this Kaala . Both this Kaala used in Prana Vayu Vikaras . Normally Prana Vayu regulates the intake of food, [40] so medicine with Grasa can stimulate the Prana Vayu thereby it can cure the Prana Vayu vitiated diseases. The factors which influence drug administration in relation to food, including pharmacokinetics, efficacy and, improving patient tolerance by minimizing gastrointestinal upset [41] Nisi Kaala provides prolonged time activity of the drug as in Nisi Kaala all the metabolic activities are slowed down compared to the day. One of the factors for drug administration depends on the state of the CNS. That might be the reason behind the medicines at night for disease above the shoulders, when CNS is relatively at rest. The time of drug administration depend up on so many factors. These include the cyclic variation of Doshas and the rate of metabolism of drugs depends

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Dr. Anishma AS et al. Chronotherapeutics in Ayurveda ISSN: 2456-3110 REVIEW ARTICLE Mar-Apr 2021 Journal of Ayurveda and Integrated Medical Sciences | Mar - Apr 2021 | Vol. 6 | Issue 2 111 on Agni Bala of the patient and presence or absence of food. Mahaveerya Bheshaja (medicines having strong potency) possess a strong energy level of action and it can stimulate the Agni at bits gross levels. This indicates the pharmacodynamic action of the Bheshaja . While discussing about the Bheshajakaala , Vatadosha is taken in to account. Etymological derivation of the term Vata is Gati, Gandhana [42] means to initiate, to excite and to stimulate. Vata Dosha controls all functions of body. Agni present in the Jathara which digests the food is served by Prana, Apana and Samana by blowing/increasing, protecting and preserving it helps other Agni to carry on their respective functions properly and which is controlled by the appropriate Aushadha Kaala. One can apply Aushadha Kaala to Pitta and Kapha according to Sthana Samanya of Dosas as which is described in table 4. Table 4: Sthana Sadharmya of Doshas Vata Prakara Sthana Sadharmya Prana Vata Avalambaka Kapha Udana Vata Avalambaka Kapha Vyana Vata Sadhaka Pitta Samana Vata Pachaka Pitta Ranchaka Pitta Kledaka Kapha Apana Vata - CONCLUSION The treatment of the curable disease is done after ascertaining the diseases on the basis of clinical features of Doshas by prescribing the therapies contrary to etiological factors and also giving due consideration to Matra (dose) and Kaala (time of administration) [43] The success of Chikitsa depends upon proper planning for use of drugs about their quantity and Kaala of administration. Hence, knower of proper planning of administration stands at a higher place than knower of drug [44] Evaluation of Shadaveksha Kaala plays an important role in deciding Bhaishajya . The ultimate goal of attaining the Dosha, Dhatu Samyata can very well be done by suggesting a proper Aushadha Sevana Kaala . Vata Dosha is given prime importance in the context of Aushadha Sevana Kaala and there is much importance for Agnibala of the patient also. It is meant for Shamana Chikitsa only. The effectiveness of many drugs in many diseases varies depending on the time of administration in associated with 24 hours biological rhythm under the control of circadian clock. Aushadha Sevana Kaala is a further dimension for research aiming that safer and efficient disease therapy in future. Treatment done earlier to the proper time or treatment not done at the proper time and treatment being either inadequate or in excess, these do not succeed even in curable diseases. REFERENCES 1 Manpreet Kaur and Rajni Bala, Chronotherapy: A Review, 1 Jauary 2013, http://dx.doi.org/10.13040/IJPSR.09758232. 4(1).90-02. 2 Manpreet Kaur and Rajni Bala, Chronotherapy: A Review, 1 Jauary 2013, http://dx.doi.org/10.13040/IJPSR.09758232. 4(1).90-02. 3 Björn Lemmer, Chronobiology, drug-delivery, and chronotherapeutics, 9 August 2007, sciencedirect 4 Prof K.R Srikantha Murthy, Ashtanga Samgraha of Vagbhata, Sutrasthana Bheshajavacaraniya adhyaya 23/12 Chaukhamba Orientalia, Varanasi, edition 2012 , 5 Pt.Hari Sadasiva Sastri Paradaka Bhisagācarya. Vagbhata, Astangahridaya with the Sarvangasundara Commentary of Arunadatta, Sutrasthanam Ayushkamiya Adhyaya 1/24, Varanasi: Chaukhamba Surbharati Prakashan;2017 6 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta. chikitsa sthana yonivyapat chikitsa 30/296. Varanasi: Chaukhamba Surbharati Prakashan;2009 Available from: http://niimh. nic.in/ebooks/echarak 7 Pt.Hari Sadasiva Sastri Paradaka Bhisagācarya. Vagbhata, Astangahridaya with the Sarvangasundara Commentary of Arunadatta, Sutrasthanam Ayushkamiya 1/6-7, Varanasi: Chaukhamba Surbharati Prakashan;2017, 8 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta. chikitsa sthana yonivyapat chikitsita 30/310-312. Varanasi: Chaukhamba Surbharati Prakashan;2009 Available from: http://niimh.nic.in/ebooks/echarak

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Dr. Anishma AS et al. Chronotherapeutics in Ayurveda ISSN: 2456-3110 REVIEW ARTICLE Mar-Apr 2021 Journal of Ayurveda and Integrated Medical Sciences | Mar - Apr 2021 | Vol. 6 | Issue 2 112 9 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta, Sutrasthana apamarga tanduleeya 2/16. Varanasi: Chaukhamba Surbharati Prakashan;2009 Available from: http://niimh.nic.in/ebooks/echarak 10 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta. Chikitsa Sthana Yonivyapat Chikitsa 30/296, Varanasi: Chaukhamba Surbharati Prakashan;2009 Available from: http://niimh. nic.in/ebooks/echarak 11 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta. Chikitsa Sthana, Yonivyapat Chikitsa 30/297. Varanasi: Chaukhamba Surbharati Prakashan;2009 Available from: http://niimh. nic.in/ebooks/echarak 12 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta, Chikitsa Sthana, Yonivyapat Chikitsa 30/302. Varanasi: Chaukhamba Surbharati Prakashan;2009 Available from: http://niimh.nic.in/ebooks/echarak 13 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta. Chikitsa Sthana, Yonivyapat Chikitsa 30/303. Varanasi: Chaukhamba Surbharati Prakashan; 2009 Available from: http://niimh. nic.in/ebooks/echarak 14 Vaidya Jadavji Trikamji Acharya and Narayan Ram Acharya Kavyatirtha, Susruta Samhita with the Nibandhasangraha commentary of Sri Dalhanacharya and the Nyayachandrika Panjika of Sri Gayadasacharya on Nidanasthana, Utharatantra 64/69 Varanasi: Chaukhamba Surbharati Prakashan, 2018 Available from: http://niimh.nic.in/ ebooks/esusruta 15 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta, chikitsa sthana 12/14, Varanasi: Chaukhamba Surbharati Prakashan; 2009 Available from: http://niimh.nic.in/ebooks/echarak 16 Murthy Srikanth KR. Editor. Reprint ed. Madhavanidana of Madhavakara, Grahaniroga Nidanam; chapter 4/17 Chaukhambha Orientalia;2009, 17 Vaidya Jadavji Trikamji Acharya and Narayan Ram Acharya Kavyatirtha, Susruta Samhita with the Nibandhasangraha commentary of Sri Dalhanacharya and the Nyayachandrika Panjika of Sri Gayadasacharya on Nidanasthana, Utharatantra 25/5, Varanasi Chaukhamba Surbharati Prakashan,2018 Available from: http://niimh.nic.in/ebooks/esusruta 18 Vaidya Jadavji Trikamji Acharya and Narayan Ram Acharya Kavyatirtha, Susruta Samhita with the Nibandhasangraha commentary of Sri Dalhanacharya and the Nyayachandrika Panjika of Sri Gayadasacharya on Nidanasthana, Utharatantra 25/7 Varanasi Chaukhamba Surbharati Prakashan,2018, Available from: http://niimh.nic.in/ ebooks/esusruta 19 Vaidya Jadavji Trikamji Acharya and Narayan Ram Acharya Kavyatirtha, Susruta Samhita with the Nibandhasangraha commentary of Sri Dalhanacharya and the Nyayachandrika Panjika of Sri Gayadasacharya on Nidanasthana, Utharatantra 25/11-12 Varanasi Chaukhamba Surbharati Prakashan,2018, Available from: http://niimh.nic.in/ebooks/esusruta 20 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta, Chikitsa Sthana Yonivyapat Chikitsa 30/304. Varanasi: Chaukhamba Surbharati Prakashan;2009 Available from: http://niimh.nic.in/ebooks/echarak 21 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta, Chikitsa Sthana Yonivyapat Chikitsa 30/298-301, Varanasi: Chaukhamba Surbharati Prakashan;2009 Available from: http://niimh.nic.in/ebooks/echarak 22 Vaidya Jadavji Trikamji Acharya and Narayan Ram Acharya Kavyatirtha, Susruta Samhita with the Nibandhasangraha commentary of Sri Dalhanacharya and the Nyayachandrika Panjika of Sri Gayadasacharya on Nidanasthana, Utharatantra swasthavrutamadyayam 64/65, Varanasi Chaukhamba Surbharati Prakashan, 2018, Available from: http://niimh.nic.in/ebooks/esusruta 23 Prof. K.R. Srikantha Murthy, Ashtanga Samgraha English translation, Vol.1, Sutrasthana Bheshajavacaraniya Adhyaya 23/12. Chaukhambha Orientalia, Varanasi, 24 Pandit Parasurama Sastri, Vidyasagar, Sarngadhara Samhita of Pandit Saragadharacharya with the commentary Adhamalla’s Dipika and Kasirama’s Gudhartha -Dipika, Pradama Khanda, chapter 2/2, Chaukhambha Orientalia, Varanasi,7 th edition:2008. 25 Prof. (Km) P.V.Tewari, Kasyapa Samhita or vruddhajivakiya tantra of maharsi marica kasyapa written by Acharya vruddha jivaka redacted by vatsya, khilasthana 3/52,varanasi,2008 26 Vaidya Jadavji Trikamji Acharya and Narayan Ram Acharya Kavyatirtha, Susruta Samhita with the Nibandhasangraha commentary of Sri Dalhanacharya and the Nyayachandrika Panjika of Sri Gayadasacharya on Nidanasthana, Utharatantra swasthavrutamadyayam 64/67 Varanasi Chaukhamba Surbharati Prakashan,2018, Available from: http://niimh.nic.in/ebooks/esusruta 27 Prof. (Km) P.V.Tewari, Kasyapa Samhita or vruddhajivakiya tantra of maharsi marica kasyapa written by Acharya vruddha jivaka redacted by vatsya, khilasthana 3/52,varanasi,2008 28 Prof. (Km) P.V.Tewari, Kasyapa Samhita or vruddhajivakiya tantra of maharsi marica kasyapa written by Acharya vruddha jivaka redacted by vatsya, khila-sthanam 3/46.2- 47.1,varanasi,2008.

[Find the meaning and references behind the names: Louise, Sharman, Work, Sharma, Cite, Aust, Sutra, Sci, Kalpana, Jun, Original, Tiwari, Open, Nil, Author, None]

Dr. Anishma AS et al. Chronotherapeutics in Ayurveda ISSN: 2456-3110 REVIEW ARTICLE Mar-Apr 2021 Journal of Ayurveda and Integrated Medical Sciences | Mar - Apr 2021 | Vol. 6 | Issue 2 113 29 Prof. (Km) P.V.Tewari, Kasyapa Samhita or vruddhajivakiya tantra of maharsi marica kasyapa written by Acharya vruddha jivaka redacted by vatsya, khila-sthana 3/ 50,varanasi,2008. 30 Prof. (Km) P.V.Tewari, Kasyapa Samhita or vruddhajivakiya tantra of maharsi marica kasyapa, written by Acharya vruddha jivaka redacted by vatsya, khila-sthanam 3/48.1 varanasi,2008. 31 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta, chikitsa sthana 12/1, Varanasi: Chaukhamba Surbharati Prakashan;2009 Available from: http://niimh. nic.in/ebooks/echarak. 32 Pandit parasurama sastri, vidyasagar, sarngadhara-samhita of Pandit saragadharacharya with the commentary adhamalla’s dipika and kasirama’s gudhartha-dipika, vataka kalpana chapter 7/94 Chaukhambha orientalia, Varanasi,7 th edition:2008. 33 Tiwari PV, Tiwari A. Editor.1 st ed.Yogaratnakara of Yogratnakara, Moulika siddhanta; 1/882, Varanasi: Choukhamba Vishvabhati;2010 34 Tiwari PV, Tiwari A. Editor.1 st ed.Yogaratnakara of Yogratnakara, Moulika siddhanta; 1/975, Varanasi: Choukhamba Vishvabhati;2010, 35 Prof.K.R. Srikantha murthy, Ashtanga Samgraha English translation, vol.1 Sutrasthana 6/40-41, Chaukhambha Orientalia, Varanasi, 36 Hemadri, Commentator, Ashtanga Hridaya, Paradkar HS, editor, Reprint 1 st edition. Chaukambha Surbharati Prakashan, Varanasi, 2002; 219. 37 Indu, Commentator, Ashtanga Sangraha, Sharma SP, editor, 1 st edition, Sutra Sthana, 13/38, Chaukambha Sanskrit Series Office,Varanasi, 2006; 179, Sutra Sthana, 23/14, 38 Vaidya Jadavji Trikamji Acharya and Narayan Ram Acharya Kavyatirtha, Susruta Samhita with the Nibandhasangraha commentary of Sri Dalhanacharya and the Nyayachandrika Panjika of Sri Gayadasacharya on Nidanasthana, Uttaratantra 64/62 Varanasi: Chaukhamba Surbharati Prakashan,2018, Available from: http://niimh.nic.in/ebooks/esusruta 39 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta, chikitsa sthana.17/8, Varanasi: Chaukhamba Surbharati Prakashan;2009, Available from: http://niimh.nic.in /ebooks/echarak 40 Pt.Hari Sadasiva Sastri Paradaka Bhisagācarya . Vagbhata, Astangahridaya with the Sarvangasundara Commentary of Arunadatta.Pt., Sutrasthana.12/4 Varanasi: Chaukhamba Surbharati Prakashan;2017 41 Louise Grannell, When should I take my medicines? Jun 3,2019. Journal -Aust Prescr PMC 6594844 42 Vaidya Jadavji Trikamji Acharya and Narayan Ram Acharya Kavyatirtha, Susruta Samhita with the Nibandhasangraha commentary of Sri Dalhanacharya and the Nyayachandrika Panjika of Sri Gayadasacharya on Nidanasthana, Sootrasthana 21/5, Varanasi Chaukhamba Surbharati Prakashan,2018, Available from: http://niimh.nic.in/ ebooks/esusruta 43 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta. sutrasthana 7/44, Varanasi: Chaukhamba Surbharati Prakashan; 2009, Available from: http://niimh. nic.in/ebooks/echarak 44 Acharya Vaidya Jadavaji Trikamji Caraka Samhita, with the Ayurveda Dipika Commentary of Chakrapanidatta. Sutrasthana 2/16, Varanasi: Chaukhamba Surbharati Prakashan;2009, Available from: http://niimh.nic.in /ebooks/echarak ******************************* How to cite this article: Dr. Anishma AS, Dr. Harita Chandran, Dr. Leena P. Nair, Dr. C. Usha Kumari, Dr. Haroon Irshad. Chronotherapeutics in Ayurveda. J Ayurveda Integr Med Sci 2021;2:105-113. Source of Support: Nil, Conflict of Interest: None declared. Copyright © 2021 The Author(s); Published by Maharshi Charaka Ayurveda Organization, Vijayapur (Regd). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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