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Disease Review/Vishaada Vishaada v/s Generalized Anxiety Disorder The Vedic literature especially Upanishads and Darshans have tried to explain the various aspects of Mana, its synonyms, its functions etc. Mana described in Ayurveda has its root in the Sankhya, Vaisheshika and Nyaya philosophies. The Ayurvedic texts have vividly described about various mental disorders and psychological disturbances. But the detailed description about these mental disorders is arbitrary except for Unmada and Apasmara. Many areas still remain untouched and unexplored. One such ill defined and incompletely described disorder is Vishaada. Vishaada is a psychological disorder as old as mankind. Its references are so scattered in most of the Indian classics which makes it is very difficult for the clinicians to differentiate and diagnose this condition. A few of earlier done research works have projected the term Vishaada as Depression. But looking into the pathophysiology and symptomatic presentation of Vishaada, this evaluation did not seem to be concrete. On the other hand ayurvedic researchers have tried to study and compare the symptomatology of Generalized Anxiety Disorder under the umbrella of several psychological entities like Chittodvega, Anavasthittachitta, Attatvabhinivesha, etc.In both the cases there has been a lacunae in establishing a concrete conclusion to establish a comparative modern clinical entity in simulation to Vishaada. Taking into consideration all these facts a hypothesis to understand Vishaada in context of Generalized Anxiety disorder was made and after studying the disorder in detail it was concluded that the psychological and somatic presentation of the disease entity Vishaada is similar to Generalized Anxiety Disorder of modern psychiatry. Etymological derivation of Vishada 1. (Pu) Vi+ Shad - Dhaj Pratyaya = Vishada[1] 2. Vi + Shad+ Kta = Vishada[2] 11 Disease Review/Vishaada Anxiety originates from Latin word ―anxietas‖ means experience of anger. In Modern Greek, we confront the word ―anesuchia‖ whose root meaning in ―not quiet‖ or ―not calm‖. The Romans used the word ―anxietas‖ which indicated a lasting state of fearfulness. Definition and symptomatology of Vishaada Various authors have derived, defined and interpreted the term Vishaada in different ways. A few of which have been described below: Shabda Kalpadruma and Vachaspatyam refer to Vishaada as [3] Avasada Vishaada=Manoavsada=Swakarya Akshamatva=Inability of mind to perform its routine functions effectively (Vachaspatyam) Monier Williams gives the meaning of Vishaada as drooping state, lassitude, depression, languor. [4] Looking into the dictionary meaning of this word it appears that Vishaada resembles to depression but having a closer look at other references present in Ayurvedic texts and the epitome of ancient psychology – Bhagvada Gita the symptomatology of Vishaada shows a great resemblance to the features of Generalized Anxiety Disorder. ―Asiddhibhayat vividheshu karmeshu apravritti vishaada‖ [5] Dalhana defines Vishaada as a condition originated from apprehension of failure resulting into incapability of mind and body to function properly. There is a significant reduction in both the activities. This condition arises out of low self esteem. Low self esteem leads to low performance expectation which again leads to high anxiety (Udvignata) and reduced effort (Apravritti). According to modern psychiatry anxiety is defined as a phenomenon which is characterized by a state of apprehension or unease arising out of anticipation of danger. [6] It is well reported that patients with generalized anxiety disorder appear to have autonomic hypo responsiveness [7] which does not necessarily mean that the patient is suffering from depression. ―Vishaado anushtheyo atmanam ashaktatajananam.‖ [8] In this definition, Chakrapani comments that Vishaada is a feeling of incompetence to accomplish or perform a desired work. 12 Disease Review/Vishaada To perform well or to achieve a goal, one needs a moderate amount of anxiety to anticipate and apprehend the consequence of a decision or behavior. But when a person is unable to cope up with this stress it leads to a feeling of incompetence to accomplish the desired goal and leads to an intense disagreeable state, associated with an undefined threat to one‘s physical and psychological self. Subjectively patient use words such as tense, panicky, terrified, jittery, nervous, wound up, and apprehensive. ―Vishada Sarvada manah khedah‖ [9] ―Vishannatvam dukhkhitvam‖ [10] Generalized anxiety disorder is characterized by a pattern of frequent, persistent worry and anxiety that is out of proportion to the impact of the event or circumstance that is the focus of the worry. [11] For getting a clear picture of Vishaada it is important to review the literature available in the acclaimed book of psychological counseling since ages i.e. Bhagwad Gita In the first chapter of Bhagwad Gita named as ‗Arjuna Vishaada Yoga‘, when Arjuna sees most of his relatives, friends and elders lined opposite to him in war he develops Vishaada which is specified by the Vishidayantee process. Due to this Vishaada he develops certain symptoms presented below which are quite similar to symptoms of Generalized Anxiety Disorder. As a result of this disorder he develops dejection and flight reaction. For which Lord Krishna begins psychological counseling and clears his misconcepts one by one. [12] A clear understanding of each symptom of Vishaada mentioned by Shri Krishna is Bhagwad Gita provides a platform for understanding the presentation of symptoms in Generalized Anxiety Disorder. Gatra Saada (Quivering of body or an involuntary vibration as if from illness or fear) The flight or fight response is an intense reaction and causes many systems of the body to react. Circulation, blood oxygen and blood carbon dioxide levels change and muscle tension is altered in preparation for action. All of these bodily changes have a profound effect on bodily sensations, feeling weak in the extremities, (arms, hands, legs or feet) is one of these sensations. Quivering is usually caused by the pooling of blood carbon dioxide in the limbs, shaking the hands, arms, legs and feet can help increase circulation to these areas. The nervous system is a 13 Disease Review/Vishaada very complex network of electrically charged nerves which are found in every square centimeter of our body, around every organ, muscle and across the skin, the largest organ in the body. Abnormal nerve impulses due to anxiety can cause a vast array of strange sensations; although quite harmless these can be very disturbing. Vepathu (Tremors) Shaking or tremor is a normal reaction to fear and/or a drop in body temperature. Shaking occurs when the muscles spasmodically contract creating friction between muscles and other body tissues. This friction creates heat which raises body temperature. During anxiety it is quite shaking or shivering is quite evident. Romaharsha (Horripulation) Horripulation is the bumps on a person's skin at the base of body hairs which may involuntarily develop when a person is cold or experiences strong emotions such as fear, nostalgia, pleasure, awe, admiration or sexual arousal.[13] .Another intense emotional situation that can cause goose bumps is the "fight or flight" response the body can employ in an extremely stressful situation. As the body prepares itself for either fighting or running, it floods the system with adrenalin, the chemical that speeds up heart rate and metabolism in the presence of extreme stress and anxiety.[14] Paridahan( Burning sensation all over body) In case of anxious state there is burning skin sensation like you have a bad sun burn, but there are no apparent marks on the skin. The burning skin sensation may remain in one location, may randomly change from location to location, or may affect the entire body. It can be intermittent or can persist indefinitely. The burning skin sensation is commonly aggravated by stressful or fearful situations. [15] Gaandivam Sransate Haste (Feeling of Muscle weakness or exhaustion) An anxious person does not feel tired or exhausted, yet he feels weak, light, unsteady, or like he may faint at any time. He may also feel like he does not have any strength or energy. Even a small or simple task seems like they require more energy than they have. There is a feeling of muscle weakness. 14 Disease Review/Vishaada Na Cha Shaknomi Avasthatum (Unable to stand at one place) In GAD patient feels suddenly unsteady, light-headed, woozy or dizzy. This is sometimes accompanied by a feeling that he might faint or pass out. It may also feel as though he is walking on a boat, or that the floor seems to move up and down and it's hard to balance. He may also have difficulty in placing his feet because his perception of the ground or floor may be incorrect. In some cases it may seem that even though the patient is standing on a firm floor, the floor may be vibrating or moving. Unsteadiness, dizziness, feeling dizzy or light-headedness are common symptoms of stress, fear, and anxiety. Mano bhraman (Reeling of mind) The patient if GAD feels like he is not a part of what is going on, or like he is in a dream state or ‗out of touch with things‘. He may also feel that he is an observer of the world, or even himself, but not able to feel a part of reality. Sometimes he may feel very unreal then think that he is losing his control over mind or will cross over into some other non-real world. These thoughts may cause him to panic with fear. Also, things around him may seem like they are shimmering, foggy, hazy, too bright, or tunnel-like. Mukhashosha (Dryness of mouth) As the fluids and blood flow are diverted for use in other parts of the body during anxiety, the mouth becomes dry. Another important symptom which is associated with dryness of mouth is Lump in throat & Difficulty swallowing. Globes Hysterics is the correct term for this symptom. It is caused by the muscles in the throat contracting due to anxiety or stress. Sometimes a person cannot swallow anything and trying to make it worse. It is totally harmless and will not cause stop breathing, eating or drinking it is just very unpleasant. [16] Other important symptoms of Vishaada are explained below Anavasthitachittam (Decreased concentration) In GAD the patient has difficulty in concentrating or it feels like the short-term memory isn‘t as good as it used to be. He may also notice that normal tasks seem hard to focus on or he has difficulty in forming thoughts or carrying on conversations. 15 Disease Review/Vishaada Dukhatvam(Feeling of Sadness) and Avasada (Depressed mood) Depression is a word that is commonly misused to describe a variety of conditions. Depression is a series of chemical imbalances that create a clinical illness that has strong links with anxiety disorders and can be a side effect of them. Anxiety has many features of depression and can mimic it quite strongly. Nidra Vaishamya (Sleep disturbances) One of the most distressing effects of anxiety is inability to fall asleep or to remain asleep. This may be accompanied by increased dreams or night mares. Dreams and nightmares tend to mimic what is going on in our daily lives. If we are relaxed and contented we have pleasant dreams and usually do not remember them. If we are disturbed or confused our dreams are more likely to be distressing. Atmano Ashakta Jananam (Feeling of inefficiency) The patient of GAD often feels that he is inefficient to perform his duties due to lowered self esteem. Low self esteem leads to low performance expectation which again leads to high anxiety (Udvignata) and reduced effort (Apravritti). Asiddhi Bhayat Apravritti (Atychiphobia) Atychiphobia is actually a unique type of phobia. It is a phobia relating to the persistent, abnormal, irrational, and unwarranted fear of failure. It may be present because of some early life causes such as demeaning or degrading parents or siblings, or traumatic events where there is failure and at the same time embarrassment. These early life causes are said to stay in the unconscious mind until a certain triggering point, event, etc. and ultimately lead to manifestation of anxiety symptoms. [17] Chittodvega (Anxious mood) This is the cardinal sign of GAD. Anxiety is a generalized mood condition that can often occur without an identifiable triggering stimulus. As such, it is distinguished from fear, which is an emotional response to a perceived threat. Additionally, fear is related to the specific behaviors 16 Disease Review/Vishaada of escape and avoidance, whereas anxiety is related to situations perceived as uncontrollable or unavoidable. [18] Prasveda (Sweating) Sweating is a normal bodily reaction and is designed to reduce the body temperature. During periods of anxiety the body is preparing itself for either flight or fight and releases sweat to cool the impending exertions. As the anxiety subsides sweat levels return to normal. Hridadrava (Palpitations) Heart palpitations feel like the patient‘s heart is pounding, racing, beating fast, beating too hard, skips a beat, or feels like it stops in his chest. It can also produce a feeling like a tickle in chest that makes him cough. The heart's rhythm may be normal or abnormal. Palpitations can be felt in your chest, throat, or neck. Aruchi (Loss of appetite) This symptom has both psychological as well as physiological impact. Sometimes the patient just doesn‘t feel like eating, or the thought of food is unappealing. Or, that even though he is eating, the food has no taste or is unsatisfying. Physiologically during periods of anxiety the body diverts blood from various parts of the body to the muscle tissues in order to supply them with the oxygen needed by them during the flight or fight response. One of the main areas where blood is used most is around the digestive tract. As blood is diverted away from the stomach during anxiety, the digestion slows and there is loss of appetite. Shrama Asahtva ( Fatigue unrelated to exertion) The patients of GAD become extremely exhausted, burnt out or have no energy. He may feel tired all of the time and find even small tasks to be unusually tiring. He has no stamina and feels that he could sleep all day and then wake up still tired. Hence, from the above description it is very clear that the symptoms of Vishaada as explained in Bhagwad Gita serve as a guiding light in understanding the symptomatology and pathogenesis of Generalized Anxiety disorder. 17 Disease Review/Vishaada Definition of Generalized Anxiety disorder Generalized Anxiety Disorder (GAD) has the key component of the worry, with associated symptoms of restlessness, fatigue impaired concentration, irritability muscle tension and sleep disturbance. The definition of GAD has changed over time. In the current version of DSM-IV TR, GAD has changed from a residual category describing individuals who do not fit other anxiety categories to a well-defined condition with sound diagnostic criteria. These criteria include a 6-month symptom requirement & more emphasis on the psychic features of the conditions symptoms and behaviors associated with Generalized Anxiety Disorder. DSM IV-TR Diagnostic Criteria for Generalized Anxiety Disorder [19] A. Excessive anxiety and worry (apprehensive expectation) about a number of events or activities (such as work or school performance) occurring more days than not for at least 6 months. B. The person finds it difficult to control the worry. C. The anxiety and worry are associated with at least three of the following six symptoms (with at least some symptoms present for more days than not, for the past 6 months): 1. Restlessness or feeling keyed up or on edge 2. Being easily fatigued 3. Difficulty concentrating or mind going blank 4. Irritability 5. Muscle tension 6. Sleep disturbance (difficulty in falling or staying asleep, or restless unsatisfying sleep) D. The focus of the anxiety and worry is not confined to features of an Axis I disorder, being embarrassed in public (as in social phobia), being contaminated (as in obsessive-compulsive disorder), being away from home or close relatives (as in separation anxiety disorder), gaining weight (as in anorexia nervosa), having multiple physical complaints (as in somatization 18 Disease Review/Vishaada disorder), or having a serious illness (as in hypochondriasis), and the anxiety and worry do not occur exclusively during posttraumatic stress disorder. E. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social or occupational functioning. F. The disturbance does not occur exclusively during a mood disorder, a psychotic disorder, pervasive developmental disorder, substance use, or general medical condition. In addition to the DSM- IV-TR framework, the symptoms of GAD can be conceptualized as being contained in three categories. 1] Excessive physiological arousal 2] Distorted cognitive process 3] Poor coping strategies In a nut shell, though the symptoms of GAD are numerous and highly variable, signs of motor tension, autonomic hyperactivity and hyper arousal are frequently the presenting problems. Patients complain of restlessness, inability to relax and fatigue. Pathological worry has been identified as the pathognomic feature of GAD.GAD worry has been distinguished from normal worry by being perceived as significantly more uncontrollable and unrealistic. [20] Normal Worry v/s Generalized Anxiety Disorder (GAD) Normal Worry Your worrying doesn‘t get in the way Generalized Anxiety Disorder of your daily activities and responsibilities. You‘re able to control your worrying. Your worries, while unpleasant, don‘t Your worrying significantly disrupts your job, activities, or social life. Your worrying is uncontrollable. Your worries are extremely upsetting and stressful. 19 Disease Review/Vishaada cause significant distress. You worry about all sorts of things, and tend to expect the worst. Your worries are limited to a specific, small number of realistic concerns. Your bouts of worrying last for only a You‘ve been worrying almost every day for at least six months. short time period. Nidaana (etiological factors) and Samprapti (pathogenesis) of Vishaada There is no direct reference of specific nidaana for Vishaada. But in general for all mental disorders basic pathogenic factors are rajas & tamas. [21] Vitiation of rajas & tamas are considered as a prime factor in causation of Vishaada. In general, common etiological factors can be categorized under three broad headings- [22] 1. Pragnaparadha 2. Asatmendriyartha samyoga 3 Parinama 1. Pragnaparadha (Dhee Dhriti Smriti Vibhramsha) Acharya Charaka states that Pragnaparadha related to mind is the first cause of all mental disorders. [23] An action carried out with a non justifiable understanding due to dhivibramsa (impairment of intellect), dhritivibramsha (impairment of will) and smritivibramsha (impairment of memory) is termed as pragnaparadha.It is caused by derangement of Manasa doshas-Rajas and Tamas. For example over affliction of mind by Kaama, Krodha, Bhaya, Moha, Shoka, Chinta,etc may lead to many mental disorders.[24] This can also be compared with the psycho-analytical theory of Freud. According to psychoanalytical theory, anxiety arises from a conflict between instinctual drive and internal inhibition and the ego‘s recognition of external danger. The ego uses various defenses to avoid the anxiety produced by both inter-psychic and intra-psychic conflict and potential external 20 Disease Review/Vishaada danger. The experience of anxiety is the result of failure of the ego to use effective defenses, for example, due to impairment of intellect there is a physical overreaction to stress. This over reaction occurs because our body perceives everyday events and situations as threats to survival. In an effort to protect yourself, your body triggers the fight or flight response even though there is no real existing danger which in turn promotes anxiety.[25] Negative thought patterns like "what-if" thinking, perfectionism, etc. can contribute to anxiety disorders. [25] Poor lifestyle habits such as overwork, lack of sleep, poor diet, and lack of regular exercise can cause unnecessary stress and promote anxiety. [25] All these factors can be understood under the broad heading of Pragnaparadha. 2. Asaatmendriyartha samyoga Unwholesome contact with the objects may be in the form of overutilization (Atiyoga),nonutilization(Ayoga) and wrong utilization(Mithyayoga).Only when they cross the individual threshold range they result into stressful conditions and cause imbalance of Sharirika and Manasika doshas.For eg. The use of and withdrawal from addictive substances, including alcohol, caffeine, and nicotine, can worsen the phenomenon of anxiety. [26] For individuals who suffer from anxiety disorders, the fear and worry they feel much of the time can be overwhelming. In the race of competing with the fast pace of world, raising a family, achieving too much in lesser time people overuse(atiyoga) or misuse(mithyayoga) their energy. This brings about severe emotional and physical stresses finally leading to Anxiety. 3. Parinama(Samprapti Kala Karmanam) Here, Parinama refers to the advent of maturity of the results of (Kala) time as well as Karma(action).Ayurveda believes that the results of all misdeeds will mature with time and when it happens the person will be afflicted by particular disorder. It is seen that all mental disorders have a phase of excitement, remission, etc. For e.g. Seasonal affective disorder (SAD), a mood disorder in which people who have normal mental health throughout most of the year experience depressive symptoms in the winter or summer,[27] spring or autumn year after year. The condition in the summer is often referred to as reverse seasonal affective disorder, and can also include heightened anxiety.[28] 21 Disease Review/Vishaada Historically, there has been a perceived association between the lunar phase and human biology and behavior that can be traced back to at least Roman times. The idea that the moon can in some way influence human biology or behavior is a phenomena that has now come to known as the ―Transylvanian effect‖. Many mental health professionals continue to hold the belief that lunar cycles can alter human behaviour. Raison et al. (1999) traces the historical roots of belief in the power of the full moon to cause disorders of the mind, insanity, and even epilepsy [29] Barr et al. (2000) reports that the mental health of patients living with the condition of schizophrenia will deteriorate during the time of the full moon. [30] This shows a relation of Kala (time factor) with anxiety. Acharya Charaka has also mentioned that Shishir, Vasanta and Grishma are included in the Adaana kala when the sun is at its full power and the moon is at its least power. In Adaana kala the sun absorbs all the Jaliya Ansha (Watery elements) from the atmosphere and creates dryness in the atmosphere with the help of pancha vayu which are its utmost strength. This creates daurbalyata (weakness) which includes both physical and mental weakness in the humans. [31] Also Vayu and Manas are directly interrelated to each other. While describing the physiological importance of Vayu Acharya Charaka has described ―Niyanta Praneta Cha Manas‖ [32] this clearly reflects that any disturbance in the given physiology of Vayu may lead to psychological disturbances like Anxiety, Irritability, Mood Swings, etc. Traumatic experiences that occur in childhood may have lasting effects that carry over into adulthood [33] .This may also be taken as an example of Kala Parinama. Sattva Vaisheshyakara Bhava’s (Factors influencing mental faculty of progeny) The reasons for the variability in the psychic temperaments among the individuals has been discussed in detail by Acharya Charaka who states that basically four factors influence and determine the psychic variants of the child. He termed them Sattva Vaisheshyakara Bhava‘s [34] 1) Maata Pitru Sattve – Mental faculty of parents 2) Shrutayah – Whatever the mother hears, reads and thinks during the pregnancy 3) Svochita Karma – Actions of past life of foetus 4) Sattva Vaisheshya Abhyasa – Practices of the past life 22 Disease Review/Vishaada The mental traits or psychic predispositions of the parents influence the psychic trait of the progeny. [35] According to Acharya Sushruta if the parents are religious, virtuous and theistic, they produce children of the same qualities. It is an accepted fact that some psychological traits are concealed in the genes and the influence of hereditary factors on the emotional plane are well documented. Many studies have shown that anxiety disorders tend to run in families. [36] For most medical conditions, this would suffice to conclude that abnormal genes must be etiologically relevant. However, it is not difficult to conceive that growing up with anxious parents or siblings might influence the development of anxiety in any individual. One compelling hypothesis is that individuals inherit a temperament like shyness, hyperactive autonomic nervous system responses, or behavioral inhibition. Then, depending on a variety of life circumstances, these genotypes are expressed as specific phenotypes—one or more of the anxiety disorders themselves. It may also be that more powerful ―anxiety genes‖ require less environmental stress to be expressed. [37] Family aggregation studies suggest that children whose parents have an anxiety disorder are at risk for developing an anxiety disorders themselves (Biederman et al. 2001), twin studies also suggest a familial transmission for e.g, concordance rates from different monozygotic (identical) and dizygotic (fraternal) twin pairs suggest a strong genetic basis for anxiety neurosis. Thalia C. Eley's (1999) review of behavioral genetic research concluded that factors in shared and non shared environments of parents with anxiety disorders have an important influence on the development and maintenance of most anxiety disorders in their children and adolescents. [38] All these facts reveal the importance of Sattva Vaisheshyakara Bhavas in the manifestation of Vishaada or GAD. Behavioral Factors The belief that child-rearing practices or early experience affects later behavior and personality is neither new nor surprising. Child-rearing antecedent conditions associated with anxiety during adolescence have been identified and include environmental factors (e.g., broken home, family conflict) as well as specific attitudes and child-rearing practices. Lack of clear family rules, a strong concern for a family's reputation, a poor relationship with the father, and frequent 23 Disease Review/Vishaada criticism and disagreement all were associated with anxiety [39] Inconsistency, harsh and unyielding attitudes, ambiguity, and family conflict appear to be among the primary predictors of the development of anxiety. Besides this children have a specific habit of observing and imitating the behaviors of others around them, especially their parents. Parents can model anxious behaviors to their children. A healthy parent child relationship leads to the child developing a sense of control over the environment. In the absence of such a relationship and development, the child may be vulnerable to anxiety. [40] This may lead to behavioral inhibition in children. Behavioral inhibition is an early temperamental trait characterized by the tendency to withdraw when exposed to unfamiliar situations. Chakrapani also supports this fact by saying that the psychic trait of the progeny is directly related to parental influence. This is due to some special effect (Prabhava) [41] Manoabhighaata (Stressful life events) While mentioning about nidanas for Manodukhaja Unmaada, Acharya Sushruta has enumerated the following causes- [42] 1. When a person is tortured mentally and physically by somebody else 2. When a person loses his property or close relative 3. When a person is unable to achieve the love of desired person 4. When a person is unable to achieve the goal etc. All these factors can lead to decreased self esteem and confidence of an individual. This causes fear of failure in future which in turn leads to loss of interest and non indulgence in routine works. So, considering these factors we can say that environmental factors are very important in the manifestation of Vishaada. Clinical experiences indicate that stressful life events may trigger GAD. The greater the number of negative life events experienced, the greater is the likelihood to develop GAD. [43] In addition to the above factors certain biochemical factors are also involved in the pathogenesis of GAD. 24 Disease Review/Vishaada Biochemical Aspects 1) Autonomic, Noradrenergic, and Neuroendocrine Systems: Patients with generalized anxiety disorder appear to have autonomic hypo responsiveness, subtle changes in adrenergic receptor sensitivity, abnormal regulation of GH secretion, and altered glucocorticoid feedback inhibition. [44] 2) Serotonergic System: The anxiolytic effects of 5-HT1A partial agonists (buspirone[BuSpar] and ipsapirone) and 5-HT2 antagonists (ritanserin and serazepine) in generalized anxiety disorder patients has suggested serotonin involvement.[44] The role of serotonin in anxiety is supported by its modulatory effects on the locus coeruleus and its dense projections to the amygdala. Decreased serotonin activity is associated with depression, and the most effective antidepressants have been shown to enhance the functioning of serotonin. Low activity of serotonin may permit the dysregulation of other neurotransmitters, including nor epinephrine. These two systems are linked so closely that notable changes in one are reflected in the other; interactions between these systems appear to be reciprocal. The precise nature of the reciprocal interaction can vary, and the activity of norepinephrine at presynaptic serotonergic terminals may lead to a decreased release of serotonin, whereas its activity at postsynaptic adrenoreceptors may lead to an increase in the release of serotonin (Ninan P, 1999) [45] 3) GABAergic System: Low levels of GABA, a neurotransmitter that reduces activity in the central nervous system, contribute to anxiety. A number of anxiolytics achieve their effect by modulating the GABA receptors. [46][47][48] 4) Amygdala: The amygdala is central to the processing of fear and anxiety, and its function may be disrupted in anxiety disorders. Another important area is the adjacent central nucleus of the amygdala, which controls species-specific fear responses, via connections to the brainstem, hypothalamus, and cerebellum areas. In those with general anxiety disorder, these connections functionally seem to be less distinct, with greater gray matter in the central nucleus. Researchers have noted "Amygdalofrontoparietal coupling in generalized anxiety disorder patients may reflect the habitual engagement of a cognitive control system to regulate excessive anxiety." [49] 25 Disease Review/Vishaada Probable Samprapti (pathogenesis) of Vishaada As Vishaada is not explained in detail in our classics, a direct reference of its samprapti (pathogenesis) cannot be found. But the samprapti (pathogenesis) can be understood and constructed considering the available references and on the basis of Dosha, Dushya involved. For this the following points should be considered: 1. Vishaada is mentioned as one of the Manasika Rogas in our classics [50]. 2. Vishada is mainly caused by vitiation of Sharirika dosha Vata and Manasika dosha Rajas. Acharya Charaka mentions Vishaada as one of the 80 Nanatmaja Vata Vyadhis. [51] Acharya Charaka while describing the sign and symptoms of Vataja Jwara names Vishaada as one of them. [52] A direct relationship between Vayu and Rajas is well explained by our Acharyas by quoting that ―Rajo Bahulo Vayu‖ and Rajas is the ―Pravartaka‖of mind. This shows that although all the three Sharirika doshas take part in the pathogenesis of Vishaada there is a dominant role of Vata dosha its pathogenesis. 3. It occurs in Hina Satva Purusha [53] and Satva Sara person is not affected by Vishaada [54] Acharya Charaka states that when a person of Hina Satva see‘s Raudra, Bhairava or listens to unpleasant stories, on seeing the flesh or blood of man or animals suffers from Vishaada, Vaivarnya, etc. This reference throws light on Hetus of Vishaada. [55] 4. In the context of Anumana Pareeksha it is told that Bhayam Vishaadena and Dhairyam Avishadena[56]. 5. It is told that Vishaada is Agrya for Roga Vardhana.Acharya Charaka while describing the best things prescribed in medicine terms Vishaada as the foremost in flaring up a diseased condition. [57] 6. Acharya Sushruta while describing the origin of Visha states that Vishada manifests with the intake of Visha. [58]. 26 Disease Review/Vishaada 7. Acharya Charaka while elaborating the diseases caused as a result of excessive sexual activity states that Vishaada and Manoavsaada etc.diseases can occur. This shows that Vishaada and Manoavasaada are distinctively different states. [59] Considering all these references a probable samprapti for Vishaada can be framed as shown in the below prepared flowchart: 27 Disease Review/Vishaada Schematic flowchart showing probable Samprapti of Vishaada Hina Satva Purusha (Weak hearted persons)+Vata-Pitta-Rajas-Tamas Prakriti Pragnaparadha, Manoabhighata, Vishasevana, Ativyavaya, etc.Nidaana Sevana Vitiation of Sharirika doshas (Vata dominant) Vitiation of Manasika doshas (Rajas dominant) Vitiation of Jatharagni Moves to Hridaya Vitiation of Rasadi dhatus By Ashraya Ashrayi Bhava Manifestation of somatic symptoms like tremors, sweating, etc. Manasa is vitiated Vitiated Doshas spread all over body through Manovaha Srotas Mano Vibhrama Buddhi Vibhrama Cheshta Vibhrama Vishaada 28 Disease Review/Vishaada As mentioned by Acharya Charaka, Sattva sara persons can resist the ill effects of emotions like Chinta, Bhaya, Udvega.etc due the predominance of Sattva guna.But the persons having Hina Sattva are prone to indulge in Pragnaparadha and are easily afflicted by negative events or stressful situations. This results in imbalance of Manodosha predominantly Rajas and also Sharirika dosha predominantly Vata. At this stage, the patient exhibits an exaggerated response i.e. Udvega. These vitiated Manasika doshas can generate psychic symptoms like Chinta (worry), Vyakulta (apprehension), Bhaya (fear), etc. and in a long run start influencing the Sharirika doshas also.At the level of Sharirika doshas especially Vata and Pitta get aggravated predominated by Vata dosha. As Vata is said to be the controller of mind and Rajas also has an established connection with Vata dosha, so it produces symptoms mainly related to aggravation of Vata dosha. These vitiated Sharirika and Manasika doshas reach Hridaya (heart) which is the main abode for Manasa (mind) and causes vitiation of mind and cause Vibhrama(Disturbances) related to Manasa, Buddhi and Cheshta. This finally leads to manifestation of Vishaada. Acharya Charaka says in brief that the prime function of Manasa is Chintya. [60] Chakrapani also says that the Chintya are those which require thinking in the aspect of its do‘s and don‘ts. [61] Achintanam (less thinking), Atichintanam (excessive thinking) or Mithya chintanam (improper thinking) will lead to pathogenesis of mental disorders. In case of GAD there is excessive, persistent and uncontrollable worry which may be taken as Atichintanam. There is also a predominance of negatively balanced verbal thought activity and an anxious apprehension about the future which may be taken as Mithya Chintanam. Hence, the thought pattern of GAD resembles Atichintanam and Mithyachintanam. Such abnormal thinking patterns cause Manovibhrama which subsequently lead to abnormality in other factors like Buddhi, Sangya, Smriti, etc. The word Buddhi implies to comprehension, intellect, understanding, knowledge, discrimination, etc. and derangement of Buddhi causes loss of discriminating power and understands things in an abnormal way. Cognitive errors are nothing but Buddhi Vibhrama. In GAD there is 29 Disease Review/Vishaada Metacognition, cognitive avoidance, intolerance of uncertainty and negative problem orientation. In GAD negative beliefs about worrying are activated during a worry episode. [62] Cheshta Vibhrama is caused by improper coordination of mind and body. It may be increased, decreased or inappropriate in nature pertaining to body, speech and mental activities leading to undesirable activities. In GAD also there is Cheshta Vibhrama which can be observed in form of inappropriate psychomotor activities like trembling, restlessness, fidgeting, etc. Hence, it can be concluded that various Cognitive errors and abnormal defense mechanisms are nothing but Mano-Buddhi-Cheshta Vibhrama explained in our Ayurvedic texts and these act as main pathological components of pathogenesis of Vishaada. On the other hand the vitiated Vatadi doshas vitiate Jatharagni followed by Rasadi dhatus. These vitiated Sharirika and Manasika doshas affect Hridaya, Manovaha srotas, vulnerable dhatus and srotas and result into psychosomatic presentation of the disease. Samprapti Ghataka’s of Vishaada Dosha Manasa - Rajas, Tamas (Predominantly Rajas) Sharira - Vata, Pitta (Predominantly Vata) Dushya Manasa,Sarvadhatu Srotas Manovaha Srotas(specifically) Agni Jatharagni Udbhavasthaana Manasa(Hridaya) Adhisthaana Hridaya(Shirohridaya) Vyaktisthaana Manasa,Sarvasharira Purvarupa Alpavyakta Rupa Manasika - Mano bhraman,Anavasthitachitta,Avsaada, Atmano Ashakta Jananam,Chittodvega,Asiddhi bhayat apravritti,etc Sharirika – Vepathu,Prasveda,Romaharsha,Gatrasaada,Mukhshosha,etc Rogamarga Madhyam 30 Disease Review/Vishaada Management of Vishaada The exact mode of treatment for Vishaada is not mentioned in our classics. But the general principles of managing mental disorders as mentioned by Acharya Charaka can be applied here, which are as follows. [63] Satmya indriyaartha samyoga (Preventive) Asaatmendriyaarta Samyoga (Indugence in improper activities) is the main causes for various psychological problems. So, to prevent the conditions like Vishaada, one should control the indriyas to indulge in improper activities. Evidence-based preventive measures vary in type of targeted population, targeted anxiety disorder, type of risk or protective factors addressed, timing (i.e. anticipatory or reactive to traumatic event) and intervention method used. The following points have been proposed by W.H.O for prevention of Anxiety Disorders: [64] Reducing traumatizing events or exposure Enhancing emotional resilience and anticipatory education Post-trauma interventions These are the following measures to prevent anxiety and at the same time prevent other further complications to arise: Facing one‘s fears in the right method. To face one‘s fear, they need not be forced directly to help you settle with it. It has to be a gradual process, and the person itself is solely responsible of what he would do to handle such circumstances. Genetics. It cannot be altered, but the power of knowing that it runs in the family allows you to understand and prepare oneself of the possibility that one day it may arise and you will experience these episodes. Gaining closure and understanding with past hurts and experiences will let an individual have peace of mind. It will enable them to have closure and be able to move on without carrying any baggage of hurt and pain. That way, the fear of getting hurt would be resolved. 31 Disease Review/Vishaada Budhya samyak veekshya aveekshya (Cognitive therapy) It is based on idea of thoughts and feeling related anxious state of mind. The individual is taught to recognize and re-examine his anxious thought in order to find alternative and more helpful way of thinking, anxious thinking - that is, attitudes, beliefs, and images - about the external world, can instigate or perpetuate anxiety and panic. These are controlled by teaching the patient how to recognize and re-examine anxious thinking so as to uncover different, more constructive, and less anxiety provoking ways of viewing the outside world. It consists of an impressive variety of technique in various anxiety disorders that includes cognitive restructuring, psycho-education, relaxation, breathing retraining exposure, graded practice and self instruction training are in both individuals and group therapies compared with long established and highly successful behavior therapy for phobia and cognitive behavior therapy for GAD in recent. Karmaanaam samyak pratipaaanena (Behavior therapy) It includes proper planning of karma (behavior or action) and avoiding improper karma (behavior or action).Acharya‘s explained sadvritta to achieve this goal. By following these techniques one can prevent pragnaparadha and its consequences. These are useful in the prevention as well as in management of Vishaada. The term behavior therapy is applied to psychological treatments based on experimental psychology and indented to change symptoms and behavior. The key aspects of successful behavior therapy are i) The patient‘s commitment to treatment ii) Clear identification of problems and objectives iii) Available alternative strategies for coping with the patient‘s feelings. Autogenic training used in GAD can also be included here. In this technique people are trained to improve their health by using signal from their own bodies. It helps the patient to learn self monitoring anxiety levels and then apply relaxation techniques to daily activity. 32 Disease Review/Vishaada Sattvavajaya Chikitsa (Psychological therapies) Sattvavajaya is one of the three major therapies mentioned by Ayurvedic classics. It is a special form of psychotherapy where the therapist attempts to divert the thought process of the patient from unwanted targets (Ahita bhavas) to beneficial targets (Hita bhavas). [65] Acharya Charaka has mentioned the following principles to adopt a virtuous path of living Avoid harmful or unwholesome regimens and adopt useful wholesome ones in regard to Dharma, Artha and Kama. Serve the persons who are well versed in understanding the nature and management of psychiatric disorders. Acquire knowledge of oneself, the place, family, time strength and the capacity. Consider again and again what is useful and what is harmful for self.[66] The concept of Achara Rasayana also has a direct effect for promotion of a normal healthy mind. [67] A number of psychotherapy are said to be effective for treating GAD, although possibly correct, most of the claims need scientific substantiation. However, since clinical experience suggest that psychotherapy augments the efficacy and shortens the length of the time of pharmacotherapy, psychotherapeutic techniques, ranging from relatively simple stress management and problem solving assistance to more complex cognitive and psychodynamic treatment, should be applied for every patient with GAD. Psychological treatments are generally effective. About half of patients regain a normal level of functioning and cognitive therapy is claimed to be the most efficacious. Yuktivyapaashraya Chikitsa (Rational therapy) Administration of proper diet and medicaments come under this category.Acharya Charaka has mentioned Panchakarma (Snehana, Swedana, Virechana, Nasya, etc), Bhojana vidhana vidhana(dietary regimen) and Nidaana Parivarjana as the key elements of Yukti vyapaashraya chikitsa. [68] 33 Disease Review/Vishaada Along with the Panchakarma therapies various palliative measures like dhoopana (inhalation), anjana (collyrium), lepan (coating with medicinal paste), dhaara (irrigation), and etc.can also be administered in Vishaada. The drugs used in the treatment are mostly medhya (nootropic) herbs or herbomineral formulations which are believed to act as brain tonics and adaptogens.These drugs help in alleviating various psychic conditions. Pharmacological treatment is still common for patients with Generalized Anxiety Disorder and panic disorder with moderate to severe symptoms .Available medications for GAD include benzodiazepine, anxiolytics, buspirone, and antidepressants. Although benzodiazepines are effective as short term anxiolytics, their use is compromised by a poor adverse event profile and, like buspirone, they lack the antidepressant efficacy important for addressing the comorbid depression experienced by many patients with GAD. Antidepressants, including paroxetine and the serotonin-nor epinephrine reuptake inhibitor venlafaxine, are effective anxiolytics and resolve symptoms of depression in patients with GAD. Drugs other than benzodiazepines include the following Beta Blockers Tricyclic antidepressants Selective serotonin reuptake inhibitors Monoamine oxidase inhibitors Antipsychotic drugs in low dose Antihistamines 34 Disease Review/Vishaada References 1. 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Agnivesha, ―Charaka Samhita‖ revised by Charaka and Dridhbala with ‗Ayurveda Dipika‘commentary by Chakrapanidatta,edited by Vaidya Yadavji Trikamji Acharya,Chaukhambha Surbharti Prakashan,Varanasi,reprint 2008, Sutrasthana 11/54,pg.77 66. Agnivesha, ―Charaka Samhita‖ revised by Charaka and Dridhbala with ‗Ayurveda Dipika‘commentary by Chakrapanidatta,edited by Vaidya Yadavji Trikamji Acharya,Chaukhambha Surbharti Prakashan,Varanasi,reprint 2008, Sutrasthana 11/46,pg.77 67. Agnivesha, ―Charaka Samhita‖ revised by Charaka and Dridhbala with ‗Ayurveda Dipika‘commentary by Chakrapanidatta,edited by Vaidya Yadavji Trikamji Acharya,Chaukhambha Surbharti Prakashan,Varanasi,reprint 2008, Chikitsasthana 1/4/3035,pg.388-389 68. Vagbhatta,Ashtanga Hridayam, with the commentaries, ‗Sarvangasundara‘ of Arundatta and ‗Ayurvedarasayan‘ of Hemadri, edited by Pt.Harishashtri Paradkar Vaidya, Chaukhambha Orientalia,Varanasi,reprint 2005,Sutrasthana 1/26,pg 16 40 Analytical Study Analytical study of Ashwagandha granules There has been an exponential growth in the field of herbal medicine in the last few decades. It is getting popularized in developing as well as in developed countries owing to its natural origin and lesser side effect. In olden times, vaidyas used to treat patients on individual basis, and prepare drug according to the requirement of the patient. But the scenario has changed now; herbal medicines are being manufactured on the large scale in Pharmaceutical units, where manufacturers come across many problems such as availability of good quality raw material, authentication of raw material, availability of standards, proper standardization methodology of single drugs and formulation, quality control parameters. [1] Hence in the present study evaluation of Ashwagandha granules was attempted following the scientific parameters including organoleptic characters, physicochemical analysis and chromatographic pattern. [2] Aims and Objectives 1. To evaluate the organoleptic characters of the drug. 2. Assessment of Physico-chemical parameters of the drug. 3. Thin layer chromatographic study of drug. 4. High-performance thin-layer chromatography study of the drug. The Pharmacognostically authenticated sample drug Ashwagandha was made into granules and it was used for the present study. The Ashwagandha granules was analyzed by using various parameters, qualitative and quantitative analysis of Phyto-chemicals, Thin Layer Chromatography (T.L.C.) and High-performance thin-layer chromatography study (H.P.T.L.C) Physico-chemical study: Ashwagandha granules were analyzed by using qualitative and quantitative parameters at Pharmaceutical Chemistry Laboratory of I. P. G.T & R. A., Gujarat Ayurved University, Jamnagar. Organoleptic characters: Apart from quality control measures, Rupa (color), Rasa (taste), Gandha (odour) and Sparsha (texture) pertaining to Pancajnanendriya Pariksha are subtle yet important parameters for the basic standardization of drug. The characters of the sample are tabulated in table no.3 57 Analytical Study Table 3 – Organoleptic characters of Ashwagandha granules Sr.No Parameters Sample - Ashwagandha Granules 1 Texture Rough 2 Colour Brownish 3 Taste Sweet, Bitter 4 Odour Non Irritant Physico-chemical parameters [3] It provides the objective parameters to fix up the standards for quality of prepared drugs. The granules were evaluated for physico chemical parameters like total ash value, loss on drying, pH value, Sugar estimation (Total sugar, Reducing Sugar, Non - Reducing Sugar), acid soluble and water-soluble extractive values. The results are placed at table no.4 1. Determination of Moisture (Loss on Drying) To know the amount of moisture present in the drug, the following procedure was utilized. Procedure 2 gm of drug sample was taken in a pre weighed dried Petri dish. It was dried in an oven at 110o C until reaching a constant weight. The Petri dish was taken out, allowed to cool and weighed immediately. The weight loss i.e. loss on drying was calculated and expressed as % w/w. 2. Determination of Extractive Values It gives an idea about the nature of the chemical constituents present in the drug. a. Water Soluble Extractives This test was carried out to determine the water-soluble extractive and approximate measures of their chemical constituents of the test drug, which are water-soluble. Procedure 5 gm. of the sample was weighed accurately. To it 100 ml of distilled water was added and kept covered overnight in the 250 ml conical flask. It was stirred intermittently in the initial period. It was filtered after keeping for 24 hours. 20 ml of the filtrate was accurately measured with a pipette and transferred to the already weighed evaporating dish. The evaporating dish was placed on a water bath for evaporation of the water. After evaporation of the water it was dried in an oven at 100o C, allowed to cool and weighed immediately. 58 Analytical Study From the weight of the extract obtained, the percentage of water-soluble extractive was calculated and expressed as % w/w. b. Alcohol Soluble Extractives This test was carried out to determine the alcohol soluble extractive of the test drug and determine the alcohol soluble chemical constituents. Procedure 2.5 gm. of the sample was weighed accurately. To it 50 ml of Methanol was added and kept covered overnight in the 250ml conical flask. It was stirred intermittently in the initial period. It was filtered after keeping for 24 hours. 20 ml of the filtrate was accurately measured with a pipette and transferred to the already weighed evaporating dish. The evaporating dish was placed on a water bath for evaporation of the Methanol. After evaporation of the Methanol it was dried in an oven at 100o C, allowed to cool and weighed immediately. From the weight of the extract obtained, the percentage of Alcohol-soluble extractive was calculated and expressed as % w/w. 3. Determination of Total Ash Value This test was conducted to determine the quality and purity of the drug and also to evaluate the percentage of inorganic radicals like carbonates, phosphates etc., naturally added as a form of adulteration. Procedure 2 gram of the sample was weighed accurately and taken in a pre weighed dried crucible. It was incinerated in a muffle furnace up to 450oC till vapors cease to be evolved; then the heat increased to 500oC until all the carbon is burnt off. The crucible was taken out, cooled and weighed immediately. From the weight of the ash, the ash value was derived with reference to the air-dried sample of the drug. It was calculated and expressed as % w/w. 4. Determination of pH Value This test is carried out to determine the pH of the test drug with the help of pH meter. Procedure 5g of test drug sample was weighted and taken in a conical flask. Then add 100 ml accurately measured distilled water was added and stirred well for few minutes; this solution was kept for some time and then filtered it through filter paper. The filtered solution was taken in a beaker. pH meter and electrodes were standardized with buffer solution of known pH i.e. 7 pH. Electrodes were rinsed with distilled water and introduce into the test solution contained 59 Analytical Study in a small beaker. pH value of solution was read. 5. Determination of Sugar This includes estimation of total, reducing and non-reducing sugars. a. Preparation of solution for analysis 2 gm of Ashwagandha granules accurately weighed was taken in 100 ml distilled water, warmed for about 5 minutes with stirring with glass rod by keeping over the water bath. Then filtered it through a filter paper and kept again over the water bath. After warmed, 5 ml of lead acetate solution was added and warmed for about 3-5 minutes to get the precipitate. Solution was filtered through filter paper. To the filtrate disodium oxalate was added to dissolve excess lead acetate and to get a clear solution. This solution was filtered through the filter bed made up of glass wool, cotton and Whattman no. 1 filter paper to get a clear solution, washing was given by distilled water and the volume was made up to 500 ml. b. Determination of reducing sugar To 50 ml. of above solution, 100 ml. each of Fehling’s A and Fehling’s B solutions were added, boiled for three minutes and filtered through filter bed (glass wool, cotton and Whattman no. 1 filter paper). Repeated washing was given by hot distilled water till clear, colourless filtrate was obtained. Precipitate of cuprous oxide (residue) was then taken with acid ferric solution to dissolve the precipitate completely in it. This solution was titrated against 0.1 N KMnO4 solution using orthophenanthrolin as indicator. At the end point the colour changes to green. From the amount of KMnO4 solution required the amount of copper was calculated. Then percentage of sugar content was determined from Hammond table. c. Determination of Total Sugar 25 ml of the clarified solution was taken; to it 5 ml of 6N HCl was added and heated on water bath at 67-71°C for three minutes. This is then treated with diluted sodium hydroxide solution by using phenolphthalein as indicator till pink color appeared. Volume was made up to 100 ml. For the determination of total sugar 50 ml of this solution was taken and the remaining procedure is same as that of reducing sugar. Percentage of total sugar was calculated from Hammond table. d. Determination of non-reducing sugar The non-reducing sugar content was obtained by subtracting reducing sugar from total sugar 60 Analytical Study i.e. Non reducing sugar = Total sugar – Reducing sugar Table 4 – Physico-chemical parameters of Ashwagandha granules Sr. No. Parameters Sample -Ashwagandha Granules 1. Loss on drying 0.105 % w/w 2. Water soluble Extract 69.6 % w/w 3. Alcohol soluble Extract 21 % w/w 4. Total Ash 6.19 % w/w 5. PH 5.16(Acidic) 6. Value Sugar Estimation Total Sugar – 50.86%w/w Reducing Sugar – 10.76%w/w Non - Reducing Sugar – 38.2% w/w Physico-chemical parameters The Common parameters mentioned for Ashwagandha in Ayurvedic Pharmacopoeia of India are total ash, pH Value, water and alcohol soluble extractives [2]. On its basis the parameters like total ash content, water and methanol soluble extractives etc., were selected. Presence of more moisture content may create problems in preservation of the sample. Hence loss on drying was also selected as one of parameters and it was found 0.105%w/w. Total ash value was 6.19 % w/w. The water-soluble extractive and methanol soluble extractive values were found to be 69.6 % and 21 % respectively; indicating considerable amount of polar compounds in the sample.The obtained pH value (5.16) was acidic in nature. Sugar estimation was considered as another parameter as the sample was in form of granules hence there is a possibility of significant sugar content. Total sugar was found to be 50.86 % w/w suggesting presence of considerable amount of sugar in the sample. Reducing and Non – reducing sugar was found to be 10.76%w/w and 38.2% w/w respectively. The details are mentioned in Table no.4. 1. Qualitative Test of Ashwagandha Granules: [4] The methanol extract of the sample was analyzed qualitatively for different functional groups. Details are placed at table no.5 1. Tests for Carbohydrate Molish’s test: 2ml of drug was taken in test tube. To it, 2 drops of fresh 10% alpha - naphthol solution in alcohol was added. Then 2ml of conc. H2SO4 was added slowly from the side of 61 Analytical Study the test tube so as to form a layer below the mixture. A violet ring at the juncture of two solutions indicates the presence of carbohydrate. 2. Tests for Steroids Libermann – Burchard reaction: The aqueous extract of test sample was taken in test tubes, by adding 2 ml chloroform. Then added 2 ml of acetic anhydride and 2 drops of conc. H 2SO4 from the sides of the test tube, the color changes to red, then blue and finally green was observed. 3. Tests for Alkaloids a. Dragendorff’s test: The methanolic extract of the sample was evaporated. On addition of a few drops of dilute 6N HCl and Dragendorff’s reagent alkaloids gave orange precipitates. 4. Tests for Flavonoids a. Shinoda test: The aqueous extract of test sample was taken in test tube, by adding 5 ml 95 % ethanol, few drops conc. HCl and 0.5 gm magnesium dust, pink color was observed. b. In the small quantity of residue, few drops of Lead acetate solution added and yellow colour precipitate was observed. 5. Tests for Saponin Glycosides Foam Test: After taking the drug shake it vigorously with distilled water. Persistent foam was observed. 6. Tests for Cardiac Glycosides Keller killiani test: To an extract of the drug in glacial acetic acid, few drops of ferric chloride and conc. H2SO4 were added. If a reddish brown colour is formed at the junction of two layer and upper layer turns bluish green, confirms the presence of cardiac glycosides. 7. Tests for Starch Iodine test: A test for the presence of starch in which the sample turns blue-black in colour when a few drops of potassium iodide solution is placed on the sample. 62 Analytical Study Table 5 – Qualitative tests for Ashwagandha granules Sr.No Test Name of Reagents Results 1 Carbohydrate Molisch’s test Positive 2 Steroid Liebermann – Burchard test Negative 3 Saponin Glycosides Foam Test Negative 4 Cardiac glycosides Keller killiani test Positive 5 Flavonoids Shinoda test Positive 6 Alkaloids Dragandroff’s test Positive 7 Starch Iodine test Positive Qualitative tests The methanol extract of the sample was tested qualitative for having an idea about the type of compound present in it. The result of the qualitative test indicates the presence of Carbohydrate, flavonoids, starch and alkaloids in the sample. Steroids and Saponin glycosides were absent in the sample. The results of the tests are shown in Table no.5 Thin Layer Chromatography [5], [6] Thin-layer chromatography is a technique, widely used for separation of an individual compound from a mixture. Thin layer chromatography (TLC) is extensively used due to its simplicity, rapidity, versatility and reproducibility. It can be used for determining the nature and amount of active substance present in a drug regardless of its origin. Even without knowing the exact chemical composition of a compound, TLC pattern can be utilized as a simple, inexpensive standard fingerprint for evaluating the quality of the sample with different solvent. TLC is mentioned as a primary tool for identification as part of monographs on all medicinal plants. [7] Sample preparation Sample was extracted for obtaining the alkaloid fraction by following the standard operating procedure. Methanol extract Granules weighing 5 gm are taken with 100 ml of methanol kept for twenty-four hours. Filtrate was prepared and evaporated till it gets dried in a flat- bottomed shallow dish and concentrated on water bath to volume of requirement. 63 Analytical Study This alkaloid fraction was used for the spotting of the TLC plate. Then the spotted TLC was run with the solvent systems separately. And the resulting TLC pattern was viewed under the daylight or under long wave ultra violet light at 366 nm or Short wave ultra violet light at 254 nm, after spraying with the reagents and drying in a hot air oven. The number of spots was recorded with their lengths and the respective retardation factor (Rf) values were calculated accordingly. Formula for the calculation of Rf value: Retardation factor (Rf) value = Distance travelled by a solute ---------------------------------Distance travelled by the solvent The Rf value is unique to each chemical entity, thus serving as a fingerprint for identifying a particular chemical substance in a given compound. Mobile phase: Chloroform (9 ml): Methanol (1 ml) Stationary phase - Silica gel - G Precoated plates Detection: a. Exposure to U.V. (254nm and 366 nm) b. Spraying with Dragandroff’s reagent Table 6: TLC of Methanol Extract of Ashwagandha Granules Extract Methanol extract Solvent system Wavelengt h Number of spots hRf value Observatio n 366 nm 2 28 60 Blue spot Blue spot 254 nm No spots - - CHCl3: MeOH (9:1) TLC of Methanol Extract of Ashwagandha Granules TLC of alcoholic extract of drug on silica get "G" plate using Chloroform (9 ml): Methanol (1 ml) shows two spots Under 366 nm U.V. at hRf 28 and 60. Where as in 254 nm no spots 64 Analytical Study were seen. On running mobile phase over stationary phase, well distributed, distinct, clear spots were observed without clumping. (Table no.6) Table 7: After spraying with Dragandroff’s reagent Extract Methanol extract Solvent system Spray Number of spots hRf value Observation CHCl3: MeOH (9:1) Dragandroff’s reagent 2 44 84 Pink spot Pink spot TLC of Methanol Extract of Ashwagandha Granules (after spraying with Dragandroff’s reagent) Thin Layer Chromatography of alcoholic extract of Ashwagandha Granules after spraying Dragandroff’s reagent followed by heating and then visualized in day light shows 2 prominent pink colour spots at hRf 44 and 84. (Table no.7) High Performance Thin layer chromatography: [8], [9] Detection and identification of a compound from the group of the compounds efficiently in the presence of pure reference compounds, otherwise, efficient separation and establishing the marker compounds is the hall mark of High performance thin layer chromatography. In these the plates are coated with high performance silica gels, which are of very small and uniform in size (about 5 μm). The high performance silica gel gives more efficient and reproducible separation than conventional grades of silica gel. Small volumes of samples are applied over it, the spots are compact and the spots can be used quantified with the help of the scanner using photo densitometry. The term HPTLC is used for the technique in which substances are accurately assayed using high performance grades of silica gel.This has been utilized on Methanolic extract of the sample Ashwagandha granules for establishing the fingerprints and to study for the presence of identical chemical constituents 65 Analytical Study Chromatographic conditions Preparation of samples- 2.5gm of powder was extracted with 50 ml methanol and kept overnight then it was filtered and 20 ml filtrate was concentrated to 10ml. This solution was used for spotting. Adsorbent Layer: Aluminum- backed Silica gel GF 60254 HPTLC plates (Merck). Sample Application: By Auto-sampler CAMAG Linomat V Mobile Phase: Chloroform (9 ml): Methanol (1 ml) Detection: 1. Viewing the TLC chromatogram at 254 nm under UV 2. Viewing the TLC chromatogram at 366 nm under UV Procedure Chromatography were performed on aluminium-backed silica gel GF 60254 plates (Merck) of 0.5 mm thickness. Before use the plates were prewashed with methanol, dried, and activated at 1100C for one hour between two glass plates of larger dimensions to prevent deformation of the plates. Sample (5μL) was applied to the plate, as 5mm bands, 5mm apart and 1cm from the edge of the plates, by means of a Camag Linomate V sample applicator fitted with a 100 μL Hamilton syringe. The data pair technique was used for application of samples to the plate. After drying of the spot, plates were placed in one of the trough of a Camag twin-trough chamber and the mobile phase Chloroform (9 ml) and Methanol (1 ml), was placed in another trough plates were left to equilibrate for 30 min. at 25 ± 20C and then placed in mobile phase. After that, plate were developed with Chloroform (9 ml) and Methanol (1 ml) as mobile phase in a Camag twin – trough chamber previously saturated with mobile phase vapor for 30 min. The development distance was 5.8 cm (development time 30 min.). After development, plates were dried in a current of hot air and then scanned at λ = 254 nm and λ = 366 using a deuterium lamp, with a Camag Scanner III under control of Win CATS software version 1.2.1 for both data acquisition and processing. The scanning wavelength was 254 nm, the scanning speed was 20 mm s-1, the offset 10%, and the sensitivity (SPAN) was optimized to 19. Peak height and peak area were integrated for the entire track (Table no. 7). Densitometric Evaluation of TLC Plate: Densitometric scanning was performed with a Camag T.L.C. scanner III in reflectance absorbance mode at 254 nm and 366 nm under 66 Analytical Study control of win CATS software (V 1.2.1 Camag). The slit dimensions were 6 mm x 0.45 mm and the scanning speed was 20 mm s-1. Table No.8: HPTLC of Methanol Extract of Ashwagandha Granules Extract Methanol extract Solvent system Wavelength Number of spots hRf value 366 nm 2 6 92 4 6 10 24 92 CHCl3: MeOH (9:1) 254 nm HPTLC of Methanol Extract of Ashwagandha Granules HPTLC of alcoholic extract of drug on aluminium-backed silica gel GF 60254 plates using Chloroform (9 ml): Methanol (1 ml) shows two spots Under 366 nm U.V. at hRf 6 and 92. Where as in 254 nm 4 spots were seen at hRf 6, 10, 24 and 92. (Table no.8) Table no.9: HPTLC - After spraying with Dragandroff’s reagent Extract Methanol extract Solvent system CHCl3: MeOH (9:1) Spray Dragandroff’s reagent No. of spots hRf value Observation 2 6 90 Pink spot Pink spot 67 Analytical Study HPTLC of Methanol Extract of Ashwagandha Granules (after spraying with Dragandroff’s reagent) HPTLC of alcoholic extract of Ashwagandha Granules after spraying Dragandroff’s reagent followed by heating and then visualized in day light shows 2 prominent pink colour spots at hRf 6 and 90. (Table no.9) References 1) Agarwal, A., Critical issues in Quality Control of Herbal Products, Pharma Times, 37(6), 09-11. 2005 2) Anonymous, The Ayurvedic Pharmacopoeia of India, Part- I, Vol I, 19, 1st Edition, 2001, Ministry of Health and Family Welfare, Department of AYUSH (Government of India) 3) Khandelwal K R, Practical Pharmacognosy, 19th Edition, Nirali Prakashan, Pune, 2008, pp 149 – 159. 4) Khandelwal K R, Practical Pharmacognosy, 19th Edition, Nirali Prakashan, Pune, 2008, pp 149 – 159. 5) Stahl E, Thin layer Chromatography- A Laboratory Handbook, 2nd edition. CBS, New Delhi, India, 1969, pg. - 60-86. 6) Touchstone J and J Sharma, Techniques and Application of Thin Layer Chromatography, 3rd edition. John Wiley and Sons, USA, 1982, p 140. 7) Eike Reich et al, TLC for the Analysis of Herbal Drugs - A Critical Review of the Status and Proposal for Improvement of Monographs, Scientific Note, Pharmeuropa 15.3, July 2003, 424-430. 8) Sethi PD, High Performance Thin Layer Chromatography, Quantitive Analysis of pharmaceutical Formulations, CBS, New Delhi, India, 1996, pp.10-18. 9) Sharma J and Fried B, Handbook of thin layer Chromatography, 2nd edition. Marcel Dekker, 1996, pp 16-17. 68