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RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES, BANGALORE ANNEXURE – II PROFORMA FOR REGISTRATION OF STUDENT FOR DISSERTATION 1. NAME OF THE CANDIDATE AND ADDRESS DR. G HARSHAVARDHAN INSTITUTE OF AEROSPACE MEDICINE INDIAN AIR FORCE VIMANPURA PO BANGALORE-560 017 2. NAME OF THE INSTITUTE INSTITUTE OF AEROSPACE MEDICINE INDIAN AIR FORCE VIMANPURA PO BANGALORE-560 017 3. COURSE OF STUDY AND SUBJECT DOCTOR OF MEDICINE (MD) IN AEROSPACE MEDICINE 4. DATE OF ADMISSION TO THE COURSE O1 JUL 13 5. TITLE OF THE TOPIC TO EXAMINE THE EFFECTS OF MODAFINIL ON SYMPATHETIC RESPONSIVENESS AND TOLERANCE TO +GZ ACCELERATION IN NON-SLEEP DEPRIVED PILOTS 1 6. BRIEF RESUME OF INTENDED WORK 6.1 NEED FOR THE STUDY: In the past, attempts have been made to find non-pharmacological and pharmacological methods to increase the tolerance to +GZ acceleration. Till date, none of the pharmacological measures are considered suitable due to associated untoward side effects. Modafinil is an agent which is currently recommended for the maintenance of performance with minimal untoward effects in prescribed doses. Modafinil has been reported to cause increase in heart rate and blood pressure with sustained adreno-medullary activation [1]. However, it does not cause an increase in muscle sympathetic nerve activity (MSNA) at rest and even attenuates it during an orthostatic stress [1]. Since Modafinil was found to enhance exercise tolerance in a study by Jacobs & Bell in 2004 [2], it is reasonable to presume that it may have a positive effect on ‘straining tolerance’. At the same time, Brun in 1998 and Mclellan in 2002 reported an increase in core body temperature after administration of Modafinil in their subjects [3, 4]. This would have a detrimental effect on tolerance to +GZ. understandably, due to increased pooling of blood facilitated by vasodilatation caused by such a rise in temperature. Literature available suggests that administration of Modafinil results into a constellation of physiological effects with opposing influence on tolerance to + GZ. In view of the above, investigating Modafinil’s ability to alter +GZ tolerance merits relevance. 6.2 REVIEW OF LITERATURE The effects of headwards acceleration in aviation have been known since Second World War and the famous ‘fainting in air’ episodes reported in Schneider cup race. In the past few decades, advances in metallurgy and technology have lead to a revolutionary change in the agility of modern high performance aircraft in military aviation. The aircraft of today can pull up to +12 GZ acceleration with relative ease. While the innate human tolerance to +GZ has remained the same, the methods and myriad means in form of manoeuvres and Anti-Gravity Suits (AGS), Anti-G Valves, changes in posture have helped him to sustain higher levels of + GZ for longer durations. It may well be presumed that a further increase in human ability to 2 sustain higher +GZ and for longer duration could now be achieved only by increasing the inherent tolerance of the pilot. The human physiology and pathophysiology under +GZ acceleration have been studied for more than seven decades and are more relevant with induction of high performance aircrafts. The physiological changes found during +GZ acceleration are fundamentally due to two main reasons, the first one being due to the increase in weight and the second due to increase in hydrostatic pressure that develops along the acceleration vector. Thus, when exposed to +GZ, the main limiting factor is cardiovascular, whereas with +Gy and +Gx, the respiratory system is the main limiting factor [5,6]. During +GZ acceleration, blood flow to all organs above the heart is diminished resulting in dimming of vision, peripheral loss of vision followed by black out which have been studied extensively. In flight, tolerance to acceleration is limited by the occurrence of unconsciousness (G induced Loss of Consciousness – G-LoC). Prior to this, there are certain less severe disturbances by which the pilot is alerted and thus can take precautionary measures to counteract them. From early research on humans, Alice M Stoll constructed a strength duration curve (Stoll’s Curve), which relates the intensity and duration of a given acceleration to the time at which loss of function occur, as indicated by blackout and unconsciousness [7]. The phenomena of grey out, black out and unconsciousness were described in the same study. It was also established that the rate of application of acceleration was important in determining the time gap between black out and unconsciousness. It was established that vision was the first faculty to be affected during positive acceleration. G Level and G Duration Tolerance Tolerance to GZ stress is usually measured as the highest level of GZ that a participant can tolerate before reaching predicted visual criteria. However, tolerance to +GZ stress has two dimensions, viz GZ level tolerance and GZ duration tolerance. The former is most frequently measured and simply referred to as GZ tolerance. It has been said that pilots of high performance aircraft must tolerate acceleration of the level >5 GZ if they are to succeed in an air combat. Sometimes, these accelerations may have to be tolerated for prolonged periods of 3 time. So the measurement of tolerance to high +GZ must consider both the level of +GZ and the time spent at that level [8]. Thus the word ‘tolerance’ in acceleration research is used to identify GZ level and duration at which specific physiological systems are significantly altered. Criteria used to quantify acceleration tolerance commonly are of visual origin, i.e, various stages of light loss: peripheral light loss (PLL) and central light loss (CLL) [9]. The GZ level tolerance is measured by the ability of the pilot to maintain vision or consciousness. GZ duration tolerance is measured as the duration for which pilots can sustain + GZ stress continuously till they become fatigued [8]. +Gz-Level Tolerance. GZ level tolerance is measured on the centrifuge using rapid GZ onset run (ROR >1G/s) or Gradual onset Run (GOR profile 0.1G/s) with subjects relaxed. As the GOR profile uses an onset rate of 0.1G/s, a considerable amount of time is required in order to reach high GZ levels. Considering that the time above 5 GZ will require some form of physical activity as the anti-G straining manoeuvre (AGSM), it is assumed that fatigue might play a significant role in this GZ level tolerance measurement. The straining GOR tolerance is thus considered to be a GZ duration tolerance rather than a GZ level tolerance [10]. Insufficient blood supply to the brain is the cause for inability to tolerate acceleration. This decrease in blood supply to the brain and eyes is the basis for the various subjective and objective methods to measure acceleration tolerance [8]. +Gz-Duration Tolerance. The pilot in a modern aircraft can tolerate high GZ levels for only limited periods with the existing anti-G protective methods. Once the GZ level is reached the duration becomes an important determinant in keeping the pilot in combat. The loss of consciousness experienced in pilots in combat after some time is mainly due to the fatigue. Hence fatigue determines the GZ duration tolerance. Fatigue based duration tolerance for high GZ is generally measured by using a GZ profile called simulated air combat manoeuvre (SACM). This uses subjective fatigue, as the tolerance end point [8]. This profile has repeating levels of GZ over time. Subjective fatigue remains the tolerance end point, which can be supported by the increasing of blood lactate level [11]. 4 The +GZ acceleration increases the weight of the columns of the blood above and below the heart, so that the vascular pressure below the heart is increased and the pressure above the heart is decreased. In most adults, the column of blood in the arterial system between the heart and the head of a seated individual is around 30 cm. If the density of blood(ρ) is assumed to be 1.06 g/ml and acceleration due to gravity, g is assumed to be 9.81m/s2, then the pressure drop at the head level caused by exposure to +1GZ may be calculated by formula (P= hρg) to be 22 mm of Hg. At higher +GZ levels the reduction in blood pressure will be in the multiples of 22 at the head level. This reduction in blood pressure is because of the pooling of the blood in the capacitance vessels of the lower limbs. These changes in intravascular pressure have an effect on the size of the blood vessels, since the latter is determined by the vascular transmural pressure, the dispensability of the vessel and the amount of blood available to fill it. In turn, changes in the size of the vessels have major effects on the regional blood flow and blood content. An increase in the transmural pressure of small arteries and arterioles below the level of heart will reduce the peripheral resistance and increase in local blood flow, while a decrease in the transmural pressure of vessels above the level of the heart can produce complete collapse of the vessels and cessation of the blood flow through them, resulting in loss of consciousness [6, 12]. Effects of drugs on innate relaxed +GZ tolerance Several non-pharmacological and pharmacological methods have been studied to improve the +GZ tolerance. Pre-flight meals, Physical fitness, ingestion of water [12] before going for flying, are shown to improve the innate tolerance to +GZ. Few drugs are also studied to know their effect on +GZ tolerance but with little success. Stewart WK (1941) found that there is no effect of Cycliton (Nikethimide) on +GZ tolerance [13]. Stewart (1941), Britton et al. (1942), Gauer (1944) have studied the effects of Psychostimulants like amphetamines, which are presumed to improve G tolerance, but found out that their effect is negligible [13, 14, 15]. Studies by Mcintyre (1942) et al. on antimalarials like Quinine and Atebrin and Jasper et al (1942) on Desoxycortisone didn’t show any improve in G tolerance [16, 17]. On adding 7% carbondioxide to oxygen systems in aircraft it was found that there was a significant increase in black out threshold [18]. Carbon dioxide may improve G tolerance because it is known to cause systemic vasoconstriction and cerebral vasodilation. Early reports by Ruff in 1938 and Matthes 5 in 1940 suggested that G tolerance is increased by 0.5 G with inspirates of 4-6% carbon dioxide. Brachial arterial pressure of dogs and monkeys at 6 G was increased by approximately 20 mm Hg with 13% carbon dioxide compared with control [19]. With 20% concentrations, the blood pressure was 45 mm Hg greater. It was necessary for carbon dioxide to be inhaled for atleast 30-60 sec before, and continued through, the acceleration period. Because some of the blood pressure benefits were associated with increased pressure at 1 G, redistribution of blood volume was speculated as a further effect of carbon dioxide. The gas provided no G protective effect when given in concentrations of 5-10%. Any protection was less if carbon dioxide was breathed for more than 7-12 min. Krutz found that human volunteers breathing 5.2 and 7.9 % carbon dioxide increased G tolerance by 0.51 and 0.88 G, respectively, compared to air breathing control values. The ROR profiles were conducted in the relaxed mode [20]. Glaister observed that relaxed G tolerance for GOR and ROR profiles increased by 0.8 and 0.9 G, respectively, when the inspirate contained 5% carbon dioxide and was given 2 min before the tests. With 7% carbon dioxide, tolerance was further increased by 0.4 and 0.7 G, respectively. Carbon dioxide however caused breathing discomfort and extreme headache. With a large number of drugs tested for possibility of improvement, none seemed to be significantly useful, as has been brought out in the reports published in the reports published by Committee on Aviation Medicine Research by the National Research Council, USA through the years 1940-1945. Modafinil in Aviation Modafinil is a wakefulness-promoting drug (eugeroic) that is approved by the United States Food and Drug Administration (FDA) for the treatment of narcolepsy, shift work sleep disorder [21, 22] and excessive daytime sleepiness associated with obstructive sleep apnea. The drug has been extensively tested and has been approved for military use by US army and US Air Force for its benefits derived out of its ability to promote performance and vigilance maintenance even in low doses in sleep deprived individuals [23]. 6 While the exact modality of its action remains largely unknown, the effects on various systems which may favour or go against its ability to affect +Gz tolerance are discussed in the succeeding paragraphs. Modafinil and its effect on CVS parameters Modafinil has been known to exert an effect on cardiovascular system. Taneja et al. in 2005, found that Modafinil increases resting heart rate (9.2±2.0 bpm; [mean ±SE], resting systolic blood pressure (SBP) (7.3±3.2 mm Hg), and resting diastolic blood pressure (DBP) (5.3±1.7 mm Hg) significantly (p<0.001). They also found that Modafinil elicited a 42% higher orthostatic increase in plasma norepinephrine (0.8±0.3 nmol/L, P=0.01), and caused a 33% increase in urine norepinephrine (5.1±1.1 nmol/L creatinine per day p=0.001), and an 81% increase in urine epinephrine (1.3±0.2 nmol/L creatinine per day p<0.001). The peroneal Microneurographic Sympathetic Nerve Activity (MSNA) is attenuated by Modafinil during orthostatic tilt (P<0.001) and α1 - Adrenoreceptor function was maintained. Hence, Modafinil substantially perturbed autonomic cardiovascular regulation by increase in heart rate and blood pressure. At baseline, MSNA burst activity was similar (placebo versus Modafinil 26±2.8 versus 23±2.4 bursts/min, respectively; p= 0.275). With increase in degrees of tilt, the MSNA activity increased for placebo and Modafinil. When comparing the two, the burst activity per minute with Modafinil was suppressed continuously than with placebo (p=0.012). The microneurographic burst activity and HR increased (decrease R-R interval) in both the phases in placebo and Modafinil, with increasing degrees of tilt, but Modafinil elicited lower burst activity and higher HR (lesser R-R interval) when compared with placebo for the same degrees of head tilt. Modafinil caused a strong central adrenergic response, as indicated by increased levels of catecholamines (plasma NE, dopa, DOPAC, urinary NE, and Epi), HR, and BP. This is attributable in part to adenomedullary discharge, as evidenced by increased Epinephrine excretion [1]. This aspect, when looked upon from the point of higher G loads suggest that there may be an effective Increased HR and BP on administration of Modafinil to humans which might be instrumental in augmenting the inherent/relaxed tolerance to +Gz. Jacobs and Bell in 2004 studied the effect of Modafinil on physical exhaustion. Mean ± SD times to exhaustion at 85% VO2max (TE) were 14.3 ± 2.8, 15.6 ± 3.8 and 18.3 ± 3.5 min for 7 the Control, Placebo, and Modafinil trials, respectively. Time to exhaustion for Modafinil was significantly longer than for the Control and Placebo trials. Oxygen uptake at exhaustion was slightly but significantly greater for Modafinil compared with Placebo and Control trials. HR increased with time and was further elevated by Modafinil. Subjective ‘Ratings of Perceived Exertion’ (RPE) were significantly lower for Modafinil compared with Control and Placebo but only after 10 min of exercise at 85% VO2max. Acute ingestion of Modafinil prolonged exercise time to exhaustion at 85% VO2max and reduced RPE. The RPE results suggest that the dampening of the sensation of fatigue was, in all probability, a factor responsible for the enhanced performance [2]. Since Modafinil has been found to enhance/prolong exercise tolerance with reduced subjective fatigue, it may be reasonable to presume that it may have a positive effect on increasing straining tolerance. Effect of Modafinil on Core Body Temperature Mclellan et al, in a study in 2002 found that the rectal temperature was elevated at rest 0.15-0.2⁰C following Modafinil ingestion throughout the period of sustained wakefulness. This increase in body temperature at rest was due to an increase in heat production during the first day of wakefulness followed by a lower evaporative heat loss during the second day [3, 4] in non-heat acclimatised males. The inhibition of GABA release following Modafinil ingestion increased sympathetic activity and lead to an increase in resting heart rate, metabolic rate, and body temperature. However, the increase in heat production that occurred with exercise was sufficient to mask the effects of the drug early during the time of sustained wakefulness. Therefore, the early effects of Modafinil on core temperature appeared to be mediated through the actions of an elevated sympathetic tone on heat production at rest that are not evident when substantial increases in heat production occur during exercise. As a result, core temperature increased under resting conditions, but the response during exercise remained matched to the relative intensity [34]. At the same time it may be pertinent to mention that 1⁰C rise in core body temperature is known to reduce the blackout threshold by 30-40 percent [6]. As the body temperature rises there is a progressive vasodilatation and large areas of the cutaneous vascular bed open up to facilitate heat exchange which in turn enhance pooling which might be directly responsible for reducing G Tolerance. 8 . The effect of Modafinil on the cardiovascular system has attracted attention because unlike analogous drugs such as amphetamine, cocaine, and ephedra alkaloids which resulted in an increased risk of myocardial infarction and extrasystoles [24], Modafinil presents no such risk when consumed in the prescribed doses for maintenance of performance. Additional is the fact that the drug has almost no history of development of tolerance and addiction [32]. Pharmacokinetics & Pharmacodynamics of Modafinil The peak of absorption of Modafinil is 2 to 4 hours of drug intake in healthy subjects [28]. Half life of Modafinil is 12 to 15 hours and its washout period is 96 hours (>5 half lives). Its pharmacokinetics are dose independent between 200 to 600 mg/day. Modafinil is primarily eliminated via metabolism, mainly in liver, with subsequent excretion in urine. Less than 10% is excreted in unchanged form. Metabolism is largely via amide hydrolysis, with lesser contribution from Cytochrome P450 mediated oxidative pathways [29]. Modafinil seems to inhibit the reuptake action of the dopamine transporter, thus leading to an increase in extracellular and thus synaptic concentrations of dopamine [30]. The locus of the monoamine action of modafinil has also been the target of studies, identifying effects on dopamine in the striatum and nucleus accumbens, norepinephrine in the hypothalamus and ventrolateral preoptic nucleus, and serotonin in the amygdala and frontal cortex [31]. The most commonly reported side effects are headache, anxiety, nervousness, nausea and dizziness. The side effects are minimal when lower doses like 100mg/200mg are administered [33]. Modafinil has been associated with statistically higher systolic BP, diastolic BP and heart rate as compared to placebo in a few studies [25]. However, other workers have reported no change in BP and pulse rate [26, 27]. As the side effects of Modafinil are minimal or negligible at prescribed doses [33] & that while aviators may use the drug for maintaining performance and vigilance, the effect on G tolerance, which is largely unknown till date, are worth investigating as any increase or decrease observed in G tolerance in the present study may have an impact on the usage by pilots in short and long term. 9 6.3 OBJECTIVE OF THE STUDY (a) To examine the core body temperature, heart rate, BP, sympathetic responsiveness, relaxed and straining tolerance to +Gz in a group of fighter pilots before and 2 hours after administration of 200 mg of Modafinil/ placebo. (b) To examine if changes in these variables after such an administration are different in the two groups. 7 MATERIAL AND METHODS 7.1 SOURCE OF DATA: (a) Inclusion Criteria: 40 healthy, young male pilots reporting to IAM for OPTRAM course will be taken as subjects (b) Exclusion criteria: Subjects who have experienced untoward effect or allergic manifestation with the administration of Modafinil. (c) 7.2 Sample size: 40 healthy, young male pilots METHOD OF COLLECTION OF DATA Material to be used: (a) Human Centrifuge in Department of Acceleration Physiology in IAM, Bangalore (b) Hand grip dynamometer (c) Sphygmomanometer (d) Thermometer Design of the study Experiment Design- It will be a placebo controlled, double blind, ‘between the groups’ design. Protocol The protocol for the study proposed is as follows 10 (a) Serving IAF pilots reporting at Institute of Aerospace Medicine (IAM), Bangalore for OPTRAM course will be recruited for the study. (b) Participants will be briefed a day prior to the commencement of experimentation as follows:(i) About the study protocol and risks involved. (ii) They would be instructed to abstain from alcohol for 24 hrs before experiment, and avoid smoking, tea/coffee on the day of the experiment atleast 2 hrs prior to the study. (iii) They would be advised to have adequate night sleep and to have a light breakfast before the experiment. (c) On the day of the experiment, they would be again briefed about the procedure and a written consent shall be obtained. (d) The Core body (oral) temperature of the participant would be measured with the help of a standard clinical thermometer. (e) Resting Pre-run heart rate will be measured using palpatory method on right radial artery in supine position. (f) Supine and sitting blood pressure will be measured (Non Invasive Blood Pressure (NIBP) method). (g) The participant would then undergo the Isometric Handgrip Test using Handgrip Dynamometer at 30% of maximal voluntary contraction for 04 min and all the above parameters will be recorded. (h) The participant would then be taken into the gondola of High Performance Human Centrifuge (HPHC). (i) The participant would be instrumented for acquiring online ECG, HR and SpO2, and harnessed to the seat in the gondola. (j) He shall be explained about the protocol of the run and operation of ‘dead-man switch’. (k) Once the participant gives a ‘Go-Ahead’ verbally on RT, the centrifuge run will commence with gondola lights switched off, and the HPHC brought to baseline of +1.4Gz. (l) Once again, the participant gives a ‘Go-ahead’, the profile (GOR 0.1 G/s) will be initiated and the centrifuge would be accelerated at the rate of 0.1G/s. 11 (m) The central & peripheral lights shall come ‘On’at +1.7Gz. Central red light and the two peripheral green lights one at each side start glowing. The participant would be instructed to fix his gaze on the central red light. (n) He would be repeatedly instructed to remain relaxed. (o) The moment he stops visualizing the peripheral green LEDs on the GRADEPS (Graded Dynamic End Point System) bar, i.e., the lights from 56⁰ to 52⁰ disappear from his visual field, he would be required to call out ‘NOW’ and start straining maximally i.e. all muscle groups in lower / upper limbs and abdomen. This point shall be referred to as ‘PLL-1’ and as such recorded as the relaxed tolerance of the participant. (p) While straining, when the participant experiences PLL again, he would release the ‘Dead-Man’s Switch’ (DMS) which would bring the centrifuge to a halt at the rate of 1G/s and that point shall be referred to as ‘PLL-2’ which is electronically recorded by the computer. (q) The exact protocol shall be repeated after 2-21/2 hours after ingestion of 200mg of Modafinil/placebo. (r) The physiological parameters shall be recorded again after each centrifuge run. Safety Precautions The run will be terminated from the control desk if any of the following occurs:(a) The participant calls that he lost lights but did not release the Dead-man switch (b) The participant experiences A-LOC or G-LOC (c) An abnormal response detects in ECG or HR (d) Loss of recording of any medical parameter (e) If any technical failure occurs in the data system, so that the medical monitor is unable to guarantee the participant’s safety. The physiological parameters will be continuously monitored in the medical monitoring system throughout the HPHC runs. 12 Recordings and measurements(a) Core Body (Oral) Temperature – Before and after administering Modafinil (b) Resting Supine HR and BP – Prior to and at the end of HPHC Runs (c) Data from Hand Grip Test - Prior to and at the end of HPHC Runs (d) Relaxed G tolerance (e) Straining G Tolerance (f) G-HR profile in the two exposures Analysis To examine the significance of difference in tolerance to +G Z (and other physiologic variables), a mixed model ANOVA will be employed. 7.3 DOES THE STUDY REQUIRE INVESTIGATION OR INTERVENTION TO BE CONDUCTED ON PATIENTS OR HUMANS OR ANIMALS? IF SO PLEASE DESCRIBE BRIFLY: Study requires human subjects. It is a non-invasive procedure. Informed consent will be obtained prior to administration of Modafinil and High Performance Human Centrifuge run. 7.4 HAS THE ETHICAL CLEARANCE BEEN OBTAINED FROM YOUR INSTITUTION IN CASE OF 7.3? Yes 8. 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The effects of Modafinil on food intake, verbal reports of drug effect, performance and cardiovascular activity in normal, healthy men and women. Obes Res. 2001; 9:181S. 26. Crabbe JB, Rogers NL, Szuba MP, Dinges DF. Modafinil does not affect heart rate and heart rate variability from 0800 to 1200 hours during 88 hours of simulated sustained operations. Sleep. 2003; 26:A173-174 15 27. Heitmann J, Cassel W, Grote L, Bickle U, Hartlaub U, Penzel T, Peter JH. Does short term treatment with Modafinil affect blood pressure in patients with obstructive sleep apnea? Clin Pharmacol Ther. 1999; 65:328-335. 28. Wong YN, King SP, Simcoe D, Gorman S, Laughton W, Mccormick GC, Grebow P. Open label, single dose pharmacokinetic study of Modafinil tablets: influence of age and gender in normal subjects. J Clin Pharmacol. 1999; 39: 281-288. 29. Robertson PR, Hellriegel ET. Clinical Pharmacokinetic profile of Modafinil. Clin Pharmacokinet, 2003, 42(2), 123-7. 30. 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Esophageal, rectal, and muscle temperature during exercise. J Appl Physiol 1966; 21: 1757-62. 9. SIGNATURE OF THE CANDIDATE Date: [DR G HARSHAVARDHAN] 16 10. REMARKS OF THE GUIDE It would be a good study with a direct relevance in the field of acceleration physiology. 11. NAME AND DESIGNATIONS 11.1 GUIDE: GP CAPT (DR) KK TRIPATHI MD, Ph.D PROFESSOR IN AVIATION MEDICINE, IAM IAF, BANGALORE - 560 017 11.2 SIGNATURE: 11.3 HEAD OF THE DEPARTMENT: WG CDR (DR) MONA DAHIYA ASST PROF & HEAD DEPARTMENT OF AP & SO IAM IAF, BANGALORE - 560 017 11.4 SIGNATURE: 17 12 REMARKS OF THE PRINCIPAL AND COMMANDANT 12.1 REMARKS: 12.2 SIGNATURE: AIR CMDE (DR) S CHOWDHARY PRINCIPAL & COMMANDANT IAM IAF, BANGALORE-560 017 18 CERTIFICATE OF ACCEPTANCE BY THE GUIDE I, Gp Capt (Dr) KK Tripathi MD, Ph.D, Professor of Aviation Medicine, IAM, IAF, Bangalore hereby certify that I accept Dr G Harshavardhan as a candidate for MD (Aerospace Medicine) course. The title of his dissertation topic is: TO EXAMINE THE EFFECTS OF MODAFINIL ON SYMPATHETIC RESPONSIVENESS AND TOLERANCE TO +GZ ACCELERATION IN NON-SLEEP DEPRIVED PILOTS He will be under my guidance during the entire period of his study and thesis work. Date: Nov 2013 GP CAPT (DR) KK TRIPATHI MD, Ph.D PROFESSOR IN AVIATION MEDICINE, IAM IAF, BANGALORE - 560 017 19 CERTIFICATE FROM THE HEAD OF THE INSTITUTION Permission is hereby accorded to the student, Dr G HARSHAVARDHAN, to undergo MD (Aerospace Medicine) course being conducted at the Institute of Aerospace Medicine, IAF, Bangalore affiliated to Rajiv Gandhi University of Health Sciences commencing from 01 July 2013 under the guidance of, Gp Capt (Dr) KK TRIPATHI, MD, Ph.D, Professor of Aviation Medicine, IAMIAF Bangalore-560 017. Date: Nov 2013 AIR CMDE (DR) S CHOWDHARY PRINCIPAL & COMMANDANT IAMIAF, BANGALORE-560 017 20