Download name of the candidate and address

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.
REFERENCES
1.
Taneja I, Diedrich A, Black BK, Byrne DW, Paranjape SY, Robertson D (2005). Modafinil
elicits sympathomedullary activation. Hypertension. 45: 612-8
2.
Jacobs, I., and D. G. Bell. Effects of Acute Modafinil Ingestion on Exercise Time to
Exhaustion. Med. Sci. Sports Exerc., Vol. 36, No. 6, pp. 1078–1082, 2004
13
3.
Mclellan TM, Ducharme MB, Canini F, Moroz D, Bell DG, Baranski JV, Gil V, Buguet A,
Radomski MW. Effect of Modafinil on core temperature during sustained wakefulness and
exercise in a warm environment. Aviat Space Environ Med 2002; 73:1079-88
4.
Brun J, Chamba G, Khalfallah Y, Girard P, Boissy I, Bastuji H, Sassolas G, Claustrat B
(1998). Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms,
rectal temperature and performance in healthy subjects during a 36 h sleep deprivation. J
Sleep Res. 7: 105-14.
5.
Glaister DH. The effects of gravity and acceleration on the lung. AGARD graph no 133.
England: Technivision services Slough; Nov 1970.
6.
Howard P. The physiology of positive acceleration. In: Gillies JA (ed.). A Text book of
Aviation Physiology. Oxford: Pergamon press, 1965. pp 551-687.
7.
Stoll AM. Human tolerance for positive G as determined by physiological endpoints. J
Aviat Med. 1956 Aug; 27(4):356-367.
8.
AGARD No 322. High G Physiological Training. NATO Publications.
9.
Burton RR. Man at high sustained +G acceleration: A review. Aerosp Med. 1974 Oct;
45(10)1115-36.
10. Burton RR. Straining GOR tolerance determinations are a measure of G duration not G
level tolerance. SAFE. 1999 Mar; 29(1):12-5.
11. Tesch PA, Hjort H, Balldin UI. Effects of strength training on G tolerance. Aviat Space
Environ Med. 1983Aug; 54(8):691-95.
12. Nicholas DC Green, Effects of long duration acceleration, Ernsting’s Aviation Medicine,
edited by David J. Rainford. 4th ed. London, England: Hodder Arnold; 2006
13. Stewart WK, (1941b) Report no 338, Flying Personnel Research Committee, Air Ministry,
London.
14. Britton SW, Corey EL, Stewart GA. 1942c. Report 56, Committee on Aviation Medicine,
National Research Council, USA
15. Gauer O, 1944. Luftfahrtmedizin. 9, 121.
14
16. Mcintyre AK, 1942. Report FR71, Committee on Flying Personnel Research, Royal
Australian Airforce.
17. Jasper HH, Clinton M, Cipriani A, Thorne GW. 1942. Report C2244, Committee on
Aviation Medicine Research, National Research Council, Canada
18. Britton SW, Pertzoff VA, French CR, Kline RF. 1947. Amer J Physiol. 150, 7
19. Van Middlesworth, L, RF Kline. Protection against acceleratory forces by carbondioxide
inhalation. Amer. J. Physiol. 152, 1948, 22-26.
20. Krutz, RW. Effects of elevated C02 breathing mixtures on +Gz tolerance. In: Review of
Air Force-sponsored Basic Research in Environmental and Acceleration Physiology,
Brooks AFB, 8-10 October 1974
21. Erman MK, Rosenberg R, Modafinil Shift Work Sleep Disorder Study Group
(2007)."Modafinil for excessive sleepiness associated with chronic shift work sleep
disorder: effects on patient functioning and health-related quality of life". Prim Care
Companion J Clin Psychiatry 9 (3): 188–94
22. Czeisler CA, Walsh JK, Roth T, Hughes RJ, Wright KP, Kingsbury L, Arora S, Schwartz
JR, Niebler GE, Dinges DF (August 2005). "Modafinil for excessive sleepiness associated
with shift-work sleep disorder".N. Engl. J. Med 353(5): 476–86
23. Caldwell JA, Mallis MM, Caldwell JL, Paul MA, Miller JC, Neri DF (2009). Fatigue
countermeasures in aviation. Aviat Space Environ Med. 80: 29-59.
24. Grzesk G, Polak G, Grabezewska Z, Kubica J. Myocardial infarction with normal coronary
angiogram: the role of ephedrine-like alkaloids. Med Sci Monit. 2004;10:CS15-CS21
25. Makris AP, Kelly TH et al. 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. Zolkowska D, Jain R, Rothman RB, Partilla JS, Roth BL, Setola V, Prisinzano TE,
Baumann MH (May 2009). "Evidence for the involvement of dopamine transporters in
behavioral stimulant effects of modafinil". J. Pharmacol. Exp. Ther. 329 (2): 738–46.
31. Ferraro L, Fuxe K, Tanganelli S, Tomasini MC, Rambert FA, Antonelli T (April 2002).
"Differential enhancement of dialysate serotonin levels in distinct brain regions of the
awake rat by modafinil: possible relevance for wakefulness and depression". J. Neurosci.
Res. 68 (1): 107–12
32. Raminder Kumar. Approved and Investigational Uses of Modafinil. Dept of Family
Medicine, University of Chicago, Chicago.
33. Saletu B, Frey R, Krupka M, Anderer P, Grun-Berger J, Barband M.J. Differential effects
of a new central adrenergic agonist Modafinil and d.amphetamine on sleep and early
morning behaviour in young healthy volunteers. Int J Chem Pharmacol Res. 1989; 3: 18395.
34. Saltin B, Hermansen L. 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