Jean E. Horn
A History of Narcolepsy and the Treatment of the Disorder
with Provigil (Modafinil).
According to Mignot (2001), in 1877 and 1878 the first
descriptions of narcolepsy and cataplexy was given by
Westphal and Fisher in Germany. The two researchers made a
connection between the narcoleptic symptoms, of sleepiness,
and the occurrence of emotionally activated muscle weakness
(Mignot, 2001). Mignot (2001) states that the hereditary
elements of narcolepsy were noted by both Westphal and
Fisher, as both Wesphal's patient, and the patient's
mother, and Fisher's patient, and the patient's sister
suffered from the disorder.
The syndrome of narcolepsy was first given its name by
Gelineau in 1880(Nishino & Mignot, 1997; Mignot 2001). The
term narcolepsy is a blending of the Greek words
'somnolence' and 'to seize' (Nishino & Mignot, 1997).
Gelineau's narcolepsy was first described as: excessive
daytime sleepiness, the occurrence of muscle weakness
activated by emotions, and sleep attacks (Nishino & Mignot,
1997). Lowenfeld in 1902 was the first, to use Gelineau's
description of narcolepsy as necessary symptoms for the
disorder of narcolepsy (Nishino & Mignot, 1997). Mignot
(2001) states that it was Lowenfeld in 1902, who was the
first to give the name of cataplexy to emotionally
activated muscle weakness. Nishino & Mignot (1997) credited
Henneberg as introducing the term cataplexy in 1916.
Ephedrine had been the treatment of choice for
excessive daytime sleepiness (EDS), before the discovery of
amphetamines in 1935 by Prinzmetal and Bloomberg (Mignot,
2001). In 1957, tricyclic antidepressants were discovered,
and imipramine was first used as a treatment for cataplexy,
by Akimoto, Honda, and Takahashi, (for a list of other
antidepressant see (Preston & Johnson, 2004, p.7) (Mignot,
2001). Mignot (2001) states that the discovery made by
(Akimoto et al.) led to the binary stimulant/antidepressant
model of treatment, which is generally used today. In 1960,
Yoss and Daly made the discovery of methylphenidate
(Ritalin), which is still used to treat excessive daytime
sleepiness (EDS) (Mignot, 2001).
Following the detection of REM sleep, it was suggested,
in 1960, by Vogel that there was an association between
irregular REM sleep and narcolepsy (Nishino & Mignot,
1997;Mignot,2001).In 1963,the researchers, Rechtschiffen,
Wolpert, Dement, Mitchell,& Fisher and Takahashi & Jimbo
separately and simultaneously made the connection that
narcoleptic patients frequently have sleep onset REM
periods (SOREMP) and the researchers further theorized that
cataplexy, sleep paralysis, and hypnologic hallucinations,
were irregular symptoms of disassociated REM sleep(Nishino
& Minot, 1997). According to(Nishino & Minot, 1997),the
researchers study results led to the now usually
acknowledged model, where the sleep disorders of narcolepsy
are separated into two different modes of disturbances:(1)
Sleep/wake disturbances (excessive daytime sleep
disturbances(EDS)/ sleep attacks and where night sleep is
fragmented;(2) Irregular REM sleep associated symptoms
(cataplexy, sleep paralysis, and hypnologic
hallucinations). As a result of the detection of
disassociated REM sleep, the MSLT (Multiple Sleep Latency
Test) was developed as a standard diagnostic test for
narcolepsy in 1970 (Mignot,2001). (For more information on
REM sleep see figure 1. (Thorpy,2001).
According to the authors, (Nishino & Mignot, 1997) the
first cases of canine narcolepsy was found in a dachshund
by (Knecht et al.1973), and a poodle by (Mitler et
al.1974).Mignot (2001) includes the beagle as a breed that
also suffers form canine narcolepsy. In 1977, canine
narcolepsy was also found in dobermann pinchers and
labrador retrievers, these breeds produced additional
litters which were affected with the disorder of canine
narcolepsy (Nishino & Mignot, 1997). The finding of
narcolepsy in dogs is important as the behavior (catalepsy)
is not a normal behavior in dogs (Palfai & Jankiewicz,
2001). The Stanford Center for Narcolepsy then began
breeding narcoleptic dobermann pinchers (first litter born
29/7/1976) for animal research, as the affected dogs show
symptoms of excessive daytime sleepiness, fragmented sleep
patterns, and emotionally activated cataplexy (Nishino &
Mignot, 1997;Mignot,2001). The authors, report that (Foutz
et al.1979; Baker et al.1982), were the first to find,
canarc 1, a recessive autosomal gene which is responsible
for the transmission of canine narcolepsy in dobermann
pinchers and labrador retrievers (Nishino & Mignot, 1997;
Nishino et al.2000). Nishino, Okura, and Mignot, (2000)
report that canine narcolepsy occurs intermittently and in
family units.
The standard procedure of animal research at Stanford
Center for Narcolepsy is as follows: Recordings of EEG are
measured for six hours in an animal or narcoleptics
following an active compound injection or the injection of
saline during the daytime (Nishino & Mignot, 1997, p.50).
In 1997, (Nishino & Mignot, 1997, p.50) evaluated the
potency and effectiveness of dextroamphetamine and
Modafinil in both control and narcoleptic dogs. The results
of the 1997 study were that Modafinil has a lower
possibility of abuse, less cardiovascular side effects, and
a reduced amount of tolerance as contrasted with
amphetamines. The authors concluded in 1997, that
Modafinil may become a replacement for amphetamine like
stimulants in the treatment of narcolepsy (Nishino &
Mignot, 1997).
At the 1975, La Grande Motte, France, International
Symposium narcolepsy was described as a sleep disorder of
an unknown source (Nishino & Mignot, 1997). The following
definition of narcolepsy symptoms was agreed upon by the
First International Symposium: Excessive daytime sleepiness
(EDS) (Nishino & Mignot, 1997; Mitler, Harsh, Hirshkowitz,
Guilleminault, 2000; Nishino et al. 2000; Thorpy, 2001;
Smith, Jackson, Neufing, McEvoy, & Gordon, 2004). REM
(Rapid Eye Movement) sleep occurrences such as cataplexy
(emotionally activated muscle weakness); sleep paralysis,
and hypnagogic hallucinations (Nishino & Mignot, 1997;
Mitler et al. 2000; Nishino et al. 2000; Thorpy, 2001).
Nishino & Mignot (1997) state that the principle
symptom of narcolepsy is not simply excessive sleep, but
more exactly the incapability to maintain both wakefulness
or consolidated sleep. Narcoleptic patients are
characteristically both extremely sleepy throughout the day
and also insomniacs at night (Nishino & Mignot, 1997).
Thorpy (2001) reports that the sleepiness related to
narcolepsy frequently results in 'sleep attacks' or
spontaneous naps on a daily basis that may happen at
unpredictable and improper times, for example, when eating,
talking, or driving. According to the International
Classification of Sleep Disorders (ICSD) Diagnostic
Criteria for Narcolepsy, 'sleep attacks' or 'spontaneous
naps', must occur on a more or less daily basis for a
minimum of three months before a diagnosis of narcolepsy
may be made (For more information see the (ICDS) Diagnostic
criteria for narcolepsy) (Nishino & Mignot, 1997,p. 33;
Thorpy,p.7, 2001).
Nishino et al. (2000) and (Chemelli, Willie, Sinton,
Elmquist, Scammell, Lee, Richardson, Williams, Xiong,
Kisanuki, Fitch, Nakazato, Hammer, Saper, and Yanagisawa
(1999) report that narcolepsy is an often under diagnosed
disorder as it affects 0.02 to 0.18% of the total populace
through out several nations. Chemelli et al. (1999) state
that both men and women are equally affected by narcolepsy
and that although rare there is a 1 to 2% risk of 1st degree
relatives having the syndrome. In 1983, it was discovered
that there is a relationship between the genetic allee HLA
DR2 and narcolepsy (Mignot, 2001). Since then, according to
(Chemelli et al.1999; Smith et al.2004), numerous studies
have reported a strong relationship among category IIHLA
halotypes on human chromosome 6 and narcolepsy. In
1992,HLADQB1*0602 and DQAI*0102 genes were found to be
located in 90% of afflicted populations contrasted with 12
to 38% in the general population indicating that
autoimmunity has a role in the syndrome (Chemelli et
al.1999; Thorpy, 2001; Mignot, 2001). Nishino et al. (2000)
report that narcolepsy and the human leukocyte antigen
(HLA) allele DQB1*0602 are strongly linked [frequently in
combination with HLA DR2 (DRB1*15)]. The researchers also
report that environmental factors are also related to the
illnesses predisposition (Nishino et al.2000).
In 1985, the hypothesis was made of a pontine
monoaminergic and cholinergic imbalance in narcolepsy
patients (Mignot, 2001, p.3). It was reported that
narcolepsy was the consequence of monoaminergic
hypoactivity and cholinergic hyperactivity in the pons, an
idea which is similar to the Hobson and McCarley model of
REM sleep regulation (Mignot, 2001, p.3). It was also found
that the amygdale has a major role in the progression of
narcolepsy as dopaminergic abnormalities were found in this
area of the brain.
According to (Mignot, 2001), at about the same time in
1998, Sakurai and LeLecea identified the neuroreceptors
hypocretins/orexins. Chemelli, Willie, Sinton, Elmquist,
Scammell, Lee, Richardson, Williams, Xiong, Kisanuki,
Fitch, Nakazato, Hammer, Saper, & Yanagisawa (1999)report
that those neurons which consist of the neuropeptide orexin
(hypocretin) are to be found solely in the lateral
hypothalamus and fire axons to many areas all through out
the central nervous system (CNS), which incorporate the
major nuclei implicated in sleep regulation. Mignot (2001)
reports that in 1999, it was found that canine narcolepsy
was the result of hypocretin receptor mutations. In 1999, a
knockout mouse was developed for the preprohypocretin gene,
and the genetically developed knockout mouse has been shown
to have sleep abnormalities similar to narcolepsy (Mignot,
2001, p.6). In 2000, there was a connection made between a
hypocretin deficiency and human narcolepsy (Mignot, 2001).
It has been suggested that the hyprocretin producing cells
are damaged in the autoimmune process in HLA associated
narcolepsy (Mignot, 2001, p.7). Mignot (2001, p.7) gives
the explanation as to why the cause of narcolepsy has been
overlooked before: There are only a few thousand cells in
the hypothalamus which produce hypocretins and a lesion in
this area may have been previously gone undetected.
In the late 1970s, French scientists discovered the
chemical ingredient Modafinil (O'Connor, 2004). Nishino &
Mignot (1997) state that Modafinil was first offered in
France as an experimental drug for the treatment of
narcolepsy in 1986. In France, Modafinil is sold under the
brand name Modiodal (Petiau & Krieger, 1997). In Canada,
Modafinil is sold under the name Alertec and over the Net
(The Good Drug Guide). Other names for Modafinil are
Vigicer and Modalert (The Good Drug Guide). In the USA
Modafinil is sold under the name Provigil (Modafinil
pronounced moe DAF i nil) (provigil.com; fda.gov).
However, regulations for the controlling of new medications
are more rigorous in the USA than in European countries
(for example, in Britain a drug may be on the market in six
months) (Palfai & Jankiewicz, 2001).
According to (Saletu, Frey, Krupka, Anderer, Grunberger,
and Barbanoj, 1989) Modafinil (CRL 40476) is a
benzhydryisulfinylacetamide and may be regarded as a
central alpha 1 adrenergic agonist with vigilance promoting
abilities. Modafinil is not a CNS stimulant, and it does
not have an affect peripherally (Saletu et al.1989;
Schwartz, Feldman, Fry, & Harsh, 2003). Instead, Modafinil
seems to elevate cortical arousal and activation through
the selective central pathways that control wakefulness
(Schwartz et al. 2003). According to (Schwartz et al. 2003;
Willie, 2005) Modafinil promotes the activation of wake
producing neurons in the tuberomammillary nucleus of the
hypothalamus, which intensifies cortical activity by way of
ascending histaminergic protrusions to the cortex. Mignot
(2001) credits Modafinil and amphetamines as wake advancing
agents which activate dopaminergic transmissions.
Willie, Renthal, Chemelli, Miller, Scammell,
Yanagisawa, and Sinton(2005,p.2) state that Modafinil
successfully improves wakefulness in every animal tested up
to this year (2005), including Drosophila, mice, rats,
cats, dogs, monkeys, and humans. Palfai & Jankiewicz,
(2001,p. 481) state that cats have similar nervous systems
as humans, but that they sleep 65 to 80% of the time, and
that cats are stimulated by medications that are a
depressant to humans. In the case of Modafinil an increase
of wakefulness in cats would be a good indication of
Modafinil usefulness as a medication for the disorder
narcolepsy. However, the effects of drugs on animal nervous
systems' are different from humans, and since it is not
easy to make predictions with animal testing, human trials
must be done (Palfai & Jankiewicz, 2001). In phase 1 of
human drug testing, the Irwin's test, founded in 1968, is
used to determine the drug successfulness in the treatment
of humans (Palfai & Jankiewicz, 2001).
Yet, the precise system of how Modafinil produces
wakefulness is still an unknown, in spite of the vast
amount of research that has been done (Willie et al.2005,
p.2). Willie et al.(2005,p.2)describes (a phase 11 study,
Palfai & Jankiewicz,2001) Modafinil as being
pharmacologically dissimilar from traditional wakefulness
inducing medications for example amphetamines,
methylphenidate(Ritalin), and pemoline, and when compared
and contrasted with other medications it is well tolerated
and Modafinil has a lesser possibility for abuse. Schwartz
et al. (2003) reported that Modafinil is the usual
treatment for (EDS) when patients are newly diagnosed with
the disorder of narcolepsy, or when the patient is
dissatisfied with other psychostimulant medications.
Methylphenidate (Ritalin) is a piperidine derivative,
which is frequently used for the treatment of narcolepsy
(Rush, Kollins, and Pazzaglia, 1998). Methylphenidate
(Ritalin) is structurally like d amphetamine (Dexedrine)
and both drugs apply their effects by way of central
dopaminergic systems (Rush et al.1998). Stoops, Lile,
Glaser, Paul, and Rush (2005) report that Methylphenidate
(Ritalin) may have a possibility of abuse as
Methylphenidate (Ritalin) and cocaine share similar
pharmacological and behavioral effects. Methylphenidate
(Ritalin) and cocaine are both dopamine reuptake blockers,
which raise dopamine levels at the synapses (Stoops et al.
2005). In the 1970s case reports of Methylphenidate
(Ritalin) abuse was starting to be reported in the literary
journals (Roehrs, Papineau, Rosenthal, and Roth, 1999).
Rush et al. (1998) reported that the DEA (Drug Enforcement
Agency) and DAWN (Drug Abuse Warning Network) had suggested
that Methylphenidate (Ritalin), like d amphetamine had the
same possibility of abuse.
Mitler et al. (2000) report of two large scale studies
which were conducted in the USA by the Narcolepsy
Multicenter Study Group (1998 & 2000), the purpose of the
studies was to test the efficacy and safety of Modafinil.
The studies were the largest ever conducted with more than
500 participants involved in the research (Mitler et
al.2000). The studies were 2 nine week, multicenter, double
blind, placebo controlled, fixed dosed trials (which is a
phase 11 study, (Palfai & Jankiewicz, 2001) (Mitler et
al.2000, p.232). Mitler et al.(2000,p.232)report that the
daily treatment consisted of 200 mg or 400 mg of Modafinil,
which produced significant improvement on standard (EDS)
tests, when conducted in a sleep laboratory. The following
test were used: The MSLT (Multiple Sleep Latency test),the
MWT(Maintenance of Wakefulness Test), CGIC (Clinical Global
Impression of Change)which showed that the symptoms of
narcolepsy were reduced by 58 to 74% of those participants
who were treated with Modafinil as contrasted with those
participants who were treated with a placebo, the ESS
(Epworth Sleepiness Scale)where participants reported a
significant decrease in the likelihood of napping in some
ordinary circumstances of daily living (Mitler et al.2000
p.232). Mitler et al. (2000, p.232) reported that one trial
incorporated a two week double blind, withdrawal segment.
The participants, according to (Mitler et al.2000) reported
a return to sleepiness as a consequence of the
discontinuance of Modafinil. Mitler et al. (2000) states
that the participants did not go through withdrawals when
Modafinil was discontinued, indicating that a dependency to
Modafinil had not built up in the nine weeks of daily
treatment at therapeutic dosage amounts.
Mitler et. al (2000) report shows that Provigil
(Modafinil) does not produce a dependency in the user, as
there were no withdrawal symptoms during the nine weeks of
treatment. In the studies, 4oo mg of Modafinil was used,
and still no dependency was shown (the FDA patent for
Provigil (Modafinil) is 100 mg to 200 mg). In the (Mitler
et al.2000) study the trials were conducted for 40 weeks,
with the same results as the other two studies, no
tolerance was developed during the 40 weeks of Modafinil
treatment.
In another study, Modafinil was found to be effective
in open label studies after 136 weeks (Schwartz et
al.2003). Open label (Phase 111) studies are conducted with
the participants being aware of the medication that they
are taking (Palfai & Jankiewicz, 2001). According to
(Palfai & Jankiewicz, 2001) the aim of the research is to
determine the safety of the drug on a large population.
As far as quality of life, Modafinil was found to
significantly improve the patient's general health, as well
as the patient's psychological and emotional health
(Schwartz et al.2003). Dinges and Weaver (2003) report that
narcoleptic patient's social functioning improved with the
use of Modafinil. Dinges and Weaver (2003) state, that
Modafinil does not disturb a patient's nighttime sleep.
Dinges and Weaver (2003) report that the American Academy
of Sleep Medicine has suggested that, Modafinil should be,
the traditional treatment for narcolepsy and OAS
(Obstructive Sleep Apnea). To further insure the quality of
life Cephalon, Inc. gives the following suggested dosage
for narcolepsy (adults 16 to 65 year old): 200 mg to be
taken in the morning as a single daily dose (provigil.com).
Lower daily dosage modifications should be made for elderly
adults (provigil.com). Patients with acute hepatic
impairment should be given a single daily dosage of 100 mg
(provigil.com). Patients taking other medications may need
a modification of their daily dosage of Provigil
(Modafinil) (provigil.com; fda.gov). Provigil (Modafinil)
should be stored at 68o to 770 F (200 to 250 C). The half
life of Provigil (modafinil) is 15 hours. Provigil
(Modafinil) may be taken with or without food, although the
absorption may be postponed by an hour or so
(provigil.com).
Ivanenko, Tauman, & Gozal (2003) report that there have
been very limited research studies of children who have
been treated with Modafinil, they report of only one other
study besides their study. When combining the number of
participants in the two studies, there have been a total of
24 children as of 2003, who have been treated with
Modafinil. Nevertheless the researchers did find a tendency
towards a decrease in REM sleep, persistence of REM sleep
latency, and an increased interval of stage NREM sleep
(Ivanenko et al.2003).
The authors of the study admit that there are
limitations to their study, for one the small number of
children who participated in each of the studies. In my
opinion more studies need to be conducted before Modafinil
is given to children. It should also be noted that
Cephalon, Inc does not recommend Modafinil to children
under 16 years of age.
Modafinil is the active chemical ingredient of Provigil,
and is not the generic form. Provigil met FDA approval
(Patent#.RE37516/4,927,855) on 24/12/1998 for the treatment
of narcolepsy (Mitler, Harsh, Hirshkowitz, Guilleminault,
2000; fda.gov). According to (Palfai & Jankiewicz, 2001, p.
498) even after Modafinil was approved by the FDA and sold,
postmarketing reports must be presented to the FDA (or any
other drug), the first year quarterly and the second year
every six months, and after two years, yearly. In 2004, the
FDA extended the approved (Patent) use of Provigil
(Modafinil) to include obstructive sleep apnea (OSA)/
hypopnea syndrome and shift work sleep disorder (SWSD)
(O'Connor, 2004; provigil.com; fda.gov). According to (The
Good Drug Guide) generic Provigil ought to be obtainable to
consumers from about 2006. Any other use of Provigil
(Modafinil) is considered an off label use(The Good Drug
Guide).The FDA has classed Provigil (Modafinil) as a
Schedule IV controlled substance, and Provigil is available
through a prescription (fda.gov; Mitler et al. 2000).
Provigil (Modafinil) tablets are sold in strengths of 100
mg to 200 mg. Provigil (Modafinil) is marketed under the
company name of Cephalon,Inc., located at West Chester, PA
(O'Connor,2004;med.stanford,2004;Willie et al. 2005). Other
branches of the company are located in France, Germany, and
U.K. (Cephalon, Inc.).
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Stoops, W. W., Lile, J. A., Glaser, P. E., Rush, C. R.
(2005). Discriminate stimulus and self reported
effects of methylphenidate, d amphetamine, and
triazolam in methylphenidate trained humans.
Experimental and Clinical Psychopharmacology 13 (1).
56 to 64. Retrieved (pages 1 to 14) 3/1/05 from
http://gateway.ut.ovid.com/gw2/ovidweb.cgi
The Good Drug Guide. Retrieved (pages 1 to 3) 3/13/05 from
http:www.modafinil.com/
Thorpy, M. (2001). Current concepts in the etiology,
diagnosis and treatment of narcolepsy. Sleep Medicine 2
(1). 5 to 17. Retrieved (pages 1 to 20) 3/1/05 form
http://www.sciencedirect.com/science?_ob=ArticleURL&
_aset=V-WA-A-W-BZ-MsSAYZ…
Willie, J. T., Renthal, W., Chemelli, R. M., Miller, M. S.,
Scammell, T. E., Yanagisawa, M., and Sinton, C. M.
(2005). Modafinil more effectively induces wakefulness
in orexin null mice than in wild type littermates.
Neuroscience 130 (4). 983 to 995. Retrieved (pages 1 to
21) 3/13/05 from http://www.sciencedirect.com.ezproxy.
humboldt.edu/science?_ob=ArticleURL&_aset=V-WA-A-W-AAZ-
MsSAYZA-UUW-U-AAABBBVWAA-AAAUEACUAA-EDEDBYZVC-AAZ-U&_
rodc=3&_fmt=full&_udi=B6TOF-4DSOOF-9&…
Figure is from: Thorpy, M., (2001). Current
concepts in the etiology, diagnosis and treatment
of narcolepsy. Sleep Medicine 2 (1). 5 to 17.
Abbreviations: Ach, acetylcholine; DA, dopamine;
NE, norepinephrine; Glu, glutamine; 5HT, 5
Hydroxytryptophan; D2,dopaminergic; D2
neuroreceptors; D3 receptors; LDT/PPT,
laterodorsal tegementum/peduncolopontine; PRF,
pontine reticular formation.
Eileen Klima
Modafinil (Provigil) Chemistry
Modafinil is a wakefulness promoting agent for oral
administration. Modafinil is considered a schedule IV drug
classification. Modafinil is an optically inactive
compound (Rx List, 2004). The chemical name for modafinil
is 2[(diphenylmethyl)sulfinyl]acetamide. The molecular
formula is C15H15NO2S and molecular weight is 273.36. The
chemical structure is (PDR, 2002):
Modafinil is a white to off white, crystalline powder
that is practically insoluble in water and cyclohexane. It
is slightly soluble in methanol and acetone. Tablets
contain 100mg to 200mg of modafinil and the following
inactive ingredients: lactose, cornstarch, magnesium
silicate, croscarmellose sodium, providone, magnesium
stearate, and talc.
Modafinil is a racemic (visually inactive) compound,
whose enantiomers (crystal molecular structure)(Davis,
2005) have different pharmacokinetics (e.g., the half life
of the l isomer [mirror image of another molecular
structure] is approximately three times that of the d
isomer in humans). The enantiomers do not interconvert.
At steady state, total exposure to the l isomer is
approximately three times that for the d isomer. The
trough (channel) concentration (Cminss) of circulating
modafinil. After daily dosing consists of 90% of the L
isomer and the minss and 10% of the d isomer. The
effective elimination halflife of modafinil after multiple
doses is about 15 hours. The enantiomer of modafinil
exhibit linear kinetics upon multiple dosing 200 to 600 mg
once daily in healthy volunteers. Apparent steady states
of total modafinil l-(-)modafinil are reached after two to
four days of dosing.
Modafinil is a reversible inhibitor of the drug
metabolizing enzyme CYP2C19 (Stanford Med. Ctr.), co
administration of modafinil with drugs such as Diazepam,
Phenytoin, and Propanolol, which largely eliminated via
that pathway, may increase the circulating levels of those
compounds. In addition, in individuals deficient in the
enzyme CYP2D6 (i.e., 7 to 10% of the Caucasian population;
similar or lower in other populations) the levels of CYP2D6
substrates such as tricyclic antidepressants and selective
serotonin reuptake inhibitors, which have alternative
routes of elimination through CYP2C19, may be increased by
co administration of modafinil.
Chronic administration of modafinil may also cause
modest induction of the metabolizing enzyme CYP3A4, thus
reducing the levels of co administered substrates for that
enzyme system, such as steroidal contraceptives,
cyclosporine and to a lesser degree, theophylline. Dose
adjustments may be necessary for patients being treated
with these and similar medications.
The precise mechanism through which modafinil promotes
wakefulness is unknown. Modafinil has wake promoting
actions like sympathomimetic agents including amphetamine,
methylphenidate, although the pharmacological profile is
not identical to that of sympathomimetic amines.
At pharmacologically relevant concentrations,
modafinil does not to most potentially relevant receptors
for sleep/wake regulation, including those for nor
epinephrine, serotonin, dopamine, GABA, adenosine,
histamine 3, melatonin, or benzodiazepines. Modafinil also
does not inhibit the activities of MAO B or
phosphodiesterases II V.
Modafinil is not direct or indirect acting dopamine
receptor agonist and is inactive in vivo preclinical models
capable of detecting enhanced dopaminergic activity. In
vitro, modafinil binds to the dopamine reuptake site and
causes an increase in extra cellular dopamine, but no
increase in dopamine release. In a preclinical model, the
wakefulness induced by amphetamine, but not modafinil, is
antagonized by the dopamine receptor antagonist
Haloperidol.
Modafinil does not appear to be a direct or indirect
alpha adrenergic agonist. Although modafinil induced
wakefulness can be attenuated by the alpha1 adrenergic
receptor antagonist prazosin, in assay systems known to be
responsive to alpha1 adrenergic agonists, modafinil has no
activity. Modafinil does not display sympathomimetic
activity in the rat vas deferens preparations (agonist
stimulated or electrically stimulated) nor does it increase
the formation of adrenergic receptor mediated second
messenger phosphatidyl inositol in vitro models. Unlike
sympathomimetic agents, does not reduce cataplexy in
narcoleptic canines and has minimal effects on
cardiovascular and hemodynamic parameters.
In the cat, equal wakefulness promoting doses of
methylphenidate and amphetamine increased neuronal
activation throughout the brain. Modafinil is equivalent
wakefulness promoting dose selectively and prominently
increased neuronal activation in more discrete regions of
the brain. The relationship of this finding in cats to the
effects of modafinil in humans is unknown.
In addition to its wakefulness promoting and increased
locomotor activity in animals, in humans, modafinil
produces psychoactive and euphoric effects, alterations in
mood, perception, and thinking, and feelings typical of
other CNS stimulants. Modafinil is reinforcing, as
evidenced by its self administration in monkeys previously
trained to self administer cocaine, modafinil was also
partially discriminated as stimulant like.
The optical enantiomers of modafinil have similar
pharmacological actions in animals. The enantiomers have
not been studied in humans. Two major metabolites of
modafinil, modafinil acid and modafinil sulfone, do not
appear to contribute to the CNS activating properties of
modafinil.
Absorption of modafinil tablets is rapid (Provigil,
2005), with peak plasma concentrations occurring at 2 to 4
hours. The bioavailability of modafinil tablets is
approximately equal to that of an aqueous suspension. The
absolute bioavailability was not determined due to the
aqueous insolubility (<1 mg/ml) of modafinil, which
precluded intravenous administration. Food has no effect
overall on modafinil bioavailability; however, its
absorption (tmax) may be delayed by one hour if taken with
food.
Modafinil is well distributed in the body tissue with
an apparent volume of distribution (~0.9 L/kg) larger than
the volume of total body water (0.6 L/kg). In human
plasma, in vitro, modafinil moderately bonded to plasma
protein (~60%, mainly to albumin). Even at much larger
concentrations (1000MM;>25 times the 40MM at steady state
at 400 mg/day), max modafinil has no effect on warfarin
binding. Modafinil acid at concentrations >500MM decreases
the extent of warfarin binding, but these concentrations
are >35 times those achieved therapeutically.
The major route of elimination (~90%) is metabolism,
primarily by the liver, with subsequent renal elimination
of the metabolites. Urine alkalinzation has no effect on
the elimination of modafinil.
Metabolism occurs through hydrolytic deamidation, S
oxidation, aromatic ring hydroxylation and glucuronide
conjugation. Less than 10% of an administered dose is
excreted as the compound. In a clinical study using
radiolabeled modafinil, a total of 81% of the administered
radioactivity was recovered in 11 days post dose,
predominantly in the urine (80% vs. 1% in the feces). The
largest fraction of the drug in urine was modafinil acid,
but at least six other metabolites were present in lower
concentrations. Only two metabolites reach appreciable
concentrations in plasma, i.e., modafinil acid and
modafinil sulfone. In preclinical models modafinil acid,
modafinil sulfone, 2[(biphenyl)sulfony]acetic acid and 4
hydroxymodafinil, were inactive or did not appear mediate
the arousal effects of modafinil.
In humans, modafinil shows a possible induction effect
on its own metabolism after chronic administration of
doses> 400 mg/day. Induction of hepatic metabolizing
enzymes, most importantly cytochrome P450(CYP)3A4, observed
in vitro after incubation of primary cultures of human
hepacytes with modafinil.
In a single dose 200 mg modafinil study, severe
chronic renal failure (creatinine cleareance <20ml/min) did
not significantly influence the pharmacokinetics of
modafinil,
but exposure to modafinil acid (an inactive metabolite) was
increased 9 fold.
Pharmacokinetics and metabolism were examined in
patients with cirrhosis of the liver (6 males and 3
females). Three patients had B or B+ cirrhosis and 6
patients had stage C or C+ cirrhosis. Clinically 8 of 9
patients were icteric and all had ascites. In these
patients the oral clearence of modafinil was decreased by
about 60%, the steady state concentration was doubled
compared to normal patients. The dose of modafinil should
be reduced in patients with severe hepatic impairment.
References:
Davis, F.A. Company (2005)Taber's Cyclopedic Medical
Dictionary. Philadelphia, PA
Palfai, T.,& Jankiewicz, H. (2001). Drugs and Human
Behavior (2nd edition). New York: McGraw Hill.
Physicians Desk Reference (2002). Medical Economics
Company, Inc.. Montvale, New Jersey.
Provigil (2005). Provigil Information. Retrieved March 22,
2005, from
http://www.provigil.com/physician/information/preclinical.a
spx
Rxlist (2004). Provigil Pharmacology. Retrieved March 12,
2005, from
http://www.rxlist.com/cgi/generic2/modafinil_cp.htm
Stanford Medical Center. (2002). Narcolepsy: Treatment and
medication. Retrieved March 25, 2005, from
http://www.StanfordMedicalCenter.com
Debra Pizzuto
Vigilance enhancing effects of Modafinil on Narcolepsy
Narcolepsy is a chronic neurological disorder,characterized
by EDS (excessive daytime sleepiness), cataplexy
(involuntary muscle weakness), and sleep paralysis, all
affecting quality of life and safety(due to a decrease of
REM sleep) in approximately .02 to .05% of the population
in the U.S. According to American sleep Disorders
Association standards of practice, clinical use of
stimulants in 94% of patients in treatment of narcolepsy is
standard practice (Nishino & Mignot 1997). The goal of
pharmacologic treatment for narcolepsy is to keep the
patient as alert as possible during the day and reduce
episodes of cataplexy while also minimizing the incidence
of undesirable side effects (Thorpy 2001). Amphetamine like
stimulants are the most commonly prescribed drug of choice.
Amphetamines important pharmacological properties are to
release catecholamines (dopamine, adrenaline and
noredrenaline)and to a lesser degree, serotonin in the CNS
and periphery.
Modafinil(Provigil, modiodal, Vigil, Alertec, modasomil) is
currently being promoted as a possible first line choice
for pharmacological treatment of narcolepsy (Nishino &
Mignot 1997). However, researchers suggest there is still
much controversy over the drugs mechanisms of action.
According to Nishino & Mignot (1997) modafinil has little
or no peripheral sympathomimetic action,less side effect
and less potential for abuse. It is tolerated well with
reported side effects comparable to placebo (Fry and the
U.S. modafinil Study Group, 1996). Modafinil selectively
stimulates adrenergic neuron receptors in the hypothalamus
and brain stem (agonist). These areas are thought to be
involved in regulation of normal wakefulness and general
alertness toward the environment without increasing motor
activity. They are receptive to noradrenaline by directly
stimulating postsynaptic receptor sites called (alpha.1
adrenergic).
According to Della Marca etal. (2004) modafinil action
probably involves several sites of action, including the
brainstem as reported by Engber et al., 1998 and Lin et al
1996. A number of neuromediators have been claimed to
account for its mechanism of action including GABA (Ferraro
et al., 1996 & Ferraro et al 1998), and indirectly,by
dopaminergic or serotonergic circuitry. It is suggested
that modafinil can exert region specific effects on GABA
circuitry in the medial preoptic area, posterior
hypothalamus and nucleus accumbens. According to Della
Marca, it does not affect GABA transmissions in the
thalamic areas. Della Marca et al.(2004) report that
glutamate releases from the brain stem afferent to thalamic
nuclei is significantly enhanced by modafinil. In
agreement with these findings, (Ferraro et al. 1999)report
similar results but in medial preoptic area and the
posterior hypothalamus as does Dela Mora et al.(1999) in
their investigation of slices of rat hypothalamus using
microdialysis. These two studies imply an indirect effect
from modafinil on these neurons. Both Ferraro et al. (1999)
and Dela Mora et al.(1999) suggest that modafinil
increases glutamate levels, strengthening the evidence for
GABA/glutamate interactions through increases in glutamate
and decreases in GABA.
Several studies suggest that modafinil does not mediate
wakefulness by a dopaminergic mechanism, therefore it is
not responsible for producing euphoric responses and abuse
potential. Ferraro et al. (1996) results suggest hat the
dopamine releasing action of modafinil is secondary to its
ability to reduce local GABAergic transmission, which leads
to the reduction of GABAa receptor signaling on the
dopamine terminals.
The differences in action between amphetamine like drugs
and modafinil are somewhat conclusive. One importanrt
difference is that modafinil does not seem to increase
spontaneous dopamine release, whereas amphetamine at the
same concentration doubles it resulting in substantial
increases in locomotor effects (Simon et al 1995). Simon et
al. concludes that the effects of modafinil does not make
it possible to exclude involvement of dopamine transmission
in this respect, just that there is clear evidence that the
mechanism of action is completely different. This research
does suggest that the involvement of a not yet defined
subtype of noradrenergic receptor is an attractive
hypothesis.
Modifinil inhibits the reuptake of noradreniline by the
noradrenergic terminal on sleep promoting neurons of the
ventrolateral preoptic nucleus. It significantly increases
excitatory glutamtergic transmission in cerebral cortex of
test animals, including freely moving guinea pigs and rats
(Tangelli et al 1994) whose results also suggest that the
balance between central noradrenaline and 5.HT transmission
is important for the regulation by modafinil of the
GABAergic release in the cerebral cortex of these subjects.
It has also been suggested that this regulation reduces
local GABAergic transmission, diminishing GABA(A) receptor
signaling on the mesolimbic dopamine terminals (the good
drug guide 2005; ). Other researchers (Zeng et al 2004)
suggest that modafinil can selectively alter GABA binding
density globus pallidus (in common marmosets) either by
preventing MPTP induced toxicity or through an action on
striatal output pathway. (Thorpy,2001; Engber et al.,
1998;)report primary mechanism of action unknown; modafinil
may inhibit GABA release via serotonergic mechanisms in
daily doses of 100-400 mg.
Touret et al.,(1995) report modafinil effects related to
the catecholaminergic system with long lasting wakefulness
related to activation of alpha and beta adrenergic
receptors in rat, cat, monkey, and mice.
Ferraro et al. (1996) suggested possible involvement of the
5HT3 recepotors in preoptic and posterior hypothalamus of
wake rats, stating that reduction of GABA transmission in
these areas may be in part involving local 5HT3 receptors.
According to Ferraro et al.,(2000) modafinil regulates
cortical serotonergic transmission. These findings suggest
that the drug preferentially acts by amplifying the
electro-neurosecretory coupling mechanisms and via
mechanisms which do not involve the reuptake process.
It is safe to conclude that the exact site of action of
modifinal has not been completely defined yet (Della Marca
et al.2004). Possible sites of action have been identified
in the cerebral cortex (de Saint hilaire et al., 2001),
thalamus (Ferraro et al., 1997), nucleus accumbens (Ferraro
et al., 1996) hippocampus (Ferrora et al 1997)medial
preoptic area and hypothalamus (Ferraro et al., 1996) and
in the brain stem (Touret et al., 1994). According to
Della Marca et al.,(2004) in theory these effects could
involve sleep related as well as non-sleep related brain
areas.
New discoveries in novel effects of neuropeptides called
hypocretins (orexins) recently identified as being
localized exclusively in cell bodies in a sub.region of the
hypothalamus (Peyron et al., 1998) suggest that hypocretins
are likely to have a role in several physiological
functions including sleep-waking cycle, relate to (Thorpy
2000) findings. Thorpy reports that narcolepsy is caused
by dysfunction of a family of wakefulness promoting and
sleep suppressing peptides known as hypocreton also known
as orexin neurons in cerebral spinal fluid thought to
originate in the lateral hypothalamic area and project
through the entire central nervous system.
According to Thorpy (2001) loss of function of the
hypocretin system could cause cataplexy through inhibition
of the brainstems motor excitatory system or reduced
excitatory output to the motor inhibitory system. It is
also possible according to Thorpy that it could increase
sleepiness through inhibiting cholinergic and aminergic
arousal systems.
(Bassetti et al., 2003) report that the full tetrad of
symptoms of human narcolepsy is present in only a minority
of narcoleptic patients, and that cataplexy is the only
pathognomonic symptom of narcolepsy. Biological markers of
narcolepsy include sleep onset REM periods on multiple
sleep latency tests. Clinical and polysomnographic
features in marker DQB1*0602 positive and negative
narcoleptic patients results from modafinil clinical trials
also support the notion cataplexy as the best clinical
predictor for DQB1*0602. While these results report
features of genetic markers, the results pertaining to
effects of modafinil on these patients remains less
conclusive, especially with regard to cataplexy, the second
most common symptom of narcolepsy.
Cataplexy has been extensively investigated in narcoleptic
dogs. According to Lin et al in (Thorpy 2001) canine
narcolepsy is phenotipically similar to human narcolepsy
and is caused by a mutation of the hypocretin receptor 2
gene. Recently, hypocretin cells have been reported to be
reduced or absent in patients with narcolepsy, further
suggesting, according to Thorpy, that hypocretins
may be the major sleep modulating neurotransmitters. The
cataplexy associated with narcolepsy in humans can be
managed with TCAs or SSRIs effectively over modafinil.
According to Thorpy (2001) treatment approaches involving
the hypocretins (orexins) hold promise and will be the
focus of new research in the future. Further research in
this area could potentially prove therapeutically novel
approach to treatment.
In conclusion, several studies not mentioned in this report
are attempting to evaluate the interaction effects between
the combined effects of TCAs, SSRIs, and modafinil on
narcolepsy, as well as the effectiveness of modafinil in
patients after sustained use of more traditional
amphetamine like compounds. Further research would increase
our current understanding pertaining to novel effects of
treatment and the mechanisms underlying sleep disorders.
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-------------------------
Eric Dick
There has always been a human desire to surpass the
natural human abilities that we all possess. This drive to
become something more than we are naturally capable of can
be seen in many aspects of our modern lives. Although
there are many ways in which we attempt to become super-
human one of the most prevalent ways is in our desire to
overcome the inevitable need for sleep. Caffeine in dollar
amounts rivals salt as a food additive. On convenient
store counters one can often buy "No-Doz" and other quick
pick me ups. We often brag to each other about how long we
stayed up with a work project or partying. In this modern
world graveyard shifts abound. The world is open 24 hours a
day and 7 days a week. One classic heroic figure of
capitalism is the CEO who never needs more than a few hours
of sleep -- he's proud of being on the go all the time.
"It's a standing joke among sleep doctors that nobody
sleeps in New York or Washington," says Helene Emsellem,
director of the Center for Sleep and Wake Disorders in
Chevy Chase. "Except in New York they do it for pleasure,
while in Washington they do it to work." Conquering sleep
has seemed to become a national past time. The great poet
Robert Frost wrote as early as 1923
The woods are lovely, dark and deep.
But I have promises to keep,
And miles to go before I sleep,
And miles to go before I sleep.
In this war on sleep, we have recently made even
greater progress. We have, or at least pharmaceutical
companies have, come across a revolutionary new find. It
is a drug called modafinil. Recent discoveries of this
drug initially made to target and help those people with
narcolepsy, who fall asleep frequently and uncontrollably,
have found that it has substantial implications for the
healthy individual as well. "In trials on healthy people
like Army helicopter pilots, modafinil has allowed humans
to stay up safely for almost two days while remaining
practically as focused, alert, and capable of dealing with
complex problems as the well rested. Then, after a good
eight hours' sleep, they can get up and do it again -- for
another 40 hours, before finally catching up on their
sleep." (Joel Garreau) Researchers say modafinil is highly
effect as a sleep deterrent without the usual jitters,
high, euphoria, crash, addictive characteristics or
potential paranoid delusions of stimulants such as
amphetamines or cocaine or even caffeine.
A writer for the on line news and opinion site Slate
recently recorded his experience as a healthy person taking
modafinil. David Plotz writes
Avoiding sleep for a week might be necessary in an
extreme situation like war, but the run-of-the-mill,
office-working, wannabe Superman requires something
different. We don't want a pill that will keep us
Exceling and Power Pointing for three days straight.
We just want something that makes us feel alert
through an entire normal day—a drug that makes us feel
as lively for the 18-hour-day we have to live as for
the 16-hour-day we ought to live…Hence my rendezvous
with modafinil. The drug, made by Cephalon, is
marketed under the creepy, pharma-Orwellian name
Provigil.
Here is the diary I kept.
Day 1, Monday
6:45 a.m.: Woken up by my daughter after the usual six
and a half hours.
7 a.m.: I open the bottle. The pills are monstrous. I
start to chicken out. I've never smoked pot, much less
taken cocaine or amphetamines. I decide to halve the
dosage. When I cut the first pill with my pocketknife,
half of it shoots off my bureau, slides across the
floor, and disappears under a dresser, no doubt to be
discovered and eaten by my daughter someday in the
near future. I pop the other 100-milligram half.
10 a.m.: At the office. I've felt no rush, but
alertness has snuck up on me. I am incredibly
attentive, but not on edge. I really, really feel like
working, a rare sensation.
12 p.m.: I reach for my usual lunchtime Coca-Cola,
then think better of it. Caffeine plus this
sprightliness and I will be ping-ponging off the
walls.
2 p.m.: This is when I usually fold. Today I am the
picture of vivacity. I am working about twice as fast
as usual. I have a desperate urge to write, to make
reporting calls, to finish my expense account—
activities I religiously avoid. I find myself talking
very loudly and quickly. A colleague says I am
grinning like a "feral chipmunk."
6 p.m.: Annoyed to have to leave the office when there
is all this lovely work to do.
9 p.m.: Home. After dinner, I race upstairs to start
working again. This is totally out of character,
especially on a Monday Night Football evening.
12 a.m.: I want the day to keep going but force myself
to go to bed. I fall asleep easily enough, but it's a
weird night. I have lots of dreams, which is unusual.
All are about Getting Things Done.
Day 2, Tuesday
6:30 a.m.: I wake up feeling good, cut another pill in
two, and pop a half.
9 a.m.-7 p.m.: I work like a fiend again. These have
been the two most productive days I've had in years.
Idea for new Provigil ad slogan: "Bosses' Little
Helper."
1 a.m.: Again I'm alert through the late evening—so
alert that I infuriate my wife by chattering at her
long past her bedtime. This time, when I do conk out,
I sleep deeply.
Day 3, Wednesday
7 a.m.: My one-man clinical trial starts to fall
apart. Everyone says modafinil is not addictive, but I
wake up worried about how long my supply will last. I
count the pills and realize I have only five and a
half left. That's just an 11-day supply. I remember
that I offered a sample to a friend yesterday. I am
annoyed—one day less for me. I start to cut up the
remaining pills, wondering if I can divide them into
thirds instead of halves.
I realize that maybe I can find a different supplier.
I log onto the Internet to see if I can get modafinil
on the sly. I find it cheap at the Discount Mexican
Pharmacy. I feel delighted and relieved. Then I feel
terrified that I am delighted and relieved. "Discount
Mexican Pharmacy"?!
7:30 a.m.: I end my experiment after two days. I am
acting like a lunatic. I stash the remaining pills in
a distant corner of the medicine cabinet. I calm
myself with the reminder that I have 11 more great
days to look forward to.
So is modafinil a drug for future superpeople? Maybe.
There are good reasons for doubt, though. The drug is
approved only for treating narcolepsy, and doctors are
not going to prescribe it like aspirin anytime soon.
Though patients don't seem to get addicted to
modafinil or to build a tolerance, according to
Walsleben, the drug has been in use for only 10 years,
and no one knows for certain that it's safe over the
long term. (Cephalon and other drug companies,
incidentally, are working on even more powerful
wakefulness drugs, but none is on the market yet.)
I loved taking modafinil for two days. I worked
supernaturally hard and well. But I'd be afraid to
make it a habit. I'll use it again for a special
occasion—when I am late for a deadline, perhaps. In
the meantime, I'll just yawn my way through the
midafternoon.
An account such as this gives us an interesting perspective
into the illicit use of modafinil by healthy individuals
seeking nothing more than a way to make their time more
effective and maintain a high level of alertness even when
excessively tired. Modafinil has also been found, as
alluded to above, to increase memory and other cognitive
abilities as well as deter sleep. In a recent United
Kingdom study with schizophrenics showed " patients with
schizophrenia performed significantly better at memory
tests involving short-term memory and, importantly, showed
improved mental flexibility, a core deficit normally seen
in patients with schizophrenia." And also ran a smaller
study on non-schizophrenic cognitive improvement and found
equal results. (Medical News) Modafinil may also be a
possible medicinal treatment for cocaine dependence, and an
aid to help overcome the drowsy symptoms of other
medications and procedures such as chemotherapy for cancer
patients. Modifinil has already found strong effectiveness
in the treatment of ADHD in which many users greatly
appreciate its small amount and smaller degree of side
effects.
Soon pharmaceutical companies will also be seeking to
release this drug to the greater public currently there are
only about 100,000 to 200,000 individuals suffering from
narcolepsy in the United State and probably a similar
amount worldwide. This is a relatively small market for a
drug that was rather expensive in its development and as a
result we will see the lobbying powers of Cephalon and
other pharmaceutical companies pushing for the general
release of this medication and life-style enhancement drug.
The use of this drug, as safe as it may seem is not
without its potential drawbacks.
William C. Dement, director of the Stanford University
Sleep Center, says, "The real problem is the accumulated
sleep debt, not daily need. It is an established fact that
lost sleep accumulates. You quickly become too tired to be
functional." Even with a substance like modafinil that can
keep you wakeful, if you don't ultimately catch up on the
sleep you missed, bad things will happen, sleep researchers
have always believed." (Joel Garreau) "Your grandmother was
right. If you don't get enough sleep, you're going to get
sick," says Chevy Chase researcher Emsellem. "Emphasize the
idea that we may be playing with fire here, who knows why
we get cancer? Chronic sleep deprivation may be a risk
factor for long-term disease. I would love to get by on
five hours of sleep because I don't like to lie in bed,
leashed by a sleep requirement. I would love to be
unleashed. But at the same time, prove that it is safe. I
don't need another round of winter flu, thank you very
much. Getting sick, being constitutionally exhausted."
As we rush into this potential world of sleeplessness
on must remember that he human being sleeps and dreams for
a reason. The restorative powers of sleep for the body
cannot be overlooked. Of course are productivity might
progress but at what cost. Years ago we thought that
development of automation and computers would give us as
people more free and recreational time. We thought that
the minutes we earned through automated processes would be
seen in the increase of our quality of life. As we know
not all of these visions of future utopian bliss held true
and I think we must also look at the implications of what
we do with all of that time. We can look at the words of
Sancho Panza in "Don Quixote" "Now blessing light on him
that first invented this same sleep!" says. It covers a man
all over, thoughts and all, like a cloak; 'tis meat for the
hungry, drink for the thirsty, heat for the cold, and cold
for the hot. 'Tis the current coin that purchases all the
pleasures of the world cheap; and the balance that sets the
king and the shepherd, the fool and the wise man even." and
take wisdom from those who have gone before us.
Resources
Joel Garreau."The Great Awakening." Washington Post.com.
Monday, June 17, 2002. Washington Post. March 9, 2005
.
David Plotz. " Wake Up, Little Susie." Slate.msn.com. March
7, 2003. Slate. February 12, 2005
Go back to the beginning
Copyright © 2005, Dr. John M. Morgan, All rights
reserved -
This page last edited 04-23, 2004
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