Re: Staying Awake Drug?

From: Patrick Wilken (patrickw@klab.caltech.edu)
Date: Sat Dec 22 2001 - 18:51:29 MST


>However, I can't find a reference to the other one they covered,
>which is a lot more powerful. They mentioned that the B1 bomber
>pilots on those 12 hour flights have been using it. Also, in tests,
>they said that people had gone for up to 4 days without sleep with
>no degradation in performance, using this. Handy, indeed, and
>available by prescription.
>
>Please, somebody tell me what the drug's name is???

Hi. I think you are thinking of Provigil (modafinil) which is
currently being used for the treatment of narcolepsy. For more
information see:

http://www.rxlist.com/cgi/generic2/modafinil.htm

MECHANISM OF ACTION AND PHARMACOLOGY

The precise mechanism(s) through which modafinil promotes wakefulness is
unknown. Modafinil has wake-promoting actions like sympathomimetic
agents including amphetamine and methylphenidate, although the
pharmacologic profile is not identical to that of sympathomimetic
amines.

At pharmacologically relevant concentrations, modafinil does not bind to
most potentially relevant receptors for sleep/wake regulation, including
those for norepinephrine, 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 a direct- or indirect-acting dopamine receptor agonist
and is inactive in several in vivo preclinical models capable of
detecting enhanced dopaminergic activity. In vitro, modafinil binds to
the dopamine reuptake site and causes an increase in extracellular
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
a1-adrenergic receptor antagonist, prazosin, in assay systems known to
be responsive to a1-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 the adrenergic receptor-mediated
second messenger phosphatidyl inositol in in vitro models. Unlike
sympathomimetic agents, modafinil 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 at an 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 effects and increased locomotor
activity in animals, in humans, PROVIGIL 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 individually 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.

PHARMACOKINETICS

Modafinil is a racemic compound, whose enantiomers have different
pharmacokinetics (e.g., the half-life of the l-isomer 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
concentration (Cminss) of circulating modafinil after once daily dosing
consists of 90% of the l-isomer and minss 10% of the d-isomer. The
effective elimination half-life of modafinil after multiple doses is
about 15 hours. The enantiomers of modafinil exhibit linear kinetics
upon multiple dosing of 200-600 mg/day once daily in healthy volunteers.
Apparent steady states of total modafinil and l-(-)-modafinil are
reached after 2-4 days of dosing.

ABSORPTION AND DISTRIBUTION

Absorption of PROVIGIL tablets is rapid, with peak plasma concentrations
occurring at 2-4 hours. The bioavailability of PROVIGIL tablets is
approximately equal to that of an aqueous suspension. The absolute oral
bioavailability was not determined due to the aqueous insolubility (<1
mg/ml) of modafinil, which precluded intravenous administration. Food
has no effect on overall PROVIGIL bioavailability; however, its
absorption (tmax) may be delayed by approximately one hour if taken with
food.

Modafinil is well distributed in 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 is moderately bound to
plasma protein (~60%, mainly to albumin). At serum concentrations
obtained at steady state after doses of 200 mg/day, modafinil exhibits
no displacement of protein binding of warfarin, diazepam, or
propranolol. Even at much larger concentrations (1000M; >25 times the C
of 40M at steady state at 400 mg/day), max modafinil has no effect on
warfarin binding. Modafinil acid at concentrations >500M decreases the
extent of warfarin binding, but these concentrations are > 35 times
those achieved therapeutically.

METABOLISM AND ELIMINATION

The major route of elimination (~90%) is metabolism, primarily by the
liver, with subsequent renal elimination of the metabolites. Urine
alkalinization 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 parent 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. 1.0% 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-[(diphenylmethyl)sulfonyl]acetic acid and 4-hydroxy modafinil, were
inactive or did not appear to 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, has also been observed in vitro after incubation of primary
cultures of human hepatocytes with modafinil. (For further discussion of
the effects of modafinil on CYP enzyme activities see PRECAUTIONS, Drug
Interactions).

DRUG-DRUG INTERACTIONS

Because modafinil is a reversible inhibitor of the drug-metabolizing
enzyme CYP2C19, co-administration of modafinil with drugs such as
diazepam, phenytoin, and propranolol, which are largely eliminated via
that pathway, may increase the circulating levels of those compounds. In
addition, in individuals deficient in the enzyme CYP2D6 (i.e., 7-10% 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 ancillary routes of
elimination through CYP2C19, may be increased by co-administration of
modafinil. Dose adjustments may be necessary for patients being treated
with these and similar medications (see PRECAUTIONS, Drug Interactions).

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 (see PRECAUTIONS, Drug Interactions).

An apparent concentration-related suppression of CYP2C9 activity was
observed in human hepatocytes after exposure to modafinil in vitro.
Although no other indication of CYP2C9 suppression has been observed,
the in vitro results suggest that there is potential for metabolic
interaction between PROVIGIL and CYP2C9 substrates, such as warfarin or
phenytoin (see PRECAUTIONS, Drug Interactions).

-- 
--------------------------------------------------------------------------
Patrick Wilken  
Postdoctoral Fellow in Biology, Caltech
                                
Editor:        PSYCHE: An International Journal of Research on Consciousness
Board Member:      The Association for the Scientific Study of Consciousness
http://psyche.cs.monash.edu.au/                     http://assc.caltech.edu/



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