3.

Neurology

3.

3.

3.1. Adrenergic Neurotransmission

3.1.

3.1. Adrenergic

The mechanism of adrafinil appears to rely on

postsynaptic -adrenergic activity, since an
increase in locomotion caused by adrafinil is
blocked by prazosin (1 antagonist), Yohimbine
(2 antagonist), or phenoxybenzamine (mixed antagonist).[10] This was confirmed in another
study using quaking mice (a model for assessing
adrenergic neurotransmission) which noted that
benefit with adrafinil was blocked by prazosin.[11]
Adrafinil is thought to act in part centrally, givn
the lack of promotion of salivary viscous
secretion, which should occur with peripheral 1
activation.[10] Its action in reducing the secretion of
pancreatic fluids can be attributed to decreasing
vagal stimulation of the pancreas.[12][13]

, -,
,
,
, (1
), (2
)
( -).[10]

(
),
,
.[11]
,

,

1 .[10]



.[12][13]

Adrafinil -,
-
,
Adrafinil (1
), (2 )
( ). [10]

(
), ,
Adrafinil
. [11] Adrafinil
, ,
GIVN
,
1. [10]



[12]. [13]

Adrafinil or its bioactive metabolite (modafinil)

seems to act on -adrenergic receptors, based on
animal data.
It has been noted that blocking synthesis of
catecholamines (with -methyltyrosine) does not
prevent the actions of adrafinil,[11] providing
further evidence differentiating the actions of
adrafinil as distinct from that of amphetamine-like
stimulants.
3.2. Wakefulness
Oral administration of adrafinil in research

() (
).
,
( -

Adrafinil
(), ,
- ,
.
,
( -)
Adrafinil, [11]

animals is known to increase activity (measured

by locomotion) at doses ranging from 64mg/kg to
256mg/kg in mice.[14][10] The effects of adrafinil
have been noted to be both time and dose
dependent in dogs.[2] When testing nocturnal
activity in monkeys, it has been noted that
60mg/kg was able to effectively double activity
after the second dose whereas 90-120mg/kg
quadrupled activity after the first dose (original
text in French, cited via review[4]). The increase in
locomotion seen in animals is deemed to be
eugregoric (increases wakefulness) rather than
amphetamine-like, due to a lack of induced
anxiety,[15] and in dogs has been noted to persist in
magnitude of efficacy over the course of 33 days
of continuous supplementation (20-40mg/kg).[16] It
is hypothesized that the adrafinil-induced increase
in locomotion is secondary to increased
wakefulness, as it has been noted to have a larger
increase in locomotion when tested in the
nocturnal period of monkeys[4]. Moreover, at least
when testing the bioactive metabolite modafinil, a
failure to increase locomotion has been noted
when testing the waking period alone despite
increases over a time frame spanning into the
nocturnal period.[17]
Adrafinil appears to dose-dependently increase
locomotion in rats, which is indicative of a
stimulatory effect. Since adrafinil lacks anxiogenic
(anxiety producing) effects and has greater
efficacy during periods when research animals
would typically be asleep, the effect of adrafinil on
locomotion is thought to be secondary to

)
,[11]

.

3.2.

, ,
(
) 64
256
.

Adrafinil
,
.
3.2.
Adrafinil , ,
(
) 64mg / 256mg /
. [14] [10] Adrafinil
,
. [2]
, , 60
/
, 90120mg /
(
, [4]).
,
eugregoric ( ),
, , -
, [15],

33
(20-40 / ). [16] ,
Adrafinil

,
,

[4]. , ,

,

promoting wakefulness.

Edit4. Safety and Toxicology

4.1. General
In rats, one month of oral treatment up to
400mg/kg or three months treatment up to
200mg/kg has failed to cause any signs of toxicity.
[4]
LD50 values vary amongst species but have been
measured at 1,250mg/kg (mice) and 3,400mg/kg
(rats). An apparent suicide attempt in a human
subject through modafinil overdosing (4,500mg
acutely) produced insomnia and hyperexcitation
which reversed after 24 hours of hospitalization.[18]

,
,
. [17]
Adrafinil -,
,
.
Adrafinil (
)
, , ,
, Adrafinil

.

4.2. Case Studies

One case study with adrafinil dosed at 900mg
daily for ten months has noted the development of
orofacial dyskinesia without tremor or other
symptoms of Parkinson's which, despite not
improving over a four month absence from
adrafinil therapy, improved with the dopamine
depleting agent tetrabenazine.[19] Such a side-effect
is also reported with modafinil therapy,[20]
suggesting that adrafinil-induced orofacial
dyskinesia may be associated with conversion to
modafinil after ingestion. Notably, the patient in
the modafinil case study had multiple medical
problems that may have led to reduced clearance
of modafinil[20], possibly causing the orofacial
dyskinesia.

Edit4.
4.1.
,
400 / 200 /
-
. [4] 50
, 1,250mg / ( )
3,400mg / ().,

(4,500mg )
hyperexcitation
24 . [18]
4.2.

Case studies indicate that adrafinil and modafinil

are capable of inducing orofacial dyskinesia that
may persist after cessation of therapy. This
phenomenon is thought to be caused by abnormal
metabolism of modafinil in these individuals,
leading to reduced clearance.

Adrafinil 900



, ,

Adrafinil ,

. [19 ]
, [20]
, Adrafinil-


. ,

,
[20],
.
,
Adrafinil
,

. , ,

, .