Alpidem was first described by 1982[6][7] and was introduced for medical use in
France in 1991.[3][8][9] It was also under development for use in other countries in the 1990s, but development was discontinued and the drug was never marketed in any other country.[8][9] Alpidem was
withdrawn from the market in France in 1993 due to liver toxicity.[10][11][12][13][3]
Medical uses
Alpidem was approved for the treatment of
generalized anxiety disorder and possibly also other
anxiety problems.[3][14][8] By 1990, 17clinical studies including more than 1,500patients had been conducted in
Europe studying alpidem for the treatment of anxiety.[2][3] In clinical trials, alpidem demonstrated effectiveness in the treatment of chronic and situational
anxiety, including
stress-related anxiety, generalized anxiety, and
adjustment disorder (situational depression) with anxiety.[2][14] It also showed preliminary effectiveness in institutionalized individuals with chronic
psychosis and high anxiety levels.[2][15] The effectiveness of alpidem for
panic disorder, on the other hand, is understudied and uncertain.[14][16]
The anxiolytic effects of alpidem are described as rapid, robust, and maintained in the long-term.[3][2] For situational anxiety, the anxiolytic effects of alpidem
onset within 1.5 to 2hours, whereas for chronic anxiety disorders the effects onset within 3 to 5days in most cases.[2] No indications of
tolerance to its anxiolytic effects or need for dose increases have been observed.[2] In people with anxiety taking alpidem, improvement in
mood and
sleep have also been found.[4]
The anxiolytic effectiveness of alpidem, for example measured by reductions on the
Hamilton Anxiety Rating Scale (HAM-A), was superior to
placebo and comparable or equivalent to that of
benzodiazepines including
diazepam (10–15mg/day),
lorazepam (1–6mg/day), and
clorazepate (30mg/day) in directly comparative
randomized controlled trials.[3][2][4][14] Alpidem has also been directly compared with
buspirone (20–30mg/day) for generalized anxiety disorder.[17] Relative to buspirone, it was found to produce more rapid improvement, to have significantly greater effectiveness, and to have fewer
side effects and a lower discontinuation rate.[17]
The recommended dose of alpidem was 75 to 150mg total per day, given in single doses of 25 to 75mg two to three times per day.[3][18][19]
Alpidem is described as
well-tolerated.[2]Side effects include
sedation (6–8%; dose-dependent),
fatigue (3–4%),
dizziness (3–4%), and
headache (2–3%), among others.[3] It is reported to have minimal sedative effects and to have virtually no negative effects on
cognition,
memory, and
psychomotor function at therapeutic doses.[3][2][4] However, some impairment of
vigilance and psychomotor function has been reported at high doses (100–200mg).[3][2] In addition,
driving ability has been studied with alpidem and has been found to be impaired.[21][22] The central side effects of alpidem were found to be no worse in elderly people than in young adults.[3][23]
The side effects of alpidem are described as quite different from those of
benzodiazepines.[3] In directly comparative trials, alpidem produced similar anxiolytic effects with less
fatigue,
asthenia,
depressive mood, and psychomotor impairment than benzodiazepines, while rates of
somnolence and
drowsiness were comparable to benzodiazepines but described as milder in severity.[2][4] Whereas benzodiazepines commonly produce
dizziness,
muscle weakness,
fatigue, and
sleepiness as side effects, these are not prominent adverse effects with doses of alpidem that have similar anxiolytic effectiveness.[3] The lack of withdrawal or rebound symptoms with alpidem upon discontinuation is also in contrast to benzodiazepines.[2] In addition, alpidem significantly antagonized the
amnestic effects of lorazepam and showed similar trends for other cognitive measures in a clinical study in which the two drugs were combined and assessed for
interaction.[3][24]
Little information is available on
overdose with alpidem.[2] Doses of as high as 300mg/day, which is 2 to 4times the recommended total daily dose, were assessed in clinical trials.[2][3][30]
Alpidem is a
GABAA receptor positive allosteric modulator (GABAkine),[31] specifically acting as an
agonist of the
benzodiazepine site of the
receptor complex (formerly known as the central benzodiazepine receptor (CBR)).[3] In addition to its
affinity for the benzodiazepine site of the GABAA receptor (Ki = 1–28nM), alpidem has similarly high affinity for the
translocator protein (TSPO) (formerly the peripheral benzodiazepine receptor (PBR)) (Ki = 0.5–7nM).[32][33][34][35][36] Alpidem shows more than 500-fold
selectivity for
α1 subunit-containing GABAA receptors over
α5 subunit-containing GABAA receptors[3] and 80-fold selectivity for α1 subunit-containing GABAA receptors over α3 subunit-containing GABAA receptors.[37] However, alpidem has also been described as
potently modulating α1,
α2, and α3 subunit-containing GABAA receptors with no effect on α5 subunit-containing GABAA receptors.[38] Findings appear to be mixed on whether alpidem is a
partial agonist or a
full agonist of the benzodiazepine site of the GABAA receptor.[3] In animals, alpidem has
anxiolytic-like effects in some but not all models, weak
anticonvulsant effects, and weak or no
sedative,
amnesic,
ataxic, or
muscle relaxant effects.[3][5][39][30] High doses of alpidem
antagonize the sedative and muscle relaxant effects of
diazepam in animals.[39]Flumazenil has been shown to antagonize the anxiolytic and anticonvulsant effects of alpidem in animals.[5] Besides acting directly via the GABAA receptor, interactions with the TSPO might also contribute to the anxiolytic effects of alpidem.[40][32][41][38] This protein mediates promotion of
neurosteroidogenesis in the
brain, for instance of
allopregnanolone.[40][32][41]
Alpidem is
structurally related to
zolpidem, and both alpidem and zolpidem are GABAA receptor positive allosteric modulators of the benzodiazepine site with preference for α1 subunit-containing receptors.[3][14] Both alpidem and zolpidem have very low affinity for α5 subunit-containing GABAA receptors, in contrast to
benzodiazepines.[42][43] Similarly, both alpidem and zolpidem are selective for
γ2 subunit-containing GABAA receptors, with very low affinity for
γ1 and
γ3 subunit-containing GABAA receptors, in contrast to other Z-drugs and to diazepam.[44] Alpidem has very high affinity for the TSPO, while zolpidem has very low affinity for this protein.[14][45][46] The affinity of alpidem for the TSPO (also previously known as the ω3 receptor)[47] was once the highest of any drug known.[45] Although benzodiazepines like diazepam are also known to bind to the TSPO, the affinity of alpidem for this protein is at least 3,000-fold higher in comparison.[45] Whereas zolpidem shows
hypnotic and
sedative effects and is used to treat
insomnia, alpidem shows mainly
anxiolytic effects and is used to treat anxiety disorders.[3][14] Alpidem was developed before the widespread use of
recombinant GABAA receptors.[3] Hence, its pharmacological profile at the GABAA receptors, including its profile at different subpopulations of these receptors, has never been fully characterized.[3]
The
pharmacodynamicmechanisms underlying the anxioselective (anxiolytic-selective) profile of alpidem as a GABAA receptor positive allosteric modulator are unclear.[3][48] In any case, subtype selectivity for different populations of GABAA receptors, partial agonism of the benzodiazepine site of the GABAA receptor, and/or interactions with the TSPO may potentially all be involved.[3][45][5][49][39][50][51] Although anxioselective profiles have been observed for many GABAA receptor positive allosteric modulators in
preclinical research, alpidem is the only GABAA receptor positive allosteric modulator for which anxioselective effects have been unambiguously demonstrated in human
clinical trials.[3]Ocinaplon has also shown preliminary signs of an anxioselective profile in clinical studies, but development of this agent was discontinued in late-stage trials due to findings of
elevated liver enzymes in a small subset of patients.[3] GABAA receptor positive allosteric modulators with selectivity for
α2 and
α3 subunit-containing GABAA receptors over α1 subunit-containing GABAA receptors, for instance
adipiplon,
L-838,417, and
darigabat—among others, have been and are under investigation as potential anxioselective agents.[3][31][52] However, no such drugs have yet completed clinical development or been marketed for medical use.[31][52][48][38] Despite many developmental failures, alpidem serves as a potential proof of concept that anxioselective GABAA receptor positive allosteric modulators may be possible.[3][48][38] However, if interactions with the TSPO are key to the anxiolytic effects of alpidem, then this may not actually be the case.[41]
Pharmacokinetics
Absorption
Alpidem is taken via
oral administration.[1] The
absorption of alpidem is rapid and it reaches
peak levels after 1.0 to 2.5hours.[1] Its overall
bioavailability is estimated to be approximately 32 to 35%, but no precise value for absolute bioavailability has been determined.[1][2] Absorption of alpidem as indicated by peak and
area-under-the-curve levels is linear across a dose range of 25 to 100mg.[1] Food increases the bioavailability of alpidem by 15 to 20%.[1]
Distribution
Alpidem is a highly
lipophiliccompound and in animals is extensively
distributed into
lipid-rich tissues.[1] Similarly, alpidem has been shown to cross the
blood–brain barrier in animals, and showed a brain/plasma ratio of about 2.0 to 2.5 following systemic administration.[1] This is related to significantly slower
efflux of alpidem from the brain than entry.[1] The
active metabolites of alpidem are also brain-penetrant, although occur in the brain at levels lower than those of alpidem.[1] Alpidem may be concentrated more in lipid-rich
white matter brain structures than
grey matter structures.[1] In humans, the
volume of distribution of alpidem is large at 8.7L•kg−1.[1] The
plasma protein binding of alpidem is 99.4%, with similar isolated fractions bound to
albumin (97.0%) and
α1-acid glycoprotein (97.3%).[1] The free fraction of alpidem is slightly higher in people with
cirrhosis (0.86 ± 0.06%) and
renal failure (0.72 ± 0.03%) relative to normal individuals (0.61 ± 0.05%).[1]
Alpidem is
eliminated mainly in
feces, with less than 0.1%
excreted in
urine.[1] A majority of alpidem is eliminated within 48 to 72hours following oral dosing.[1] Only trace amounts of unchanged alpidem are found in feces and urine.[1] The metabolites of alpidem are excreted mainly in via the
bile in feces, with less than 5% eliminated via urine.[1]
The
elimination half-life of alpidem was mean 18.8 ± 0.8hours (range 7 to 44hours) following a single 50-mg oral dose given to young individuals.[1] In elderly individuals, a trend toward a longer half-life was observed (22.6 ± 2.3hours).[1] Conversely, in children age 8 to 12years, the half-life of alpidem was considerably reduced (11.4 ± 1.9hours).[1] The half-lives of alpidem and its metabolites are significantly prolonged in people with
hepatic impairment.[1] Conversely, the half-lives of alpidem and its metabolites were unchanged in people with different stages of
renal impairment, though plasma concentrations were significantly increased.[1] The
clearance of alpidem was estimated to be 0.86 ± 0.04L•h−1•kg−1 in healthy individuals.[1]
Alpidem is the
generic name of the drug and its
INNTooltip International Nonproprietary Name,
USANTooltip United States Adopted Name,
BANTooltip British Approved Name, and
DCFTooltip Dénomination Commune Française.[6][54] The developmental code name of alpidem was SL 80.0342.[54][8] Alpidem was previously marketed under the brand name Ananxyl.[6][54]
Availability
Alpidem was previously marketed in
France, but is no longer available in any country.[3][8][9]
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