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| Trade names | Ananxyl |
| Other names | SL 80.0342; SL800342; SL-800342 |
| Routes of administration | Oral administration |
| Drug class | Nonbenzodiazepine;GABAA receptor positive allosteric modulator;Anxiolytic |
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| Bioavailability | 32–35% (estimated)[1][2] |
| Protein binding | 99.4%[1] |
| Metabolism | Extensive (hydroxylation,dealkylation,conjugation)[1] |
| Metabolites | Many (some active)[1] |
| Onset of action | 1.0–2.5 hours (Cmax)[1] |
| Eliminationhalf-life | Young adults: 19 hours (7–44 hours)[1] Elderly: 22.6 ± 2.3 hours[1] Children: 11.4 ± 1.9 hours[1] |
| Excretion | Mainlyfeces[1] |
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| ECHA InfoCard | 100.216.305 |
| Chemical and physical data | |
| Formula | C21H23Cl2N3O |
| Molar mass | 404.34 g·mol−1 |
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Alpidem, sold under the brand nameAnanxyl, is anonbenzodiazepineanxiolytic medication which was briefly used to treatanxiety disorders but is no longer marketed.[3] It was previously marketed inFrance, but wasdiscontinued due toliver toxicity.[3] Alpidem is takenby mouth.[1]
Side effects of alpidem includesedation,fatigue,dizziness, andheadache, among others.[3][2][4] It has much less to no impact oncognition,memory, andpsychomotor function relative tobenzodiazepines.[3][5] Similarly, noreboundanxiety orwithdrawal symptoms have been observed with alpidem.[3][2] Rarely, alpidem can cause seriousliver toxicity, includingliver failure and death.[3] Alpidem is anonbenzodiazepine of theimidazopyridine family,structurally related to theZ-drugzolpidem,[1] and acts as aGABAA receptor positive allosteric modulator of thebenzodiazepine site of thereceptor complex.[3] In contrast to zolpidem however, alpidem hasanxiolytic effects rather thansedative orhypnotic effects at normal therapeutic doses.[3]
Alpidem was first described by 1982[6][7] and was introduced for medical use inFrance 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 waswithdrawn from the market in France in 1993 due to liver toxicity.[10][11][12][13][3]
Alpidem was approved for the treatment ofgeneralized anxiety disorder and possibly also otheranxiety problems.[3][14][8] By 1990, 17 clinical studies including more than 1,500 patients had been conducted inEurope studying alpidem for the treatment of anxiety.[2][3] In clinical trials, alpidem demonstrated effectiveness in the treatment of chronic and situationalanxiety, includingstress-related anxiety, generalized anxiety, andadjustment disorder (situational depression) with anxiety.[2][14] It also showed preliminary effectiveness in institutionalized individuals with chronicpsychosis and high anxiety levels.[2][15] The effectiveness of alpidem forpanic 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 alpidemonset within 1.5 to 2 hours, whereas for chronic anxiety disorders the effects onset within 3 to 5 days in most cases.[2] No indications oftolerance to its anxiolytic effects or need for dose increases have been observed.[2] In people with anxiety taking alpidem, improvement inmood andsleep have also been found.[4]
The anxiolytic effectiveness of alpidem, for example measured by reductions on theHamilton Anxiety Rating Scale (HAM-A), was superior toplacebo and comparable or equivalent to that ofbenzodiazepines includingdiazepam (10–15 mg/day),lorazepam (1–6 mg/day), andclorazepate (30 mg/day) in directly comparativerandomized controlled trials.[3][2][4][14] Alpidem has also been directly compared withbuspirone (20–30 mg/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 fewerside effects and a lower discontinuation rate.[17]
The recommended dose of alpidem was 75 to 150 mg total per day, given in single doses of 25 to 75 mg two to three times per day.[3][18][19]
Alpidem was provided in the form of 50-mgoraltablets.[20]
Alpidem is described aswell-tolerated.[2]Side effects includesedation (6–8%; dose-dependent),fatigue (3–4%),dizziness (3–4%), andheadache (2–3%), among others.[3] It is reported to have minimal sedative effects and to have virtually no negative effects oncognition,memory, andpsychomotor function at therapeutic doses.[3][2][4] However, some impairment ofvigilance and psychomotor function has been reported at high doses (100–200 mg).[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]
Alpidem does not altersleep architecture as measured byelectroencephalography.[2] Inlaboratory tests, 0.9% of patients treated with alpidem showed alterations.[2] No adverse effects oncardiovascular orrespiratory function were seen in clinical trials.[2]
Noreboundanxiety orwithdrawal symptoms have been observed with alpidem after abruptdiscontinuation following 4 weeks to 6–12 months of treatment.[3][2][4] Conversely, substantial withdrawal symptoms, including rebound anxiety, were observed withlorazepam.[4]
The side effects of alpidem are described as quite different from those ofbenzodiazepines.[3] In directly comparative trials, alpidem produced similar anxiolytic effects with lessfatigue,asthenia,depressive mood, and psychomotor impairment than benzodiazepines, while rates ofsomnolence anddrowsiness were comparable to benzodiazepines but described as milder in severity.[2][4] Whereas benzodiazepines commonly producedizziness,muscle weakness,fatigue, andsleepiness 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 theamnestic effects of lorazepam and showed similar trends for other cognitive measures in a clinical study in which the two drugs were combined and assessed forinteraction.[3][24]
Following marketing authorization in France, several cases of severeliver toxicity were reported in people taking alpidem.[3][25] This resulted in one death and several cases ofliver transplantation.[3][25][26] As a result, alpidem was soonwithdrawn from the market.[3] The liver toxicity of alpidem was subsequently characterized inpreclinical research.[27][28][29][19] It may be related to interactions of alpidem with thetranslocator protein (TSPO), which is present in high amounts in theliver and which may mediate toxic effects in this tissue.[28][29][17][19]
Little information is available onoverdose with alpidem.[2] Doses of as high as 300 mg/day, which is 2 to 4 times the recommended total daily dose, were assessed in clinical trials.[2][3][30]
Alpidem mayinteract withalcohol, but to a lesser extent thanbenzodiazepines.[4]
Alpidem is aGABAA receptor positive allosteric modulator (GABAkine),[31] specifically acting as anagonist of thebenzodiazepine site of thereceptor complex (formerly known as the central benzodiazepine receptor (CBR)).[3] In addition to itsaffinity for the benzodiazepine site of the GABAA receptor (Ki = 1–28 nM), alpidem has similarly high affinity for thetranslocator protein (TSPO) (formerly the peripheral benzodiazepine receptor (PBR)) (Ki = 0.5–7 nM).[32][33][34][35][36] Alpidem shows more than 500-foldselectivity forα1 subunit-containing GABAA receptors overα5 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 aspotently 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 apartial agonist or afull agonist of the benzodiazepine site of the GABAA receptor.[3] In animals, alpidem hasanxiolytic-like effects in some but not all models, weakanticonvulsant effects, and weak or nosedative,amnesic,ataxic, ormuscle relaxant effects.[3][5][39][30] High doses of alpidemantagonize the sedative and muscle relaxant effects ofdiazepam 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 ofneurosteroidogenesis in thebrain, for instance ofallopregnanolone.[40][32][41]
Alpidem isstructurally related tozolpidem, 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 tobenzodiazepines.[42][43] Similarly, both alpidem and zolpidem are selective forγ2 subunit-containing GABAA receptors, with very low affinity forγ1 andγ3 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 showshypnotic andsedative effects and is used to treatinsomnia, alpidem shows mainlyanxiolytic effects and is used to treat anxiety disorders.[3][14] Alpidem was developed before the widespread use ofrecombinant 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]
Thepharmacodynamicmechanisms 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 inpreclinical research, alpidem is the only GABAA receptor positive allosteric modulator for which anxioselective effects have been unambiguously demonstrated in humanclinical 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 ofelevated liver enzymes in a small subset of patients.[3] GABAA receptor positive allosteric modulators with selectivity forα2 andα3 subunit-containing GABAA receptors over α1 subunit-containing GABAA receptors, for instanceadipiplon,L-838,417, anddarigabat—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]
Alpidem is taken viaoral administration.[1] Theabsorption of alpidem is rapid and it reachespeak levels after 1.0 to 2.5 hours.[1] Its overallbioavailability 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 andarea-under-the-curve levels is linear across a dose range of 25 to 100 mg.[1] Food increases the bioavailability of alpidem by 15 to 20%.[1]
Alpidem is a highlylipophiliccompound and in animals is extensivelydistributed intolipid-rich tissues.[1] Similarly, alpidem has been shown to cross theblood–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 slowerefflux of alpidem from the brain than entry.[1] Theactive 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-richwhite matter brain structures thangrey matter structures.[1] In humans, thevolume of distribution of alpidem is large at 8.7 L•kg−1.[1] Theplasma protein binding of alpidem is 99.4%, with similar isolated fractions bound toalbumin (97.0%) andα1-acid glycoprotein (97.3%).[1] The free fraction of alpidem is slightly higher in people withcirrhosis (0.86 ± 0.06%) andrenal failure (0.72 ± 0.03%) relative to normal individuals (0.61 ± 0.05%).[1]
Alpidem is extensivelymetabolized, including byhydroxylation,dealkylation, andconjugation.[1] Manymetabolites of alpidem have been identified, and some of these metabolites may contribute to its pharmacological activity.[1]
Alpidem iseliminated mainly infeces, with less than 0.1%excreted inurine.[1] A majority of alpidem is eliminated within 48 to 72 hours 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 thebile in feces, with less than 5% eliminated via urine.[1]
Theelimination half-life of alpidem was mean 18.8 ± 0.8 hours (range 7 to 44 hours) 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 ± 2.3 hours).[1] Conversely, in children age 8 to 12 years, the half-life of alpidem was considerably reduced (11.4 ± 1.9 hours).[1] The half-lives of alpidem and its metabolites are significantly prolonged in people withhepatic impairment.[1] Conversely, the half-lives of alpidem and its metabolites were unchanged in people with different stages ofrenal impairment, though plasma concentrations were significantly increased.[1] Theclearance of alpidem was estimated to be 0.86 ± 0.04 L•h−1•kg−1 in healthy individuals.[1]
Alpidem is anonbenzodiazepine, and hence is notstructurally related tobenzodiazepines.[1][53] It is a member of theimidazopyridine group of compounds.[1][14] Alpidem is structurally related to theZ-drugzolpidem, which is also an imidazopyridine.[1][14]
Alpidem was developed bySynthélabo Recherche (subsequentlySanofi-Synthélabo and nowSanofi-Aventis).[4][9] It was developed under the code name SL 80.0342 and was first described in the literature by 1982.[54][6][7][8] Alpidem was introduced for medical use inFrance in 1991.[3][8][9] It was also undergoing development in the 1990s for use in other countries such as theUnited States and otherEuropean countries likeGermany, theNetherlands, andSpain.[8] The drug reachedphase 3clinical trials in these countries.[8] However, development in the United States was halted in 1992 due to "divergent results".[55][8] All development in other countries was discontinued by 1999.[8] Alpidem waswithdrawn from the market in France in 1993 due to liver toxicity.[10][11][12][13][3] It was never marketed in any other country.[8][54][9]
Alpidem is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française.[6][54] The developmental code name of alpidem wasSL 80.0342.[54][8] Alpidem was previously marketed under the brand nameAnanxyl.[6][54]
Alpidem was previously marketed inFrance, but is no longer available in any country.[3][8][9]
