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==Medical uses==
==Medical uses==
Alpidem was approved for the treatment of [[generalized anxiety disorder]] and possibly also other [[anxiety disorder|anxiety problem]]s.<ref name="pmid22981367" /><ref name="pmid8748388" /><ref name="pmid8748388" /><ref name="AdisInsight" /> By 1990, 17{{nbsp}}clinical studies including more than 1,500{{nbsp}}patients had been conducted in [[Europe]] studying alpidem for the treatment of anxiety.<ref name="pmid1974073" /><ref name="pmid22981367" /> In clinical trials, alpidem demonstrated effectiveness in the treatment of chronic and situational [[anxiety]], including [[psychological stress|stress]]-related anxiety, generalized anxiety, and anxiety associated with [[adjustment disorder]]s.<ref name="pmid1974073">{{cite journal | vauthors = Morselli PL | title = On the therapeutic action of alpidem in anxiety disorders: an overview of the European data | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 129–34 | date = May 1990 | pmid = 1974073 | doi = 10.1055/s-2007-1014549 | url = }}</ref><ref name="pmid8748388" /> It also showed preliminary effectiveness in institutionalized individuals with chronic [[psychosis]] and high anxiety levels.<ref name="pmid1974073" /> The effectiveness of alpidem for [[panic disorder]], on the other hand, is understudied and uncertain.<ref name="pmid8748388" /><ref name="pmid8096527">{{cite journal | vauthors = Schneier FR, Carrasco JL, Hollander E, Campeas R, Fallon B, Saoud JB, Feerick J, Liebowitz MR | title = Alpidem in the treatment of panic disorder | journal = J Clin Psychopharmacol | volume = 13 | issue = 2 | pages = 150–3 | date = April 1993 | pmid = 8096527 | doi = | url = }}</ref>
Alpidem was approved for the treatment of [[generalized anxiety disorder]] and possibly also other [[anxiety disorder|anxiety problem]]s.<ref name="pmid22981367" /><ref name="pmid8748388" /><ref name="pmid8748388" /><ref name="AdisInsight" /> By 1990, 17{{nbsp}}clinical studies including more than 1,500{{nbsp}}patients had been conducted in [[Europe]] studying alpidem for the treatment of anxiety.<ref name="pmid1974073" /><ref name="pmid22981367" /> In clinical trials, alpidem demonstrated effectiveness in the treatment of chronic and situational [[anxiety]], including [[psychological stress|stress]]-related anxiety, generalized anxiety, and anxiety associated with [[adjustment disorder]]s.<ref name="pmid1974073">{{cite journal | vauthors = Morselli PL | title = On the therapeutic action of alpidem in anxiety disorders: an overview of the European data | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 129–34 | date = May 1990 | pmid = 1974073 | doi = 10.1055/s-2007-1014549 | url = }}</ref><ref name="pmid8748388" /> It also showed preliminary effectiveness in institutionalized individuals with chronic [[psychosis]] and high anxiety levels.<ref name="pmid1974073" /><ref name="pmid28686934">{{cite journal | vauthors = Kishi T, Inada K, Matsui Y, Iwata N | title = Z-drug for schizophrenia: A systematic review and meta-analysis | journal = Psychiatry Res | volume = 256 | issue = | pages = 365–370 | date = October 2017 | pmid = 28686934 | doi = 10.1016/j.psychres.2017.06.063 | url = }}</ref> The effectiveness of alpidem for [[panic disorder]], on the other hand, is understudied and uncertain.<ref name="pmid8748388" /><ref name="pmid8096527">{{cite journal | vauthors = Schneier FR, Carrasco JL, Hollander E, Campeas R, Fallon B, Saoud JB, Feerick J, Liebowitz MR | title = Alpidem in the treatment of panic disorder | journal = J Clin Psychopharmacol | volume = 13 | issue = 2 | pages = 150–3 | date = April 1993 | pmid = 8096527 | doi = | url = }}</ref>


The anxiolytic effects of alpidem are described as rapid, robust, and maintained in the long-term.<ref name="pmid22981367" /><ref name="pmid1974073" /> For situational anxiety, the anxiolytic effects of alpidem [[onset of action|onset]] within 1.5 to 2{{nbsp}}hours, whereas for chronic anxiety disorders the effects onset within 3 to 5{{nbsp}}days in most cases.<ref name="pmid1974073" /> No indications of [[drug tolerance|tolerance]] to its anxiolytic effects or need for dose increases have been observed.<ref name="pmid1974073" /> In people with anxiety taking alpidem, improvement in [[mood (psychology)|mood]] and [[sleep]] have also been found.<ref name="pmid1974071" />
The anxiolytic effects of alpidem are described as rapid, robust, and maintained in the long-term.<ref name="pmid22981367" /><ref name="pmid1974073" /> For situational anxiety, the anxiolytic effects of alpidem [[onset of action|onset]] within 1.5 to 2{{nbsp}}hours, whereas for chronic anxiety disorders the effects onset within 3 to 5{{nbsp}}days in most cases.<ref name="pmid1974073" /> No indications of [[drug tolerance|tolerance]] to its anxiolytic effects or need for dose increases have been observed.<ref name="pmid1974073" /> In people with anxiety taking alpidem, improvement in [[mood (psychology)|mood]] and [[sleep]] have also been found.<ref name="pmid1974071" />


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 [[benzodiazepine]]s including [[diazepam]] (10–15{{nbsp}}mg/day), [[lorazepam]] (1–6{{nbsp}}mg/day), and [[clorazepate]] (30{{nbsp}}mg/day) in directly comparative [[randomized controlled trial]]s.<ref name="pmid22981367" /><ref name="pmid1974073" /><ref name="pmid1974071" /><ref name="pmid8748388" />
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 [[benzodiazepine]]s including [[diazepam]] (10–15{{nbsp}}mg/day), [[lorazepam]] (1–6{{nbsp}}mg/day), and [[clorazepate]] (30{{nbsp}}mg/day) in directly comparative [[randomized controlled trial]]s.<ref name="pmid22981367" /><ref name="pmid1974073" /><ref name="pmid1974071" /><ref name="pmid8748388" /> Alpidem has also been compared with [[buspirone]] (20–30{{nbsp}}mg/day) for generalized anxiety disorder.<ref name="PotokarNutt1994" /> Compared to buspirone, it was found to produce more rapid improvement, to have significantly greater effectiveness, and to have fewer [[side effect]]s and a lower discontinuation rate.<ref name="PotokarNutt1994" />


The recommended dose of alpidem was 75 to 150{{nbsp}}mg total per day, given in single doses of 25 to 75{{nbsp}}mg two to three times per day.<ref name="pmid22981367" /><ref name="VersterPandi-PerumalRamaekers2009">{{cite book | editor1 = Joris C. Verster | editor2 = S. R. Pandi-Perumal | editor3 = Jan G. Ramaekers | editor4 = Johan J. de Gier | date = 29 August 2009 | title = Drugs, Driving and Traffic Safety | publisher = Springer Science & Business Media | pages = 301– | isbn = 978-3-7643-9923-8 | oclc = 1005763473 | url = https://books.google.com/books?id=ZLv887ijMIUC&pg=PA301}}</ref>
The recommended dose of alpidem was 75 to 150{{nbsp}}mg total per day, given in single doses of 25 to 75{{nbsp}}mg two to three times per day.<ref name="pmid22981367" /><ref name="VersterPandi-PerumalRamaekers2009">{{cite book | editor1 = Joris C. Verster | editor2 = S. R. Pandi-Perumal | editor3 = Jan G. Ramaekers | editor4 = Johan J. de Gier | date = 29 August 2009 | title = Drugs, Driving and Traffic Safety | publisher = Springer Science & Business Media | pages = 301– | isbn = 978-3-7643-9923-8 | oclc = 1005763473 | url = https://books.google.com/books?id=ZLv887ijMIUC&pg=PA301}}</ref><ref name="InxightDrugs">https://drugs.ncats.io/drug/I93SC245QZ</ref>


===Available forms===
===Available forms===
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==Side effects==
==Side effects==
Alpidem is described as [[tolerability|well-tolerated]].<ref name="pmid1974073" /> [[Side effect]]s include [[sedation]] (6–8%; dose-dependent), [[fatigue (medical)|fatigue]] (3–4%), [[dizziness]] (3–4%), and [[headache]] (2–3%), among others.<ref name="pmid22981367" /> It is reported to have minimal sedative effects and to have virtually no negative effects on [[cognition]], [[memory]], and [[psychomotor function|psychomotor]] function at therapeutic doses.<ref name="pmid22981367" /><ref name="pmid1974073" /><ref name="pmid1974071" /> However, some impairment of [[vigilance]] and psychomotor function has been reported at high doses (100–200{{nbsp}}mg).<ref name="pmid22981367" /><ref name="pmid1974073" />
Alpidem is described as [[tolerability|well-tolerated]].<ref name="pmid1974073" /> [[Side effect]]s include [[sedation]] (6–8%; dose-dependent), [[fatigue (medical)|fatigue]] (3–4%), [[dizziness]] (3–4%), and [[headache]] (2–3%), among others.<ref name="pmid22981367" /> It is reported to have minimal sedative effects and to have virtually no negative effects on [[cognition]], [[memory]], and [[psychomotor function|psychomotor]] function at therapeutic doses.<ref name="pmid22981367" /><ref name="pmid1974073" /><ref name="pmid1974071" /> However, some impairment of [[vigilance]] and psychomotor function has been reported at high doses (100–200{{nbsp}}mg).<ref name="pmid22981367" /><ref name="pmid1974073" /> The central side effects of alpidem were found to be no worse in elderly people.<ref name="pmid22981367" /><ref name="pmid1974072">{{cite journal | vauthors = Hindmarch I | title = Alpidem and psychological performance in elderly subjects | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 124–8 | date = May 1990 | pmid = 1974072 | doi = 10.1055/s-2007-1014548 | url = }}</ref>


Alpidem does not alter [[sleep architecture]] as measured by [[electroencephalography]].<ref name="pmid1974073" /> In [[blood test|laboratory tests]], 0.9% of patients treated with alpidem showed alterations.<ref name="pmid1974073" /> No adverse effects on [[cardiovascular]] or [[respiratory]] function were seen in clinical trials.<ref name="pmid1974073" />
Alpidem does not alter [[sleep architecture]] as measured by [[electroencephalography]].<ref name="pmid1974073" /> In [[blood test|laboratory tests]], 0.9% of patients treated with alpidem showed alterations.<ref name="pmid1974073" /> No adverse effects on [[cardiovascular]] or [[respiratory]] function were seen in clinical trials.<ref name="pmid1974073" />
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The side effects of alpidem are described as quite different from those of [[benzodiazepine]]s.<ref name="pmid22981367" /> In directly comparative trials, alpidem produced similar anxiolytic effects with less [[fatigue (medical)|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.<ref name="pmid1974073" /><ref name="pmid1974071" /> Whereas benzodiazepines commonly produce [[dizziness]], [[muscle weakness]], [[fatigue (medical)|fatigue]], and [[sleepiness]] as side effects, these are not prominent adverse effects with doses of alpidem that have similar anxiolytic effectiveness.<ref name="pmid22981367" /> The lack of withdrawal or rebound symptoms with alpidem upon discontinuation is also in contrast to benzodiazepines.<ref name="pmid1974073" /> 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 [[drug interaction|interaction]].<ref name="pmid22981367" /><ref name="pmid22298734">{{cite journal | vauthors = Patat A, Perault MC, Vandel B, Danjou P, Brohier S, Zieleniuk I, Rosenzweig P | title = Assessment of the interaction between a partial agonist and a full agonist of benzodiazepine receptors, based on psychomotor performance and memory, in healthy volunteers | journal = J Psychopharmacol | volume = 9 | issue = 2 | pages = 91–101 | date = January 1995 | pmid = 22298734 | doi = 10.1177/026988119500900203 | url = }}</ref>
The side effects of alpidem are described as quite different from those of [[benzodiazepine]]s.<ref name="pmid22981367" /> In directly comparative trials, alpidem produced similar anxiolytic effects with less [[fatigue (medical)|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.<ref name="pmid1974073" /><ref name="pmid1974071" /> Whereas benzodiazepines commonly produce [[dizziness]], [[muscle weakness]], [[fatigue (medical)|fatigue]], and [[sleepiness]] as side effects, these are not prominent adverse effects with doses of alpidem that have similar anxiolytic effectiveness.<ref name="pmid22981367" /> The lack of withdrawal or rebound symptoms with alpidem upon discontinuation is also in contrast to benzodiazepines.<ref name="pmid1974073" /> 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 [[drug interaction|interaction]].<ref name="pmid22981367" /><ref name="pmid22298734">{{cite journal | vauthors = Patat A, Perault MC, Vandel B, Danjou P, Brohier S, Zieleniuk I, Rosenzweig P | title = Assessment of the interaction between a partial agonist and a full agonist of benzodiazepine receptors, based on psychomotor performance and memory, in healthy volunteers | journal = J Psychopharmacol | volume = 9 | issue = 2 | pages = 91–101 | date = January 1995 | pmid = 22298734 | doi = 10.1177/026988119500900203 | url = }}</ref>


Following marketing authorization in France, several cases of severe [[liver toxicity]] were reported in people taking alpidem.<ref name="pmid22981367" /><ref name="pmid7750686">{{cite journal | vauthors = Baty V, Denis B, Goudot C, Bas V, Renkes P, Bigard MA, Boissel P, Gaucher P | title = [Hepatitis induced by alpidem (Ananxyl). Four cases, one of them fatal] | language = French | journal = Gastroenterol Clin Biol | volume = 18 | issue = 12 | pages = 1129–31 | date = 1994 | pmid = 7750686 | doi = | url = }}</ref> This resulted in one death and several cases of [[liver transplantation]].<ref name="pmid22981367" /><ref name="pmid7750686" /> As a result, alpidem was soon [[list of withdrawn drugs|withdrawn from the market]].<ref name="pmid22981367" /> The liver toxicity of alpidem was subsequently characterized in [[preclinical research]].<ref name="pmid18705745">{{cite journal | vauthors = Labbe G, Pessayre D, Fromenty B | title = Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies | journal = Fundam Clin Pharmacol | volume = 22 | issue = 4 | pages = 335–53 | date = August 2008 | pmid = 18705745 | doi = 10.1111/j.1472-8206.2008.00608.x | url = }}</ref><ref name="pmid20020267">{{cite journal | vauthors = Pessayre D, Mansouri A, Berson A, Fromenty B | title = Mitochondrial involvement in drug-induced liver injury | journal = Handb Exp Pharmacol | volume = | issue = 196 | pages = 311–65 | date = 2010 | pmid = 20020267 | doi = 10.1007/978-3-642-00663-0_11 | url = }}</ref><ref name="pmid11602696">{{cite journal | vauthors = Berson A, Descatoire V, Sutton A, Fau D, Maulny B, Vadrot N, Feldmann G, Berthon B, Tordjmann T, Pessayre D | title = Toxicity of alpidem, a peripheral benzodiazepine receptor ligand, but not zolpidem, in rat hepatocytes: role of mitochondrial permeability transition and metabolic activation | journal = J Pharmacol Exp Ther | volume = 299 | issue = 2 | pages = 793–800 | date = November 2001 | pmid = 11602696 | doi = | url = }}</ref><ref name="InxightDrugs" /> It may be related to activation of the peripheral benzodiazepine receptor or TSPO, which is present in high amounts in the [[liver]].<ref name="pmid20020267" /><ref name="pmid11602696" /><ref name="PotokarNutt1994">{{cite journal | last1 = Potokar | first1 = John | last2 = Nutt | first2 = David J. | title = Anxiolytic Potential of Benzodiazepine Receptor Partial Agonists | journal = CNS Drugs | date = April 1994 | volume = 1 | issue = 4 | pages = 305–315 | issn = 1172-7047 | doi = 10.2165/00023210-199401040-00007 | pmid = | url = }}</ref><ref name="InxightDrugs" />
Following marketing authorization in France, several cases of severe [[liver toxicity]] were reported in people taking alpidem.<ref name="pmid22981367" /> This resulted in one death and several cases of [[liver transplantation]].<ref name="pmid22981367" /> As a result, alpidem was soon [[list of withdrawn drugs|withdrawn from the market]].<ref name="pmid22981367" />


==Overdose==
==Overdose==
Little information is available on [[overdose]] with alpidem.<ref name="pmid1974073" /> Doses of as high as 300{{nbsp}}mg/day, which is 2 to 4{{nbsp}}times the recommended total daily dose, were assessed in clinical trials.<ref name="pmid1974073" /><ref name="pmid22981367" />
Little information is available on [[overdose]] with alpidem.<ref name="pmid1974073" /> Doses of as high as 300{{nbsp}}mg/day, which is 2 to 4{{nbsp}}times the recommended total daily dose, were assessed in clinical trials.<ref name="pmid1974073" /><ref name="pmid22981367" /><ref name="pmid2901120">{{cite journal | vauthors = Musch B, Morselli PL, Priore P | title = Clinical studies with the new anxiolytic alpidem in anxious patients: an overview of the European experiences | journal = Pharmacol Biochem Behav | volume = 29 | issue = 4 | pages = 803–6 | date = April 1988 | pmid = 2901120 | doi = 10.1016/0091-3057(88)90211-0 | url = }}</ref>

==Interactions==
Alpidem may [[drug interaction|interact]] with [[alcohol (drug)|alcohol]], but to a lesser extent than [[benzodiazepine]]s.<ref name="pmid1974071">{{cite journal | vauthors = Morton S, Lader M | title = Studies with alpidem in normal volunteers and anxious patients | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 120–3 | date = May 1990 | pmid = 1974071 | doi = 10.1055/s-2007-1014547 | url = }}</ref>


==Pharmacology==
==Pharmacology==


===Pharmacodynamics===
===Pharmacodynamics===
Alpidem is a [[GABAA receptor positive allosteric modulator|GABA<sub>A</sub> receptor positive allosteric modulator]], specifically acting as an [[agonist]] of the [[benzodiazepine site]] of the [[receptor complex]].<ref name="pmid22981367" /> In addition to its [[binding affinity|affinity]] for the so-called [[central benzodiazepine receptor]] (CBR) (K<sub>i</sub> 1–28{{nbsp}}nM), alpidem also has similarly high affinity for the peripheral benzodiazepine receptor (PBR) or [[translocator protein]] (TSPO) (K<sub>i</sub> 0.5–7{{nbsp}}nM).<ref name="Bourguignon1993">{{cite book | vauthors = Bourguignon JJ | chapter = Endogenous and Synthetic Ligand of Mitochondrial Benzodiazepine Receptors: Structure-Affinity Relationships. | title = Peripheral Benzodiazepine Receptors | veditors = Giesen-Crouse E | publisher = Academic Press | location = London | date = 1993 | pages = 59–85 }}</ref><ref name="CostaROmeoAuta1991">{{cite book | vauthors = Costa E, Romeo E, Auta J, Papadopoulos V, Kozikowski A, Guidotti A | chapter = Is There a Pharmacology of Brain Steroidogenesis? In Neurosteroid and Brain Function | title = Fidia ResearchFundation Symposium Series | publisher = Thieme Medical Publisher, Inc. | location = New York | date = 1991 | pages = 171–176 | veditors = Costa E, Paul SM }}</ref><ref name="pmid1326631">{{cite journal | vauthors = Romeo E, Auta J, Kozikowski AP, Ma D, Papadopoulos V, Puia G, Costa E, Guidotti A | display-authors = 6 | title = 2-Aryl-3-indoleacetamides (FGIN-1): a new class of potent and specific ligands for the mitochondrial DBI receptor (MDR) | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 262 | issue = 3 | pages = 971–8 | date = September 1992 | pmid = 1326631 }}</ref><ref name="KozikowskiRomeoAuta1992">{{cite journal | vauthors = Kozikowski AP, Ma D, Romeo E, Auta J, Papadopoulos V, Puia G, Costa E, Guidotti A | title = Synthesis of (2‐Arylindol‐3‐yl) acetamides as Probes of Mitochondrial Steroidogenesis—A New Mechanism for GABAA Receptor Modulation. | journal = Angewandte Chemie International Edition in English | date = August 1992 | volume = 31 | issue = 8 | pages = 1060–2 | doi = 10.1002/anie.199210601 }}</ref> Alpidem shows more than 500-fold [[binding selectivity|selectivity]] for [[GABRA1|α<sub>1</sub> subunit]]-containing GABA<sub>A</sub> receptors over [[GABRA5|α<sub>5</sub> subunit]]-containing GABA<sub>A</sub> receptors.<ref name="pmid22981367" /> Findings appear to be mixed on whether alpidem is a [[partial agonist]] or a [[full agonist]] of the benzodiazepine site of the GABA<sub>A</sub> receptor.<ref name="pmid22981367" /> In animals, alpidem has [[anxiolytic]]-like effects in some but not all models, weak [[anticonvulsant]] effects, and weak or no [[sedation|sedative]], [[ataxic]], or [[muscle relaxant]] effects.<ref name="pmid22981367" /><ref name="pmid1974069">{{cite journal | vauthors = Zivkovic B, Morel E, Joly D, Perrault G, Sanger DJ, Lloyd KG | title = Pharmacological and behavioral profile of alpidem as an anxiolytic | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 108–13 | date = May 1990 | pmid = 1974069 | doi = 10.1055/s-2007-1014545 | url = }}</ref><ref name="pmid1980040">{{cite journal | vauthors = Haefely W, Martin JR, Schoch P | title = Novel anxiolytics that act as partial agonists at benzodiazepine receptors | journal = Trends Pharmacol Sci | volume = 11 | issue = 11 | pages = 452–6 | date = November 1990 | pmid = 1980040 | doi = 10.1016/0165-6147(90)90126-s | url = }}</ref> High doses of alpidem [[receptor antagonist|antagonize]] the sedative and muscle relaxant effects of [[diazepam]] in animals.<ref name="pmid1980040" /> [[Flumazenil]] has been shown to antagonize the anxiolytic and anticonvulsant effects of alpidem in animals.<ref name="pmid1974069" />
Alpidem is a [[GABAA receptor positive allosteric modulator|GABA<sub>A</sub> receptor positive allosteric modulator]], specifically acting as an [[agonist]] of the [[benzodiazepine site]] of the [[receptor complex]].<ref name="pmid22981367" /> In addition to its [[binding affinity|affinity]] for the so-called [[central benzodiazepine receptor]] (CBR) (K<sub>i</sub> 1–28{{nbsp}}nM), alpidem also has similarly high affinity for the peripheral benzodiazepine receptor (PBR) or [[translocator protein]] (TSPO) (K<sub>i</sub> 0.5–7{{nbsp}}nM).<ref name="Bourguignon1993">{{cite book | vauthors = Bourguignon JJ | chapter = Endogenous and Synthetic Ligand of Mitochondrial Benzodiazepine Receptors: Structure-Affinity Relationships. | title = Peripheral Benzodiazepine Receptors | veditors = Giesen-Crouse E | publisher = Academic Press | location = London | date = 1993 | pages = 59–85 }}</ref><ref name="CostaROmeoAuta1991">{{cite book | vauthors = Costa E, Romeo E, Auta J, Papadopoulos V, Kozikowski A, Guidotti A | chapter = Is There a Pharmacology of Brain Steroidogenesis? In Neurosteroid and Brain Function | title = Fidia ResearchFundation Symposium Series | publisher = Thieme Medical Publisher, Inc. | location = New York | date = 1991 | pages = 171–176 | veditors = Costa E, Paul SM }}</ref><ref name="pmid1326631">{{cite journal | vauthors = Romeo E, Auta J, Kozikowski AP, Ma D, Papadopoulos V, Puia G, Costa E, Guidotti A | display-authors = 6 | title = 2-Aryl-3-indoleacetamides (FGIN-1): a new class of potent and specific ligands for the mitochondrial DBI receptor (MDR) | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 262 | issue = 3 | pages = 971–8 | date = September 1992 | pmid = 1326631 }}</ref><ref name="KozikowskiRomeoAuta1992">{{cite journal | vauthors = Kozikowski AP, Ma D, Romeo E, Auta J, Papadopoulos V, Puia G, Costa E, Guidotti A | title = Synthesis of (2‐Arylindol‐3‐yl) acetamides as Probes of Mitochondrial Steroidogenesis—A New Mechanism for GABAA Receptor Modulation. | journal = Angewandte Chemie International Edition in English | date = August 1992 | volume = 31 | issue = 8 | pages = 1060–2 | doi = 10.1002/anie.199210601 }}</ref> Alpidem shows more than 500-fold [[binding selectivity|selectivity]] for [[GABRA1|α<sub>1</sub> subunit]]-containing GABA<sub>A</sub> receptors over [[GABRA5|α<sub>5</sub> subunit]]-containing GABA<sub>A</sub> receptors.<ref name="pmid22981367" /> Findings appear to be mixed on whether alpidem is a [[partial agonist]] or a [[full agonist]] of the benzodiazepine site of the GABA<sub>A</sub> receptor.<ref name="pmid22981367" /> In animals, alpidem has [[anxiolytic]]-like effects in some but not all models, weak [[anticonvulsant]] effects, and weak or no [[sedation|sedative]], [[amnesia|amnesic]], [[ataxic]], or [[muscle relaxant]] effects.<ref name="pmid22981367" /><ref name="pmid1974069">{{cite journal | vauthors = Zivkovic B, Morel E, Joly D, Perrault G, Sanger DJ, Lloyd KG | title = Pharmacological and behavioral profile of alpidem as an anxiolytic | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 108–13 | date = May 1990 | pmid = 1974069 | doi = 10.1055/s-2007-1014545 | url = }}</ref><ref name="pmid1980040">{{cite journal | vauthors = Haefely W, Martin JR, Schoch P | title = Novel anxiolytics that act as partial agonists at benzodiazepine receptors | journal = Trends Pharmacol Sci | volume = 11 | issue = 11 | pages = 452–6 | date = November 1990 | pmid = 1980040 | doi = 10.1016/0165-6147(90)90126-s | url = }}</ref><ref name="pmid2901120" /> High doses of alpidem [[receptor antagonist|antagonize]] the sedative and muscle relaxant effects of [[diazepam]] in animals.<ref name="pmid1980040" /> [[Flumazenil]] has been shown to antagonize the anxiolytic and anticonvulsant effects of alpidem in animals.<ref name="pmid1974069" />


Alpidem is [[chemical structure|structurally]] related to zolpidem, and both alpidem and zolpidem are GABA<sub>A</sub> receptor positive allosteric modulators of the benzodiazepine site with preference for α<sub>1</sub> subunit-containing receptors.<ref name="pmid22981367" /><ref name="pmid8748388">{{cite journal | vauthors = Kunovac JL, Stahl SM | title = Future directions in anxiolytic pharmacotherapy | journal = Psychiatr Clin North Am | volume = 18 | issue = 4 | pages = 895–909 | date = December 1995 | pmid = 8748388 | doi = 10.1016/S0193-953X(18)30030-3 | url = }}</ref> Both alpidem and zolpidem have very low affinity for α<sub>5</sub> subunit-containing GABA<sub>A</sub> receptors, in contrast to [[benzodiazepine]]s.<ref name="pmid7984354">{{cite journal | vauthors = Sanger DJ, Benavides J, Perrault G, Morel E, Cohen C, Joly D, Zivkovic B | title = Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes | journal = Neurosci Biobehav Rev | volume = 18 | issue = 3 | pages = 355–72 | date = 1994 | pmid = 7984354 | doi = 10.1016/0149-7634(94)90049-3 | url = }}</ref><ref name="LangerFaure-HalleySeeburg1992">{{cite journal | last1 = Langer | first1 = S.Z. | last2 = Faure-Halley | first2 = C. | last3 = Seeburg | first3 = P. | last4 = Graham | first4 = D. | last5 = Arbilla | first5 = S. | title = The selectivity of zolpidem and alpidem for the α1-subunit of the GABAA receptor | journal = European Neuropsychopharmacology | date = September 1992 | volume = 2 | issue = 3 | pages = 232–234 | issn = 0924-977X | doi = 10.1016/0924-977X(92)90081-I | pmid = | url = }}</ref> Alpidem has high affinity for the peripheral benzodiazepine receptor or TSPO similarly to benzodiazepines, while zolpidem has very low affinity for this receptor.<ref name="pmid8748388" /><ref name="Pleuvry2004">{{cite journal | last1 = Pleuvry | first1 = Barbara J | title = Anxiolytics and hypnotics | journal = Anaesthesia & Intensive Care Medicine | date = August 2004 | volume = 5 | issue = 8 | pages = 252–256 | issn = 1472-0299 | doi = 10.1383/anes.5.8.252.43294 | pmid = | url = }}</ref> 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.<ref name="pmid22981367" /><ref name="pmid8748388" /> Alpidem was developed before the widespread use of [[recombinant]] GABA<sub>A</sub> receptors, so its pharmacological profile at the GABA<sub>A</sub> receptors and different subpopulations of these receptors has never been fully characterized.<ref name="pmid22981367" />
Alpidem is [[chemical structure|structurally]] related to zolpidem, and both alpidem and zolpidem are GABA<sub>A</sub> receptor positive allosteric modulators of the benzodiazepine site with preference for α<sub>1</sub> subunit-containing receptors.<ref name="pmid22981367" /><ref name="pmid8748388">{{cite journal | vauthors = Kunovac JL, Stahl SM | title = Future directions in anxiolytic pharmacotherapy | journal = Psychiatr Clin North Am | volume = 18 | issue = 4 | pages = 895–909 | date = December 1995 | pmid = 8748388 | doi = 10.1016/S0193-953X(18)30030-3 | url = }}</ref> Both alpidem and zolpidem have very low affinity for α<sub>5</sub> subunit-containing GABA<sub>A</sub> receptors, in contrast to [[benzodiazepine]]s.<ref name="pmid7984354">{{cite journal | vauthors = Sanger DJ, Benavides J, Perrault G, Morel E, Cohen C, Joly D, Zivkovic B | title = Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes | journal = Neurosci Biobehav Rev | volume = 18 | issue = 3 | pages = 355–72 | date = 1994 | pmid = 7984354 | doi = 10.1016/0149-7634(94)90049-3 | url = }}</ref><ref name="LangerFaure-HalleySeeburg1992">{{cite journal | last1 = Langer | first1 = S.Z. | last2 = Faure-Halley | first2 = C. | last3 = Seeburg | first3 = P. | last4 = Graham | first4 = D. | last5 = Arbilla | first5 = S. | title = The selectivity of zolpidem and alpidem for the α1-subunit of the GABAA receptor | journal = European Neuropsychopharmacology | date = September 1992 | volume = 2 | issue = 3 | pages = 232–234 | issn = 0924-977X | doi = 10.1016/0924-977X(92)90081-I | pmid = | url = }}</ref> Alpidem has high affinity for the peripheral benzodiazepine receptor or TSPO similarly to benzodiazepines, while zolpidem has very low affinity for this receptor.<ref name="pmid8748388" /><ref name="Pleuvry2004">{{cite journal | last1 = Pleuvry | first1 = Barbara J | title = Anxiolytics and hypnotics | journal = Anaesthesia & Intensive Care Medicine | date = August 2004 | volume = 5 | issue = 8 | pages = 252–256 | issn = 1472-0299 | doi = 10.1383/anes.5.8.252.43294 | pmid = | url = }}</ref> 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.<ref name="pmid22981367" /><ref name="pmid8748388" /> Alpidem was developed before the widespread use of [[recombinant]] GABA<sub>A</sub> receptors, so its pharmacological profile at the GABA<sub>A</sub> receptors and different subpopulations of these receptors has never been fully characterized.<ref name="pmid22981367" />
Line 132: Line 135:


==History==
==History==
Alpidem was developed by [[Synthélabo Recherche]] (subsequently [[Sanofi-Synthélabo]] and now part of [[Sanofi-Aventis]]).<ref name="pmid1974071">{{cite journal | vauthors = Morton S, Lader M | title = Studies with alpidem in normal volunteers and anxious patients | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 120–3 | date = May 1990 | pmid = 1974071 | doi = 10.1055/s-2007-1014547 | url = }}</ref><ref name="Micromedex">https://www.micromedexsolutions.com/micromedex2/librarian/</ref> It was developed under the code name SL 80.0342 and was first described in the literature by 1982.<ref name="SwissPharmaceutialSociety2000" /><ref name="Elks2014" /><ref name="pmid2883214">{{cite journal | vauthors = Saletu B, Grünberger J, Linzmayer L | title = Pharmacokinetic and dynamic studies with a new anxiolytic imidazo-pyridine alpidem utilizing pharmaco-EEG and psychometry | journal = Int Clin Psychopharmacol | volume = 1 | issue = 2 | pages = 145–64 | date = April 1986 | pmid = 2883214 | doi = 10.1097/00004850-198604000-00006 | url = }}</ref><ref name="AdisInsight" /> Alpidem was introduced for medical use in [[France]] in 1991.<ref name="pmid22981367" /><ref name="AdisInsight" /><ref name="Micromedex" /> Alpidem was also undergoing development in the 1990s for use in other countries such as the [[United States]] and other [[Europe]]an countries like [[Germany]], the [[Netherlands]], and [[Spain]].<ref name="AdisInsight">https://adisinsight.springer.com/drugs/800000646</ref> It reached [[Phases of clinical research#Phase III|phase 3]] [[clinical trial]]s in these countries.<ref name="AdisInsight" /> However, development in the United States was halted in 1992 due to "divergent results".<ref name="ThePharmaLetter1992">https://www.thepharmaletter.com/article/us-trials-of-alpidem-halted</ref><ref name="AdisInsight" /> All development in other countries was discontinued by 1999.<ref name="AdisInsight" /> Alpidem was [[list of withdrawn drugs|withdrawn from the market]] in France by 1994 or 1995 due to liver toxicity.<ref name="WHO1994">[https://web.archive.org/web/20030319124143/http://whqlibdoc.who.int/druginfo/DRUG_INFO_8_2_1994.pdf WHO Drug Information Vol. 8, No. 2, 1994, page 64]</ref><ref name="pmid22981367" /> It was never marketed in any other country.<ref name="AdisInsight" /><ref name="SwissPharmaceutialSociety2000" /><ref name="Micromedex" />
Alpidem was developed by [[Synthélabo Recherche]] (subsequently [[Sanofi-Synthélabo]] and now [[Sanofi-Aventis]]).<ref name="pmid1974071">{{cite journal | vauthors = Morton S, Lader M | title = Studies with alpidem in normal volunteers and anxious patients | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 120–3 | date = May 1990 | pmid = 1974071 | doi = 10.1055/s-2007-1014547 | url = }}</ref><ref name="Micromedex">https://www.micromedexsolutions.com/micromedex2/librarian/</ref> It was developed under the code name SL 80.0342 and was first described in the literature by 1982.<ref name="SwissPharmaceutialSociety2000" /><ref name="Elks2014" /><ref name="pmid2883214">{{cite journal | vauthors = Saletu B, Grünberger J, Linzmayer L | title = Pharmacokinetic and dynamic studies with a new anxiolytic imidazo-pyridine alpidem utilizing pharmaco-EEG and psychometry | journal = Int Clin Psychopharmacol | volume = 1 | issue = 2 | pages = 145–64 | date = April 1986 | pmid = 2883214 | doi = 10.1097/00004850-198604000-00006 | url = }}</ref><ref name="AdisInsight" /> Alpidem was introduced for medical use in [[France]] in 1991.<ref name="pmid22981367" /><ref name="AdisInsight" /><ref name="Micromedex" /> It was also undergoing development in the 1990s for use in other countries such as the [[United States]] and other [[Europe]]an countries like [[Germany]], the [[Netherlands]], and [[Spain]].<ref name="AdisInsight">https://adisinsight.springer.com/drugs/800000646</ref> The drug reached [[Phases of clinical research#Phase III|phase 3]] [[clinical trial]]s in these countries.<ref name="AdisInsight" /> However, development in the United States was halted in 1992 due to "divergent results".<ref name="ThePharmaLetter1992">https://www.thepharmaletter.com/article/us-trials-of-alpidem-halted</ref><ref name="AdisInsight" /> All development in other countries was discontinued by 1999.<ref name="AdisInsight" /> Alpidem was [[list of withdrawn drugs|withdrawn from the market]] in France by 1994 or 1995 due to liver toxicity.<ref name="WHO1994">[https://web.archive.org/web/20030319124143/http://whqlibdoc.who.int/druginfo/DRUG_INFO_8_2_1994.pdf WHO Drug Information Vol. 8, No. 2, 1994, page 64]</ref><ref name="pmid22981367" /> It was never marketed in any other country.<ref name="AdisInsight" /><ref name="SwissPharmaceutialSociety2000" /><ref name="Micromedex" />


==Society and culture==
==Society and culture==
Line 144: Line 147:
==References==
==References==
{{Reflist}}
{{Reflist}}

==Further reading==
* {{cite journal | vauthors = Musch B, Morselli PL, Priore P | title = Clinical studies with the new anxiolytic alpidem in anxious patients: an overview of the European experiences | journal = Pharmacol Biochem Behav | volume = 29 | issue = 4 | pages = 803–6 | date = April 1988 | pmid = 2901120 | doi = 10.1016/0091-3057(88)90211-0 | url = }}
* {{cite journal | vauthors = Langer SZ, Arbilla S, Benavides J, Scatton B | title = Zolpidem and alpidem: two imidazopyridines with selectivity for omega 1- and omega 3-receptor subtypes | journal = Adv Biochem Psychopharmacol | volume = 46 | issue = | pages = 61–72 | date = 1990 | pmid = 1981304 | doi = | url = }}
* {{cite journal | vauthors = Langer SZ, Arbilla S, Tan S, Lloyd KG, George P, Allen J, Wick AE | title = Selectivity for omega-receptor subtypes as a strategy for the development of anxiolytic drugs | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 103–7 | date = May 1990 | pmid = 1974068 | doi = 10.1055/s-2007-1014544 | url = }}
* {{cite journal | vauthors = Zivkovic B, Morel E, Joly D, Perrault G, Sanger DJ, Lloyd KG | title = Pharmacological and behavioral profile of alpidem as an anxiolytic | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 108–13 | date = May 1990 | pmid = 1974069 | doi = 10.1055/s-2007-1014545 | url = }}
* {{cite journal | vauthors = Morton S, Lader M | title = Studies with alpidem in normal volunteers and anxious patients | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 120–3 | date = May 1990 | pmid = 1974071 | doi = 10.1055/s-2007-1014547 | url = }}
* {{cite journal | vauthors = Hindmarch I | title = Alpidem and psychological performance in elderly subjects | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 124–8 | date = May 1990 | pmid = 1974072 | doi = 10.1055/s-2007-1014548 | url = }}
* {{cite journal | vauthors = Morselli PL | title = On the therapeutic action of alpidem in anxiety disorders: an overview of the European data | journal = Pharmacopsychiatry | volume = 23 Suppl 3 | issue = | pages = 129–34 | date = May 1990 | pmid = 1974073 | doi = 10.1055/s-2007-1014549 | url = }}
* {{cite journal | vauthors = Durand A, Thénot JP, Bianchetti G, Morselli PL | title = Comparative pharmacokinetic profile of two imidazopyridine drugs: zolpidem and alpidem | journal = Drug Metab Rev | volume = 24 | issue = 2 | pages = 239–66 | date = 1992 | pmid = 1576937 | doi = 10.3109/03602539208996294 | url = }}
* {{cite journal | vauthors = Sanger DJ, Benavides J, Perrault G, Morel E, Cohen C, Joly D, Zivkovic B | title = Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes | journal = Neurosci Biobehav Rev | volume = 18 | issue = 3 | pages = 355–72 | date = 1994 | pmid = 7984354 | doi = 10.1016/0149-7634(94)90049-3 | url = }}
* {{cite journal | vauthors = Skolnick P | title = Anxioselective anxiolytics: on a quest for the Holy Grail | journal = Trends Pharmacol Sci | volume = 33 | issue = 11 | pages = 611–20 | date = November 2012 | pmid = 22981367 | pmc = 3482271 | doi = 10.1016/j.tips.2012.08.003 | url = }}

==External links==
* [https://adisinsight.springer.com/drugs/800000646 Alpidem - Sanofi-Synthelabo - AdisInsight]




Revision as of 02:47, 5 February 2023

Alpidem
Clinical data
Trade namesAnanxyl
Other namesSL 80.0342; SL800342; SL-800342
Routes of
administration		Oral administration
Drug classNonbenzodiazepine; GABAA receptor positive allosteric modulator; Anxiolytic
ATC code
  • None
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability32–35% (estimated)[1][2]
Protein binding99.4%[1]
MetabolismExtensive (hydroxylation, dealkylation, conjugation)[1]
MetabolitesMany (some active)[1]
Onset of action1.0–2.5 hours (Cmax)[1]
Elimination half-lifeYoung adults: 19 hours (7–44 hours)[1]
Elderly: 22.6 ± 2.3 hours[1]
Children: 11.4 ± 1.9 hours[1]
ExcretionMainly feces[1]
Identifiers
  • 2-[6-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]-N,N-dipropylacetamide
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.216.305 Edit this at Wikidata
Chemical and physical data
FormulaC21H23Cl2N3O
Molar mass404.34 g·mol−1
3D model (JSmol)
  • CCCN(CCC)C(=O)CC1=C(N=C2N1C=C(C=C2)Cl)C3=CC=C(C=C3)Cl
  • InChI=1S/C21H23Cl2N3O/c1-3-11-25(12-4-2)20(27)13-18-21(15-5-7-16(22)8-6-15)24-19-10-9-17(23)14-26(18)19/h5-10,14H,3-4,11-13H2,1-2H3 checkY
  • Key:JRTIDHTUMYMPRU-UHFFFAOYSA-N checkY
  (verify)

Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine medication which was briefly used to treat anxiety disorders but is no longer marketed.[3] It was previously marketed in France, but was discontinued due to liver toxicity.[3] Alpidem is taken by mouth.[1]

Side effects of alpidem include sedation, fatigue, dizziness, and headache, among others.[3][2][4] It has much less to no impact on cognition, memory, and psychomotor function relative to benzodiazepines.[3][5] Similarly, no rebound anxiety or withdrawal symptoms have been observed with alpidem.[3][2] Rarely, alpidem can cause serious liver toxicity, including liver failure and death.[3] Alpidem is a nonbenzodiazepine of the imidazopyridine family, structurally related to the Z-drug zolpidem,[1] and acts as a GABAA receptor positive allosteric modulator of the benzodiazepine site of the receptor complex.[3] In contrast to zolpidem however, alpidem has anxiolytic effects rather than sedative or hypnotic effects at normal therapeutic doses.[3]

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 by the mid-1990s due to liver toxicity.[10][3]

Medical uses

Alpidem was approved for the treatment of generalized anxiety disorder and possibly also other anxiety problems.[3][11][11][8] By 1990, 17 clinical studies including more than 1,500 patients 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 anxiety associated with adjustment disorders.[2][11] It also showed preliminary effectiveness in institutionalized individuals with chronic psychosis and high anxiety levels.[2][12] The effectiveness of alpidem for panic disorder, on the other hand, is understudied and uncertain.[11][13]

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 2 hours, whereas for chronic anxiety disorders the effects onset within 3 to 5 days 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 (10–15 mg/day), lorazepam (1–6 mg/day), and clorazepate (30 mg/day) in directly comparative randomized controlled trials.[3][2][4][11] Alpidem has also been compared with buspirone (20–30 mg/day) for generalized anxiety disorder.[14] Compared 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.[14]

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][15][16]

Available forms

Alpidem was provided in the form of 50-mg oral tablets.[17]

Side effects

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 (100–200 mg).[3][2] The central side effects of alpidem were found to be no worse in elderly people.[3][18]

Alpidem does not alter sleep architecture as measured by electroencephalography.[2] In laboratory tests, 0.9% of patients treated with alpidem showed alterations.[2] No adverse effects on cardiovascular or respiratory function were seen in clinical trials.[2]

No rebound anxiety or withdrawal symptoms have been observed with alpidem after abrupt discontinuation following 4 weeks to 6–12 months of treatment.[3][2][4] Conversely, substantial withdrawal symptoms, including rebound anxiety, were observed with lorazepam.[4]

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][19]

Following marketing authorization in France, several cases of severe liver toxicity were reported in people taking alpidem.[3][20] This resulted in one death and several cases of liver transplantation.[3][20] As a result, alpidem was soon withdrawn from the market.[3] The liver toxicity of alpidem was subsequently characterized in preclinical research.[21][22][23][16] It may be related to activation of the peripheral benzodiazepine receptor or TSPO, which is present in high amounts in the liver.[22][23][14][16]

Overdose

Little information is available on overdose 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][24]

Interactions

Alpidem may interact with alcohol, but to a lesser extent than benzodiazepines.[4]

Pharmacology

Pharmacodynamics

Alpidem is a GABAA receptor positive allosteric modulator, specifically acting as an agonist of the benzodiazepine site of the receptor complex.[3] In addition to its affinity for the so-called central benzodiazepine receptor (CBR) (Ki 1–28 nM), alpidem also has similarly high affinity for the peripheral benzodiazepine receptor (PBR) or translocator protein (TSPO) (Ki 0.5–7 nM).[25][26][27][28] Alpidem shows more than 500-fold selectivity for α1 subunit-containing GABAA receptors over α5 subunit-containing GABAA receptors.[3] 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][29][24] High doses of alpidem antagonize the sedative and muscle relaxant effects of diazepam in animals.[29] Flumazenil has been shown to antagonize the anxiolytic and anticonvulsant effects of alpidem in animals.[5]

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][11] Both alpidem and zolpidem have very low affinity for α5 subunit-containing GABAA receptors, in contrast to benzodiazepines.[30][31] Alpidem has high affinity for the peripheral benzodiazepine receptor or TSPO similarly to benzodiazepines, while zolpidem has very low affinity for this receptor.[11][32] 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][11] Alpidem was developed before the widespread use of recombinant GABAA receptors, so its pharmacological profile at the GABAA receptors and different subpopulations of these receptors has never been fully characterized.[3]

The pharmacodynamic mechanisms underlying the anxioselective (anxiolytic-selective) profile of alpidem as a GABAA receptor positive allosteric modulator are unclear.[3] 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 peripheral benzodiazepine receptor or TSPO may potentially all be involved.[3][33][5][34][29][35] 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 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][36][37] However, no such drugs have yet completed clinical development or been marketed for medical use.[36][37]

Pharmacokinetics

Absorption

Alpidem is taken via oral administration.[1] The absorption of alpidem is rapid and it reaches peak levels after 1.0 to 2.5 hours.[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 100 mg.[1] Food increases the bioavailability of alpidem by 15 to 20%.[1]

Distribution

Alpidem is a highly lipophilic compound 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 8.7 L•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]

Metabolism

Alpidem is extensively metabolized, including by hydroxylation, dealkylation, and conjugation.[1] Many metabolites of alpidem have been identified, and some of these metabolites may contribute to its pharmacological activity.[1]

Elimination

Alpidem is eliminated mainly in feces, with less than 0.1% excreted in urine.[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 the bile in feces, with less than 5% eliminated via urine.[1]

The elimination 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 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 ± 0.04 L•h-1•kg-1 in healthy individuals.[1]

Chemistry

Alpidem is a nonbenzodiazepine, and hence is not structurally related to benzodiazepines.[1][38] It is a member of the imidazopyridine group of compounds.[1][11] Alpidem is structurally related to the Z-drug zolpidem.[1][11]

History

Alpidem was developed by Synthélabo Recherche (subsequently Sanofi-Synthélabo and now Sanofi-Aventis).[4][9] It was developed under the code name SL 80.0342 and was first described in the literature by 1982.[39][6][7][8] Alpidem was introduced for medical use in France in 1991.[3][8][9] It was also undergoing development in the 1990s for use in other countries such as the United States and other European countries like Germany, the Netherlands, and Spain.[8] The drug reached phase 3 clinical trials in these countries.[8] However, development in the United States was halted in 1992 due to "divergent results".[40][8] All development in other countries was discontinued by 1999.[8] Alpidem was withdrawn from the market in France by 1994 or 1995 due to liver toxicity.[10][3] It was never marketed in any other country.[8][39][9]

Society and culture

Names

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][39] The developmental code name of alpidem was SL 80.0342.[39][8] Alpidem was previously marketed under the brand name Ananxyl.[6][39]

Availability

Alpidem was previously marketed in France, but is now longer available in any country.[3][8][9]

References

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am Durand A, Thénot JP, Bianchetti G, Morselli PL (1992). "Comparative pharmacokinetic profile of two imidazopyridine drugs: zolpidem and alpidem". Drug Metab Rev. 24 (2): 239–66. doi:10.3109/03602539208996294. PMID 1576937.
  2. ^ a b c d e f g h i j k l m n o p q r s t u v Morselli PL (May 1990). "On the therapeutic action of alpidem in anxiety disorders: an overview of the European data". Pharmacopsychiatry. 23 Suppl 3: 129–34. doi:10.1055/s-2007-1014549. PMID 1974073.
  3. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap Skolnick P (November 2012). "Anxioselective anxiolytics: on a quest for the Holy Grail". Trends Pharmacol Sci. 33 (11): 611–20. doi:10.1016/j.tips.2012.08.003. PMC 3482271. PMID 22981367.
  4. ^ a b c d e f g h i Morton S, Lader M (May 1990). "Studies with alpidem in normal volunteers and anxious patients". Pharmacopsychiatry. 23 Suppl 3: 120–3. doi:10.1055/s-2007-1014547. PMID 1974071.
  5. ^ a b c d Zivkovic B, Morel E, Joly D, Perrault G, Sanger DJ, Lloyd KG (May 1990). "Pharmacological and behavioral profile of alpidem as an anxiolytic". Pharmacopsychiatry. 23 Suppl 3: 108–13. doi:10.1055/s-2007-1014545. PMID 1974069.
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  18. ^ Hindmarch I (May 1990). "Alpidem and psychological performance in elderly subjects". Pharmacopsychiatry. 23 Suppl 3: 124–8. doi:10.1055/s-2007-1014548. PMID 1974072.
  19. ^ Patat A, Perault MC, Vandel B, Danjou P, Brohier S, Zieleniuk I, Rosenzweig P (January 1995). "Assessment of the interaction between a partial agonist and a full agonist of benzodiazepine receptors, based on psychomotor performance and memory, in healthy volunteers". J Psychopharmacol. 9 (2): 91–101. doi:10.1177/026988119500900203. PMID 22298734.
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  24. ^ a b Musch B, Morselli PL, Priore P (April 1988). "Clinical studies with the new anxiolytic alpidem in anxious patients: an overview of the European experiences". Pharmacol Biochem Behav. 29 (4): 803–6. doi:10.1016/0091-3057(88)90211-0. PMID 2901120.
  25. ^ Bourguignon JJ (1993). "Endogenous and Synthetic Ligand of Mitochondrial Benzodiazepine Receptors: Structure-Affinity Relationships.". In Giesen-Crouse E (ed.). Peripheral Benzodiazepine Receptors. London: Academic Press. pp. 59–85.
  26. ^ Costa E, Romeo E, Auta J, Papadopoulos V, Kozikowski A, Guidotti A (1991). "Is There a Pharmacology of Brain Steroidogenesis? In Neurosteroid and Brain Function". In Costa E, Paul SM (eds.). Fidia ResearchFundation Symposium Series. New York: Thieme Medical Publisher, Inc. pp. 171–176.
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  28. ^ Kozikowski AP, Ma D, Romeo E, Auta J, Papadopoulos V, Puia G, Costa E, Guidotti A (August 1992). "Synthesis of (2‐Arylindol‐3‐yl) acetamides as Probes of Mitochondrial Steroidogenesis—A New Mechanism for GABAA Receptor Modulation". Angewandte Chemie International Edition in English. 31 (8): 1060–2. doi:10.1002/anie.199210601.
  29. ^ a b c Haefely W, Martin JR, Schoch P (November 1990). "Novel anxiolytics that act as partial agonists at benzodiazepine receptors". Trends Pharmacol Sci. 11 (11): 452–6. doi:10.1016/0165-6147(90)90126-s. PMID 1980040.
  30. ^ Sanger DJ, Benavides J, Perrault G, Morel E, Cohen C, Joly D, Zivkovic B (1994). "Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes". Neurosci Biobehav Rev. 18 (3): 355–72. doi:10.1016/0149-7634(94)90049-3. PMID 7984354.
  31. ^ Langer, S.Z.; Faure-Halley, C.; Seeburg, P.; Graham, D.; Arbilla, S. (September 1992). "The selectivity of zolpidem and alpidem for the α1-subunit of the GABAA receptor". European Neuropsychopharmacology. 2 (3): 232–234. doi:10.1016/0924-977X(92)90081-I. ISSN 0924-977X.
  32. ^ Pleuvry, Barbara J (August 2004). "Anxiolytics and hypnotics". Anaesthesia & Intensive Care Medicine. 5 (8): 252–256. doi:10.1383/anes.5.8.252.43294. ISSN 1472-0299.
  33. ^ Langer SZ, Arbilla S, Tan S, Lloyd KG, George P, Allen J, Wick AE (May 1990). "Selectivity for omega-receptor subtypes as a strategy for the development of anxiolytic drugs". Pharmacopsychiatry. 23 Suppl 3: 103–7. doi:10.1055/s-2007-1014544. PMID 1974068.
  34. ^ Langer SZ, Arbilla S, Benavides J, Scatton B (1990). "Zolpidem and alpidem: two imidazopyridines with selectivity for omega 1- and omega 3-receptor subtypes". Adv Biochem Psychopharmacol. 46: 61–72. PMID 1981304.
  35. ^ Sanger DJ, Perrault G, Morel E, Joly D, Zivkovic B (1991). "Animal models of anxiety and the development of novel anxiolytic drugs". Prog Neuropsychopharmacol Biol Psychiatry. 15 (2): 205–12. doi:10.1016/0278-5846(91)90082-c. PMID 1678541.
  36. ^ a b Cerne R, Lippa A, Poe MM, Smith JL, Jin X, Ping X, Golani LK, Cook JM, Witkin JM (June 2022). "GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors". Pharmacol Ther. 234: 108035. doi:10.1016/j.pharmthera.2021.108035. PMID 34793859.
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  38. ^ Diamond BI, Nguyen H, O'Neal E, Ochs R, Kaffeman M, Borison RL (1991). "A comparative study of alpidem, a nonbenzodiazepine, and lorazepam in patients with nonpsychotic anxiety". Psychopharmacology Bulletin. 27 (1): 67–71. PMID 1677774.
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  40. ^ https://www.thepharmaletter.com/article/us-trials-of-alpidem-halted

Further reading

  • Musch B, Morselli PL, Priore P (April 1988). "Clinical studies with the new anxiolytic alpidem in anxious patients: an overview of the European experiences". Pharmacol Biochem Behav. 29 (4): 803–6. doi:10.1016/0091-3057(88)90211-0. PMID 2901120.
  • Langer SZ, Arbilla S, Benavides J, Scatton B (1990). "Zolpidem and alpidem: two imidazopyridines with selectivity for omega 1- and omega 3-receptor subtypes". Adv Biochem Psychopharmacol. 46: 61–72. PMID 1981304.
  • Langer SZ, Arbilla S, Tan S, Lloyd KG, George P, Allen J, Wick AE (May 1990). "Selectivity for omega-receptor subtypes as a strategy for the development of anxiolytic drugs". Pharmacopsychiatry. 23 Suppl 3: 103–7. doi:10.1055/s-2007-1014544. PMID 1974068.
  • Zivkovic B, Morel E, Joly D, Perrault G, Sanger DJ, Lloyd KG (May 1990). "Pharmacological and behavioral profile of alpidem as an anxiolytic". Pharmacopsychiatry. 23 Suppl 3: 108–13. doi:10.1055/s-2007-1014545. PMID 1974069.
  • Morton S, Lader M (May 1990). "Studies with alpidem in normal volunteers and anxious patients". Pharmacopsychiatry. 23 Suppl 3: 120–3. doi:10.1055/s-2007-1014547. PMID 1974071.
  • Hindmarch I (May 1990). "Alpidem and psychological performance in elderly subjects". Pharmacopsychiatry. 23 Suppl 3: 124–8. doi:10.1055/s-2007-1014548. PMID 1974072.
  • Morselli PL (May 1990). "On the therapeutic action of alpidem in anxiety disorders: an overview of the European data". Pharmacopsychiatry. 23 Suppl 3: 129–34. doi:10.1055/s-2007-1014549. PMID 1974073.
  • Durand A, Thénot JP, Bianchetti G, Morselli PL (1992). "Comparative pharmacokinetic profile of two imidazopyridine drugs: zolpidem and alpidem". Drug Metab Rev. 24 (2): 239–66. doi:10.3109/03602539208996294. PMID 1576937.
  • Sanger DJ, Benavides J, Perrault G, Morel E, Cohen C, Joly D, Zivkovic B (1994). "Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes". Neurosci Biobehav Rev. 18 (3): 355–72. doi:10.1016/0149-7634(94)90049-3. PMID 7984354.
  • Skolnick P (November 2012). "Anxioselective anxiolytics: on a quest for the Holy Grail". Trends Pharmacol Sci. 33 (11): 611–20. doi:10.1016/j.tips.2012.08.003. PMC 3482271. PMID 22981367.

External links


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