Alpidem, sold under the brand name Ananxyl, is a

nonbenzodiazepine Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...

anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

medication which was briefly used to treat

anxiety disorder Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal functions are significantly impaired. Anxiety may cause phys ...

s but is no longer marketed. It was previously marketed in

France France, officially the French Republic, is a country located primarily in Western Europe. Overseas France, Its overseas regions and territories include French Guiana in South America, Saint Pierre and Miquelon in the Atlantic Ocean#North Atlan ...

, but was discontinued due to

liver toxicity Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury (DILI) is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdr ...

. Alpidem is taken

by mouth Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of alpidem include

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to Balance disorder, disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a ...

, and

headache A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...

, among others. It has much less to no impact on

cognition Cognition is the "mental action or process of acquiring knowledge and understanding through thought, experience, and the senses". It encompasses all aspects of intellectual functions and processes such as: perception, attention, thought, ...

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembe ...

, and psychomotor function relative to

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s. Similarly, no rebound

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

or withdrawal symptoms have been observed with alpidem. Rarely, alpidem can cause serious

, including

liver failure Liver failure is the inability of the liver to perform its normal synthetic and metabolic functions as part of normal physiology. Two forms are recognised, acute and chronic (cirrhosis). Recently, a third form of liver failure known as acute- ...

and death. Alpidem is a

of the

imidazopyridine An imidazopyridine is a nitrogen containing heterocycle that is also a class of medication, drugs that contain this same chemical substructure. In general, they are GABAA receptor, GABAA receptor receptor_agonist, agonists, however recently proto ...

family,

structurally A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

related to the

Z-drug Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...

zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...

, and acts as a GABA_A receptor positive allosteric modulator of the

benzodiazepine site The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic tra ...

of the receptor complex. In contrast to zolpidem however, alpidem has

effects rather than

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...

effects at normal therapeutic doses. Alpidem was first described by 1982 and was introduced for medical use in

in 1991. 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. Alpidem was withdrawn from the market in France in 1993 due to liver toxicity.WHO Drug Information Vol. 8, No. 2, 1994, page 64
/ref>

Medical uses

Alpidem was approved for the treatment of

generalized anxiety disorder Generalized anxiety disorder (GAD) is an anxiety disorder characterized by excessive, uncontrollable and often irrational worry about events or activities. Worry often interferes with daily functioning. Individuals with GAD are often overly con ...

and possibly also other anxiety problems. By 1990, 17clinical studies including more than 1,500patients had been conducted in

Europe Europe is a continent located entirely in the Northern Hemisphere and mostly in the Eastern Hemisphere. It is bordered by the Arctic Ocean to the north, the Atlantic Ocean to the west, the Mediterranean Sea to the south, and Asia to the east ...

studying alpidem for the treatment of anxiety. In clinical trials, alpidem demonstrated effectiveness in the treatment of chronic and situational

, including stress-related anxiety, generalized anxiety, and

adjustment disorder Adjustment disorder is a Mental disorder, mental and Abnormality (behavior), behavioral Mental disorder, disorder defined by a maladaptive response to a psychosocial stressor. The maladaptive response usually involves otherwise normal emotional a ...

(situational depression) with anxiety. It also showed preliminary effectiveness in institutionalized individuals with chronic

psychosis In psychopathology, psychosis is a condition in which a person is unable to distinguish, in their experience of life, between what is and is not real. Examples of psychotic symptoms are delusions, hallucinations, and disorganized or inco ...

and high anxiety levels. The effectiveness of alpidem for

panic disorder Panic disorder is a mental disorder, specifically an anxiety disorder, characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath ...

, on the other hand, is understudied and uncertain. The anxiolytic effects of alpidem are described as rapid, robust, and maintained in the long-term. 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. No indications of tolerance to its anxiolytic effects or need for dose increases have been observed. In people with anxiety taking alpidem, improvement in mood and

sleep Sleep is a state of reduced mental and physical activity in which consciousness is altered and certain Sensory nervous system, sensory activity is inhibited. During sleep, there is a marked decrease in muscle activity and interactions with th ...

have also been found. The anxiolytic effectiveness of alpidem, for example measured by reductions on the Hamilton Anxiety Rating Scale (HAM-A), was superior to

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

and comparable or equivalent to that of

s including

diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...

(10–15mg/day),

lorazepam Lorazepam, sold under the brand name Ativan, Tavor among others, is a benzodiazepine medication. It is used to treat anxiety (including anxiety disorders), insomnia, severe agitation, active seizures including status epilepticus, alcoh ...

(1–6mg/day), and clorazepate (30mg/day) in directly comparative

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

s. Alpidem has also been directly compared with

buspirone Buspirone, sold under the brand name Buspar among others, is an anxiolytic, a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder (GAD). It is a serotonin 5-HT1A receptor, 5-HT1A receptor partial ag ...

(20–30mg/day) for generalized anxiety disorder. Relative to buspirone, it was found to produce more rapid improvement, to have significantly greater effectiveness, and to have fewer

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s and a lower discontinuation rate. 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.

Available forms

Alpidem was provided in the form of 50-mg

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid **Oral administration of medicines ** Oral examination (also known as an oral exam or ora ...

tablets.

Side effects

Alpidem is described as well-tolerated.

s include

(6–8%; dose-dependent),

(3–4%),

(3–4%), and

(2–3%), among others. It is reported to have minimal sedative effects and to have virtually no negative effects on

, and psychomotor function at therapeutic doses. However, some impairment of

vigilance Vigilance may refer to: * Alertness * Vigilance, a creature ability in the ''Magic: The Gathering'' collectible card game * ''Vigilance'' (album), by Threat Signal * Vigilance (behavioural ecology), the watchfulness of prey for nearby predator ...

and psychomotor function has been reported at high doses (100–200mg). In addition,

driving Driving is the controlled operation and movement of a land vehicle, including cars, motorcycles, trucks, and buses. A driver's permission to drive on public highways is granted based on a set of conditions being met, and drivers are required to ...

ability has been studied with alpidem and has been found to be impaired. The central side effects of alpidem were found to be no worse in elderly people than in young adults. Alpidem does not alter sleep architecture as measured by

electroencephalography Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignal, bio signals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in ...

. In

laboratory tests A laboratory (; ; colloquially lab) is a facility that provides controlled conditions in which scientific or technological research, experiments, and measurement may be performed. Laboratories are found in a variety of settings such as schools, u ...

, 0.9% of patients treated with alpidem showed alterations. No adverse effects on

cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...

respiratory The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies gr ...

function were seen in clinical trials. No rebound

or withdrawal symptoms have been observed with alpidem after abrupt

discontinuation Medication discontinuation is the ceasing of a medication treatment for a patient by either the clinician or the patient themself. When initiated by the clinician, it is known as deprescribing. Medication discontinuation is an important medical ...

following 4weeks to 6–12months of treatment. Conversely, substantial withdrawal symptoms, including rebound anxiety, were observed with

. The side effects of alpidem are described as quite different from those of

s. In directly comparative trials, alpidem produced similar anxiolytic effects with less

asthenia Weakness is a symptom of many different medical conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, ...

, depressive mood, and psychomotor impairment than benzodiazepines, while rates of

somnolence Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling aslee ...

and

drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

were comparable to benzodiazepines but described as milder in severity. Whereas benzodiazepines commonly produce

muscle weakness Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includ ...

, and

sleepiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

as side effects, these are not prominent adverse effects with doses of alpidem that have similar anxiolytic effectiveness. The lack of withdrawal or rebound symptoms with alpidem upon discontinuation is also in contrast to benzodiazepines. 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. Following marketing authorization in France, several cases of severe

were reported in people taking alpidem. This resulted in one death and several cases of

liver transplantation Liver transplantation or hepatic transplantation is the replacement of a diseased liver with the healthy liver from another person (allograft). Liver transplantation is a treatment option for end-stage liver disease and acute liver failure, al ...

. As a result, alpidem was soon withdrawn from the market. The liver toxicity of alpidem was subsequently characterized in

preclinical research In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...

. It may be related to interactions of alpidem with the translocator protein (TSPO), which is present in high amounts in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and which may mediate toxic effects in this tissue.

Overdose

Little information is available on

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

with alpidem. Doses of as high as 300mg/day, which is 2 to 4times the recommended total daily dose, were assessed in clinical trials.

Interactions

Alpidem may interact with

alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...

, but to a lesser extent than

Pharmacology

Pharmacodynamics

Alpidem is a GABA_A receptor positive allosteric modulator (GABAkine), specifically acting as an

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

of the

of the receptor complex (formerly known as the central benzodiazepine receptor (CBR)). In addition to its

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the benzodiazepine site of the GABA_A receptor (K_i = 1–28nM), alpidem has similarly high affinity for the translocator protein (TSPO) (formerly the peripheral benzodiazepine receptor (PBR)) (K_i = 0.5–7nM). Alpidem shows more than 500-fold

selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...

for α₁ subunit-containing GABA_A receptors over α₅ subunit-containing GABA_A receptors and 80-fold selectivity for α₁ subunit-containing GABA_A receptors over α₃ subunit-containing GABA_A receptors. However, alpidem has also been described as potently modulating α₁, α₂, and α₃ subunit-containing GABA_A receptors with no effect on α₅ subunit-containing GABA_A receptors. Findings appear to be mixed on whether alpidem is a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

or a

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...

of the benzodiazepine site of the GABA_A receptor. In animals, alpidem has

-like effects in some but not all models, weak

anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...

effects, and weak or no

amnesic Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...

, ataxic, or

muscle relaxant A muscle relaxant is a drug that affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeu ...

effects. High doses of alpidem antagonize the sedative and muscle relaxant effects of

in animals.

Flumazenil Flumazenil, also known as flumazepil, is a selective GABAA receptor, GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (partic ...

has been shown to antagonize the anxiolytic and anticonvulsant effects of alpidem in animals. Besides acting directly via the GABA_A receptor, interactions with the TSPO might also contribute to the anxiolytic effects of alpidem. This protein mediates promotion of neurosteroidogenesis in the

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

, for instance of

allopregnanolone Allopregnanolone is a natural product, naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to t ...

. Alpidem is

related to

, and both alpidem and zolpidem are GABA_A receptor positive allosteric modulators of the benzodiazepine site with preference for α₁ subunit-containing receptors. Both alpidem and zolpidem have very low affinity for α₅ subunit-containing GABA_A receptors, in contrast to

s. Similarly, both alpidem and zolpidem are selective for γ₂ subunit-containing GABA_A receptors, with very low affinity for γ₁ and γ₃ subunit-containing GABA_A receptors, in contrast to other Z-drugs and to diazepam. Alpidem has very high affinity for the TSPO, while zolpidem has very low affinity for this protein. The affinity of alpidem for the TSPO (also previously known as the ω₃ receptor) was once the highest of any drug known. 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. Whereas zolpidem shows

and

effects and is used to treat

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

, alpidem shows mainly

effects and is used to treat anxiety disorders. Alpidem was developed before the widespread use of recombinant GABA_A receptors. Hence, its pharmacological profile at the GABA_A receptors, including its profile at different subpopulations of these receptors, has never been fully characterized. The

pharmacodynamic Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...

mechanisms underlying the anxioselective (anxiolytic-selective) profile of alpidem as a GABA_A receptor positive allosteric modulator are unclear. In any case, subtype selectivity for different populations of GABA_A receptors, partial agonism of the benzodiazepine site of the GABA_A receptor, and/or interactions with the TSPO may potentially all be involved. Although anxioselective profiles have been observed for many GABA_A receptor positive allosteric modulators in

, alpidem is the only GABA_A receptor positive allosteric modulator for which anxioselective effects have been unambiguously demonstrated in human

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

s. 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. GABA_A receptor positive allosteric modulators with selectivity for α₂ and α₃ subunit-containing GABA_A receptors over α₁ subunit-containing GABA_A receptors, for instance adipiplon,

L-838,417 L-838,417 is an anxiolytic drug used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. The compound was developed by Merck, Sharp and Dohme. ...

, and darigabat—among others, have been and are under investigation as potential anxioselective agents. However, no such drugs have yet completed clinical development or been marketed for medical use. Despite many developmental failures, alpidem serves as a potential proof of concept that anxioselective GABA_A receptor positive allosteric modulators may be possible. However, if interactions with the TSPO are key to the anxiolytic effects of alpidem, then this may not actually be the case.

Pharmacokinetics

Absorption

Alpidem is taken via

oral administration Oral administration is a route of administration whereby a substance is taken through the Human mouth, mouth, swallowed, and then processed via the digestive system. This is a common route of administration for many medications. Oral administ ...

. The

absorption Absorption may refer to: Chemistry and biology *Absorption (biology), digestion **Absorption (small intestine) *Absorption (chemistry), diffusion of particles of gas or liquid into liquid or solid materials *Absorption (skin), a route by which su ...

of alpidem is rapid and it reaches peak levels after 1.0 to 2.5hours. Its overall

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

is estimated to be approximately 32 to 35%, but no precise value for absolute bioavailability has been determined. Absorption of alpidem as indicated by peak and area-under-the-curve levels is linear across a dose range of 25 to 100mg. Food increases the bioavailability of alpidem by 15 to 20%.

Distribution

Alpidem is a highly

lipophilic Lipophilicity (from Greek language, Greek λίπος "fat" and :wikt:φίλος, φίλος "friendly") is the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such compounds are c ...

compound and in animals is extensively

distributed Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations *Probability distribution, the probability of a particular value or value range of a varia ...

into

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

-rich tissues. Similarly, alpidem has been shown to cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

in animals, and showed a brain/plasma ratio of about 2.0 to 2.5 following systemic administration. This is related to significantly slower efflux of alpidem from the brain than entry. The

active metabolite An active metabolite, or pharmacologically active metabolite is a biologically active metabolite of a xenobiotic substance, such as a drug or environmental chemical. Active metabolites may produce therapeutic effects, as well as harmful effects. ...

s of alpidem are also brain-penetrant, although occur in the brain at levels lower than those of alpidem. Alpidem may be concentrated more in lipid-rich

white matter White matter refers to areas of the central nervous system that are mainly made up of myelinated axons, also called Nerve tract, tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distr ...

brain structures than

grey matter Grey matter, or gray matter in American English, is a major component of the central nervous system, consisting of neuronal cell bodies, neuropil ( dendrites and unmyelinated axons), glial cells ( astrocytes and oligodendrocytes), synapses, ...

structures. In humans, the

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of alpidem is large at 8.7L•kg⁻¹. The

plasma protein binding Plasma protein binding refers to the degree to which medications attach to blood proteins within the blood plasma. A drug's efficacy may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse o ...

of alpidem is 99.4%, with similar isolated fractions bound to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

(97.0%) and α₁-acid glycoprotein (97.3%). The free fraction of alpidem is slightly higher in people with

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

(0.86 ± 0.06%) and

renal failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

(0.72 ± 0.03%) relative to normal individuals (0.61 ± 0.05%).

Metabolism

Alpidem is extensively

metabolized Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

, including by

hydroxylation In chemistry, hydroxylation refers to the installation of a hydroxyl group () into an organic compound. Hydroxylations generate alcohols and phenols, which are very common functional groups. Hydroxylation confers some degree of water-solubility ...

, dealkylation, and

conjugation Conjugation or conjugate may refer to: Linguistics *Grammatical conjugation, the modification of a verb from its basic form *Emotive conjugation or Russell's conjugation, the use of loaded language Mathematics *Complex conjugation, the change o ...

. Many

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...

s of alpidem have been identified, and some of these metabolites may contribute to its pharmacological activity.

Elimination

Alpidem is eliminated mainly in

feces Feces (also known as faeces American and British English spelling differences#ae and oe, or fæces; : faex) are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the ...

, with less than 0.1% excreted in

urine Urine is a liquid by-product of metabolism in humans and many other animals. In placental mammals, urine flows from the Kidney (vertebrates), kidneys through the ureters to the urinary bladder and exits the urethra through the penile meatus (mal ...

. A majority of alpidem is eliminated within 48 to 72hours following oral dosing. Only trace amounts of unchanged alpidem are found in feces and urine. The metabolites of alpidem are excreted mainly in via the

bile Bile (from Latin ''bilis''), also known as gall, is a yellow-green/misty green fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water, is pro ...

in feces, with less than 5% eliminated via urine. The

elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...

of alpidem was mean 18.8 ± 0.8hours (range 7 to 44hours) following a single 50-mg oral dose given to young individuals. In elderly individuals, a trend toward a longer half-life was observed (22.6 ± 2.3hours). Conversely, in children age 8 to 12years, the half-life of alpidem was considerably reduced (11.4 ± 1.9hours). The half-lives of alpidem and its metabolites are significantly prolonged in people with hepatic impairment. Conversely, the half-lives of alpidem and its metabolites were unchanged in people with different stages of

renal impairment Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...

, though plasma concentrations were significantly increased. The clearance of alpidem was estimated to be 0.86 ± 0.04L•h⁻¹•kg⁻¹ in healthy individuals.

Chemistry

Alpidem is a

, and hence is not

related to

s. It is a member of the

group of compounds. Alpidem is structurally related to the

, which is also an imidazopyridine.

History

Alpidem was developed by Synthélabo Recherche (subsequently Sanofi-Synthélabo and now

Sanofi-Aventis Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Synthélabo merg ...

). It was developed under the code name SL 80.0342 and was first described in the literature by 1982. Alpidem was introduced for medical use in

in 1991. It was also undergoing development in the 1990s for use in other countries such as the

United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...

and other

an countries like

Germany Germany, officially the Federal Republic of Germany, is a country in Central Europe. It lies between the Baltic Sea and the North Sea to the north and the Alps to the south. Its sixteen States of Germany, constituent states have a total popu ...

, the

Netherlands , Terminology of the Low Countries, informally Holland, is a country in Northwestern Europe, with Caribbean Netherlands, overseas territories in the Caribbean. It is the largest of the four constituent countries of the Kingdom of the Nether ...

, and

Spain Spain, or the Kingdom of Spain, is a country in Southern Europe, Southern and Western Europe with territories in North Africa. Featuring the Punta de Tarifa, southernmost point of continental Europe, it is the largest country in Southern Eur ...

. The drug reached phase 3

s in these countries. However, development in the United States was halted in 1992 due to "divergent results". All development in other countries was discontinued by 1999. Alpidem was withdrawn from the market in France in 1993 due to liver toxicity. It was never marketed in any other country.

Society and culture

Names

''Alpidem'' is the generic name of the drug and its , , , and . The developmental code name of alpidem was ''SL 80.0342''. Alpidem was previously marketed under the brand name ''Ananxyl''.

Availability

Alpidem was previously marketed in

, but is no longer available in any country.

References

External links

Alpidem - Sanofi-Synthelabo - AdisInsight
{{Translocator protein modulators Anxiolytics Carboxamides 4-Chlorophenyl compounds GABAA receptor positive allosteric modulators Hepatotoxins Imidazopyridines Nonbenzodiazepines Propyl compounds Sanofi TSPO ligands Withdrawn drugs

Medical uses

Available forms

Side effects

Overdose

Interactions

Pharmacology

Pharmacodynamics

Pharmacokinetics

Absorption

Distribution

Metabolism

Elimination

Chemistry

History

Society and culture

Names

Availability

See also

References

Further reading

External links