Lorpiprazole (INN) (brand name Normarex) is a marketed anxiolytic drug of the phenylpiperazine group.
It has been described as a serotonin antagonist and reuptake inhibitor (SARI) in the same group as trazodone, nefazodone, and etoperidone.
Enpiprazole (INN, BAN) is an anxiolytic drug of the phenylpiperazine group that was never marketed.
It produces anxiolytic-like effects in animals, though these effects appear to be biphasic and may reverse at high doses.
It is known to produce ortho-chlorophenylpiperazine (oCPP) as a metabolite.
Acaprazine (INN) is an anxiolytic and “adrenolytic” drug of the phenylpiperazine group that was never marketed.
Mepiprazole (INN, BAN) (brand name Psigodal) is an anxiolytic drug of the phenylpiperazine group with additional antidepressant properties that is marketed in Spain.
It acts as a 5-HT2A and α1-adrenergic receptor antagonist and inhibits the reuptake and induces the release of serotonin, dopamine, and norepinephrine to varying extents, and has been described as a serotonin antagonist and reuptake inhibitor (SARI).
Controlled clinical trials of mepiprazole in patients with irritable bowel syndrome (IBS) were also carried out and suggested some benefits of the drug in relieving symptoms of IBS in some patients.
Similarly to other phenylpiperazines like trazodone, nefazodone, and etoperidone, mepiprazole produces mCPP as an active metabolite
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Charles Brenner (18 November 1913, in Boston to 19 May 2008) was an American psychoanalyst who served as president of the New York Psychoanalytic Society, and is perhaps best known for his contributions to drive theory, the structure of the mind, and conflict theory.
He was for half a century an exemplary figure for psychoanalysis in America, being termed by Janet Malcolm “the intransigent purist of American psychoanalysis”.
Brenner first made his name as the author of the Elementary Textbook of Psychoanalysis, which Eric Berne paired with Freud’s Outline of Psychoanalysis as the best guide to the subject. In it he stressed for example how, unlike ‘conscience’, the superego functions mainly or entirely unconsciously.
He went on to co-author, with Jacob Arlow, Psychoanalytic Concepts and the Structural Theory, which, initially controversial, would become a standard advanced text. Brenner himself conceded that probably “my most significant influence was as author of An Elementary Textbook”.
While Brenner favoured a cool, aseptic analytic technique, and opposed the idea that the transference could be separated off from the so-called working alliance, he also challenged the mechanical use of the analysis of defences without consideration of the instinctual impulses involved.
Brenner pointed out that just as “it is presumptuous to act the analyst, unbidden, in a social or family situation. It is a technical lapse to be other than an analyst in one’s relations with an analytic patient”. His technique epitomised what Malcolm called “taking respect for individual experience and generosity of spirit toward human frailty very far indeed’”.
Brenner has been notable for his readiness to challenge psychoanalytic dogmas, something perhaps most apparent with his late revision of Freud’s structural theory, culminating in his article “Conflict, Compromise Formation, and Structural Theory”(2002) which he himself considered “the most useful and valuable contribution I have been able to make to the field of psychoanalysis”.
His late development of conflict theory went back to Freud’s early concept of ‘compromise formation’, as well as drawing on Arlow’s idea of ‘fantasy function’ in a mixture of conservatism and innovation. Arguably the result was to produce the leading analytic theory for 21stC American psychoanalytic training.
Brenner has been criticised for a tendency to follow his own theoretical furrow, rather than engage with other points of view.
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Lurasidone, sold under the trade name Latuda among others, is an antipsychotic medication used to treat schizophrenia and bipolar disorder. It is taken by mouth.
Common side effects include sleepiness, movement disorders, nausea, and diarrhoea. Serious side effects are valid for all atypical antipsychotics and may include the potentially permanent movement disorder tardive dyskinesia, as well as neuroleptic malignant syndrome, an increased risk of suicide, angioedema, and high blood sugar levels, although lurasidone is less likely to cause high blood sugar levels in most patients, hyperosmolar hyperglycaemic syndrome may occur. In older people with psychosis as a result of dementia, it may increase the risk of dying. Use during pregnancy is of unclear safety.
Lurasidone was first approved for medical use in the United States in 2010. In 2013, it was approved in Canada, and by the United States Food and Drug Administration, to treat bipolar depression, either as monotherapy or adjunctively with lithium or valproate. Generic versions were approved in the United States in 2019, and became available in 2023. In 2020, it was the 259th most commonly prescribed medication in the United States, with more than 1 million prescriptions.
Lurasidone was first synthesised circa 2003.
Lurasidone is a structural analogue of ziprasidone. Lurasidone shows a very close pharmacological profile and has been synthesized similarly to ziprasidone.
Lurasidone is chemically similar to perospirone (also a chemical analogue of ziprasidone), as well as risperidone, paliperidone and iloperidone.
It has approval from the US Food and Drug Administration (FDA) for treating schizophrenia since 2010, and for treating depressive episodes in adults with bipolar I disorder since 2013.
Lurasidone is used to treat schizophrenia and bipolar disorder. In bipolar disorder, It has been studied both as a monotherapy and adjunctive treatment to lithium or valproate.
The European Medicines Agency approved lurasidone for the treatment of schizophrenia for people aged 13 years and older, but not for bipolar disorder. In the United States, it is used to treat schizophrenia for people aged 13 years and older, as well as depressive episodes of bipolar disorder age 10 and over as a monotherapy, and in conjunction with lithium or valproate in adults.
In July 2013, lurasidone received approval for bipolar I depression.
In June 2020, lurasidone was approved in Japan, eight years after its first approval in the United States. In Japan it is approved for bipolar depression and schizophrenia.
Few available atypical antipsychotics are known to possess antidepressant efficacy in bipolar disorder (with the notable exceptions being quetiapine, olanzapine and possibly asenapine) as a monotherapy, even though the majority of atypical antipsychotics are known to possess significant antimanic activity, which is yet to be clearly demonstrated for lurasidone.
In the early post approval period lurasidone-treated patients with bipolar disorder were retrospectively found to have more complex clinical profiles, comorbidities, and prior treatment history compared to patients initiated with other atypical antipsychotics. The study authors suggest this may be due to:
“the overall clinical profile of lurasidone, the role perceived for lurasidone in the therapeutic armamentarium by practitioners, and the recent introduction of lurasidone into clinical practice during the study period.”
Lurasidone is not approved by the FDA for the treatment of behaviour disorders in older adults with dementia.
Lurasidone is contraindicated in individuals who are taking strong inhibitors of the liver enzyme CYP3A4 (ketoconazole, clarithromycin, ritonavir, levodropropizine, etc.) or inducers (carbamazepine, St. John’s wort, phenytoin, rifampicin etc.). The use of lurasidone in pregnant women has not been studied and is not recommended; in animal studies, no risks have been found. Excretion in breast milk is also unknown; lurasidone is not recommended for breastfeeding women. In the United States it is not indicated for use in children. The enzyme CYP3A4 is involved in the digestion of drugs. Inhibitors such as grapefruit juice block its function resulting in too much drug in the body.
Side effects are generally similar to other antipsychotics. The drug has a relatively well tolerated side effect profile, with low propensity for QTc interval changes, weight gain and lipid-related adverse effects. In a 2013 meta-analysis of the efficacy and tolerability of 15 antipsychotic drugs it was found to produce the second least (after haloperidol) weight gain, the least QT interval prolongation, the fourth most extrapyramidal side effects (after haloperidol, zotepine and chlorpromazine) and the sixth least sedation (after paliperidone, sertindole, amisulpride, iloperidone, and aripiprazole).
As with other atypical neuroleptics, lurasidone should be used with caution in the elderly because it puts them at an increased risk for a stroke or transient ischemic attack; however, these risks are not likely to be greater than those associated with antipsychotics of other classes. Similarly, lurasidone should not be used to treat dementia-related psychosis, as evidence has shown increased mortality with antipsychotic use.
Weight gain is reported in up to 15% and 16% of users. Other possible side effects include vomiting, akathisia, dystonia, parkinsonism, somnolence, dizziness, sedation and nausea.
The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. Other symptoms may include restlessness, increased sweating, and trouble sleeping. Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. Symptoms generally resolve after a short period of time.
There is tentative evidence that discontinuation of antipsychotics can result in psychosis. It may also result in reoccurrence of the condition that is being treated. Rarely tardive dyskinesia can occur when the medication is stopped.
Blood plasma concentrations may be increased when combined with CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, ritonavir, and voriconazole) possibly leading to more side effects. This has been clinically verified for ketoconazole, which increases lurasidone exposure by a factor of 9, and is also expected for other 3A4 inhibitors such as grapefruit juice. Co-administration of CYP3A4 inducers like rifampicin, carbamazepine or St. John’s wort can reduce plasma levels of lurasidone and its active metabolite, and consequently decrease the effects of the drug. For rifampicin, the reduction was sixfold in a study.
Lurasidone [(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl) piperazin-1-ylmethyl]-cyclohexylmethyl}-hexahydro-4,7-methano-2Hisoindole-1,3-dione hydrochloride]] is an azapirone derivative and acts as an antagonist of the dopamine D2 and D3 receptors, and the serotonin 5-HT2A and 5-HT7 receptors, and the α2C-adrenergic receptor, and as a partial agonist of the serotonin 5-HT1A receptor. It has moderate-affinity antagonism at α2C-adrenergic receptors; low to very low-affinity antagonism at α1A-adrenergic α2A-adrenergic receptors.
It has only low and likely clinically unimportant affinity for the serotonin 5-HT2C receptor, which may underlie its low propensity for appetite stimulation and weight gain. The drug also has negligible affinity for the histamine H1 receptor and the muscarinic acetylcholine receptors, and hence has no antihistamine or anticholinergic effects. Drowsiness (somnolence) side effect is not explained by its antagonist activity to histamine.
The relationship between dose and D2 receptor occupancy levels were 41–43% for 10 mg, 51–55% for 20 mg, 63–67% for 40 mg, 77–84% for 60 mg, and 73–79% for 80 mg.
Lurasidone is taken by mouth and has an estimated absorption rate of 9 to 19%. Studies have shown that when lurasidone is taken with food, absorption increases about twofold. Peak blood plasma concentrations are reached after one to three hours. About 99% of the circulating substance are bound to plasma proteins. Efficacy data for lurasidone have been evaluated for doses of 20 mg to 120 mg daily
Lurasidone is extensively metabolised by CYP3A4 leading to contraindication of both strong inhibitors as well as strong inducers of this enzyme, but has negligible affinity to other cytochrome P450 enzymes. It is transported by P-glycoprotein and ABCG2 and also inhibits these carrier proteins in vitro. It also inhibits the solute carrier protein SLC22A1, but no other relevant transporters.
Main metabolism pathways are oxidative N-dealkylation between the piperazine and cyclohexane rings, hydroxylation of the norbornane ring, and S-oxidation. Other pathways are hydroxylation of the cyclohexane ring and reductive cleavage of the isothiazole ring followed by S-methylation. The two relevant active metabolites are the norbornane hydroxylation products called ID-14283 and ID-14326, the former reaching pharmacologically relevant blood plasma concentrations. The two major inactive metabolites are the N-dealkylation products (the carboxylic acid ID-20219 and the piperazine ID-11614), and a norbornane hydroxylated derivative of ID-20219 (ID-20220). Of lurasidone and its metabolites circulating in the blood, the native drug makes up 11%, the main active metabolite 4%, and the inactive carboxylic acids 24% and 11%, respectively. Several dozen metabolites have been identified altogether.
Biological half-life is given as 18 hours or 20 to 40 hours in different sources. 80% or 67% of a radiolabelled dose was recovered from the faeces, and 9% or 19% from the urine.
In Canada, as of 2014, lurasidone is generally more expensive than risperidone and quetiapine but less expensive than aripiprazole.
In the US, because a number of doses have the same price per tablet, pill splitting has been used to decrease costs. In 2019, generic versions were approved in the United States; however, they only became available in 2023 due to drug patents.
In India, this drug is available under the brand names of Atlura, Lurace, Lurafic, Luramax (Sun Pharma), Lurasid, Lurastar, Latuda, Lurata and additionally as Alsiva, Emsidon, Lurakem, Luratrend, Tablura, and Unison.
Lurasidone was approved in the United States for the treatment of schizophrenia in October 2010 and for the treatment of depressive episodes associated with bipolar I disorder in June 2013. It received regulatory approval in the United Kingdom in September 2014. In October 2014, NHS Scotland advised use of lurasidone for schizophrenic adults who have not seen improvements with previous antipsychotics due to problems that arise from weight gain or changes in metabolic pathways when taking other medications. The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion for it in January 2014, and it was approved for medical use by the EMA in March 2014. It was launched in Canada for the treatment of schizophrenia in September 2012, Health Canada giving their Summary Basis of Decision (SBD) as favourable on 15 October 2012. European Commission has granted a marketing authorization for once-daily oral lurasidone for the treatment of schizophrenia in adults. It is approved for use in the EU.
Generic versions of lurasidone were approved for use in the United States in January 2019 and became available in 2023.
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Lubazodone (developmental code names YM-992, YM-35995) is an experimental antidepressant which was under development by Yamanouchi for the treatment for major depressive disorder in the late 1990s and early 2000s but was never marketed.
It acts as a serotonin reuptake inhibitor (Ki for SERTTooltip serotonin transporter = 21 nM) and 5-HT2A receptor antagonist (Ki = 86 nM), and hence has the profile of a serotonin antagonist and reuptake inhibitor (SARI). The drug has good selectivity against a range of other monoamine receptors, with its next highest affinities being for the α1-adrenergic receptor (Ki = 200 nM) and the 5-HT2C receptor (Ki = 680 nM).
Lubazodone is structurally related to trazodone and nefazodone, but is a stronger serotonin reuptake inhibitor and weaker as a 5-HT2A receptor antagonist in comparison to them and is more balanced in its actions as a SARI. It reached phase II clinical trials for depression, but development was discontinued in 2001 reportedly due to the “erosion of the SSRITooltip selective serotonin reuptake inhibitor market in the United States”.
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Gepirone, sold under the brand name Exxua, is a medication used for the treatment of major depressive disorder. It is taken orally.
Side effects of gepirone include dizziness, nausea, insomnia, abdominal pain, and dyspepsia (indigestion). Gepirone acts as a partial agonist of the serotonin 5-HT1A receptor. An active metabolite of gepirone, 1-(2-pyrimidinyl)piperazine, is an α2-adrenergic receptor antagonist. Gepirone is a member of the azapirone group of compounds.
Gepirone was synthesized by Bristol-Myers Squibb in 1986 and was developed and marketed by Fabre-Kramer Pharmaceuticals. It was approved for the treatment of major depressive disorder in the United States in September 2023. This came after the drug had been rejected by the US Food and Drug Administration (FDA) three times over two decades due to insufficient evidence of effectiveness.
Gepirone was developed by Bristol-Myers Squibb in 1986, but was out-licensed to Fabre-Kramer in 1993. The FDA rejected approval for gepirone in 2002 and 2004. It was submitted for the preregistration (NDA) phase again in May 2007 after adding additional information from clinical trials as the FDA required in 2009. However, in 2012 it once again failed to convince the FDA of its qualities for treating anxiety and depression. In December 2015, the FDA once again gave gepirone a negative review for depression due to concerns of efficacy. However, in March 2016, the FDA reversed its decision and gave gepirone ER a positive review. Gepirone ER was finally approved for the treatment of major depressive disorder in the United States in September 2023.
Gepirone is indicated for the treatment of major depressive disorder in adults. Of 15 clinical trials of gepirone for major depressive disorder submitted to the FDA, three were excluded for methodological reasons, three were deemed “failed” and “uninformative”, seven were deemed negative and did not demonstrate effectiveness, and two were deemed positive and did show effectiveness. Two positive trials are needed for FDA drug approval, with this being the case regardless of the number of negative trials. In the two positive trials of gepirone for depression, the drug significantly outperformed placebo in terms of depressive symptom reduction and showed effect sizes similar to those of other approved antidepressants. In both trials, gepirone reduced depressive symptoms by about 2.5 points more than placebo on the 52-point Hamilton Depression Rating Scale (17-item version or HAMD-17). The baseline depression scores in the trials ranged from 22.7 to 24.2 in the different patient groups.
Gepirone comes in the form of extended-release tablets of the hydrochloride salt, gepirone hydrochloride, in the strengths 18.2 mg, 36.3 mg, 54.5 mg, and 72.6 mg.
Side effects of gepirone include dizziness, nausea, insomnia, abdominal pain, and dyspepsia (indigestion).
The CYP3A4 inhibitors ketoconazole and verapamil strongly increase exposure to gepirone, whereas lithium, paroxetine, and warfarin have no effect on exposure to gepirone. The CYP3A4 inducer rifampin profoundly decreases exposure to gepirone.
Gepirone acts as a selective partial agonist of the 5-HT1A receptor. Unlike its relative buspirone, however, gepirone has greater efficacy in activating the 5-HT1A and has negligible affinity for the D2 receptor (30- to 50-fold lower in comparison to buspirone). However, similarly to buspirone, gepirone metabolises into 1-(2-pyrimidinyl)piperazine (1-PP), which is known to act as a potent antagonist of the α2-adrenergic receptor.
The absolute bioavailability of gepirone is 14 to 17%. The time to peak concentrations of gepirone with the extended-release formulation is 6 hours. When taken with a high-fat meal, the time to peak levels decreases to 3 hours. A high-fat meal increases exposure to gepirone, with the effect increasing dependent on the amount of fat in the meal. Peak concentrations were increased by 27% with a low-fat meal, 55% with a medium-fat meal, and 62% with a high-fat meal, while area-under-the-curve levels of gepirone were increased by 14% with a low-fat meal, 22% with a medium-fat meal, and 32 to 37% with a high-fat meal. The effect was similar for the metabolites of gepirone, 1-PP and 3′-hydroxygepirone (3′-OH-gepirone).
The apparent volume of distribution of gepirone is approximately 94.5 L. The plasma protein binding of gepirone in vitro is 72% and is independent of concentration. The plasma protein binding of 3′-OH-gepirone is 59% and of 1-PP is 42%.
Gepirone is metabolised primarily by CYP3A4. Its major metabolites are 1-PP and 3′-OH-gepirone, both of which are pharmacologically active. These metabolites are present in the circulation at higher concentrations than gepirone.
With a single oral dose of radiolabeled gepirone, 81% is recovered in urine and 13% is recovered in faeces as metabolites. About 60% of the gepirone is eliminated in urine within 24 hours.
The terminal half-life of gepirone as the extended-release form is approximately 5 hours.
Gepirone is a member of the azapirone group of compounds and is structurally related to buspirone, tandospirone, and other azapirones.
The brand name of gepirone is Exxua. Former tentative brand names which were never used included Ariza, Variza, and Travivo.
Gepirone is under development for the treatment of decreased libido and generalized anxiety disorder. As of October 2023, it is in phase 3 clinical trials for these indications. The pro-sexual effects of gepirone appear to be independent of its antidepressant and anxiolytic effects.
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Fencamfamin (INN), also known as fencamfamine or by the brand names Glucoenergan and Reactivan, is a stimulant which was developed by Merck in the 1960s.
Fencamfamin is still used, though rarely, for treating depressive day-time fatigue, lack of concentration and lethargy, particularly in individuals who have chronic medical conditions, as its favourable safety profile makes it the most suitable drug in some cases.
Fencamfamin is well tolerated and causes minimal circulatory effects. Extended use may result in a dryness of the mouth.
Not to be used with heart diseases, angina pectoris and decompensated cardiac insufficiency, glaucoma, hyper-excitability and thyrotoxicosis or while treated with monoamine oxidase inhibitors.
Symptoms of overdose are nausea, agitation and restlessness, dryness of the mouth, dizziness and tremor. In gross overdosage also associated with dyspnoea, tachycardia, disorientation and convulsions.
In a study on slices of rat corpus striatum and substantia nigra fencamfamin acted as an indirect dopamine agonist. It released dopamine by a similar mechanism to amphetamines, but was ten times less potent than dexamphetamine at producing this effect. The main mechanism of action was instead inhibition of dopamine reuptake. Also unlike amphetamines, fencamfamin does not inhibit the action of monoamine oxidase enzymes. It was concluded that, at least in the models employed, the in vitro profile of fencamfamin is more similar to that of nomifensine, a reportedly pure uptake inhibitor, than to d-amphetamine.
In animal experiments on place preference fencamfamin produced a significant place preference only at the dose of 3.5 mg/kg. The experiments suggested a relation to dopamine D1 receptors, and also to opioid receptors in the reinforcement produced by fencamfamin, as place preference was blocked by the selective dopamine D1 antagonist SCH 23390 and by the opioid antagonist naloxone. A similar place preference, which was blocked by naloxone and by SCH 23390 and by raclopride, has been seen in a study on rats with drinking water. Animals treated with naloxone before the conditioning sessions showed a place aversion instead of the place preference found in saline-treated animals. Naloxone also reduced drinking. It was proposed that naloxone induced a state of frustrative nonreward. It was suggested that both dopamine and (endogenous) opioids are important for water-induced reinforcement. Possible interactions between these two neurotransmitter systems were discussed.
Fencamfamin may be synthesized in a straightforward fashion via the Diels-Alder reaction between cyclopentadiene and β-nitrostyrene (1-nitro-2-phenyl-ethene). The C=C double bond and the nitro-group in the resulting norcamphene derivative are then reduced to give the saturated norcamphane derivative. Finally, the amino-group is ethylated.
Although β-nitrostyrene is commercially available, it is also very easily prepared using the Henry Reaction between benzaldehyde and nitromethane.
The Diels-Alder reaction of β-nitrostyrene and cyclopentadiene is described in a number of early papers.
The reduction of the nitroalkene may be carried out sequentially. The alkene’s double bond is typically reduced using hydrogen and a transition metal catalyst like Ni or Pt, while the nitro group is reduced to the amine with a metal/acid combination, such as Fe/HCl. The reduction of both functional groups can also be achieved simultaneously by the use of Raney nickel, and this transformation has recently been optimized by Russian chemists.
Originally achieved under reductive amination conditions involving the reaction of the amine with acetaldehyde in the presence of Pt, ethylation of the amino-group has been improved by the use of Ra-Ni and ethanol.
The stereochemical consequences of the steps involved in the reaction sequence outlined above have been studied. Thus, the Diels-Alder cycloaddition leads to a product in which the nitro- and phenyl- groups are in a trans- relationship to each other. This product is actually a mixture of stereoisomers, in which the pair of enantiomers having the nitro- group in the endo- position and the phenyl- group in the exo- position predominates over the enantiomeric pair with exo-nitro and endo-phenyl groups. Although the isomeric composition of the Diels-Alder adduct itself does not seem to have been determined, Poos et al. reported a ratio of ~3:1 for the saturated un-ethylated amine derived from it. Novakov and co-workers, citing a thesis study, report that the corresponding ratio of endo-N-ethyl/exo-Φ : exo-N-ethyl/endo-Φ enantiomeric pairs is ~9:1 in fencamfamin itself.
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Ethylphenidate (EPH) is a psychostimulant and a close analogue of methylphenidate.
Ethylphenidate acts as both a dopamine reuptake inhibitor and norepinephrine reuptake inhibitor, meaning it effectively boosts the levels of the norepinephrine and dopamine neurotransmitters in the brain, by binding to, and partially blocking the transporter proteins that normally remove those monoamines from the synaptic cleft.
However, considering the close similarities between ethylphenidate and methylphenidate and the fact that methylphenidate, like cocaine, actually does not primarily act as a “classical” reuptake inhibitor, but rather as an “inverse agonist at the DAT” (also called a “negative allosteric modulator at the DAT”), it is at least very likely that ethylphenidate also primarily acts as an inverse DAT agonist instead of (or at least only secondarily) as a classical reuptake inhibitor (which could be called a “competitive antagonist at the DAT” using a similar terminology as “negative allosteric modulator at the DAT”, which per definition means that its mechanism is non-competitive).
Ethylphenidate metabolises into methylphenidate and ritalinic acid.
Tiny amounts of ethylphenidate can be formed in vivo when ethanol and methylphenidate are coingested, via hepatic transesterification. Ethylphenidate formation appears to be more common when large quantities of methylphenidate and alcohol are consumed at the same time, such as in non-medical use or overdose scenarios. However, the transesterfication process of methylphenidate to ethylphenidate, as tested in mice liver, was dominant in the inactive (−)-enantiomer but showed a prolonged and increased maximal plasma concentration of the active (+)-enantiomer of methylphenidate. Additionally, only a small percent of the consumed methylphenidate is converted to ethylphenidate.
This carboxylesterase-dependent transesterification process is also known to occur when cocaine and alcohol are consumed together, forming cocaethylene.
All available data on ethylphenidate’s pharmacodynamics are drawn from studies conducted on rodents. Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound, but has significantly less activity on the norepinephrine transporter (NET). Its dopaminergic pharmacodynamic profile is nearly identical to methylphenidate, and is primarily responsible for its euphoric and reinforcing effects.
The eudysmic ratio for ethylphenidate is superior to that of methylphenidate.
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