Chemistry:Amisulpride

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Short description: Atypical antipsychotic and antiemetic medication
Amisulpride
Amisulpride.svg
Amisulpride-xtal-1990-ball-and-stick-model.png
Clinical data
Trade namesSolian, Barhemsys, others
Other namesAPD421
AHFS/Drugs.comMonograph
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability48%[4][5]
Protein binding16%[5]
MetabolismLiver (minimal; most excreted unchanged)[5]
Elimination half-life12 hours[4]
ExcretionKidney[4] (23–46%),[6][7] Faecal[5]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H27N3O4S
Molar mass369.48 g·mol−1
3D model (JSmol)
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Amisulpride is an antiemetic and antipsychotic medication used at lower doses intravenously to prevent and treat postoperative nausea and vomiting; and at higher doses by mouth to treat schizophrenia and acute psychotic episodes. It is sold under the brand names Barhemsys[8] (as an antiemetic) and Solian, Socian, Deniban and others (as an antipsychotic).[5] At very low doses it is also used to treat dysthymia.[9]

It is usually classed with the atypical antipsychotics. Chemically it is a benzamide and like other benzamide antipsychotics, such as sulpiride, it is associated with a high risk of elevating blood levels of the lactation hormone, prolactin (thereby potentially causing the absence of the menstrual cycle, breast enlargement, even in males, breast milk secretion not related to breastfeeding, impaired fertility, impotence, breast pain, etc.), and a low risk, relative to the typical antipsychotics, of causing movement disorders.[10][11][12]

Amisulpride is indicated for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.[8]

Amisulpride is believed to work by blocking, or antagonizing, the dopamine D2 receptor, reducing its signalling. The effectiveness of amisulpride in treating dysthymia and the negative symptoms of schizophrenia is believed to stem from its blockade of the presynaptic dopamine D2 receptors. These presynaptic receptors regulate the release of dopamine into the synapse, so by blocking them amisulpride increases dopamine concentrations in the synapse. This increased dopamine concentration is theorized to act on dopamine D1 receptors to relieve depressive symptoms (in dysthymia) and the negative symptoms of schizophrenia.[9]

It was introduced by Sanofi-Aventis in the 1990s. Its patent expired by 2008, and generic formulations became available.[13] It is marketed in all English-speaking countries except for Canada.[12]

Medical uses

Schizophrenia

Although according to other studies it appears to have comparable efficacy to olanzapine in the treatment of schizophrenia,[14] amisulpride augmentation, similarly to sulpiride augmentation, has been considered a viable treatment option (although this is based on low-quality evidence) in clozapine-resistant cases of schizophrenia.[15][16] Another recent study concluded that amisulpride is an appropriate first-line treatment for the management of acute psychosis.[17]

Postoperative nausea and vomiting

Amisulpride is indicated for use in the United States in adults for the prevention of postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; and to treat PONV in those who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis.[8]

Contraindications

Amisulpride's use is contraindicated in the following disease states and populations[5][18][10]

Neither is it recommended to use amisulpride in patients with hypersensitivities to amisulpride or the excipients found in its dosage form.[5]

Adverse effects

Very Common (≥10% incidence)[3]
  • Extrapyramidal side effects (EPS; including dystonia, tremor, akathisia, parkinsonism).
Common (≥1%, <10% incidence)[3][5][19][18][10]
  • Hyperprolactinaemia (which can lead to galactorrhoea, breast enlargement and tenderness, sexual dysfunction, etc.)
  • Weight gain (produces less weight gain than chlorpromazine, clozapine, iloperidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, zotepine and more (although not statistically significantly) weight gain than haloperidol, lurasidone, ziprasidone and approximately as much weight gain as aripiprazole and asenapine)[11]
  • Anticholinergic side effects (although it does not bind to the muscarinic acetylcholine receptors and hence these side effects are usually quite mild) such as
- constipation
- dry mouth
- disorder of accommodation
- Blurred vision
Rare (<1% incidence)[3][5][19][18][10]
  • Blood dyscrasias such as leucopenia, neutropenia and agranulocytosis
  • QT interval prolongation (in a recent meta-analysis of the safety and efficacy of 15 antipsychotic drugs amisulpride was found to have the 2nd highest effect size for causing QT interval prolongation[11])

Hyperprolactinaemia results from antagonism of the D2 receptors located on the lactotrophic cells found in the anterior pituitary gland. Amisulpride has a high propensity for elevating plasma prolactin levels as a result of its poor blood–brain barrier penetrability and hence the resulting greater ratio of peripheral D2 occupancy to central D2 occupancy. This means that to achieve the sufficient occupancy (~60–80%[20]) of the central D2 receptors in order to elicit its therapeutic effects a dose must be given that is enough to saturate peripheral D2 receptors including those in the anterior pituitary.[21][22]

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[23] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[24] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[24] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[24] Symptoms generally resolve after a short period of time.[24]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[25] It may also result in reoccurrence of the condition that is being treated.[26] Rarely tardive dyskinesia can occur when the medication is stopped.[24]

Overdose

Torsades de pointes is common in overdose.[27][28] Amisulpride is moderately dangerous in overdose (with the TCAs being very dangerous and the SSRIs being modestly dangerous).[29][30]

Interactions

Amisulpride should not be used in conjunction with drugs that prolong the QT interval (such as citalopram, bupropion, clozapine, tricyclic antidepressants, sertindole, ziprasidone, etc.),[29] reduce heart rate and those that can induce hypokalaemia. Likewise it is imprudent to combine antipsychotics due to the additive risk for tardive dyskinesia and neuroleptic malignant syndrome.[29]

Pharmacology

Pharmacodynamics

Site Ki (nM) Species Ref
SERT >10,000 Human [31]
NET >10,000 Human [31]
DAT >10,000 Human [31]
5-HT1A >10,000 Human [31]
5-HT1B 1,744 Human [31]
5-HT1D 1,341 Human [31]
5-HT1E >10,000 Human [31]
5-HT2A 8,304 Human [31]
5-HT2B 13 Human [31]
5-HT2C >10,000 Human [31]
5-HT3 >10,000 Human [31]
5-HT5A >10,000 Human [31]
5-HT6 4,154 Human [31]
5-HT7 11.5 Human [31]
α1A >10,000 Human [31]
α1B >10,000 Human [31]
α1D >10,000 Human [31]
α2A 1,114 Human [31]
α2C 1,540 Human [31]
β1 >10,000 Human [31]
β2 >10,000 Human [31]
β3 >10,000 Human [31]
D1 >10,000 Human [31]
D2 3.0 Human [31]
D3 3.5 Rat [31]
D4 2,369 Human [31]
D5 >10,000 Human [31]
H1 >10,000 Human [31]
H2 >10,000 Human [31]
H4 >10,000 Human [31]
M1 >10,000 Human [31]
M2 >10,000 Human [31]
M3 >10,000 Human [31]
M4 >10,000 Human [31]
M5 >10,000 Human [31]
σ1 >10,000 Rat [31]
σ2 >10,000 Rat [31]
MOR >10,000 Human [31]
DOR >10,000 Human [31]
KOR >10,000 Human [31]
GHBHigh 50 (IC50) Rat [32]
NMDA
(PCP)		 >10,000 Rat [33]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Amisulpride functions primarily as a dopamine D2 and D3 receptor antagonist. It has high affinity for these receptors with dissociation constants of 3.0 and 3.5 nM, respectively.[31] Although standard doses used to treat psychosis inhibit dopaminergic neurotransmission, low doses preferentially block inhibitory presynaptic autoreceptors. This results in a facilitation of dopamine activity, and for this reason, low-dose amisulpride has also been used to treat dysthymia.[5]

Amisulpride and its relatives sulpiride, levosulpiride, and sultopride have been shown to bind to the high-affinity GHB receptor at concentrations that are therapeutically relevant (IC50 = 50 nM for amisulpride).[32]

Amisulpride, sultopride and sulpiride respectively present decreasing in vitro affinities for the D2 receptor (IC50 = 27, 120 and 181 nM) and the D3 receptor (IC50 = 3.6, 4.8 and 17.5 nM).[34]

Though it was long widely assumed that dopaminergic modulation is solely responsible for the respective antidepressant and antipsychotic properties of amisulpride, it was subsequently found that the drug also acts as a potent antagonist of the serotonin 5-HT7 receptor (Ki = 11.5 nM).[31] Several of the other atypical antipsychotics such as risperidone and ziprasidone are potent antagonists at the 5-HT7 receptor as well, and selective antagonists of the receptor show antidepressant properties themselves. To characterize the role of the 5-HT7 receptor in the antidepressant effects of amisulpride, a study prepared 5-HT7 receptor knockout mice.[31] The study found that in two widely used rodent models of depression, the tail suspension test, and the forced swim test, those mice did not exhibit an antidepressant response upon treatment with amisulpride.[31] These results suggest that 5-HT7 receptor antagonism mediates the antidepressant effects of amisulpride.[31]

Amisulpride also appears to bind with high affinity to the serotonin 5-HT2B receptor (Ki = 13 nM), where it acts as an antagonist.[31] The clinical implications of this, if any, are unclear.[31] In any case, there is no evidence that this action mediates any of the therapeutic effects of amisulpride.[31]

Amisulpride shows stereoselectivity in its actions.[35] Aramisulpride ((R)-amisulpride) has higher affinity for the 5-HT7 receptor (Ki = 47 nM vs. 1,900 nM) while esamisulpride ((S)-amisulpride) has higher affinity for the D2 receptor (4.0 nM vs. 140 nM).[35][36] An 85:15 ratio of aramisulpride to esamisulpride (SEP-4199) which provides more balanced 5-HT7 and D2 receptor antagonism than racemic amisulpride (50:50 ratio of enantiomers) is under development for the treatment of bipolar depression.[37]

Through a high direct unmetabolized excretion, it has, despite its high usual dose, also high affinity for dopamine-D2-D3-receptors. Also the available literature gives us hints about also relatively high receptor dissociation kinetics (through a delayed but high occupancy at dopamine receptors after 6 hours from a 100 mg exposure). Moreover, this dopamine exposure could be slightly more "balanced" providing some little advantages over haloperidol in using it for drug exposure. Due to its lack of compensatory serotonin effects and also not having an anticholinergic profile, it may not considered as an effective alternative if akathasia is a problem.[4][22][38]

Society and culture

Brand names

Brand names include: Amazeo, Amipride (Australia ), Amival, Solian (Australia , IE, RU, United Kingdom , South Africa ), Soltus, Sulpitac (India ), Sulprix (Australia ), Midora (RO) and Socian (Brazil ).[39][40]

Availability

Amisulpride is not approved by the Food and Drug Administration for use in the United States in psychiatric indications, but it is approved and in use throughout Europe,[40] Asia, Mexico, New Zealand and Australia[5] to treat psychosis and schizophrenia.[41][42]

An IV formulation of Amisulpride was approved for the treatment of postoperative nausea and vomiting ("PONV") in the United States in February 2020.[43][8][44]

History of US clinical development

The U.S. Food and Drug Administration (FDA) approved a 10 mg/4mL amisulpride IV formulation for use in post-operative nausea based on evidence from four clinical trials of 2323 subjects undergoing surgery or experiencing nausea and vomiting after the surgery.[44] The trials were conducted at 80 sites in the United States, Canada and Europe.[44]

Two trials (Trials 1 and 2) enrolled subjects scheduled to have surgery.[44] Subjects were randomly assigned to receive either amisulpride or a placebo drug at the beginning of general anesthesia.[44] In Trial 1, subjects received amisulpride or placebo alone, and in Trial 2, they received amisulpride or placebo in combination with one medication approved for prevention of nausea and vomiting.[44] Neither the subjects nor the health care providers knew which treatment was being given until after the trial was complete.[44]

The trials counted the number of subjects who had no vomiting and did not use additional medications for nausea or vomiting in the first day (24 hours) after the surgery.[44] The results then compared amisulpride to placebo.[44]

The other two trials (Trials 3 and 4) enrolled subjects who were experiencing nausea and vomiting after surgery.[44] In Trial 3, subjects did not receive any medication to prevent nausea and vomiting before surgery and in Trial 4 they received the medication, but the treatment did not work.[44] In both trials, subjects were randomly assigned to receive either amisulpride or placebo.[44] Neither the subjects nor the health care providers knew which treatment was being given until after the trial was complete.[44]

The trials counted the number of subjects who had no vomiting and did not use additional medications for nausea or vomiting in the first day (24 hours) after the treatment.[44] The trial compared amisulpride to placebo.[44]

The FDA has not approved amisulpride for use in any psychiatric indication. LB Pharmaceuticals is developing N-methyl amisulpride for the use in the treatment of schizophrenia; a Phase 2 first-in-patient study is planned for 2023.[45]

See also

  • SEP-4199, a non-racemic form of amisulpride

References

  1. ↑ "Australian Product Information – Solian (Amisulpride) Tablets And Solution". https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01659-3. 
  2. ↑ 2.0 2.1 "Amisulpride (Barhemsys) Use During Pregnancy". 2 September 2020. https://www.drugs.com/pregnancy/amisulpride.html. 
  3. ↑ 3.0 3.1 3.2 3.3 "Amisulpride 100 mg Tablets - Summary of Product Characteristics (SmPC)". 5 July 2019. https://www.medicines.org.uk/emc/product/2726/smpc. 
  4. ↑ 4.0 4.1 4.2 4.3 "A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers". Human Psychopharmacology 17 (1): 1–13. January 2002. doi:10.1002/hup.320. PMID 12404702. 
  5. ↑ 5.00 5.01 5.02 5.03 5.04 5.05 5.06 5.07 5.08 5.09 5.10 "Solian tablets and solution product information" (PDF). Sanofi-Aventis Australia Pty Ltd. 27 September 2019. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-01659-3. 
  6. ↑ "Biotransformation of post-clozapine antipsychotics: pharmacological implications". Clinical Pharmacokinetics 38 (5): 393–414. May 2000. doi:10.2165/00003088-200038050-00002. PMID 10843459. 
  7. ↑ "Amisulpride: A Review of its Clinical Potential in Dysthymia". CNS Drugs 12 (6): 471–483. December 1999. doi:10.2165/00023210-199912060-00005. 
  8. ↑ 8.0 8.1 8.2 8.3 "Barhemsys (amisulpride) injection, for intravenous use". U.S. Food and Drug Administration (FDA). February 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209510s000lbl.pdf. 
  9. ↑ 9.0 9.1 "The substituted benzamides and their clinical potential on dysthymia and on the negative symptoms of schizophrenia". Molecular Psychiatry 7 (3): 247–253. 2002. doi:10.1038/sj.mp.4001040. PMID 11920152. 
  10. ↑ 10.0 10.1 10.2 10.3 Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 978-0-9805790-9-3. 
  11. ↑ 11.0 11.1 11.2 "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet 382 (9896): 951–962. September 2013. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. 
  12. ↑ 12.0 12.1 "Amisulpride: Martindale: The Complete Drug Reference". Pharmaceutical Press. June 2017. https://www.medicinescomplete.com/mc/martindale/current/1759-d.htm. 
  13. ↑ "Pharmaceutical patents and the quality of mental healthcare in low- and middle-income countries". The Psychiatrist 32 (4): 121–23. April 2008. doi:10.1192/pb.bp.107.015651. 
  14. ↑ "Amisulpride versus other atypical antipsychotics for schizophrenia". The Cochrane Database of Systematic Reviews (1): CD006624. January 2010. doi:10.1002/14651858.CD006624.pub2. PMID 20091599. 
  15. ↑ "Current perspectives in the treatment of resistant schizophrenia". Indian Journal of Psychiatry 51 (4): 254–260. Oct–Dec 2009. doi:10.4103/0019-5545.58289. PMID 20048449. 
  16. ↑ "Augmentation strategies of clozapine with antipsychotics in the treatment of ultraresistant schizophrenia". Clinical Neuropharmacology 29 (1): 28–33. 2006. doi:10.1097/00002826-200601000-00009. PMID 16518132. 
  17. ↑ "The use of amisulpride in the treatment of acute psychosis". Therapeutics and Clinical Risk Management 3 (1): 3–11. March 2007. doi:10.2147/tcrm.2007.3.1.3. PMID 18360610. 
  18. ↑ 18.0 18.1 18.2 British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. 2013. ISBN 978-0-85711-084-8. https://archive.org/details/bnf65britishnati0000unse. 
  19. ↑ 19.0 19.1 Truven Health Analytics, Inc. DRUGDEX System (Internet) [cited 2013 Sep 19]. Greenwood Village, CO: Thomsen Healthcare; 2013.
  20. ↑ Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. 2010. ISBN 978-0-07-162442-8. 
  21. ↑ "Amisulpride: a review of its use in the management of schizophrenia". CNS Drugs 18 (13): 933–956. 2004. doi:10.2165/00023210-200418130-00007. PMID 15521794. 
  22. ↑ 22.0 22.1 "Amisulpride the 'atypical' atypical antipsychotic--comparison to haloperidol, risperidone and clozapine". Schizophrenia Research 105 (1–3): 224–235. October 2008. doi:10.1016/j.schres.2008.07.005. PMID 18710798. 
  23. ↑ Joint Formulary Committee, ed (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN 978-0-85369-845-6. "Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse." 
  24. ↑ 24.0 24.1 24.2 24.3 24.4 (in en) Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. 2004. pp. 207–216. ISBN 978-0-19-852748-0. https://books.google.com/books?id=CWR7DwAAQBAJ&pg=PA207. 
  25. ↑ "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatrica Scandinavica 114 (1): 3–13. July 2006. doi:10.1111/j.1600-0447.2006.00787.x. PMID 16774655. 
  26. ↑ (in en) Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. 2013. p. 85. ISBN 978-8-84-702679-7. https://books.google.com/books?id=odE-AgAAQBAJ&pg=PA85. 
  27. ↑ "Amisulpride overdose is frequently associated with QT prolongation and torsades de pointes". Journal of Clinical Psychopharmacology 30 (4): 391–395. August 2010. doi:10.1097/JCP.0b013e3181e5c14c. PMID 20531221. 
  28. ↑ "Prediction of torsade de pointes from the QT interval: analysis of a case series of amisulpride overdoses". Clinical Pharmacology and Therapeutics 90 (2): 243–245. August 2011. doi:10.1038/clpt.2011.107. PMID 21716272. 
  29. ↑ 29.0 29.1 29.2 Maudsley Prescribing Guidelines in Psychiatry (11th ed.). West Sussex: Wiley-Blackwell. 2012. ISBN 978-0-47-097948-8. 
  30. ↑ "Overdose of atypical antipsychotics: clinical presentation, mechanisms of toxicity and management". CNS Drugs 26 (7): 601–611. July 2012. doi:10.2165/11631640-000000000-00000. PMID 22668123. 
  31. ↑ 31.00 31.01 31.02 31.03 31.04 31.05 31.06 31.07 31.08 31.09 31.10 31.11 31.12 31.13 31.14 31.15 31.16 31.17 31.18 31.19 31.20 31.21 31.22 31.23 31.24 31.25 31.26 31.27 31.28 31.29 31.30 31.31 31.32 31.33 31.34 31.35 31.36 31.37 31.38 31.39 31.40 31.41 31.42 31.43 31.44 31.45 31.46 31.47 "Amisulpride is a potent 5-HT7 antagonist: relevance for antidepressant actions in vivo". Psychopharmacology 205 (1): 119–128. July 2009. doi:10.1007/s00213-009-1521-8. PMID 19337725. 
  32. ↑ 32.0 32.1 "Displacement of [3H] gamma-hydroxybutyrate binding by benzamide neuroleptics and prochlorperazine but not by other antipsychotics". European Journal of Pharmacology 256 (2): 211–214. April 1994. doi:10.1016/0014-2999(94)90248-8. PMID 7914168. 
  33. ↑ "Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity". The Journal of Pharmacology and Experimental Therapeutics 280 (1): 83–97. January 1997. PMID 8996185. 
  34. ↑ "Amisulpride, Sultopride and Sulpiride: Comparison of Conformational and Physico-Chemical Properties" (in en). Molecular Modeling and Prediction of Bioactivity. Springer US. 2000. pp. 404–405. doi:10.1007/978-1-4615-4141-7_97. ISBN 978-1-4613-6857-1. 
  35. ↑ 35.0 35.1 "Discovery of Nonracemic Amisulpride to Maximize Benefit/Risk of 5-HT7 and D2 Receptor Antagonism for the Treatment of Mood Disorders". Clinical Pharmacology and Therapeutics 110 (3): 808–815. September 2021. doi:10.1002/cpt.2282. PMID 33961287. 
  36. ↑ "Antipsychotic Benzamides Amisulpride and LB-102 Display Polypharmacy as Racemates, S Enantiomers Engage Receptors D2 and D3, while R Enantiomers Engage 5-HT7". ACS Omega 4 (9): 14151–14154. August 2019. doi:10.1021/acsomega.9b02144. PMID 31497735. 
  37. ↑ "SEP 4199". AdisInsight. Springer Nature Switzerland AG. https://adisinsight.springer.com/drugs/800052192. 
  38. ↑ "Pharmacological management of antipsychotic-induced akathisia: An update and treatment algorithm". BJPsych Advances 21 (5): 342–344. 2015. doi:10.1192/apt.bp.114.013797. 
  39. ↑ "Amisulpride international". 3 February 2020. https://www.drugs.com/international/amisulpride.html. 
  40. ↑ 40.0 40.1 "Active substance: amisulpride". 28 September 2017. https://www.ema.europa.eu/docs/en_GB/document_library/Periodic_safety_update_single_assessment/2017/10/WC500236063.pdf. 
  41. ↑ "Consensus on the Practical Use of Amisulpride, an Atypical Antipsychotic, in the Treatment of Schizophrenia". Neuropsychobiology 44 (1): 41–46. 2001. doi:10.1159/000054913. PMID 11408792. 
  42. ↑ "Psychotropic Medications Around the World". Psychiatric Times 21 (5). 2004. http://www.psychiatrictimes.com/showArticle.jhtml?articleID=175802519. 
  43. ↑ "Barhemsys: FDA-Approved Drugs". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=209510. 
  44. ↑ 44.00 44.01 44.02 44.03 44.04 44.05 44.06 44.07 44.08 44.09 44.10 44.11 44.12 44.13 44.14 "Drug Trials Snapshots: Barhemsys". 26 February 2020. http://www.fda.gov/drugs/development-approval-process-drugs/drug-trials-snapshots-barhemsys.  This article incorporates text from this source, which is in the public domain.
  45. ↑ "Investor Presentation". LB Pharmaceuticals. December 2022. http://lbpharma.us/wp-content/uploads/2022/12/LB-Investor-Presentation-December-2022.pdf. 

External links



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