iprindole

Iprindole was used in the treatment of major depressive disorder in dosages similar to those of other TCAs.{{cite book | vauthors = Paykel ES | chapter = Treatment for Affective Disorders | veditors = Wing L, Wing JK | title = Psychoses of uncertain aetiology | publisher = Cambridge University Press | location = Cambridge, UK | year = 1982 | isbn = 0-521-28438-4 | chapter-url = https://books.google.com/books?id=QFI4AAAAIAAJ&pg=PA167}}

Iprindole has been associated with jaundice and hepatotoxicity and should not be taken by alcoholics or people with pre-existing liver disease.{{cite book | vauthors = Aronson JK | title = Meyler's Side Effects of Psychiatric Drugs (Meylers Side Effects) | publisher = Elsevier Science | location = Amsterdam | year = 2008 | isbn = 978-0-444-53266-4 | url = https://books.google.com/books?id=s0XYvuPVgaAC&q=iprindole&pg=PA87}}{{cite journal | vauthors = Ajdukiewicz AB, Grainger J, Scheuer PJ, Sherlock S | title = Jaundice due to iprindole | journal = Gut | volume = 12 | issue = 9 | pages = 705–708 | date = September 1971 | pmid = 4106521 | pmc = 1411804 | doi = 10.1136/gut.12.9.705 }}{{cite journal | vauthors = Clift AD | title = Allergy to iprindole (Prondole) with hepatotoxicity | journal = British Medical Journal | volume = 2 | issue = 5763 | pages = 712 | date = June 1971 | pmid = 5556082 | pmc = 1796275 | doi = 10.1136/bmj.2.5763.712 }} If such symptoms are encountered iprindole should be discontinued immediately.

Anticholinergic side effects such as dry mouth and constipation are either greatly reduced in comparison to imipramine and most other TCAs or fully lacking with iprindole.{{cite journal | vauthors = Launchbury AP | title = Some recently introduced drugs | journal = Progress in Medicinal Chemistry | volume = 7 | issue = 1 | pages = 1–67 (25) | date = 1970 | pmid = 4250600 | doi = 10.1016/s0079-6468(08)70351-5 | url = https://books.google.com/books?id=hNcBVxpSfGUC&pg=PA25 |publisher=Butterworth-Heinemann|isbn=978-0-408-70013-9 | url-access = subscription }} However, it still has significant antihistamine effects and therefore can produce sedation, though this is diminished relative to other TCAs similarly. Iprindole also lacks significant alpha-blocking properties, and hence does not pose a risk of orthostatic hypotension.

{{Main|Tricyclic antidepressant overdose}}

In overdose, iprindole is much less toxic than most other TCAs and is considered relatively benign.{{cite journal | vauthors = Cassidy S, Henry J | title = Fatal toxicity of antidepressant drugs in overdose | journal = British Medical Journal | volume = 295 | issue = 6605 | pages = 1021–1024 | date = October 1987 | pmid = 3690249 | pmc = 1248068 | doi = 10.1136/bmj.295.6605.1021 }} For instance, between 1974 and 1985, only two deaths associated with iprindole were recorded in the United Kingdom, whereas 278 were reported for imipramine, although imipramine is used far more often than iprindole.

Iprindole has been shown to be a potent inhibitor of the aromatic hydroxylation and/or N-dealkylation-mediated metabolism of many substances including, but not limited to octopamine, amphetamine, methamphetamine, fenfluramine, phenelzine, tranylcypromine, trimipramine, and fluoxetine, likely via inactivating cytochrome P450 enzymes.{{cite journal | vauthors = Sedlock ML, Ravitch J, Edwards DJ | title = The effects of imipramine and iprindole on the metabolism of octopamine in the rat | journal = Neuropharmacology | volume = 24 | issue = 8 | pages = 705–708 | date = August 1985 | pmid = 3939325 | doi = 10.1016/0028-3908(85)90002-4 | s2cid = 39933551 }}{{cite journal | vauthors = Hegadoren KM, Baker GB, Coutts RT, Dewhurst WG | title = Interactions of iprindole with fenfluramine metabolism in rat brain and liver | journal = Journal of Psychiatry & Neuroscience | volume = 16 | issue = 1 | pages = 5–11 | date = March 1991 | pmid = 2049371 | pmc = 1188281 }}{{cite journal | vauthors = Yamamoto T, Takano R, Egashira T, Yamanaka Y | title = Metabolism of methamphetamine, amphetamine and p-hydroxymethamphetamine by rat-liver microsomal preparations in vitro | journal = Xenobiotica; the Fate of Foreign Compounds in Biological Systems | volume = 14 | issue = 11 | pages = 867–875 | date = November 1984 | pmid = 6506759 | doi = 10.3109/00498258409151485 }}{{cite journal | vauthors = Coutts RT, Hussain MS, Baker GB | title = Effect of iprindole on the metabolism of trimipramine in the rat | journal = Journal of Psychiatry & Neuroscience | volume = 16 | issue = 5 | pages = 272–275 | date = December 1991 | pmid = 1797102 | pmc = 1188365 }}{{cite journal | vauthors = Aspeslet LJ, Baker GB, Coutts RT, Torok-Both GA | title = The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine | journal = Chirality | volume = 6 | issue = 2 | pages = 86–90 | year = 1994 | pmid = 8204417 | doi = 10.1002/chir.530060208 }} It also inhibits its own metabolism.

On account of these interactions, caution should be used when combining iprindole with other drugs. As an example, when administered with amphetamine or methamphetamine, iprindole increases their brain concentrations and prolongs their terminal half-lives by 2- to 3-fold, strongly augmenting both their physiological effects and neurotoxicity in the process.{{cite journal | vauthors = Fuller RW, Baker JC, Molloy BB | title = Biological disposition of rigid analogs of amphetamine | journal = Journal of Pharmaceutical Sciences | volume = 66 | issue = 2 | pages = 271–272 | date = February 1977 | pmid = 839428 | doi = 10.1002/jps.2600660235 }}{{cite journal | vauthors = Fuller RW, Hemrick-Luecke S | title = Long-lasting depletion of striatal dopamine by a single injection of amphetamine in iprindole-treated rats | journal = Science | volume = 209 | issue = 4453 | pages = 305–307 | date = July 1980 | pmid = 7384808 | doi = 10.1126/science.7384808 | bibcode = 1980Sci...209..305F }}{{cite journal | vauthors = Peat MA, Warren PF, Gibb JW | title = Effects of a single dose of methamphetamine and iprindole on the serotonergic and dopaminergic system of the rat brain | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 225 | issue = 1 | pages = 126–131 | date = April 1983 | pmid = 6187915 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=6187915 }}

{{See also|Pharmacology of antidepressants|Tricyclic antidepressant#Binding profiles}}

Iprindole is unique compared to most other TCAs in that it is a very weak and negligible inhibitor of the reuptake of serotonin and norepinephrine and appears to act instead as a selective albeit weak antagonist of 5-HT₂ receptors; hence its classification by some as "second-generation".{{cite journal | vauthors = Zis AP, Goodwin FK | title = Novel antidepressants and the biogenic amine hypothesis of depression. The case for iprindole and mianserin | journal = Archives of General Psychiatry | volume = 36 | issue = 10 | pages = 1097–1107 | date = September 1979 | pmid = 475543 | doi = 10.1001/archpsyc.1979.01780100067006 }}{{cite journal | vauthors = Jaramillo J, Greenberg R | title = Comparative pharmacological studies on butriptyline and some related standard tricyclic antidepressants | journal = Canadian Journal of Physiology and Pharmacology | volume = 53 | issue = 1 | pages = 104–112 | date = February 1975 | pmid = 166748 | doi = 10.1139/y75-014 }}{{cite journal | vauthors = Horn AS, Trace RC | title = Structure-activity relations for the inhibition of 5-hydroxytryptamine uptake by tricyclic antidepressants into synaptosomes from serotoninergic neurones in rat brain homogenates | journal = British Journal of Pharmacology | volume = 51 | issue = 3 | pages = 399–403 | date = July 1974 | pmid = 4451753 | pmc = 1776771 | doi = 10.1111/j.1476-5381.1974.tb10675.x }} Additionally, iprindole has very weak/negligible antiadrenergic and anticholinergic activity and weak although possibly significant antihistamine activity; as such, side effects of iprindole are much less prominent relative to other TCAs, and it is well tolerated. However, iprindole may not be as effective as other TCAs, particularly in terms of anxiolysis.{{cite journal | vauthors = Rickels K, Chung HR, Csanalosi I, Sablosky L, Simon JH | title = Iprindole and imipramine in non-psychotic depressed out-patients | journal = The British Journal of Psychiatry | volume = 123 | issue = 574 | pages = 329–339 | date = September 1973 | pmid = 4583430 | doi = 10.1192/bjp.123.3.329 | s2cid = 23126539 }} Based on animal research, the antidepressant effects of iprindole may be mediated through downstream dopaminergic mechanisms.{{cite journal | vauthors = Berettera C, Invernizzi R, Pulvirenti L, Samanin R | title = Chronic treatment with iprindole reduces immobility of rats in the behavioural 'despair' test by activating dopaminergic mechanisms in the brain | journal = The Journal of Pharmacy and Pharmacology | volume = 38 | issue = 4 | pages = 313–315 | date = April 1986 | pmid = 2872301 | doi = 10.1111/j.2042-7158.1986.tb04576.x | s2cid = 27863022 }}

The binding affinities of iprindole for various biological targets are presented in the table to the right. It is presumed to act as an inhibitor or antagonist/inverse agonist of all sites. Considering the range of its therapeutic concentrations (e.g., 63–271 nM at 90 mg/day), only the actions of iprindole on the 5-HT₂ and histamine receptors might be anticipated to be of possible clinical significance. However, it is unknown whether these actions are in fact responsible for the antidepressant effects of iprindole. The plasma protein binding of iprindole and hence its free percentage and potentially bioactive concentrations do not seem to be known.

Only one study appears to have evaluated the pharmacokinetics of iprindole.{{cite journal | vauthors = Goodnick PJ | title = Pharmacokinetic optimisation of therapy with newer antidepressants | journal = Clinical Pharmacokinetics | volume = 27 | issue = 4 | pages = 307–330 | date = October 1994 | pmid = 7834966 | doi = 10.2165/00003088-199427040-00005 | s2cid = 46783536 }} A single oral dose of 60 mg iprindole to healthy volunteers has been found to achieve mean peak plasma concentrations of 67.1 ng/mL (236 nmol/L) after 2 to 4 hours. The mean terminal half-life of iprindole was 52.5 hours, which is notably much longer than that of other TCAs like amitriptyline and imipramine. Following chronic treatment with 90 mg/day iprindole for 3 weeks, plasma concentrations of the drug ranged between 18 and 77 ng/mL (63–271 nmol/L). Theoretical steady-state concentrations should be reached by 99% within 15 to 20 days of treatment.

Iprindole is a tricyclic compound, specifically a cyclooctaindole (that is, an indole nucleus joined with a cyclooctyl ring), and possesses three rings fused together with a side chain attached in its chemical structure.{{cite book| vauthors = Tyrer PJ | chapter = Tricyclic Antidepressants |title=Drugs in Psychiatric Practice| chapter-url = https://books.google.com/books?id=6gglBQAAQBAJ&pg=PA195 |date=22 October 2013|publisher=Elsevier|isbn=978-1-4831-9193-5|pages=195–}} It is a tertiary amine TCA, although its ring system and pharmacological properties are very different from those of other TCAs.{{cite journal | vauthors = Baxter BL, Gluckman MI | title = Iprindole: an antidepressant which does not block REM sleep | journal = Nature | volume = 223 | issue = 5207 | pages = 750–752 | date = August 1969 | pmid = 4308422 | doi = 10.1038/223750a0 | s2cid = 4181062 | bibcode = 1969Natur.223..750B }} Other tertiary amine TCAs that are similar to iprindole include butriptyline and trimipramine.{{cite book| vauthors = Anthony PK, Powers CA | chapter = Drugs that Affect the Central Nervous System | veditors = Anthony PK |title=Pharmacology Secrets|chapter-url=https://books.google.com/books?id=_QQsj3PAUrEC&pg=PA39|year=2002|publisher=Elsevier Health Sciences|isbn=1-56053-470-2|pages=39–}}{{cite book| vauthors = Cowen P, Harrison P, Burns T | chapter = Drugs and other physical treatments |title=Shorter Oxford Textbook of Psychiatry| chapter-url = https://books.google.com/books?id=Y1DtSGq-LnoC&pg=PA532|date=9 August 2012|publisher=OUP Oxford|isbn=978-0-19-162675-3|pages=532–}} The chemical name of iprindole is 3-(6,7,8,9,10,11-hexahydro-5H-cycloocta[b]indol-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C₁₉H₂₈N₂ with a molecular weight of 284.439 g/mol. The drug has been used commercially as both the free base and the hydrochloride salt. The CAS Registry Number of the free base is 5560-72-5 and of the hydrochloride is 20432-64-8.

Iprindole was developed by Wyeth and was marketed in 1967.{{cite book | vauthors = Dawson AH | chapter = Cyclic Antidepressant Drugs| veditors = Dart RC |title=Medical Toxicology| chapter-url = https://books.google.com/books?id=BfdighlyGiwC&pg=PA836 |year=2004|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-2845-4|pages=836–}}

Iprindole is the English and French generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|DCF|Dénomination Commune Française}}, while iprindole hydrochloride is its {{abbrlink|BANM|British Approved Name}}.{{cite book| vauthors = Elks J |title=The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies|url=https://books.google.com/books?id=0vXTBwAAQBAJ&pg=PA702|date=14 November 2014|publisher=Springer|isbn=978-1-4757-2085-3|pages=702–}}{{cite book|title=Index Nominum 2000: International Drug Directory|url=https://books.google.com/books?id=5GpcTQD_L2oC&pg=PA569|year=2000|publisher=Taylor & Francis|isbn=978-3-88763-075-1|pages=569–}}{{cite book | vauthors = Morton IK, Hall JM |title=Concise Dictionary of Pharmacological Agents: Properties and Synonyms|url=https://books.google.com/books?id=tsjrCAAAQBAJ&pg=PA156|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-94-011-4439-1|pages=156–}} Its generic name in Spanish and German is iprindol while its generic name in Latin is iprindolum. Iprindole was originally known unofficially as pramindole.

Iprindole has been marketed under the brand name Prondol by Wyeth in the United Kingdom and Ireland for the indication of major depressive disorder,{{cite book | veditors = Sweetman SC | title = Martindale: The Complete Drug Reference | edition = 36th | publisher = Pharmaceutical Press | location = London | year = 2009 | isbn = 978-0-85369-840-1 }} and has also been sold as Galatur and Tertran by Wyeth.

Iprindole was previously available in the United Kingdom and Ireland but seems to no longer be available for medical use in any country.

{{Reflist|30em}}

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• {{cite journal | vauthors = de Montigny C | title = Iprindole: a cornerstone in the neurobiological investigation of antidepressant treatments | journal = Modern Problems of Pharmacopsychiatry | volume = 18 | pages = 102–116 | year = 1982 | pmid = 6285182 | doi = 10.1159/000406238 | isbn = 978-3-8055-3428-4 | series = Modern Trends in Pharmacopsychiatry }}
• {{cite journal |vauthors=Horn AS, Trace RC | title = Second generation antidepressants: The pharmacological and clinical significance of selected examples | journal = Drug Development Research | volume = 3 | issue = 3 | pages = 203–211 |date=January 1983 | doi = 10.1002/ddr.430030302 | s2cid = 84018071 | url = https://onlinelibrary.wiley.com/doi/10.1002/ddr.430030302| url-access = subscription }}

{{refend}}

{{Antidepressants}}

{{Histamine receptor modulators}}

{{Serotonin receptor modulators}}

{{Tricyclics}}

Category:5-HT2 antagonists

Category:Abandoned drugs

Category:Nitrogen heterocycles

Category:Drugs with unknown mechanisms of action

Category:H1 receptor antagonists

Category:Indoles

Category:Tricyclic antidepressants

Category:Heterocyclic compounds with 3 rings

Category:Dimethylamino compounds