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{{Short description|Chemical compound}}
{{Drugbox
{{Drugbox
| Verifiedfields = changed
| drug_name = Proglumide
| Watchedfields = changed
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| IUPAC_name = (''RS'')-''N''<sup>2</sup>-benzoyl-''N'',''N''-dipropyl-α-glutamine
| verifiedrevid = 405764009
| synonyms = <small>4-benzamido-5-(dipropylamino)-5-oxopentanoic acid</small>
| IUPAC_name = 4-Benzamido-5-(dipropylamino)-5-oxopentanoic acid
| image = Proglumide.svg
| image = Proglumide structure.svg
| imagename = 1 : 1 mixture (racemate)
| width = 200px
| width = 200px
| caption =
⚫
| CAS_number = 6620-60-6

⚫
| ATC_prefix = A02
<!--Clinical data-->
⚫
| ATC_suffix = BX06
| tradename = Milid
⚫
| PubChem = 4922
| Drugs.com = {{drugs.com|international|proglumide}}
⚫
| IUPHAR_ligand = 893
⚫
| pregnancy_category =
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| C = 18 | H = 26 | N = 2 | O = 4
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| legal_status = Rx-only
| molecular_weight = 334.41 g/mol
⚫
| bioavailability =
⚫
| metabolism =
⚫
| elimination_half-life = ~24 hours
⚫
| excretion =
⚫
| pregnancy_category =
⚫
| legal_status = Rx-only
| routes_of_administration = Oral
| routes_of_administration = Oral

<!--Pharmacokinetic data-->
⚫
| bioavailability =
| protein_bound =
⚫
| metabolism =
| metabolites =
⚫
| elimination_half-life = ~24 hours
⚫
| excretion =

<!--Identifiers-->
| CAS_number_Ref = {{cascite|correct|??}}
⚫
| CAS_number = 6620-60-6
⚫
| ATC_prefix = A02
⚫
| ATC_suffix = BX06
⚫
| PubChem = 4922
⚫
| IUPHAR_ligand = 893
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = EPL8W5565D
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 32058
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = 316561
| smiles = CCCN(CCC)C(=O)C(CCC(=O)O)NC(=O)c1ccccc1
| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}
| ChemSpiderID = 4753
⚫
| synonyms = (''RS'')-''N''<sup>2</sup>-benzoyl-''N'',''N''-dipropyl-α-glutamine

<!--Chemical data-->
⚫
| C=18 | H=26 | N=2 | O=4
| StdInChI_Ref = {{stdinchicite|changed|chemspider}}
| StdInChI = 1S/C18H26N2O4/c1-3-12-20(13-4-2)18(24)15(10-11-16(21)22)19-17(23)14-8-6-5-7-9-14/h5-9,15H,3-4,10-13H2,1-2H3,(H,19,23)(H,21,22)
| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}
| StdInChIKey = DGMKFQYCZXERLX-UHFFFAOYSA-N
}}
}}


'''Proglumide''' ('''Milid''') is a [[drug]] that inhibits [[gastrointestinal]] [[motility]] and reduces [[gastric]] [[secretion]]s. It acts as a [[cholecystokinin antagonist]],<ref>Bunney BS, Chiodo LA, Freeman AS. Further studies on the specificity of proglumide as a selective cholecystokinin antagonist in the central nervous system. ''Annals of the New York Academy of Sciences''. 1985;448:345-51.</ref> which blocks both the [[Cholecystokinin A receptor|CCK<sub>A</sub>]] and [[Cholecystokinin B receptor|CCK<sub>B</sub>]] subtypes.<ref>González-Puga C, García-Navarro A, Escames G, León J, López-Cantarero M, Ros E, Acuña-Castroviejo D. Selective CCK-A but not CCK-B receptor antagonists inhibit HT-29 cell proliferation: synergism with pharmacological levels of melatonin. ''Journal of Pineal Research''. 2005 Oct;39(3):243-50. {{DOI|10.1111/j.1600-079X.2005.00239.x}} PMID 16150104</ref> It was used mainly in the treatment of [[stomach ulcers]],<ref>Bergemann W, Consentius K, Braun HE, Hirschmann H, Marowski B, Munck A, Rehs HU, Stopik D, Wilke G. Duodenal ulcer - multicenter double-blind study with proglumide. (German) ''Medizinische Klinik''. 1981 Apr 10;76(8):226-9.</ref><ref>Tariq M, Parmar NS, Ageel AM. Gastric and duodenal antiulcer and cytoprotective effects of proglumide in rats. ''Journal of Pharmacology and Experimental Therapeutics''. 1987 May;241(2):602-7.</ref> although it has now been largely replaced by newer drugs for this application.
'''Proglumide''', sold under the brand name '''Milid''', is a [[drug]] that inhibits [[gastrointestinal]] [[motility]] and reduces [[gastric secretion]]s. It acts as a [[cholecystokinin antagonist]],<ref>{{cite journal | vauthors = Bunney BS, Chiodo LA, Freeman AS | title = Further studies on the specificity of proglumide as a selective cholecystokinin antagonist in the central nervous system | journal = Annals of the New York Academy of Sciences | volume = 448 | issue = 1 | pages = 345–351 | year = 1985 | pmid = 2862828 | doi = 10.1111/j.1749-6632.1985.tb29929.x | bibcode = 1985NYASA.448..345B | s2cid = 28298172 }}</ref> which blocks both the [[Cholecystokinin A receptor|CCK<sub>A</sub>]] and [[Cholecystokinin B receptor|CCK<sub>B</sub>]] subtypes.<ref>{{cite journal | vauthors = González-Puga C, García-Navarro A, Escames G, León J, López-Cantarero M, Ros E, Acuña-Castroviejo D | title = Selective CCK-A but not CCK-B receptor antagonists inhibit HT-29 cell proliferation: synergism with pharmacological levels of melatonin | journal = Journal of Pineal Research | volume = 39 | issue = 3 | pages = 243–250 | date = October 2005 | pmid = 16150104 | doi = 10.1111/j.1600-079X.2005.00239.x | s2cid = 20187767 }}</ref> It was used mainly in the treatment of [[stomach ulcers]],<ref>{{cite journal | vauthors = Bergemann W, Consentius K, Braun HE, Hirschmann H, Marowski B, Munck A, Rehs HU, Stopik D, Wilke G | display-authors = 6 | title = [Duodenal ulcer - multicenter double-blind study with proglumide] | journal = Medizinische Klinik | volume = 76 | issue = 8 | pages = 226–229 | date = April 1981 | pmid = 7231338 }}</ref><ref>{{cite journal | vauthors = Tariq M, Parmar NS, Ageel AM | title = Gastric and duodenal antiulcer and cytoprotective effects of proglumide in rats | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 241 | issue = 2 | pages = 602–607 | date = May 1987 | pmid = 3572816 }}</ref> although it has now been largely replaced by newer drugs for this application.


An interesting side effect of proglumide is that it enhances the [[analgesia]] produced by [[opioid]] drugs,<ref>McCleane GJ. The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine. ''Clinical Journal of Pain''. 2003 May-Jun;19(3):200-1.</ref> and can prevent or even reverse the development of [[Drug tolerance|tolerance]] to opioid drugs.<ref>Watkins LR, Kinscheck IB, Mayer DJ. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. ''Science''. 1984 Apr 27;224(4647):395-6.</ref><ref>Tang J, Chou J, Iadarola M, Yang HY, Costa E. Proglumide prevents and curtails acute tolerance to morphine in rats. ''Neuropharmacology''. 1984 Jun;23(6):715-8.</ref> This can make it a useful [[adjuvant]] treatment to use alongside opioid drugs in the treatment of chronic pain conditions such as cancer, where opioid analgesics may be required for long periods and development of tolerance reduces clinical efficacy of these drugs.<ref>Bernstein ZP, Yucht S, Battista E, Lema M, Spaulding MB. Proglumide as a morphine adjunct in cancer pain management. ''Journal of Pain and Symptom Management''. 1998 May;15(5):314-20.</ref><ref>McCleane GJ. The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain. ''Anesthesia and Analgesia''. 1998 Nov;87(5):1117-20.</ref>
An interesting side effect of proglumide is that it enhances the [[analgesia]] produced by [[opioid]] drugs,<ref>{{cite journal | vauthors = McCleane GJ | title = The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine | journal = The Clinical Journal of Pain | volume = 19 | issue = 3 | pages = 200–201 | year = 2003 | pmid = 12792559 | doi = 10.1097/00002508-200305000-00008 | s2cid = 29229782 }}</ref> and can prevent or even reverse the development of [[Drug tolerance|tolerance]] to opioid drugs.<ref>{{cite journal | vauthors = Watkins LR, Kinscheck IB, Mayer DJ | title = Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide | journal = Science | volume = 224 | issue = 4647 | pages = 395–396 | date = April 1984 | pmid = 6546809 | doi = 10.1126/science.6546809 | bibcode = 1984Sci...224..395W }}</ref><ref>{{cite journal | vauthors = Tang J, Chou J, Iadarola M, Yang HY, Costa E | title = Proglumide prevents and curtails acute tolerance to morphine in rats | journal = Neuropharmacology | volume = 23 | issue = 6 | pages = 715–718 | date = June 1984 | pmid = 6462377 | doi = 10.1016/0028-3908(84)90171-0 | s2cid = 33168040 }}</ref> This can make it a useful [[adjuvant]] treatment to use alongside opioid drugs in the treatment of chronic pain conditions such as cancer, where opioid analgesics may be required for long periods and development of tolerance reduces clinical efficacy of these drugs.<ref>{{cite journal | vauthors = Bernstein ZP, Yucht S, Battista E, Lema M, Spaulding MB | title = Proglumide as a morphine adjunct in cancer pain management | journal = Journal of Pain and Symptom Management | volume = 15 | issue = 5 | pages = 314–320 | date = May 1998 | pmid = 9654837 | doi = 10.1016/s0885-3924(98)00003-7 | doi-access = free }}</ref><ref>{{cite journal | vauthors = McCleane GJ | title = The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain | journal = Anesthesia and Analgesia | volume = 87 | issue = 5 | pages = 1117–1120 | date = November 1998 | pmid = 9806692 | doi = 10.1213/00000539-199811000-00025 | s2cid = 10735834 }}</ref>


Proglumide has also been shown to act as a [[delta Opioid receptor|δ-opioid]] agonist, which may contribute to its analgesic effects.<ref>Rezvani A, Stokes KB, Rhoads DL, Way EL. Proglumide exhibits delta opioid agonist properties. ''Alcohol and Drug Research''. 1987;7(3):135-46.</ref>
Proglumide has also been shown to act as a [[delta Opioid receptor|δ-opioid receptor]] (DOR) agonist, which may contribute to its analgesic effects.<ref>{{cite journal | vauthors = Rezvani A, Stokes KB, Rhoads DL, Way EL | title = Proglumide exhibits delta opioid agonist properties | journal = Alcohol and Drug Research | volume = 7 | issue = 3 | pages = 135–146 | year = 1987 | pmid = 3030338 }}</ref> However, other studies show that proglumide has low affinity to the [[μ-opioid receptor]] (MOR) and the [[κ-opioid receptor]] (KOR) (13% of MOR and 17% of KOR occupancy at 100 μM), but no affinity to DOR.<ref>{{cite journal | vauthors = Gaudreau P, Lavigne GJ, Quirion R | title = Cholecystokinin antagonists proglumide, lorglumide and benzotript, but not L-364,718, interact with brain opioid binding sites | journal = Neuropeptides | volume = 16 | issue = 1 | pages = 51–55 | date = May 1990 | pmid = 2174522 | doi = 10.1016/0143-4179(90)90029-X | s2cid = 25646937 }}</ref> It is questionable whether this is clinically significant, since the concentration they used was very high, and the occupancies were low even at that point.


Proglumide also works as a placebo effect amplifier for pain conditions. When injected visibly to a subject, its analgesic effect is bigger than a similarly administered placebo. When injected secretly, it does not have any effect, whereas standard pain drugs have an effect, even if they are administered without the subject's awareness.<ref>Benedetti F, Amanzio M, Maggi G Potentiation of placebo analgesia by proglumide. ''Lancet''. 1995 Nov 4;346(8984):1231.</ref> The supposed mechanism is an enhancement of the neural pathways of expectation.
Proglumide also works as a [[Placebo Effect|placebo effect]] amplifier for pain conditions. When injected visibly to a subject, its analgesic effect is bigger than a similarly administered placebo. When injected secretly, it does not have any effect, whereas standard pain drugs have an effect, even if they are administered without the subject's awareness.<ref>{{cite journal | vauthors = Benedetti F, Amanzio M, Maggi G | title = Potentiation of placebo analgesia by proglumide | journal = Lancet | volume = 346 | issue = 8984 | pages = 1231 | date = November 1995 | pmid = 7475687 | doi = 10.1016/S0140-6736(95)92938-X | doi-access = free }}</ref> The supposed mechanism is an enhancement of the neural pathways of expectation as a result of dopamine and endogenous opioids being suddenly released throughout numerous structures of the brain and spinal cord.

The [[ventral tegmental area]] is the structure believed to mediate proglumide's analgesic and euphoric effects, however dozens of areas with a wide range of physical and psychological functions are implicated in the mediation of the placebo effect (this accounts for proglumide's ability to produce physically measurable effects on [[vital signs]] such as heart rate, blood pressure, respiration rate, and [[tidal volume]] which cannot be accounted for by its clinically insignificant δ-opioid affinity.


== See also ==
== See also ==
* [[Proglumetacin]]
* [[Proglumetacin]]
* [[Benzotript]]


== References ==
== References ==
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{{Drugs for peptic ulcer and GORD}}
{{Drugs for peptic ulcer and GORD}}
{{Opioid receptor modulators}}
{{Analgesics}}
{{Anxiolytics}}
{{Neuropeptide agonists and antagonists}}
{{Opioids}}


[[Category:Cholecystokinin antagonists]]
[[Category:Benzamides]]
[[Category:Benzamides]]
[[Category:Amides]]
[[Category:Cholecystokinin antagonists]]
[[Category:Propyl compounds]]
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