Drugs

Pyridostigmine

Other Names: Mestinon, PDG, Regonol, pyridostigmine bromide Drug Class: Immune Modulators
Molecular Formula: C9 H13 N2 O2Br
Registry Number: 101-26-8 (CAS) Chemical Name: 3-hydroxy-1-methylpyridinium bromide dimethylcarbamate Chemical Class: Carbamates Phase of Development: Pyridostigmine is in Phase 2 development as an HIV treatment.

Chemical Image:

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pyridostigmine bromide

pyridostigmine bromide

Molecular Weight: 261.1177

(Compound details obtained from ChemIDplus Advanced,1 Treatment Action Group HIV TB HCV Pipeline Report 2018,2 and Current Neuropharmacology article3)

Pharmacology


Mechanism of Action: Immune modulator.2 Pyridostigmine is a reversible acetylcholinesterase inhibitor that is FDA-approved for treating myasthenia gravis and reversing the effects of muscle relaxants.4–6 It has also been used in the military as a pretreatment for exposure to the chemical nerve agent Soman.7 Pyridostigmine works by inhibiting the acetylcholinesterase (AChE) enzyme from breaking down the neurotransmitter acetylcholine (ACh), and thereby increases the bioavailability of ACh and enhances the transmission of nerve impulses at neuromuscular junctions.3–5

As a potential HIV immune modulator, pyridostigmine is thought to simulate the effect of the cholinergic anti-inflammatory pathway (CAP). The CAP is a physiological neural reflex that regulates the immune system and suppresses inflammation through the release of ACh and subsequent modification of cytokine production.4,8 In a previous proof-of-concept trial in individuals with HIV, pyridostigmine administration was shown to reduce T cell activation and proliferation, as well as increase the anti-inflammatory cytokine IL-10 and decrease the proinflammatory cytokine IFN-gamma.9 Additionally, in a Phase 2 pilot study (NCT00518154), pyridostigmine demonstrated its ability to increase CD4 counts in individuals with HIV who were virologically suppressed but had incomplete immunological response.4,10 Further evaluation of pyridostigmine for HIV immune restoration is currently ongoing in another Phase 2 trial (NCT03312244).11

Half-life (T1/2): Following intravenous (IV) (4 mg) and oral (60 mg) administration of pyridostigmine bromide in healthy participants, the mean plasma elimination half-life of pyridostigmine was 200 minutes for the oral dose and 97 minutes for the IV dose.12

Metabolism/Elimination: Pyridostigmine is metabolized via hydrolysis by cholinesterases, as well as by liver enzymes. It is excreted in the urine by tubular secretion as unchanged drug and as metabolites.12


Select Clinical Trials


Study Identifiers: NCT00518154
Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Phase: 2
Status: This study has been completed.
Study Purpose: The purpose of this open-label pilot study was to evaluate whether adding pyridostigmine to ART would increase CD4 counts in individuals with suboptimal immunologic response despite viral suppression on ART.
Study Population: Participants were adults with HIV who had undetectable viral load levels while on ART for at least 2 years but had suboptimal immunologic response.10
Selected Study Results:
Study Identifiers: NCT03312244
Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
Phase: 2
Status: This study has been enrolling by invitation.
Study Purpose: The purpose of this study is to evaluate whether adding pyridostigmine to ART can increase CD4 counts in individuals with HIV who have viral suppression on ART.
Study Population: Participants are adults with HIV who have had undetectable viral load levels while on ART for the past 6 months.11


Adverse Events


NCT00518154:

In this Phase 2 pilot study, seven participants were enrolled to receive pyridostigmine as add-on therapy to ART. One of the seven participants withdrew from the trial prior to study completion for reasons unrelated to the study drug. No adverse events (AEs) related to pyridostigmine, including cardiovascular, respiratory, gastrointestinal, or genitourinary AEs, were identified during the study. Also, no cholinergic AEs affecting central nervous system (CNS) functions were observed.4

Additional AEs known to be associated with pyridostigmine are described in the FDA-approved Full Prescribing Information for Mestinon.5


Drug Interactions


Because pyridostigmine is mainly excreted renally as unchanged drug by active tubular secretion, some drug-drug interactions may potentially occur between pyridostigmine and coadministered HIV antiretrovirals that undergo active renal secretion.13

Additional known interactions between pyridostigmine and coadministered drugs may be described in the FDA-approved Full Prescribing Information for Mestinon or the Health Canada-approved Product Monograph for Mestinon.5,12


References


  1. United States National Library of Medicine. ChemIDplus Advanced: Pyridostigmine bromide. https://chem.nlm.nih.gov/chemidplus/rn/101-26-8. Accessed October 24, 2019
  2. Jefferys R. The research toward a cure and immune-based therapies pipeline. Treatment Action Group HIV TB HCV Pipeline Report 2018. http://pipelinereport.org/sites/default/files/pipeline_2018_cure_ibt_rj_web3.pdf. Accessed October 24, 2019
  3. Colovic MB, Krstic DZ, Lazarevic-Pašti TD, Bondžic AM, Vasic VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Curr Neuropharmacol. 2013;11(3):315-335. doi:10.2174/1570159X11311030006
  4. Valdés-Ferrer SI, Crispín JC, Belaunzarán-Zamudio PF, et al. Add-on pyridostigmine enhances CD4+ T-cell recovery in HIV-1-infected immunological non-responders: a proof-of-concept study. Front Immunol. 2017;8. doi:10.3389/fimmu.2017.01301
  5. Valeant Pharmaceuticals North America LLC. Mestinon: full prescribing information, June 6, 2017. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a851795e-b7a8-40c3-9922-5e79d3eb4d92. Accessed October 24, 2019
  6. Sandoz Inc. Regonol: full prescribing information, December 29, 2011. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=208af931-a44e-43bf-a265-8e08534dc55f. Accessed October 24, 2019
  7. Valeant Canada Limited. Pyridostigmine bromide: full prescribing information, October 27, 2008. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=68e8abb9-979e-4c84-9e17-0c6584958ae3. Accessed October 24, 2019
  8. Wang DW, Zhou RB, Yao YM. Role of cholinergic anti-inflammatory pathway in regulating host response and its interventional strategy for inflammatory diseases. Chinese Journal of Traumatology (English Edition). 2009;12(6):355-364. doi:10.3760/cma.j.issn.1008-1275.2009.06.007
  9. Valdés-Ferrer SI, Crispín JC, Belaunzarán PF, Cantú-Brito CG, Sierra-Madero J, Alcocer-Varela J. Acetylcholine-esterase inhibitor pyridostigmine decreases T cell overactivation in patients infected by HIV. AIDS Res Hum Retroviruses. 2009;25(8):749-755. doi:10.1089/aid.2008.0257
  10. Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. Pilot study of an ACh-E inhibitor upon immune activation markers in HIV-1 infected patients receiving highly active antiretroviral therapy (HAART) showing an incomplete immune response. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered August 17, 2007. NLM Identifier: NCT00518154. https://clinicaltrials.gov/ct2/show/NCT00518154. Accessed October 24, 2019
  11. Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. Study of the role of peripheral acetylcholinesterase inhibitor pyridostigmine as immunomodulators in a population of patients living with human immunodeficiency virus infection. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered April 1, 2017. NLM Identifier: NCT03312244. https://clinicaltrials.gov/ct2/show/NCT03312244. Accessed October 24, 2019
  12. Valeant Canada LP. Mestinon: product monograph. Health Canada. https://pdf.hres.ca/dpd_pm/00026983.PDF. Accessed October 24, 2019
  13. University of Liverpool. HIV drug interactions: interaction checker. https://www.hiv-druginteractions.org/checker. Accessed October 24, 2019


Last Reviewed: October 24, 2019