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Pharmacological Properties and Therapeutic Potential of Papaverine: A Comprehensive Review

Yıl 2025, Cilt: 7 Sayı: 1, 1 - 4

Öz

Papaverine, a prominent benzylisoquinoline alkaloid extracted from Papaver somniferum L., has long been used for its vasodilatory properties in clinical settings. Despite its structural distinction from opiate alkaloids, papaverine is known for inhibiting cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterase in smooth muscle cells, leading to increased intracellular concentrations of these molecules. This mechanism contributes to the dilation of cerebral, coronary, and pulmonary arteries and enhances cerebral blood flow while reducing vascular resistance. Beyond its established use, recent research has revealed papaverine’s extensive pharmacological activities, including its effects in treating erectile dysfunction, managing postoperative vasospasms, and alleviating pulmonary vasoconstriction. Furthermore, its antiviral, anti-inflammatory, cardioprotective, neuroprotective, and anticancer properties have garnered significant attention. Notably, papaverine has demonstrated potential in controlling the cytopathic effects of SARS-CoV-2, positioning it as a candidate for therapeutic development against viral infections. Despite promising findings, further research is needed to understand the full spectrum of its molecular mechanisms and to address concerns about its long-term safety and toxicity. This review aims to provide an in-depth analysis of papaverine’s pharmacological actions, therapeutic applications, and the molecular pathways involved, with an emphasis on its potential as a versatile agent in modern medicine.

Kaynakça

  • Arora L, Hosn MA. Spinal cord perfusion protection for thoraco-abdominal aortic aneurysm surgery. Curr Opin Anaesthesiol. 2019;32:72–79.
  • Grdina DJ, Murley JS, Kataoka Y. Radioprotectants: Current status and new directions. Oncology. 2002;63:2–10.
  • Weiss JF, Landauer MR. Protection against ionizing radiation by antioxidant nutrients and phytochemicals. Toxicology. 2003;189:1–20.
  • Alam S, Emon N, Shahriar S, Richi F, Haque M, Islam M, et al. Pharmacological and computer-aided studies provide new insights into Millettia peguensis Ali (Fabaceae). Saudi Pharm J. 2020;28:1777–1790.
  • Ashrafi S, Alam S, Emon N, Ahsan M. Isolation, characterization and pharmacological investigations of a new phenolic compound along with four others firstly reported phytochemicals from Glycosmis. Molecules. 2022;27:5972.
  • Amin MN, Emdadul M, Mukul H, Millat MS, Saif M, Rashed U. Phytochemical nature and pharmacological evaluation of chloroform extract of Pandanus fascicularis L. (Fruits): an in vivo study. J Bioanal Biomed. 2017;9:4.
  • Pyne ME, Narcross L, Fossati E, Bourgeois L, Burton E, Gold ND, et al. Reconstituting plant secondary metabolism in Saccharomyces cerevisiae for production of high-value benzylisoquinoline alkaloids. Methods Enzymol. 2016;575:195–224.
  • Ziegler J, Facchini PJ. Alkaloid biosynthesis: metabolism and trafficking. Annu Rev Plant Biol. 2008;59:735–769.
  • Benej M, Hong X, Vibhute S, Scott S, Wu J, Graves E, et al. Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci U S A. 2018;115:10756–10761.
  • Butnariu M, Quispe C, Herrera-Bravo JJ, Pentea M, Sarac I, Küşümler A, et al. Papaver plants: current insights on phytochemical and nutritional composition along with biotechnological applications. Oxid Med Cell Longev. 2022;2022:2041769.
  • Peter KV. Handbook of herbs and spices. Amsterdam: Elsevier; 2012.
  • Shamma M. The Isoquinoline Alkaloids Chemistry and Pharmacology. Amsterdam: Elsevier; 2012.
  • Desgagné-Penix I, Facchini PJ. Systematic silencing of benzylisoquinoline alkaloid biosynthetic genes reveals the major route to papaverine in opium poppy. Plant J. 2012;72:331–344.
  • Yan J, Mi JQ, He JT, Guo ZQ, Zhao MP, Chang WB. Development of an indirect competitive ELISA for the determination of papaverine. Talanta. 2005;66:1005–1011.
  • Han X, Lamshöft M, Grobe N, Ren X, Fist A, Kutchan T, et al. The biosynthesis of papaverine proceeds via (S)-reticuline. Phytochemistry. 2010;71:1305–1312.
  • Gaber A, Alsanie WF, Kumar DN, Refat MS, Saied EM. Novel papaverine metal complexes with potential anticancer activities. Molecules. 2020;25:5447.
  • Srivastava A, Agrawal L, Raj R, Jaidi M, Raj SK, Gupta S, et al. Ageratum enation virus infection induces programmed cell death and alters metabolite biosynthesis in Papaver somniferum. Front Plant Sci. 2017;8:1172.
  • Agarwal P, Pathak S, Kumar RS, Dhar YV, Pandey A, Shukla S, et al. 3′O-methyltransferase, Ps3′OMT, from opium poppy: involvement in papaverine biosynthesis. Plant Cell Rep. 2019;38:1235–1248.
  • Beaudoin GAW, Facchini PJ. Benzylisoquinoline alkaloid biosynthesis in opium poppy. Planta. 2014;240:19–32.
  • Ivanova B, Spiteller M. On the biosynthetic pathway of papaverine via (S)-reticuline—theoretical vs. experimental study. Nat Prod Commun. 2012;7:581–586.
  • Pathak S, Lakhwani D, Gupta P, Mishra BK, Shukla S, Asif MH, et al. Comparative transcriptome analysis using high papaverine mutant of Papaver somniferum reveals pathway and uncharacterized steps of papaverine biosynthesis. PLoS One. 2013;8.
  • Pienkny S, Brandt W, Schmidt J, Kramell R, Ziegler J. Functional characterization of a novel benzylisoquinoline O-methyltransferase suggests its involvement in papaverine biosynthesis in opium poppy (Papaver somniferum L.). Plant J. 2009;60:56–67.
  • Abusnina A, Lugnier C. Therapeutic potentials of natural compounds acting on cyclic nucleotide phosphodiesterase families. Cell Signal. 2017;39:55–65.
  • Debnath B, Singh W, Das M, Goswami S, Singh M, Maiti D, et al. Role of plant alkaloids on human health: a review of biological activities. Mater Today Chem. 2018;9:56–72.
  • Dong HH, Guang YB, Tae KY, Byung SS, Yong GK, Chul JK. The effect of papaverine on ion channels in rat basilar smooth muscle cells. Neurol Res. 2007;29:544–550.
  • Gomes D, Joubert A, Visagie M. In vitro effects of papaverine on cell proliferation, reactive oxygen species, and cell cycle progression in cancer cells. Molecules. 2021;26:6388.
  • Shimizu K, Yoshihara E, Takahashi M, Gotoh K, Orita S, Urakawa N, et al. Mechanism of relaxant response to papaverine on the smooth muscle of non-pregnant rat uterus. J Smooth Muscle Res. 2000;36:83–91.
  • Liu JK, Couldwell WT. Intra-arterial papaverine infusions for the treatment of cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2005;2:124–132.
  • Hebb ALO, Robertson HA, Denovan-Wright EM. Phosphodiesterase 10A inhibition is associated with locomotor and cognitive deficits and increased anxiety in mice. Eur Neuropsychopharmacol. 2008;18:339–363.
  • Weber M, Breier M, Ko D, Thangaraj N, Marzan DE, Swerdlow NR. Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine. Psychopharmacology. 2009;203:723–735.
  • Lee YY, Park JS, Leem YH, Park JE, Kim DY, Choi YH, et al. The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models. J Neuroinflammati• Bakr AM, El-Sakka AA, El-Sakka AI. Considerations for prescribing pharmacotherapy for the treatment of erectile dysfunction. Expert Opin Pharmacother. 2020;22:821–834.
  • Fusi F, Manetti F, Durante M, Sgaragli G, Saponara S. The vasodilator papaverine stimulates L-type Ca2+ current in rat tail artery myocytes via a PKA-dependent mechanism. Vascul Pharmacol. 2016;76:53–61.
  • Berkó S, Zsikó S, Deák G, Gácsi A, Kovács A, Budai-Szűcs M, et al. Papaverine hydrochloride containing nanostructured lyotropic liquid crystal formulation as a potential drug delivery system for the treatment of erectile dysfunction. Drug Des Devel Ther. 2018;12:2923–2931.
  • Bivalacqua TJ, Champion HC, Hellstrom WJG, Kadowitz PJ. Pharmacotherapy for erectile dysfunction. Trends Pharmacol Sci. 2000;21:484–489.
  • Mcmahon CG. Current diagnosis and management of erectile dysfunction. Med J Aust. 2019;210:469–476.
  • Padma-Nathan H, Christ G, Adaikan G, Becher E, Brock G, Carrier S, et al. Pharmacotherapy for erectile dysfunction. J Sex Med. 2010;7:524–540.

Papaverinin Farmakolojik Özellikleri ve Tedavi Potansiyeli: Kapsamlı Bir Derleme

Yıl 2025, Cilt: 7 Sayı: 1, 1 - 4

Öz

Papaver somniferum L.’den elde edilen önemli bir benzilizokinolin alkaloidi olan papaverin, klinik ortamlarda uzun süredir vazodilatör özellikleri ile kullanılmaktadır. Opiat alkaloidlerinden yapısal olarak farklı olmasına rağmen, papaverin, düz kas hücrelerinde siklik adenozin monofosfat (cAMP) ve siklik guanozin monofosfat (cGMP) fosfodiesterazını inhibe etmesiyle bilinir. Bu mekanizma, bu moleküllerin hücre içi konsantrasyonlarının artmasına yol açar ve bu da serebral, koroner ve pulmoner arterlerin genişlemesine, serebral kan akışının artmasına ve vasküler direncin azalmasına katkı sağlar. Yerleşik kullanımının ötesinde, son araştırmalar papaverinin erektil disfonksiyon tedavisi, postoperatif vazospazmların yönetimi ve pulmoner vazokonstriksiyonun hafifletilmesi gibi kapsamlı farmakolojik aktivitelerini ortaya koymuştur. Ayrıca, antiviral, anti-inflamatuar, kardiyoprotektif, nöroprotektif ve antikanser özellikleri büyük ilgi görmektedir. Özellikle, papaverin, SARS-CoV-2’nin sitopatik etkilerinin kontrolünde potansiyel göstermiş ve viral enfeksiyonlara karşı tedavi geliştirilmesi için bir aday olarak öne çıkmıştır. Umut verici bulgulara rağmen, moleküler mekanizmalarının tam olarak anlaşılması ve uzun vadeli güvenliği ve toksisitesi konusundaki endişelerin giderilmesi için daha fazla araştırmaya ihtiyaç vardır. Bu derleme, papaverinin farmakolojik etkilerini, tedavi uygulamalarını ve ilgili moleküler yolları derinlemesine analiz etmeyi ve modern tıpta çok yönlü bir ajan olarak potansiyelini vurgulamayı amaçlamaktadır.

Kaynakça

  • Arora L, Hosn MA. Spinal cord perfusion protection for thoraco-abdominal aortic aneurysm surgery. Curr Opin Anaesthesiol. 2019;32:72–79.
  • Grdina DJ, Murley JS, Kataoka Y. Radioprotectants: Current status and new directions. Oncology. 2002;63:2–10.
  • Weiss JF, Landauer MR. Protection against ionizing radiation by antioxidant nutrients and phytochemicals. Toxicology. 2003;189:1–20.
  • Alam S, Emon N, Shahriar S, Richi F, Haque M, Islam M, et al. Pharmacological and computer-aided studies provide new insights into Millettia peguensis Ali (Fabaceae). Saudi Pharm J. 2020;28:1777–1790.
  • Ashrafi S, Alam S, Emon N, Ahsan M. Isolation, characterization and pharmacological investigations of a new phenolic compound along with four others firstly reported phytochemicals from Glycosmis. Molecules. 2022;27:5972.
  • Amin MN, Emdadul M, Mukul H, Millat MS, Saif M, Rashed U. Phytochemical nature and pharmacological evaluation of chloroform extract of Pandanus fascicularis L. (Fruits): an in vivo study. J Bioanal Biomed. 2017;9:4.
  • Pyne ME, Narcross L, Fossati E, Bourgeois L, Burton E, Gold ND, et al. Reconstituting plant secondary metabolism in Saccharomyces cerevisiae for production of high-value benzylisoquinoline alkaloids. Methods Enzymol. 2016;575:195–224.
  • Ziegler J, Facchini PJ. Alkaloid biosynthesis: metabolism and trafficking. Annu Rev Plant Biol. 2008;59:735–769.
  • Benej M, Hong X, Vibhute S, Scott S, Wu J, Graves E, et al. Papaverine and its derivatives radiosensitize solid tumors by inhibiting mitochondrial metabolism. Proc Natl Acad Sci U S A. 2018;115:10756–10761.
  • Butnariu M, Quispe C, Herrera-Bravo JJ, Pentea M, Sarac I, Küşümler A, et al. Papaver plants: current insights on phytochemical and nutritional composition along with biotechnological applications. Oxid Med Cell Longev. 2022;2022:2041769.
  • Peter KV. Handbook of herbs and spices. Amsterdam: Elsevier; 2012.
  • Shamma M. The Isoquinoline Alkaloids Chemistry and Pharmacology. Amsterdam: Elsevier; 2012.
  • Desgagné-Penix I, Facchini PJ. Systematic silencing of benzylisoquinoline alkaloid biosynthetic genes reveals the major route to papaverine in opium poppy. Plant J. 2012;72:331–344.
  • Yan J, Mi JQ, He JT, Guo ZQ, Zhao MP, Chang WB. Development of an indirect competitive ELISA for the determination of papaverine. Talanta. 2005;66:1005–1011.
  • Han X, Lamshöft M, Grobe N, Ren X, Fist A, Kutchan T, et al. The biosynthesis of papaverine proceeds via (S)-reticuline. Phytochemistry. 2010;71:1305–1312.
  • Gaber A, Alsanie WF, Kumar DN, Refat MS, Saied EM. Novel papaverine metal complexes with potential anticancer activities. Molecules. 2020;25:5447.
  • Srivastava A, Agrawal L, Raj R, Jaidi M, Raj SK, Gupta S, et al. Ageratum enation virus infection induces programmed cell death and alters metabolite biosynthesis in Papaver somniferum. Front Plant Sci. 2017;8:1172.
  • Agarwal P, Pathak S, Kumar RS, Dhar YV, Pandey A, Shukla S, et al. 3′O-methyltransferase, Ps3′OMT, from opium poppy: involvement in papaverine biosynthesis. Plant Cell Rep. 2019;38:1235–1248.
  • Beaudoin GAW, Facchini PJ. Benzylisoquinoline alkaloid biosynthesis in opium poppy. Planta. 2014;240:19–32.
  • Ivanova B, Spiteller M. On the biosynthetic pathway of papaverine via (S)-reticuline—theoretical vs. experimental study. Nat Prod Commun. 2012;7:581–586.
  • Pathak S, Lakhwani D, Gupta P, Mishra BK, Shukla S, Asif MH, et al. Comparative transcriptome analysis using high papaverine mutant of Papaver somniferum reveals pathway and uncharacterized steps of papaverine biosynthesis. PLoS One. 2013;8.
  • Pienkny S, Brandt W, Schmidt J, Kramell R, Ziegler J. Functional characterization of a novel benzylisoquinoline O-methyltransferase suggests its involvement in papaverine biosynthesis in opium poppy (Papaver somniferum L.). Plant J. 2009;60:56–67.
  • Abusnina A, Lugnier C. Therapeutic potentials of natural compounds acting on cyclic nucleotide phosphodiesterase families. Cell Signal. 2017;39:55–65.
  • Debnath B, Singh W, Das M, Goswami S, Singh M, Maiti D, et al. Role of plant alkaloids on human health: a review of biological activities. Mater Today Chem. 2018;9:56–72.
  • Dong HH, Guang YB, Tae KY, Byung SS, Yong GK, Chul JK. The effect of papaverine on ion channels in rat basilar smooth muscle cells. Neurol Res. 2007;29:544–550.
  • Gomes D, Joubert A, Visagie M. In vitro effects of papaverine on cell proliferation, reactive oxygen species, and cell cycle progression in cancer cells. Molecules. 2021;26:6388.
  • Shimizu K, Yoshihara E, Takahashi M, Gotoh K, Orita S, Urakawa N, et al. Mechanism of relaxant response to papaverine on the smooth muscle of non-pregnant rat uterus. J Smooth Muscle Res. 2000;36:83–91.
  • Liu JK, Couldwell WT. Intra-arterial papaverine infusions for the treatment of cerebral vasospasm induced by aneurysmal subarachnoid hemorrhage. Neurocrit Care. 2005;2:124–132.
  • Hebb ALO, Robertson HA, Denovan-Wright EM. Phosphodiesterase 10A inhibition is associated with locomotor and cognitive deficits and increased anxiety in mice. Eur Neuropsychopharmacol. 2008;18:339–363.
  • Weber M, Breier M, Ko D, Thangaraj N, Marzan DE, Swerdlow NR. Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine. Psychopharmacology. 2009;203:723–735.
  • Lee YY, Park JS, Leem YH, Park JE, Kim DY, Choi YH, et al. The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson’s disease mouse models. J Neuroinflammati• Bakr AM, El-Sakka AA, El-Sakka AI. Considerations for prescribing pharmacotherapy for the treatment of erectile dysfunction. Expert Opin Pharmacother. 2020;22:821–834.
  • Fusi F, Manetti F, Durante M, Sgaragli G, Saponara S. The vasodilator papaverine stimulates L-type Ca2+ current in rat tail artery myocytes via a PKA-dependent mechanism. Vascul Pharmacol. 2016;76:53–61.
  • Berkó S, Zsikó S, Deák G, Gácsi A, Kovács A, Budai-Szűcs M, et al. Papaverine hydrochloride containing nanostructured lyotropic liquid crystal formulation as a potential drug delivery system for the treatment of erectile dysfunction. Drug Des Devel Ther. 2018;12:2923–2931.
  • Bivalacqua TJ, Champion HC, Hellstrom WJG, Kadowitz PJ. Pharmacotherapy for erectile dysfunction. Trends Pharmacol Sci. 2000;21:484–489.
  • Mcmahon CG. Current diagnosis and management of erectile dysfunction. Med J Aust. 2019;210:469–476.
  • Padma-Nathan H, Christ G, Adaikan G, Becher E, Brock G, Carrier S, et al. Pharmacotherapy for erectile dysfunction. J Sex Med. 2010;7:524–540.
Toplam 36 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Halk Sağlığı (Diğer)
Bölüm Derleme
Yazarlar

Gamze Mercan 0000-0001-5515-999X

Zümrüt Varol Selçuk 0000-0001-5015-0291

Erken Görünüm Tarihi 6 Mart 2025
Yayımlanma Tarihi
Gönderilme Tarihi 19 Ekim 2024
Kabul Tarihi 10 Ocak 2025
Yayımlandığı Sayı Yıl 2025 Cilt: 7 Sayı: 1

Kaynak Göster

Vancouver Mercan G, Varol Selçuk Z. Pharmacological Properties and Therapeutic Potential of Papaverine: A Comprehensive Review. Phnx Med J. 2025;7(1):1-4.

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