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Annals of Surgical Oncology Aug 2022During robot-assisted partial nephrectomy (RAPN), renal artery clamping is necessary to optimize the surgical field. However, renal artery clamping can induce renal... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
During robot-assisted partial nephrectomy (RAPN), renal artery clamping is necessary to optimize the surgical field. However, renal artery clamping can induce renal blood flow reduction and postoperative renal dysfunction. Papaverine is used as a potent vasodilator agent. We determined if periarterial administration of papaverine after renal artery clamping improved intraoperative renal artery blood flow and early postoperative glomerular filtration rate (GFR) compared with placebo in RAPN.
PATIENTS AND METHODS
In this randomized controlled trial, 96 patients who underwent RAPN were enrolled between November 2019 and December 2020. Patients were administered periarterial normal saline as a placebo (placebo group) or papaverine (papaverine group) just after renal artery declamping. The primary outcome was renal artery blood flow by Doppler ultrasound 2 min after periarterial administration of papaverine or placebo after renal artery declamping. The secondary outcome was GFR estimated by renal scan 3 months after RAPN.
RESULTS
Renal artery blood flow and GFR were significantly higher in the papaverine group than in the placebo group (538.0 [376.6-760.0] mL/min versus 338.8 [205.8-603.4] mL/min, P = 0.002 and 93.5 ± 17.1 mL/min/1.73 m versus 85.9 ± 15.8 mL/min/1.73 m, P = 0.033, respectively).
CONCLUSIONS
Periarterial papaverine administration increased intraoperative renal artery blood flow and early postoperative GFR in RAPN, suggesting that papaverine administration has beneficial effects on renal perfusion after renal artery clamping and could be a valuable option for improving renal function after RAPN.
Topics: Humans; Kidney Neoplasms; Nephrectomy; Papaverine; Renal Artery; Renal Circulation; Retrospective Studies; Robotic Surgical Procedures; Robotics; Treatment Outcome
PubMed: 35368220
DOI: 10.1245/s10434-022-11586-1 -
Nature Chemical Biology Sep 2022A key bottleneck in the microbial production of therapeutic plant metabolites is identifying enzymes that can improve yield. The facile identification of genetically...
A key bottleneck in the microbial production of therapeutic plant metabolites is identifying enzymes that can improve yield. The facile identification of genetically encoded biosensors can overcome this limitation and become part of a general method for engineering scaled production. We have developed a combined screening and selection approach that quickly refines the affinities and specificities of generalist transcription factors; using RamR as a starting point, we evolve highly specific (>100-fold preference) and sensitive (half-maximum effective concentration (EC) < 30 μM) biosensors for the alkaloids tetrahydropapaverine, papaverine, glaucine, rotundine and noscapine. High-resolution structures reveal multiple evolutionary avenues for the malleable effector-binding site and the creation of new pockets for different chemical moieties. These sensors further enabled the evolution of a streamlined pathway for tetrahydropapaverine, a precursor to four modern pharmaceuticals, collapsing multiple methylation steps into a single evolved enzyme. Our methods for evolving biosensors enable the rapid engineering of pathways for therapeutic alkaloids.
Topics: Alkaloids; Biosensing Techniques; Plants
PubMed: 35799063
DOI: 10.1038/s41589-022-01072-w -
ACS Pharmacology & Translational Science May 2024CDK5 kinase plays a central role in the regulation of neuronal functions, and its hyperactivation has been associated with neurodegenerative pathologies and more...
CDK5 kinase plays a central role in the regulation of neuronal functions, and its hyperactivation has been associated with neurodegenerative pathologies and more recently with several human cancers, in particular lung cancer. However, ATP-competitive inhibitors targeting CDK5 are poorly selective and suffer limitations, calling for new classes of inhibitors. In a screen for allosteric modulators of CDK5, we identified ethaverine and closely related derivative papaverine and showed that they inhibit cell proliferation and migration of non small cell lung cancer cell lines. Moreover the efficacy of these compounds is significantly enhanced when combined with the ATP-competitive inhibitor roscovitine, suggesting an additive dual mechanism of inhibition targeting CDK5. These compounds do not affect CDK5 stability, but thermodenaturation studies performed with A549 cell extracts infer that they interact with CDK5 . Furthermore, the inhibitory potentials of ethaverine and papaverine are reduced in A549 cells treated with siRNA directed against CDK5. Taken together, our results provide unexpected and novel evidence that ethaverine and papaverine constitute promising leads that can be repurposed for targeting CDK5 in lung cancer.
PubMed: 38751642
DOI: 10.1021/acsptsci.4c00023 -
World Neurosurgery Dec 2022Papaverine, a vasodilator approved for use by the U.S. Food and Drug Administration, has shown efficacy in treating vasospasm in cardiology, urology, and nephrology. The...
BACKGROUND
Papaverine, a vasodilator approved for use by the U.S. Food and Drug Administration, has shown efficacy in treating vasospasm in cardiology, urology, and nephrology. The vasodilatory effect of papaverine is also hoped to protect the facial nerve from ischemic damage and nerve manipulation during vestibular schwannoma surgery. Our institution uses intracisternal papaverine irrigation during vestibular schwannoma resection to protect the facial nerve in patients with neuromonitoring changes. Our objective was to investigate the safety and facial nerve outcomes of intracisternal papaverine irrigation during vestibular schwannoma resection.
METHODS
We retrospectively reviewed patients who underwent resection of vestibular schwannoma at our institution between 2008 and 2021. Patients received papaverine if the intraoperative facial nerve stimulation threshold increased above 0.05 mA. Postoperative outcomes were compared with control patients who did not receive papaverine.
RESULTS
A total of 283 cases were included in our analysis. Patients who received papaverine (n = 60) had lower immediate postoperative House-Brackmann (HB) grades than did control individuals (mean, 1.54 vs. 1.95; P = 0.029) and a lower likelihood of immediate postoperative HB grade >1 (odds ratio, 0.514; P = 0.039). At long-term follow-up, there was no significant difference in HB grade. Papaverine use was not associated with increased rates of perioperative complications (P = 0.24).
CONCLUSIONS
The off-label use of intracisternal papaverine irrigation during vestibular schwannoma resection can certainly be used safely for select cases. It is associated with improved immediate postoperative facial nerve outcomes, similar long-term facial nerve outcomes, and no significant increase in complications.
Topics: Humans; Facial Nerve; Neuroma, Acoustic; Papaverine; Retrospective Studies; Facial Nerve Injuries; Postoperative Complications
PubMed: 36216244
DOI: 10.1016/j.wneu.2022.10.017 -
Advances in Clinical and Experimental... Oct 2019Papaverine is used to induce maximal hyperemia for index of coronary microcirculatory resistance (IMR) measurement in animal experiments, although it can lead to...
Effectiveness and safety of intracoronary papaverine, alprostadil, and high dosages of nicorandil and adenosine triphosphate for measurement of the index of coronary microcirculatory resistance in a pig model.
BACKGROUND
Papaverine is used to induce maximal hyperemia for index of coronary microcirculatory resistance (IMR) measurement in animal experiments, although it can lead to polymorphic ventricular tachycardia and ventricular fibrillation.
OBJECTIVES
This study investigated the effect of an intracoronary (IC) bolus of high adenosine triphosphate (ATP) and nicorandil doses for IMR measurement and explored the possibility of inducing maximal hyperemia with an IC alprostadil bolus.
MATERIAL AND METHODS
Index of coronary microcirculatory resistance was measured in a hyperemic state induced by 7 experimental conditions in 21 pigs (IC bolus of papaverine (18 mg), ATP (40 μg, 80 μg, 160 μg, and 240 μg), and nicorandil (2 mg and 4 mg)). The 7 conditions were induced sequentially, and the average IMR was calculated. Because of the long-term hyperemic condition in the pilot experiments, the IMR was measured 1, 3, 5, 8, and 10 min after an IC bolus of alprostadil (10 μg) in another 7 pigs.
RESULTS
The IMR induced by 240 μg of ATP or 4 mg of nicorandil was not significantly different from that induced by 18 mg of papaverine (both p > 0.05). A strong linear correlation was observed between IMRs with papaverine (18 mg) and nicorandil (4 mg) (R2 = 0.936, p < 0.001) and with papaverine (18 mg) and ATP (240 μg) (R2 = 0.838, p < 0.05). The IC bolus of nicorandil (4 mg) produced the smallest changes, whereas papaverine caused the most significant changes in mean blood pressure and heart rate (p < 0.05). Tachypnea and transient ST depression were more common with increasing ATP dosages (especially 240 μg). Alprostadil (5 min) yielded a significant hyperemic response but reduced baseline blood pressure by almost 40% for a long time.
CONCLUSIONS
Intracoronary bolus administration of 4 mg of nicorandil was better than 18 mg of papaverine or 240 μg of ATP for induction of maximal hyperemia and IMR measurement in a pig model, whereas alprostadil was not suitable for IMR measurement.
Topics: Adenosine Triphosphate; Alprostadil; Animals; Coronary Circulation; Microcirculation; Nicorandil; Papaverine; Swine; Vasodilator Agents
PubMed: 31638745
DOI: 10.17219/acem/104541 -
Archives of Medical Science : AMS 2022Autologous saphenous vein (SV) and internal mammary artery (IMA) are used as bypass conduits during coronary artery bypass graft surgery. Vasospasm of the arterial and...
INTRODUCTION
Autologous saphenous vein (SV) and internal mammary artery (IMA) are used as bypass conduits during coronary artery bypass graft surgery. Vasospasm of the arterial and venous grafts may constitute a significant clinical problem. Pretreatment with a vasodilator drug of the graft or intraluminal injection before implantation may be used for spasm prophylaxis. This study was designed to assess the vasoactive effects and time-dependent changes of botulinum toxin A (BTX-A) and papaverine pretreatment on vasospasm of human SV and IMA grafts. Also, histomorphology of the vessels was assessed.
MATERIAL AND METHODS
SV and IMA segments were suspended in organ baths, and isometric contraction responses to 2 different concentrations of 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) were recorded after incubation with 2 different concentrations of BTX-A and papaverine at 2 time points (0 h and 2 h).
RESULTS
The results revealed the following: 1) incubation with BTX-A and papaverine relaxes both SV and IMA rings contracted with 5-HT and ET-1; 2) the duration of the relaxant effect of BTX-A lasts longer than papaverine; and 3) no apparent histomorphological changes were observed in the grafts under light microscopy.
CONCLUSIONS
This study demonstrates that in human SV and IMA grafts, pretreatment with both BTX-A and papaverine are safe and have a potent inhibitory effect depending on the vessel and vasoconstrictor agent. The long-lasting vasodilatory effect of BTX-A on vascular smooth muscle may provide promising results in the prevention of venous and arterial graft spasm.
PubMed: 36457963
DOI: 10.5114/aoms/110157 -
Annals of Cardiac Anaesthesia 2021
Topics: Administration, Topical; Hemodynamics; Humans; Mammary Arteries; Papaverine; Stellate Ganglion
PubMed: 33938858
DOI: 10.4103/aca.ACA_171_20 -
Journal of Materials Science. Materials... May 2023Vasospasm during reconstructive microsurgery is a common, uncertain, and devastating phenomena concerning flap survival. Topical vasodilators as antispasmodic agents are...
Vasospasm during reconstructive microsurgery is a common, uncertain, and devastating phenomena concerning flap survival. Topical vasodilators as antispasmodic agents are widely used to reduce vasospasm and enhance microvascular anastomosis in reconstructive microsurgery. In this study, thermo-responsive hydrogel (CNH) was fabricated by grafting chitosan (CS) and hyaluronic acid (HA) to poly(N-isopropylacrylamide) (PNIPAM). Papaverine, an anti-spasmodic agent, was then loaded to evaluate its effect on rat skin flap survival. Post-operative flap survival area and water content of rat dorsal skin flap were measured at 7 days after intradermal application of control hydrogel (CNHP0.0) and papaverine loaded hydrogel (CNHP0.4). Tissue malondialdehyde (MDA) content and superoxide dismutase (SOD) activity was measured using enzyme linked immunosorbent assay (ELISA) to determine oxidative stress in flaps. Hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) were performed to evaluate flap angiogenesis and inflammatory markers. Results showed that CNHP0.4 hydrogel could reduce tissue edema (35.63 ± 4.01%), improve flap survival area (76.30 ± 5.39%), increase SOD activity and decrease MDA content. Consequently, it also increased mean vessel density, upregulated expression of CD34 and VEGF, decreased macrophage infiltration, and reduced CD68 and CCR7 expression based on IHC staining. Overall, these results indicate that CNHP0.4 hydrogel can enhance angiogenesis with anti-oxidative and anti-inflammatory effects and promote skin flap survival by preventing vascular spasm.
Topics: Rats; Animals; Rats, Sprague-Dawley; Papaverine; Hydrogels; Surgical Flaps; Graft Survival; Superoxide Dismutase
PubMed: 37209216
DOI: 10.1007/s10856-023-06732-4 -
European Journal of Medicinal Chemistry Dec 2021Alkaloids are one of the most important classes of plant bioactives. Among these isoquinoline alkaloids possess varied structures and exhibit numerous biological... (Review)
Review
Alkaloids are one of the most important classes of plant bioactives. Among these isoquinoline alkaloids possess varied structures and exhibit numerous biological activities. Basically these are biosynthetically produced via phenylpropanoid pathway. However, occasionally some mixed pathways may also occur to provide structural divergence. Among the various biological activities anticancer, antidiabetic, antiinflammatory, and antimicrobial are important. A few notable bioactive isoquinoline alkaloids are antidiabetic berberine, anti-tussive codeine, analgesic morphine, and muscle relaxant papaverine etc. Berberine is one of the most discussed bioactives from this class possessing broad-spectrum pharmacological activities. Present review aims at recent updates of isoquinoline alkaloids with major emphasis on berberine, its detailed chemistry, important biological activities, structure activity relationship and implementation in future research.
Topics: Anti-Infective Agents; Anti-Inflammatory Agents; Berberine; Humans; Hydrastis; Hypoglycemic Agents; Molecular Structure
PubMed: 34536668
DOI: 10.1016/j.ejmech.2021.113839 -
Journal of Virology Feb 2020Influenza viruses are highly infectious and are the leading cause of human respiratory diseases and may trigger severe epidemics and occasional pandemics. Although...
Influenza viruses are highly infectious and are the leading cause of human respiratory diseases and may trigger severe epidemics and occasional pandemics. Although antiviral drugs against influenza viruses have been developed, there is an urgent need to design new strategies to develop influenza virus inhibitors due to the increasing resistance of viruses toward currently available drugs. In this study, we examined the antiviral activity of natural compounds against the following influenza virus strains: A/WSN/33 (H1N1), A/Udorn/72 (H3N2), and B/Lee/40. Papaverine (a nonnarcotic alkaloid that has been used for the treatment of heart disease, impotency, and psychosis) was found to be an effective inhibitor of multiple strains of influenza virus. Kinetic studies demonstrated that papaverine inhibited influenza virus infection at a late stage in the virus life cycle. An alteration in influenza virus morphology and viral ribonucleoprotein (vRNP) localization was observed as an effect of papaverine treatment. Papaverine is a well-known phosphodiesterase inhibitor and also modifies the mitogen-activated protein kinase (MAPK) pathway by downregulating the phosphorylation of MEK and extracellular signal-regulated kinase (ERK). Thus, the modulation of host cell signaling pathways by papaverine may be associated with the nuclear retention of vRNPs and the reduction of influenza virus titers. Interestingly, papaverine also inhibited paramyxoviruses parainfluenza virus 5 (PIV5), human parainfluenza virus 3 (HPIV3), and respiratory syncytial virus (RSV) infections. We propose that papaverine can be a potential candidate to be used as an antiviral agent against a broad range of influenza viruses and paramyxoviruses. Influenza viruses are important human pathogens that are the causative agents of epidemics and pandemics. Despite the availability of an annual vaccine, a large number of cases occur every year globally. Here, we report that papaverine, a vasodilator, shows inhibitory action against various strains of influenza virus as well as the paramyxoviruses PIV5, HPIV3, and RSV. A significant effect of papaverine on the influenza virus morphology was observed. Papaverine treatment of influenza-virus-infected cells resulted in the inhibition of virus at a later time in the virus life cycle through the suppression of nuclear export of vRNP and also interfered with the host cellular cAMP and MEK/ERK cascade pathways. This study explores the use of papaverine as an effective inhibitor of both influenza viruses as well as paramyxoviruses.
Topics: Animals; Antiviral Agents; Dogs; Drug Evaluation, Preclinical; Drug Repositioning; HEK293 Cells; Humans; MAP Kinase Signaling System; Madin Darby Canine Kidney Cells; Orthomyxoviridae; Orthomyxoviridae Infections; Papaverine; Paramyxoviridae Infections; Paramyxovirinae
PubMed: 31896588
DOI: 10.1128/JVI.01888-19