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Acta Gastro-enterologica Belgica Mar 2011Due to their high morbidity and mortality, anastomotic leakage and disruption are still serious problems in colonic surgery. Bowel clamps applied during anastomosis in...
Trace element levels in ischemia-reperfusion injury after left colonic anastomosis in rats and effects of papaverine and pentoxiphylline on vascular endothelial growth factor in anastomosis healing.
BACKGROUND AND STUDY AIMS
Due to their high morbidity and mortality, anastomotic leakage and disruption are still serious problems in colonic surgery. Bowel clamps applied during anastomosis in order to prevent abdominal contamination with colonic contents, may cause microcirculation and perfusion problems and subsequent ischemia-reperfusion injury. Papaverine, a myorelaxant and vasodilatator, and pentoxiphylline, a hemorrheologic agent are used for microcirculation disorders and vascular endothelial growth factor (VEGF) is a stimulator of angiogenesis. With this experimental study, we aimed to measure trace element [copper (Cu) and zinc (Zn)] levels in ischemia-reperfusion injury due to clamps after left colonic anastomosis in rats and show the effects of papaverine and pentoxiphylline on VEGF that stimulates angiogenesis in anastomotic healing.
MATERIALS AND METHODS
50 female Wistar albino rats were randomized in 5 groups (n: 10). Laparotomy in group 1, left colonic transsection and anastomosis in group 2, and clamp application 1 cm proximal and distal to the anastomosis (for about 20 minutes long) during left colonic transsection and anastomosis in groups 3, 4 and 5 were performed. Additionally, after the operations, pentoxiphylline (Group 4) and papaverin (Group 5) were injected intraperitoneally. On the 10th postoperative day, plasma trace element and plasma VEGF levels were measured.
RESULTS
In this study, VEGF levels in group 1 were significantly low and this was explained as being exposed to hypoxic damage less than the other groups. In group 3, VEGF levels were significantly higher showing that the hypoxic stimulus continued without any treatment and in Group 4, significantly lower than Group 3 related to the inhibition of pentoxiphylline. Lower VEGF levels in Group 1 were thought to be related to lower VEGF induction due to less hypoxic effect. Zinc, an important trace element of the antioxidant system showed significantly higher levels in Group 4 with pentoxiphylline treatment, and this was thought to be related to the antioxidant characteristics of pentoxiphylline.
CONCLUSIONS
During surgical procedures, care should be taken not to cause ischemia to the intestinal tissues, and trace elements that are important in ischemia reperfusion injury should be replaced appropriately. Although the antioxidant effect of pentoxiphylline in ischemia reperfusion injury may be benefical in treatment, its inhibition of VEGF is a disadvantage in wound healing.
Topics: Animals; Colon; Female; Papaverine; Pentoxifylline; Rats; Rats, Wistar; Reperfusion Injury; Trace Elements; Vascular Endothelial Growth Factor A; Vasodilator Agents; Wound Healing
PubMed: 21563650
DOI: No ID Found -
Journal of Neuroinflammation Dec 2019Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson's disease (PD). Thus, the development of agents that can control neuroinflammation has been...
The phosphodiesterase 10 inhibitor papaverine exerts anti-inflammatory and neuroprotective effects via the PKA signaling pathway in neuroinflammation and Parkinson's disease mouse models.
BACKGROUND
Neuroinflammation plays a pivotal role in the pathogenesis of Parkinson's disease (PD). Thus, the development of agents that can control neuroinflammation has been suggested as a promising therapeutic strategy for PD. In the present study, we investigated whether the phosphodiesterase (PDE) 10 inhibitor has anti-inflammatory and neuroprotective effects in neuroinflammation and PD mouse models.
METHODS
Papaverine (PAP) was utilized as a selective inhibitor of PDE10. The effects of PAP on the expression of pro-inflammatory molecules were examined in lipopolysaccharide (LPS)-stimulated BV2 microglial cells by ELISA, RT-PCR, and Western blot analysis. The effects of PAP on transcription factors were analyzed by the electrophoretic mobility shift assay, the reporter gene assay, and Western blot analysis. Microglial activation and the expression of proinflammatory molecules were measured in the LPS- or MPTP-injected mouse brains by immunohistochemistry and RT-PCR analysis. The effect of PAP on dopaminergic neuronal cell death and neurotrophic factors were determined by immunohistochemistry and Western blot analysis. To assess mouse locomotor activity, rotarod and pole tests were performed in MPTP-injected mice.
RESULTS
PAP inhibited the production of nitric oxide and proinflammatory cytokines in LPS-stimulated microglia by modulating various inflammatory signals. In addition, PAP elevated intracellular cAMP levels and CREB phosphorylation. Treatment with H89, a PKA inhibitor, reversed the anti-inflammatory effects of PAP, suggesting the critical role of PKA signaling in the anti-inflammatory effects of PAP. We verified the anti-inflammatory effects of PAP in the brains of mice with LPS-induced systemic inflammation. PAP suppressed microglial activation and proinflammatory gene expression in the brains of these mice, and these effects were reversed by H89 treatment. We further examined the effects of PAP on MPTP-injected PD model mice. MPTP-induced dopaminergic neuronal cell death and impaired locomotor activity were recovered by PAP. In addition, PAP suppressed microglial activation and proinflammatory mediators in the brains of MPTP-injected mice.
CONCLUSIONS
PAP has strong anti-inflammatory and neuroprotective effects and thus may be a potential candidate for treating neuroinflammatory disorders such as PD.
Topics: Animals; Anti-Inflammatory Agents; Cell Line, Transformed; Cyclic AMP-Dependent Protein Kinases; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Neuroprotective Agents; Papaverine; Parkinsonian Disorders; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Random Allocation; Signal Transduction
PubMed: 31791357
DOI: 10.1186/s12974-019-1649-3 -
Internal Medicine (Tokyo, Japan) 2017Objectives The fractional flow reserve (FFR) is an index of the severity of coronary stenosis that has been clinically validated in several studies. The instantaneous... (Comparative Study)
Comparative Study
A Comparison between the Instantaneous Wave-free Ratio and Resting Distal Coronary Artery Pressure/Aortic Pressure and the Fractional Flow Reserve: The Diagnostic Accuracy Can Be Improved by the Use of both Indices.
Objectives The fractional flow reserve (FFR) is an index of the severity of coronary stenosis that has been clinically validated in several studies. The instantaneous wave-free ratio (iFR) and the resting distal coronary artery pressure/aortic pressure (Pd/Pa) are nonhyperemic pressure-derived indices of the severity of stenosis. This study sought to examine the diagnostic accuracy of the iFR and resting Pd/Pa with respect to hyperemic FFR. Methods Following an intracoronary injection of papaverine, the iFR, resting Pd/Pa, and FFR were continuously measured in 123 lesions in 103 patients with stable coronary disease. Results The iFR and resting Pd/Pa values were strongly correlated with the FFR (R=0.794, p<0.001, R=0.832, p<0.0001, respectively). A receiver operator curve (ROC) analysis revealed that the optimal iFR cut-off value for predicting an FFR of <0.80 was 0.89 (AUC 0.901, sensitivity 84.1%, specificity 80.0%, positive predictive value 69.8%, negative predictive value 90.0%, diagnostic accuracy 81.3%), while the optimal resting Pd/Pa cut-off value was 0.92 (AUC 0.925, sensitivity 90.9%, specificity 78.5%, positive predictive value 70.2%, negative predictive value 93.9%, diagnostic accuracy 82.9%). The lesions with an iFR value of ≤0.89 and a Pd/Pa value of ≤0.92 were defined as double-positive lesions, while the lesions with an iFR value of >0.89 and a Pd/Pa value of >0.92 were defined as double-negative lesions. In these 109 lesions, the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were 92.3%, 82.9%, 75.0%, 95.1%, and 86.2%, respectively. Conclusion This analysis demonstrated that the iFR and resting Pd/Pa were strongly correlated with the FFR and that the diagnostic accuracy of the iFR was similar to that of the resting Pd/Pa. The diagnostic accuracy can be improved with the use of both the iFR and the resting Pd/Pa.
Topics: Aged; Aorta; Arterial Pressure; Coronary Angiography; Coronary Artery Disease; Coronary Stenosis; Female; Fractional Flow Reserve, Myocardial; Heart; Humans; Hyperemia; Male; Middle Aged; Papaverine; Sensitivity and Specificity; Severity of Illness Index; Vasodilator Agents
PubMed: 28381739
DOI: 10.2169/internalmedicine.56.7857 -
Journal of Ultrasound in Medicine :... Nov 2008To achieve ultrasound-controlled drug delivery using echogenic liposomes (ELIPs), we assessed ultrasound-triggered release of hydrophilic and lipophilic agents in vitro...
OBJECTIVE
To achieve ultrasound-controlled drug delivery using echogenic liposomes (ELIPs), we assessed ultrasound-triggered release of hydrophilic and lipophilic agents in vitro using color Doppler ultrasound delivered with a clinical 6-MHz compact linear array transducer.
METHODS
Calcein, a hydrophilic agent, and papaverine, a lipophilic agent, were each separately loaded into ELIPs. Calcein-loaded ELIP (C-ELIP) and papaverine-loaded ELIP (P-ELIP) solutions were circulated in a flow model and treated with 6-MHz color Doppler ultrasound or Triton X-100. Treatment with Triton X-100 was used to release the encapsulated calcein or papaverine content completely. The free calcein concentration in the solution was measured directly by spectrofluorimetry. The free papaverine in the solution was separated from liposome-bound papaverine by spin column filtration, and the resulting papaverine concentration was measured directly by absorbance spectrophotometry. Dynamic changes in echogenicity were assessed with low-output B-mode ultrasound (mechanical index, 0.04) as mean digital intensity.
RESULTS
Color Doppler ultrasound caused calcein release from C-ELIPs compared with flow alone (P < .05) but did not induce papaverine release from P-ELIPs compared with flow alone (P > .05). Triton X-100 completely released liposome-associated calcein and papaverine. Initial echogenicity was higher for C-ELIPs than P-ELIPs. Color Doppler ultrasound and Triton X-100 treatments reduced echogenicity for both C-ELIPs and P-ELIPs (P < .05).
CONCLUSIONS
The differential efficiency of ultrasound-mediated pharmaceutical release from ELIPs for water- and lipid-soluble compounds suggests that water-soluble drugs are better candidates for the design and development of ELIP-based ultrasound-controlled drug delivery systems.
Topics: Diffusion; Drug Delivery Systems; Fluoresceins; Hydrophobic and Hydrophilic Interactions; Liposomes; Papaverine; Phosphodiesterase Inhibitors; Sonication
PubMed: 18946099
DOI: 10.7863/jum.2008.27.11.1597 -
Journal of Cardiothoracic Surgery Dec 2021Internal thoracic arteries (ITAs) are the gold standard conduits for coronary revascularization because of their long-term patency and anti-atherosclerotic properties.... (Review)
Review
Internal thoracic arteries (ITAs) are the gold standard conduits for coronary revascularization because of their long-term patency and anti-atherosclerotic properties. Harvesting and preparation of ITAs for revascularization is a technically demanding procedure with multiple challenges. Over the last few decades, various methods and techniques for ITAs harvesting have been introduced by different surgeons and applied in clinical practice with different results. Harvesting of ITAs in pedicled or skeletonized fashion, with electrocautery or harmonic scalpel, with open or intact pleura, with clipping the end or keeping it perfused; papaverine delivery with intraluminal injection, perivascular injection, injecting into endothoracic fascia, and papaverine topical spray are the different techniques introduced by the number of researchers. At the same time, access to the ITAs for harvesting has also been studied. Access and harvesting through median sternotomy, mini anterolateral thoracotomy, thoracoscopic, and robotic-assisted harvesting of ITAs are the different techniques used in clinical practice. However, the single standard method for harvesting and preparation of ITAs has yet to be determined. In this review article, we aimed to discuss and analyze all these techniques of harvesting and preparing ITAs with the help of literature to find the best way for ITAs harvesting and preparation for myocardial revascularization.
Topics: Humans; Mammary Arteries; Myocardial Revascularization; Papaverine; Thoracotomy; Tissue and Organ Harvesting
PubMed: 34961523
DOI: 10.1186/s13019-021-01733-2 -
PloS One 2016Papaverine is used to prevent vasospasm in human saphenous veins (HSV) during vein graft preparation prior to implantation as a bypass conduit. Papaverine is a...
OBJECTIVE
Papaverine is used to prevent vasospasm in human saphenous veins (HSV) during vein graft preparation prior to implantation as a bypass conduit. Papaverine is a nonspecific inhibitor of phosphodiesterases, leading to increases in both intracellular cGMP and cAMP. We hypothesized that papaverine reduces force by decreasing intracellular calcium concentrations ([Ca2+]i) and myosin light chain phosphorylation, and increasing actin depolymerization via regulation of actin regulatory protein phosphorylation.
APPROACH AND RESULTS
HSV was equilibrated in a muscle bath, pre-treated with 1 mM papaverine followed by 5 μM norepinephrine, and force along with [Ca2+]i levels were concurrently measured. Filamentous actin (F-actin) level was measured by an in vitro actin assay. Tissue was snap frozen to measure myosin light chain and actin regulatory protein phosphorylation. Pre-treatment with papaverine completely inhibited norepinephrine-induced force generation, blocked increases in [Ca2+]i and led to a decrease in the phosphorylation of myosin light chain. Papaverine pre-treatment also led to increased phosphorylation of the heat shock-related protein 20 (HSPB6) and the vasodilator stimulated phosphoprotein (VASP), as well as decreased filamentous actin (F-actin) levels suggesting depolymerization of actin.
CONCLUSIONS
These results suggest that papaverine-induced force inhibition of HSV involves [Ca2+]i-mediated inhibition of myosin light chain phosphorylation and actin regulatory protein phosphorylation-mediated actin depolymerization. Thus, papaverine induces sustained inhibition of contraction of HSV by the modulation of both myosin cross-bridge formation and actin cytoskeletal dynamics and is a pharmacological alternative to high pressure distention to prevent vasospasm.
Topics: Actins; Calcium; Humans; Immunoblotting; Muscle, Smooth, Vascular; Myosin Light Chains; Papaverine; Phosphorylation; Saphenous Vein; Tissue Culture Techniques
PubMed: 27136356
DOI: 10.1371/journal.pone.0154460 -
Journal of Cardiothoracic Surgery Jan 2019Radial artery (RA) is widely used in coronary artery bypass (CABG) surgery and the prevention of spasm is crucial for graft patency. Botulinum toxin A (BTX-A) and B are...
BACKGROUND
Radial artery (RA) is widely used in coronary artery bypass (CABG) surgery and the prevention of spasm is crucial for graft patency. Botulinum toxin A (BTX-A) and B are commonly used for aesthetic reasons and neuromuscular disorders. They are proven to raise blood flow and increase survival of ischemic skin flaps. In this study we evaluated and compared the vasodilator effects of BTX-A and papaverine on human RA grafts.
METHODS
After resting 60 min in isolated organ baths, human RA grafts were examined. Contraction responses for different doses of serotonin (5-HT) and endothelin-1 (ET-1) were evaluated as a percent of maximum contraction response elicited by 80 mM potassium chloride (KCl). The inhibitory effects of BTX-A and papaverine on contraction responses taken at the 0th hour were compared with the 1st and 2nd hour responses. Inhibitory effects of BTX-A and papaverine against the contractile agent were evaluated by comparing the results of the first and last (0th and 2nd hour) application.
RESULTS
In low concentrations, when we compared the effects of BTX-A (10 M) and papaverine (10 M) on 5-HT, papaverine was found to be more effective at both the 0th and 2nd hour (p < 0.05). Both BTX-A and papaverine inhibited the maximum contractile effect of ET-1 to the same extent at the 0th hour; but, the inhibitory effect of BTX-A was significantly stronger at the 2nd hour (p < 0.05). In high concentrations, when we compared the effects of BTX-A (10 M) and papaverine (10 M) on 5-HT, papaverine showed stronger inhibition (p < 0.05), whereas both agents had similar action of inhibition on ET-1 mediated maximum contraction responses.
CONCLUSION
BTX-A inhibits both ET-1 and 5-HT induced contractions and its effectiveness does not decrease over time as observed with papaverine. This study is the first in the literature using human RA for prevention of vasospasm by BTX-A.
Topics: Adult; Aged; Botulinum Toxins, Type A; Coronary Artery Bypass; Coronary Artery Disease; Female; Humans; Male; Middle Aged; Neuromuscular Agents; Papaverine; Radial Artery; Vasoconstriction; Vasodilator Agents
PubMed: 30665449
DOI: 10.1186/s13019-019-0837-7 -
Molecules (Basel, Switzerland) Apr 2024Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether...
Unraveling the Nephroprotective Potential of Papaverine against Cisplatin Toxicity through Mitigating Oxidative Stress and Inflammation: Insights from In Silico, In Vitro, and In Vivo Investigations.
Cisplatin is a potent compound in anti-tumor chemotherapy; however, its clinical utility is hampered by dose-limiting nephrotoxicity. This study investigated whether papaverine could mitigate cisplatin-induced kidney damage while preserving its chemotherapeutic efficacy. Integrative bioinformatics analysis predicted papaverine modulation of the mechanistic pathways related to cisplatin renal toxicity; notably, mitogen-activated protein kinase 1 (MAPK1) signaling. We validated protective effects in normal kidney cells without interfering with cisplatin cytotoxicity on a cancer cell line. Concurrent in vivo administration of papaverine alongside cisplatin in rats prevented elevations in nephrotoxicity markers, including serum creatinine, blood urea nitrogen, and renal oxidative stress markers (malondialdehyde, inducible nitric oxide synthase (iNOS), and pro-inflammatory cytokines), as tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and interleukin-6 (IL-6). Papaverine also reduced apoptosis markers such as Bcl2 and Bcl-2-associated X protein (Bax) and kidney injury molecule-1 (KIM-1), and histological damage. In addition, it upregulates antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) while boosting anti-inflammatory signaling interleukin-10 (IL-10). These effects were underlined by the ability of Papaverine to downregulate MAPK-1 expression. Overall, these findings show papaverine could protect against cisplatin kidney damage without reducing its cytotoxic activity. Further research would allow the transition of these results to clinical practice.
Topics: Cisplatin; Papaverine; Oxidative Stress; Animals; Rats; Inflammation; Humans; Kidney; Male; Apoptosis; Antineoplastic Agents; Protective Agents; Antioxidants; Cytokines; Computer Simulation; Biomarkers
PubMed: 38731418
DOI: 10.3390/molecules29091927 -
AJNR. American Journal of Neuroradiology Apr 1994Five cases of ipsilateral pupillary dilatation that developed during local intraarterial infusion of papaverine are reported. All patients were being treated for...
Five cases of ipsilateral pupillary dilatation that developed during local intraarterial infusion of papaverine are reported. All patients were being treated for symptomatic vasospasm secondary to subarachnoid hemorrhage. In each case, the tip of the infusion catheter was positioned in the internal carotid artery in close proximity to the ostium of the ophthalmic artery. Pupillary dilatation in all patients readily resolved after termination of the infusion.
Topics: Adult; Aged; Carotid Artery, Internal; Female; Humans; Infusions, Intra-Arterial; Ischemic Attack, Transient; Male; Middle Aged; Mydriasis; Ophthalmic Artery; Papaverine; Subarachnoid Hemorrhage
PubMed: 8010274
DOI: No ID Found -
The Journal of Investigative Dermatology Aug 1978The comparative inhibitory potency of papaverine and Ro 20-1724 (4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone) on cyclic AMP-phosphodiesterase (cAMP-PDE) and cyclic...
The comparative inhibitory potency of papaverine and Ro 20-1724 (4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone) on cyclic AMP-phosphodiesterase (cAMP-PDE) and cyclic GMP-phosphodiesterase (cGMP-PDE) activities and their effect on the levels of cAMP and cGMP were examined in psoriatic epidermis. At concentrations of 5 X 10(-4) M, papaverine inhibited the hydrolysis of both cAMP and cGMP by either the low or high Km psoriatic epidermal PDE nearly 100% (p less than .0001) while Ro 20-1724 selectively inhibited the hydrolysis of cAMP 94% (p less than .0001) but had no significant effect on cGMP hydrolysis. When keratomed psoriatic epidermal slices were incubated in 5 X 10(-4) M papaverine or Ro 20-1724 the tissue levels of cAMP were increased 343% or 1395% respectively (p less than .001) with no concomitant change in the levels of cGMP. Selective inhibition of cAMP hydrolysis by Ro 20-1724 and its greater effectiveness in elevating cAMP levels in slices of psoriatic epidermis is one explanation for its clinical superiority in treating psoriatic lesions.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3',5'-Cyclic-GMP Phosphodiesterases; 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Cyclic AMP; Epidermis; Humans; Imidazoles; In Vitro Techniques; Papaverine; Psoriasis
PubMed: 210235
DOI: 10.1111/1523-1747.ep12546928