The effect of papaverine on tendon healing and adhesion in rats following Achilles tendon repair.

OBJECTIVES: The study aimed to examine the histopathological and biomechanical effects of papaverine administered intraperitoneally and locally on Achilles tendon healing in a rat model. MATERIALS AND METHODS: Forty-eight adult male Sprague-Dawley rats (range, 300 to 400 g) were used in this study conducted between October and November 2022. The rats were divided into three groups, with each group further subdivided into two for sacrifice on either the 15th (early period) or 30th (late period) day after surgery. The first (control) group received no treatment following Achilles tendon repair, while papaverine was intraperitoneally administered every other day for 10 days in the second group and locally in the third group after surgery. On the 15th and 30th days, the rats were sacrificed, and their Achilles tendons were subjected to biomechanical testing and histopathological evaluation. RESULTS: Histopathologically, there were no significant differences among the groups on the 15th day. However, on the 30th day, the locally applied papaverine group exhibited superior histopathological outcomes compared to the control group (p<0.05). Concerning the highest tensile strength values before rupture, the biomechanical assessment showed that the group receiving local papaverine treatment in the early period and both the group with systemic papaverine treatment and the one with local papaverine treatment in the late period displayed a statistically significant advantage compared to the control group (p<0.05). CONCLUSION: Locally administered papaverine has positive biomechanical effects in the early period and exhibits a positive correlation both histopathologically and biomechanically in the late period. Novel therapeutic options may be provided for patients through these findings.

Demonstration of ameliorating effect of papaverine in sepsis-induced acute lung injury on rat model through radiology and histology.

BACKGROUND: Our target was to show the role of high mobility group box-1/receptor for (HMGB1/RAGE) interaction in feces intraperitoneal injection procedure (FIP)-induced acute lung injury (ALI) pathophysiology, to investigate the effect of papaverine on RAGE associated NF-κB pathway by determining the level of soluble RAGE (sRAGE) and HMGB1, and to support this hypothesis by evaluating inflammatory biochemical, oxidative stress markers, Hounsfield unit (HU) value in computed tomography (CT), and histo-pathological results. METHODS: FIP was performed on 37 Wistar rats for creating a sepsis-induced ALI model. The animals were assigned into four groups as follows: Normal control (no treatment), placebo (FIP and saline), and receiving 20 mg/kg and 40 mg/kg per day papaverine. Twenty h after FIP, CT examination was performed for all animals, and HU value of the lung parenchyma was measured. The plasma levels of tumor necrosis factor (TNF)-α, HMGB1, sRAGE, C-reactive protein (CRP) and malondialdehyde (MDA), and lactic acid (LA) were determined and PaO2 and PaCO2 were measured from arterial blood sample. Lung damage was assessed by histopathological. RESULTS: TNF-, IL-6, CRP, HMGB1, MDA, LA levels, histopathologic scores, and HU values of CT were significantly increased and sRAGE levels were decreased in the saline-treated group against normal group (all P<0.05). Papaverine significantly reversed all results regardless of the dose (all P<0.05) and demonstrated inhibition of HMGB1/RAGE interaction through increasing sRAGE levels and suppresses the pro-inflammatory cytokines. CONCLUSION: We concluded that papaverine has ameliorating effects in rat model of ALI.

Evaluation of DeGIR registry data on endovascular treatment of cerebral vasospasm in Germany 2018-2021: an overview of the current care situation. / Auswertung der DeGIR-Registerdaten zur endovaskulären Therapie von zerebralen Vasospasmen in Deutschland 2018­2021: Ein Überblick über die aktuelle Versorgungssituation.

BACKGROUND: Evaluation of endovascular therapies for cerebral vasospasm (CVS) documented in the DeGIR registry from 2018-2021 to analyse the current clinical care situation in Germany. METHODS: Retrospective analysis of the clinical and procedural data on endovascular spasm therapies (EST) documented anonymously in the DeGIR registry. We analysed: pre-interventional findings of CTP and consciousness; radiation dose applied, interventional-technical parameters (local medication, devices, angiographic result), post-interventional symptoms, complications and mortality. RESULTS: 3584 patients received a total of 7628 EST (median age/patient: 53 [range: 13-100, IQR: 44-60], 68.2 % women) in 91 (2018), 92 (2019), 100 (2020) and 98 (2021) centres; 5388 (70.6 %) anterior circulation and 378 (5 %) posterior circulation (both involved in 1862 cases [24.4 %]). EST was performed once in 2125 cases (27.9 %), with a mean of 2.1 EST/patient. In 7476 times, purely medicated EST were carried out (nimodipine: 6835, papaverine: 401, nitroglycerin: 62, other drug not specified: 239; combinations: 90). Microcatheter infusions were documented in 1132 times (14.8 %). Balloon angioplasty (BA) (additional) was performed in 756 EST (9.9 %), other mechanical recanalisations in 154 cases (2 %) and stenting in 176 of the EST (2.3 %). The median dose area product during ET was 4069 cGycm² (drug: 4002/[+]BA: 8003 [p < 0.001]). At least 1 complication occurred in 95 of all procedures (1.2 %) (drug: 1.1 %/[+]BA: 4.2 % [p < 0.001]). Mortality associated with EST was 0.2 % (n = 18). After EST, overall improvement or elimination of CVS was found in 94.2 % of cases (drug: 93.8 %/[+]BA: 98.1 % [p < 0.001]). In a comparison of the locally applied drugs, papaverine eliminated CVS more frequently than nimodipine (p = 0.001). CONCLUSION: EST have a moderate radiation exposure and can be performed with few complications. Purely medicated EST are predominantly performed, especially with nimodipine. With (additional) BA, radiation exposure, complication rates and angiographic results are higher or better. When considering drug EST alone, there is evidence for an advantage of papaverine over nimodipine, but a different group size has to be taken into account. In the analysis of EST, the DeGIR registry data are suitable for answering more specific questions, especially due to the large number of cases; for this purpose, further subgroupings should be sought in the data documentation. KEY POINTS: · In Germany, there are currently no guidelines for the endovascular treatment of cerebral vasospasm following spontaneous subarachnoid hemorrhage.. · In addition to oral nimodipine administration endovascular therapy is used to treat cerebral vasospasm in most hospitals.. · This is the first systematic evaluation of nationwide registry data on endovascular treatment of cerebral vasopasm in Germany.. · This real-world data shows that endovascular treatment for cerebral vasospasm has a moderate radiation exposure and can be performed with few complications overall. With (additional) balloon angioplasty, radiation exposure, complication rates and angiographic therapy results are higher or better.. CITATION FORMAT: · Neumann A, Weber W, Küchler J et al. Evaluation of DeGIR registry data on endovascular treatment of cerebral vasospasm in Germany 2018-2021: an overview of the current care situation. Fortschr Röntgenstr 2023; 195: 1018 - 1026.

INFLUENCE OF PAPAVERINE AND COMMERCIAL DIETARY SUPPLEMENTS ON BLOOD GLUCOSE AND BODY WEIGHT IN OBESE DOGS.

Our experiments showed that papaverine inhibits sugar absorption in vivo as well as in vitro. Papaverine blocks the absorption of sugar both in healthy and diabetic animals. Oral administration of papaverine significantly reduced blood sugar level but after an hour blood sugar level showed tendency to come back to the initial levels that were characteristic for these diabetic dogs. Dietary supplement made of herbal remedies and papaverine has proven to be quite effective in reducing body weight in dogs. For a month, dogs with initial overweight lost on average more than 1 kg (10+%), that is a very good result for their size.

Diluted intracisternal papaverine for microvascular protection of cranial nerves during vestibular schwannoma and cerebello-pontine angle surgery. Commentary and review of the literature.

Vasospasm after resection of skull base tumors is a rare complication that often produces relevant ischemic sequelae. This review of the literature reports a number of published experiences that can help determine the potential causes of vasospasm after cerebello-pontine angle (CPA) tumor and -in particular-vestibular schwannoma (VS) resection, the ways to prevent it, and the methods to obtain the correct diagnosis. The cause appears to be multifactorial and the surgical approach may contribute to the pathogenesis of vasospasm. Neurosurgeons must pay attention to detect possible vasospasm at an early stage of cerebello-pontine. Cerebral blood flow measurement and transcranial Doppler are useful monitoring tools. Intra-operative prevention of vasospasm during CPA tumor resection with papaverine hydrochloride (PPV) seems to play a relevant role. In particular, PPV is a direct-acting vasodilator used to manage vasospasm during various neurosurgical operations. There is large uncertainty about intracisternal PPV dose-related efficacy and side effects. Dilution of PPV in saline prior to application is recommended to avoid complications. In our experience, in line with the literature, we use a pure PPV without excipients 60 mg/2 ml diluted in 20 cc of 0,9% saline solution (0,3%) to prevent Hearing Loss during Posterior Fossa Microvascular Decompression for Typical Trigeminal Neuralgia and other cranial nerves potentially involved during VS and other CPA tumor resection. The aim of this commentary is to analyze and discuss the role of diluted intracisternal PPV for microvascular protection of cranial nerves during CPA tumor surgery.

Papaverine, a promising therapeutic agent for the treatment of COVID-19 patients with underlying cardiovascular diseases (CVDs).

The causative agent of coronavirus disease-2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), enters the host cells via an angiotensin-converting enzyme 2 (ACE2)-mediated endocytosis-dependent manner. Because ACE2 is highly expressed in the heart, SARS-CoV-2 can severely infect heart tissue and arteries, causing acute and chronic damage to the cardiovascular system. Therefore, special attention should be paid to finding appropriate agents to protect this vital system during COVID-19 treatment. Papaverine is a unique vasodilator alkaloid that is clinically used in the treatment of vasospasm. Interestingly, this compound has potent and direct effects on a wide range of viruses, and could also prevent viral exploitation mechanisms of the host cell facilities by inhibiting some cellular signaling pathways such as p38 MAPK. This pathway was recently introduced as a promising target for the treatment of COVID-19. Papaverine also has anti-inflammatory effects which is useful in combating the hyper-inflammatory phase of the COVID-19. Unlike some medications that have severe dosage-restrictions in the treatment of COVID-19 due to cardiac side effects, papaverine is recommended for use in many heart disorders. The ability of papaverine to treat COVID-19 has become more promising when the results of some extensive screenings showed the strong ability of this compound to inhibit the cytopathic effects of SARS-CoV-2 with EC50 of 1.1 µM. Having several therapeutic effects along with desired safety profile raises this hypothesis that papaverine could be a promising compound for the suppression of SARS-CoV-2 and prevention of ischemia/vasoconstriction-related complications in COVID-19 disease, especially in patients with underlying cardiovascular diseases (CVDs).

Intraarterial papaverine for relief of catheter-induced peripheral arterial vasospasm during pediatric cardiac surgery: A randomized double-blind controlled trial.

BACKGROUND: Maintaining the patency of peripheral arterial lines in pediatric patients during surgery can be challenging due to multiple factors, and catheter-related arterial vasospasm is a potentially modifiable cause. Papaverine, a potent vasodilator, improves arterial line patency when used as a continuous infusion in the pediatric intensive care setting, but this method is not convenient during surgery. AIM: Extrapolating from the benefit seen in the intensive care unit, the authors hypothesize that a small-volume intraarterial bolus of papaverine immediately after arterial line placement will reduce vasospasm-related arterial line malfunction. METHODS: This was a prospective, randomized, double-blind study. Patients less than 17 years of age undergoing cardiac surgery were enrolled. Patients were randomized into the heparin or papaverine groups. Immediately after arterial line insertion, an intraarterial bolus of heparin (2 units/ml, 1 ml) or papaverine (0.12 mg/ml, 1 ml) was administered (T1, Figure 1). An optimal waveform was defined as the ease of aspirating a standardized blood sample within 30 s, absence of cavitation when sampling, absence of color change at the catheter site during injection, and presence of a dicrotic notch. The primary outcome evaluated was the presence of an optimal arterial waveform at 5 min after the first randomized dose (T1 + 5 min). The secondary outcomes were the presence of optimal arterial waveform an hour after the first dose and the ability of papaverine to rescue suboptimal waveforms. RESULTS: A total of 100 patients were enrolled in the study. Twelve patients were excluded from the analysis. Complete datasets after randomization were available in 88 patients (heparin group, n = 46; papaverine group, n = 42). At baseline, groups were similar for age, weight, arterial vessel size, and arterial line patency. At T1 + 5 min, an improvement in the waveform characteristics was observed in the papaverine group (heparin,39% [8/46] vs. papaverine, 64% [27/42]; p = .02; odds ratio, 2.8; 95% CI, 1.2 to 6.6, Figure 3, Table 2). At the end of 1 h, both groups showed continued improvement in arterial line patency. After the second dose, a higher number of patients in the heparin group had suboptimal waveforms and were treated with papaverine (heparin,37% [17/46] vs. papaverine,17% [7/42], p = .05). Patients in the heparin group treated with papaverine showed significant improvement in patency (13/17 vs. 3/7, p = .01). No serious adverse events were reported. CONCLUSIONS: In pediatric patients, papaverine injection immediately after peripheral arterial catheter placement was associated with relief of vasospasm and improved initial arterial line patency. Further, papaverine can be used as a rescue to improve and maintain arterial line patency.

The Influence of Oral Drotaverine Administration on Materno-Fetal Circulation during the Second and Third Trimester of Pregnancy.

Background and Objectives: The study aimed to evaluate the effect of the oral administration of drotaverine on maternal and fetal circulation as measured by Doppler sonography in women with a risk of preterm birth. Materials and Methods: The present prospective study was conducted on 34 women with singleton pregnancy at 26-36 weeks of gestation. Doppler flow and pulsatility index (PI) assessments of the umbilical artery, fetal middle cerebral artery, and uterine arteries were performed before and 90-120 min after oral drotaverine administration. Results: There were no statistically significant differences between the Doppler assessment (PI Uma-umbilical artery, MCA-middle cerebral artery, and ltUta-left uterine artery) before drotaverine administration and 90-120 min after oral intake, but there were statistically significant differences between the PI assessment of the rtUta (right uterine artery, 0.55 vs. 0.75, p = 0.05) and the mean of the Uta (0.66 vs. 0.74, p = 0.03). For changes in the CUR (cerebro-umbilical ratio) and % changes in the CUR and mean PI of the Uta, there was no correlation with obstetric history, AFI (amniotic fluid index), gestation week, infertility history, systolic pressure, or diastolic pressure. There was a statistically positive correlation between changes in the CUR and % change in the CUR and body weight and in height. Conclusions: Drotaverine has no statistically significant influence on the MCA and Uma PI. The oral administration of drotaverine has an impact on PI rtUta and the mean PI Uta.

Clinical Efficacy of Intracoronary Papaverine After Nicorandil Administration for Safe and Optimal Fractional Flow Reserve Measurement.

Fractional flow reserve (FFR) is considered the standard for assessment of the physiological significance of coronary artery stenosis. Intracoronary papaverine (PAP) is the most potent vasodilator used for the achievement of maximal hyperemia. However, its use can provoke ventricular tachycardia (VT) due to excessive QT prolongation. We evaluated the clinical efficacy and safety of the administration of PAP after nicorandil (NIC), a potassium channel opener that prevents VT, for optimal FFR measurement.A total of 127 patients with 178 stenoses were enrolled. The FFR values were measured using NIC (NIC-FFR) and PAP (PAP-FFR). We administered PAP following NIC (NIC-PAP). Changes in the FFR and electrogram parameters (baseline versus NIC versus PAP) were assessed and the incidence of arrhythmias after PAP was evaluated. In addition, we analyzed another 41 patients with 51 stenoses by assessing the FFR using PAP before NIC (PAP-NIC). After propensity score matching, the electrogram parameters between 2 groups were compared.The mean PAP-FFR was significantly lower than the mean NIC-FFR (0.82 ± 0.11 versus 0.81 ± 0.11, P < 0.05). The mean baseline-QTc, NIC-QTc, and PAP-QTc values were 425 ± 37 ms1/2, 424 ± 41 ms1/2, and 483 ± 54 ms1/2, respectively. VT occurred in only 1 patient (0.6%). Although PAP induced QTc prolongation (P < 0.05), the PAP-QTc duration was significantly shorter in NIC-PAP compared to PAP-NIC (P < 0.05).The administration of PAP with NIC may induce sufficient hyperemia and prevent fatal arrhythmia through reductions in the PAP-induced QTc prolongation during FFR measurement.

Drotaverine Inhibitor of PDE4: Reverses the Streptozotocin Induced Alzheimer's Disease in Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with decline in memory and cognitive impairments. Phosphodiesterase IV (PDE4) protein, an intracellular cAMP levels regulator, when inhibited act as potent neuroprotective agents by virtue of ceasing the activity of Pro-inflammatory mediators. The complexity of AD etiology has ever since compelled the researchers to discover multifunctional compounds to combat the AD and neurodegeneration. The aim of this study was to probe into role of drotaverine a PDE4 inhibitor in the management of AD. Albino mice were divided into seven groups (n = 10). Group 1 control group received carboxy methyl cellulose (CMC 1 mL/kg), group II diseased group treated with streptozotocin (STZ 3 mg/kg) by intracerebroventricular (ICV) route, group III administered standard drug Piracetam 200 mg/kg and groups IV-VII were given drotaverine (10, 20, 40, and 80 mg/kg i/p respectively). Groups II-VII were given STZ (3 mg/kg, ICV) on 1st and 3rd day of treatment to induce AD. All the groups were given their respective treatments for 23 days. Improvement in learning and memory was evaluated by using behavioral tests like open field test, elevated plus maze test, Morris water maze test and passive avoidance test. Furthermore, brain levels of biochemical markers of oxidative stress, neurotransmitters, ß-amyloid and tau protein were also measured. Drotaverine showed statistically significant dose dependent improvement in behavioral and biochemical markers of AD: the maximum response was achieved at a dose level of 80 mg/kg. The Study concluded that drotaverine ameliorates cognitive impairment and as well as exhibited modulated the brain levels of neurotransmitters.

Papaverine Perfusion via the Aortic Root before Heart Re-beating Alleviates Myocardial Injury after Heart Valve Replacement.

AIM: Myocardial injury is inevitable during cardiac surgical procedures and reducing myocardial injury in patients with CPB surgery is the focus of current research. Papaverine is accepted as an ideal coronary vasodilator. This study was to estimate the effect of papaverine perfusion via the aortic root before heart re-beating on patients undergoing heart valve replacement. METHODS: All the patients enrolled in this study were admitted during 2013-2015. The basic clinical characteristics of the patients preoperative, intraoperative, and postoperative were compared. The immunochemistry assays and enzyme-linked immunosorbent assay (ELISA) were performed to assess the serum biomarkers. Western blot and immunohistochemistry (IHC) were undertaken to detect the expression of associated proteins. RESULTS: Patients receiving papaverine perfusion via the aortic root before heart re-beating during heart valve replacement surgery under CPB showed less extracorporeal circulation time and CPB time, higher automatic heartbeat recovery rate, less mechanical ventilation time, shorter ICU and in-hospital stay, less leak of cTnI and CK-MB, and weaker inflammatory response than the patients in control group. In addition, the protein expression of IL-6/8/10 and TNF-α was reduced by the perfusion of papaverine. The IHC staining for NFκB was depressed in papaverine group. CONCLUSION: Papaverine perfusion presented positive effect during valve replacement; this cardioprotective effect may be associated with inhibition of inflammatory response and NF-κB. These findings provided new clues for reduction of myocardial injury during cardiac surgery.

Attenuation of neurobehavioural abnormalities by papaverine in prenatal valproic acid rat model of ASD.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Phosphodiesterase-10A (PDE10A) inhibition has shown to provide benefits in various brain conditions. We investigated the role of a PDE10A inhibitor, papaverine on core phenotypes in prenatal-valproic acid (Pre-VPA) model of ASD. In order to identify probable mechanisms involved, the effects on several protein markers of neuronal function such as, neurogenesis-DCX, neuronal survival-BDNF, synaptic transmission-synapsin-IIa, neuronal transcription factor-pCREB, neuronal inflammation (IL-6, IL-10 and TNF-α) and neuronal oxidative stress (TBARS and GSH) were studied in frontal cortex, cerebellum, hippocampus and striatum. Pre-VPA induced impairments in social behaviour, presence of repetitive behaviour, hyper-locomotion, anxiety, and diminished nociception were studied in male Albino Wistar rats. Administration of papaverine to Pre-VPA animals resulted in improvements of social behaviour, corrected repetitive behaviour, anxiety, locomotor, and nociceptive changes. Also, papaverine resulted in a significant increase in the levels of BDNF, synapsin-IIa, DCX, pCREB, IL-10 and GSH along with significant decrease in TNF-α, IL-6 and TBARS in different brain areas of Pre-VPA group. Finally, high association between behavioural parameters and biochemical parameters was observed upon Pearson's correlation analysis. Papaverine, administration rectified core behavioural phenotype of ASD, possibly by altering protein markers associated with neuronal survival, neurogenesis, neuronal transcription factor, neuronal transmission, neuronal inflammation, and neuronal oxidative stress. Implicating PDE10A as a possible target for furthering our understanding of ASD phenotypes.

Comprehensive Treatment of Single Finger Frostbite: A Case Study.

Third- and fourth-degree frostbites usually result in loss of skin and tissue requiring amputation, and scarring. The 3- to 6-week waiting period is often necessary to determine the severity of the lesion. This period is also a critical time for the rescue of frostbitten tissue. This patient was a 30-year-old man who developed frostbite of his right index finger. He presented to our hospital 4 hours after injury with loss of sensation on the whole index finger and early signs of necrosis. The patient received a series of comprehensive treatments, including fasciotomy, injection of papaverine hydrochloride, baking lamp irradiation, and negative pressure treatment. At the time of discharge, he had re-epithelialization of the index finger by 21 days after injury. The conclusion of this paper is that the comprehensive treatments combined with negative pressure wound treatment has certain clinical application value for the rescue of deep frostbite tissues.

Papaverine ameliorates prenatal alcohol-induced experimental attention deficit hyperactivity disorder by regulating neuronal function, inflammation, and oxidative stress.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with complex aetiology and phenotypes. Phosphodiesterase10A (PDE10A) has been shown to provide benefits in various brain conditions. We investigated the role of papaverine, a selective PDE10A inhibitor on core phenotypes in prenatal alcohol exposure (PAE) model of ADHD. In order to identify probable mechanisms involved, the effects on several protein markers of neuronal function such as, neuronal survival-BDNF, neuronal transcription factor-pCREB, brain inflammation (IL-6, IL-10, and TNF-α), and brain oxidative stress (TBARS and GSH) were studied in frontal cortex, cerebellum, and striatum. PAE resulting hyper-locomotion, inattention, and anxiety were studied by the use of open-field, y-maze, and elevated plus maze, respectively. Administration of papaverine (15/30 mg kg-1 ) to PAE group of animals resulted in amelioration of hyperactivity, inattention, and anxiety. Also, papaverine resulted in significant increase of the levels in BDNF, pCREB, IL-10, and GSH along with significant decrease of TNF-α, IL-6, and TBARS in different brain areas of PAE group. Papaverine, a selective PDE10A inhibitor rectified behavioural phenotypes associated with ADHD, possibly by altering the protein markers associated with neuronal survival, neuronal transcription factor, brain inflammation, and brain oxidative stress. Implicating PDE10A as a possible target for furthering our understanding of ADHD phenotypes.

Antinociceptive activity of the novel RAGE inhibitor, papaverine, in a mouse model of chronic inflammatory pain.

Extracellular high-mobility group box 1 (HMGB1) is known to mediate the inflammatory response through pattern recognition receptors, including the receptor for advanced glycation end products (RAGE) or the toll-like receptors (TLRs). The aim of the present study was to investigate whether papaverine, a novel RAGE inhibitor, could suppress inflammatory pain in mice after several time points, which was induced by the injection of complete Freund's adjuvant (CFA). We also investigated the influence of redox modulation during a state of chronic inflammatory pain. Although papaverine did not suppress CFA-induced mechanical allodynia on Day 7, papaverine significantly suppressed CFA-induced mechanical allodynia on Days 14 and 28. In contrast, the radical scavenger N-tert-Butyl-α-phenylnitrone (PBN) suppressed mechanical allodynia in mice on Days 7 and 14, but not on Day 28. We demonstrated that the RAGE inhibitor improves mechanical allodynia in chronic inflammatory conditions. Moreover, we also found that high levels of reactive oxygen species (ROS) contributed to the early phase of CFA-induced mechanical allodynia. Precisely, lower ROS levels contributed to the inflammatory pain response via the all-thiol HMGB1/RAGE signaling pathway during the chronic state. These findings led us to propose that ROS levels modulate RAGE and/or TLR4-mediated inflammatory allodynia by regulating the concentrations of disulfide HMGB1 or all-thiol HMGB1.

Comparison of the Apoptotic Effects of Topically Applied Papaverine, Diltiazem, and Nitroprusside to Internal Thoracic Artery.

OBJECTIVE: To detect and to compare the apoptotic effects of intraoperatively topically applied diltiazem, papaverine, and nitroprusside. METHODS: Internal thoracic artery segments of ten patients were obtained during coronary bypass grafting surgery. Each internal thoracic artery segment was divided into four pieces and immersed into four different solutions containing separately saline (Group S), diltiazem (Group D), papaverine (Group P), and nitroprusside (Group N). Each segment was examined with both hematoxylin-eosin and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in order to determine and quantify apoptosis. RESULTS: Apoptotic cells were counted in 50 microscopic areas of each segment. No significant difference was observed among the four groups according to hematoxylin-eosin staining. However, the TUNEL method revealed a significant increase in mean apoptotic cells in the diltiazem group when compared with the other three groups (Group S=4.25±1.4; Group D=13.31±2.8; Group N=9.48±2.09; Group P=10.75±2.37). The differences between groups were significant (P=0.0001). No difference was observed between the samples of the diabetic and non-diabetic patients in any of the study groups. CONCLUSION: The benefit of topically applied vasodilator drugs must outweigh the potential adverse effects. In terms of apoptosis, diltiazem was found to have the most deleterious effects on internal thoracic artery graft segments. Of the analyzed medical agents, nitroprusside was found to have the least apoptotic activity, followed by papaverine. Diabetes did not have significant effect on the occurrence of apoptosis in left internal thoracic artery grafts.

Comparison of the apoptotic effects of topically applied papaverine, diltiazem, and nitroprusside to internal thoracic artery

Abstract Objective: To detect and to compare the apoptotic effects of intraoperatively topically applied diltiazem, papaverine, and nitroprusside. Methods: Internal thoracic artery segments of ten patients were obtained during coronary bypass grafting surgery. Each internal thoracic artery segment was divided into four pieces and immersed into four different solutions containing separately saline (Group S), diltiazem (Group D), papaverine (Group P), and nitroprusside (Group N). Each segment was examined with both hematoxylin-eosin and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method in order to determine and quantify apoptosis. Results: Apoptotic cells were counted in 50 microscopic areas of each segment. No significant difference was observed among the four groups according to hematoxylin-eosin staining. However, the TUNEL method revealed a significant increase in mean apoptotic cells in the diltiazem group when compared with the other three groups (Group S=4.25±1.4; Group D=13.31±2.8; Group N=9.48±2.09; Group P=10.75±2.37). The differences between groups were significant (P=0.0001). No difference was observed between the samples of the diabetic and non-diabetic patients in any of the study groups. Conclusion: The benefit of topically applied vasodilator drugs must outweigh the potential adverse effects. In terms of apoptosis, diltiazem was found to have the most deleterious effects on internal thoracic artery graft segments. Of the analyzed medical agents, nitroprusside was found to have the least apoptotic activity, followed by papaverine. Diabetes did not have significant effect on the occurrence of apoptosis in left internal thoracic artery grafts.

Papaverine inhibits α-synuclein aggregation by modulating neuroinflammation and matrix metalloproteinase-3 expression in the subacute MPTP/P mouse model of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor impairments. Most PD drugs act by improving motor impairments, whereas very few drugs that efficiently recover PD-related neuropathological features, particularly α-synuclein-related toxicity, have been developed. In this study, we found that papaverine (PAP) attenuated behavioral deficits and protected against nigrostriatal dopaminergic degeneration in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/P) mouse model of PD. Histological analysis of tissue dissected from mice sacrificed nearly 3 weeks after the completion of treatment revealed that PAP significantly ameliorated microglia/astrocyte activation in the striatum and substantia nigra of MPTP/P-treated mice. In addition, PAP diminished α-synuclein expression and aggregation in this model. Furthermore, PAP inhibited the phosphorylation of α-synuclein at serine 129, which may underlie the observed reduction in α-synuclein aggregation. PAP also reduced the expression of matrix metalloproteinase-3 (MMP-3), and the MMP3-positive area co-labeled with thioflavin-S. Taken together, our data suggest that PAP inhibits dopaminergic neuronal cell death and α-synuclein aggregation by suppressing neuroinflammation and MMP-3 expression in the subacute MPTP/P mouse model of PD. Accordingly, PAP may be a promising drug for the treatment of PD.

Pluripotent anti-inflammatory immunomodulatory effects of papaverine against cerebral ischemic-reperfusion injury.

The mechanism of the papaverine (PV) for the treatment of cerebral ischemia remains unclear. A total of 42 mice induced with focal cerebral ischemia were randomly divided into three groups: PV,baicalin (BA)and vehicle group. Both PV and BA could significantly reduce the ischemic infarct volume (P < 0.05). Pathway enrichment analysis was performed on MetaCore™ to search the molecular pathways associated with the gene expression profile of PV, compared with vehicle and BA. Compared with vehicle, we found that 60% of the top 10 pathways in PV group were related to immune response. The top 10 biological processes of the targeted pathways were mainly related to the multiple immunomodulatory process of neuro-vascular inflammation, including immune_Th17-deried cytokins, regulation of angiogenesis, cell adhesion_Leucocyte chemotaxis, antigen presentation, cell adhesion_synaptic contact, and inflammation related to Amphoterin signaling. Moreover, compared with BA, 17 pathways of PV were identified, and 58.82% (10/17) were also related to immune response, especially, half of the top 10 pathways with the lower p-value. In these top 10 pathways, 4 were the cytokine-mediated signaling pathways, which play key role in inflammation, like IL-17 signaling pathways with the activation of G-CSF,IL-23,RANKL, p38MAPK and NF-κB.These findings indicate that PV may be an efficacious pluripotent anti-inflammatory agent against cerebral ischemic-reperfusion injury by targeting on multiple immunomodulatory process of neuro-vascular inflammation.

Local Intra-arterial Vasodilator Infusion in Non-Occlusive Mesenteric Ischemia Significantly Increases Survival Rate.

PURPOSE: To investigate the outcome of local intra-arterial papaverine infusion therapy in patients with non-occlusive mesenteric ischemia (NOMI), and factors influencing survival, in comparison with a conservative approach. METHODS: From 2013 to 2019, patients with NOMI confirmed by imaging were included in a retrospective two-center study. According to different in-house standard procedures, patients were treated in each center either conservatively or interventionally by a standardized local infusion of intra-arterial papaverine into the splanchnic arteries. Thirty-day mortality and factors influencing the outcome, such as different demographics and laboratories, were compared between groups using Kaplan-Meier survival analysis and Cox regression, respectively. RESULTS: A total of 66 patients with NOMI were included, with n = 35 treated interventionally (21 males, mean age 67.7 ± 12.3 years) and n = 31 treated conservatively (18 females, mean age 71.6 ± 9.6 years). There was a significant difference in 30-day mortality between the interventional (65.7%; 12/35 survived) and the conservative group (96.8%; 1/31 survived) (hazard ratio 2.44; P = 0.005). Thresholds associated with a worse outcome of interventional therapy are > 7.68 mmol/l for lactate, < 7.31 for pH and < - 4.55 for base excess. CONCLUSION: Local intra-arterial papaverine infusion therapy in patients with NOMI significantly increases survival rate in comparison with conservative treatment. High lactate levels, low pH and high base excess, and high demand for catecholamines are associated with a poor outcome. LEVEL OF EVIDENCE: Level III.