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.

Vasodilating Effects of Antispasmodic Agents and Their Cytotoxicity in Vascular Smooth Muscle Cells and Endothelial Cells-Potential Application in Microsurgery.

This study aimed to elucidate the vasodilatory effects and cytotoxicity of various vasodilators used as antispasmodic agents during microsurgical anastomosis. Rat smooth muscle cells (RSMCs) and human coronary artery endothelial cells (HCAECs) were used to investigate the physiological concentrations and cytotoxicity of various vasodilators (lidocaine, papaverine, nitroglycerin, phentolamine, and orciprenaline). Using a wire myograph system, we determined the vasodilatory effects of each drug in rat abdominal aortic sections at the concentration resulting in maximal vasodilation as well as at the surrounding concentrations 10 min after administration. Maximal vasodilation effect 10 min after administration was achieved at the following concentrations: lidocaine, 35 mM; papaverine, 0.18 mM; nitroglycerin, 0.022 mM; phentolamine, 0.11 mM; olprinone, 0.004 mM. The IC50 for lidocaine, papaverine, and nitroglycerin was measured in rat abdominal aortic sections, as well as in RSMCs after 30 min and in HCAECs after 10 min. Phentolamine and olprinone showed no cytotoxicity towards RSMCs or HCAECs. The concentrations of the various drugs required to achieve vasodilation were lower than the reported clinical concentrations. Lidocaine, papaverine, and nitroglycerin showed cytotoxicity, even at lower concentrations than those reported clinically. Phentolamine and olprinone show antispasmodic effects without cytotoxicity, making them useful candidates for local administration as antispasmodics.

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.

Papaverine loaded injectable and thermosensitive hydrogel system for improving survival of rat dorsal skin flaps.

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.

Current status of intracavernosal injection therapy in erectile dysfunction.

INTRODUCTION: Erectile dysfunction (ED) is defined as the inability to attain and/or maintain a penile erection. The first introduction of intracavernosal injection (ICI) for the treatment of erectile failure was in 1982 by Virag who reported the positive effects of papaverine on erectile tissue, followed by Brindley concurrently conducting research on ICI therapy with alpha-blockade. ICI remains a viable option for the treatment of ED, even after FDA approval of phosphodiesterase type 5 inhibitors in 1998. The American Urological Association (AUA) and the European Association of Urology (EAU) both recommend ICI as a second-line therapy for the treatment of ED. We herein provide an overview of the current state of ICI therapy for the treatment of ED. AREAS COVERED: We performed a literature review from 1977-2022, using PubMed and the current AUA and EAU guidelines to discuss the current state of ICI for the treatment of ED. EXPERT OPINION: Although other oral agents are considered first line for the treatment of ED, the current guidelines and literature demonstrate that ICI is a safe and effective option for patients; however, careful patient selection and counseling should be performed to maximize the effectiveness and safety of this ED treatment.

Papaverine: A Miraculous Alkaloid from Opium and Its Multimedicinal Application.

The pharmacological actions of benzylisoquinoline alkaloids are quite substantial, and have recently attracted much attention. One of the principle benzylisoquinoline alkaloids has been found in the unripe seed capsules of Papaver somniferum L. Although it lacks analgesic effects and is unrelated to the compounds in the morphine class, it is a peripheral vasodilator and has a direct effect on vessels. It is reported to inhibit the cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) phosphodiesterase in smooth muscles, and it has been observed to increase intracellular levels of cAMP and cGMP. It induces coronary, cerebral, and pulmonary artery dilatation and helps to lower cerebral vascular resistance and enhance cerebral blood flow. Current pharmacological research has revealed that papaverine demonstrates a variety of biological activities, including activity against erectile dysfunction, postoperative vasospasms, and pulmonary vasoconstriction, as well as antiviral, cardioprotective, anti-inflammatory, anticancer, neuroprotective, and gestational actions. It was recently demonstrated that papaverine has the potential to control SARS-CoV-2 by preventing its cytopathic effect. These experiments were carried out both in vitro and in vivo and require an extensive understanding of the mechanisms of action. With its multiple mechanisms, papaverine can be considered as a natural compound that is used to develop therapeutic drugs. To validate its applications, additional research is required into its precise therapeutic mechanisms as well as its acute and chronic toxicities. Therefore, the goal of this review is to discuss the major studies and reported clinical studies looking into the pharmacological effects of papaverine and the mechanisms of action underneath these effects. Additionally, it is recommended to conduct further research via significant pharmacodynamic and pharmacokinetic studies.

Blood flow characteristics of the bilateral internal thoracic artery: implications of optimal graft configuration for coronary artery bypass grafting to maximize blood supply.

PURPOSE: There is controversy regarding which internal thoracic artery (ITA) should be anastomosed to the left anterior descending artery (LAD). Here, we propose an optimal graft design based on measurement of blood flow in the ITA. METHODS: Sixty-one patients (53 men, median age 68 [62-75] years) undergoing first elective coronary artery bypass grafting were enrolled. Fifty-seven left ITAs (LITAs) and 28 right ITAs (RITAs) were harvested in either a semi-skeletonized manner using a harmonic scalpel covered with papaverine-soaked gauze (group-A, n = 45) or a fully skeletonized manner using electrocautery with intraluminal papaverine injection (group-B, n = 41). Free flow of 33 ITAs was measured after pharmacological dilatation and in situ ITA-LAD flow was measured in 59 patients by transit-time flowmetry. RESULTS: RITA and LITA free flow were 147.0 [87.8-213.0] mL/min and 108.0 [90.0-144.0] mL/min, respectively (P = 0.199). The group-B had significantly higher ITA free flow (135.0 [102.0-171.0] mL/min) than group-A (63.0 [36.0-96.0] mL/min, P = 0.009). In 13 patients with bilateral ITA harvesting, free flow of the RITA (138.0 [79.5-204.0] mL/min) was also significantly higher than the LITA (102.0 [81.0-138.0] mL/min, P = 0.046). There was no significant difference between RITA and LITA flow anastomosed to the LAD. The group-B had significantly higher ITA-LAD flow (56.5 [32.3-73.6] mL/min) than group-A (40.9 [20.1-53.7] mL/min, P = 0.023). CONCLUSION: RITA provides significantly higher free flow than LITA but similar blood flow to the LAD. Full skeletonization with intraluminal papaverine injection maximizes both free flow and ITA-LAD flow.

An insight from computational approach to explore novel, high-affinity phosphodiesterase 10A inhibitors for neurological disorders.

The enzyme Phosphodiesterase 10A (PDE10A) plays a regulatory role in the cAMP/protein kinase A (PKA) signaling pathway by means of hydrolyzing cAMP and cGMP. PDE10A emerges as a relevant pharmacological drug target for neurological conditions such as psychosis, schizophrenia, Parkinson's, Huntington's disease, and other memory-related disorders. In the current study, we subjected a set of 1,2,3-triazoles to be explored as PDE10A inhibitors using diverse computational approaches, including molecular docking, classical molecular dynamics (MD) simulations, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations, steered MD, and umbrella sampling simulations. Molecular docking of cocrystallized ligands papaverine and PFJ, along with a set of in-house synthesized molecules, suggested that molecule 3i haded the highest binding affinity, followed by 3h and 3j. Furthermore, the structural stability studies using MD and MM-PBSA indicated that the 3h and 3j formed stable complexes with PDE10A. The binding free energy of -240.642 kJ/mol and -201.406 kJ/mol was observed for 3h and 3j, respectively. However, the cocrystallized ligands papaverine and PFJ exhibited comparitively higher binding free energy values of -202.030 kJ/mol and -138.764 kJ/mol, respectively. Additionally, steered MD and umbrella sampling simulations provided conclusive evidence that the molecules 3h and 3j could be exploited as promising candidates to target PDE10A.Communicated by Ramaswamy H. Sarma.

The Detailed Pharmacodynamics of the Gut Relaxant Effect and GC-MS Analysis of the Grewia tenax Fruit Extract: In Vivo and Ex Vivo Approach.

The study was performed to assess and rationalize the traditional utilization of the fruit part of Grewia tenax (G. tenax). The phytoconstituents present in the methanolic extract were analyzed using Gas-Chromatography-Mass Spectroscopy (GC-MS), while the anti-diarrheal activity was investigated in the Swiss albino mice against castor oil-provoked diarrhea in vivo. The antispasmodic effect and the possible pharmacodynamics of the observed antispasmodic effect were determined in an isolated rat ileum using the organ bath setup as an ex vivo model. GC-MS findings indicate that G. tenax is rich in alcohol (6,6-dideutero-nonen-1-ol-3) as the main constituent (20.98%), while 3-Deoxy-d-mannoic lactone (15.36%) was detected as the second major constituents whereas methyl furfural, pyranone, carboxylic acid, vitamin E, fatty acid ester, hydrocarbon, steroids, sesquiterpenes, phytosterols, and ketones were verified as added constituents in the methanolic extract. In mice, the orally administered G. tenax inhibited the diarrheal episodes significantly (p < 0.05) at 200 mg/kg (40% protection), and this protection was escalated to 80% with the next higher dose of 400 mg/kg. Loperamide (10 mg/kg), a positive control drug, imparted 100% protection, whereas no protection was shown by saline. In isolated rat ileum, G. tenax completely inhibited the carbamylcholine (CCh; 1 µM) and KCl (high K+; 80 mM)-evoked spasms in a concentrations-mediated manner (0.03 to 3 mg/mL) by expressing equal potencies (p > 0.05) against both types of evoked spasms, similar to papaverine, having dual inhibitory actions at phosphodiesterase enzyme (PDE) and Ca2+ channels (CCB). Similar to papaverine, the inhibitory effect of G. tenax on PDE was further confirmed indirectly when G. tenax (0.1 and 0.3 mg/mL) preincubated ileal tissues shifted the isoprenaline-relaxation curve towards the left. Whereas, pre-incubating the tissue with 0.3 and 1 mg/mL of G. tenax established the CCB-like effect by non-specific inhibition of CaCl2−mediated concentration-response curves towards the right with suppression of the maximum peaks, similar to verapamil, a standard CCB. Thus, the present investigation revealed the phytochemical constituents and explored the detailed pharmacodynamic basis for the curative use of G. tenax in diarrhea and hyperactive gut motility disorders.

The Biological Relevance of Papaverine in Cancer Cells.

Papaverine (PPV), a benzylisoquinoline alkaloid, extracted from the Papaverine somniferum plant, is currently in clinical use as a vasodilator. Research has shown that PPV inhibits phosphodiesterase 10A (PDE10A,) resulting in the accumulation of cyclic adenosine 3', 5'-monophosphate (cAMP) that affects multiple downstream pathways, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), a mammalian target of rapamycin (mTOR) and vascular endothelial growth factor (VEGF). The accumulation of cAMP can further affect mitochondrial metabolism through the activation of protein kinase A (PKA), which activates the mitochondrial complex I. Literature has shown that PPV exerts anti-proliferative affects in several tumorigenic cell lines including adenocarcinoma alveolar cancer (A549) and human hepatoma (HepG-2) cell lines. Cell cycle investigations have shown varying results with the effects dependent on concentration and cell type with data suggesting an increase in cells occupying the sub-G1 phase, which is indicative of cell death. These results suggest that PPV may be a beneficial compound to explore for the use in anticancer studies. More insight into the effects of the compound on cellular and molecular mechanisms is needed. Understanding the effects PPV may exert on tumorigenic cells may better researchers' understanding of phytomedicines and the effects of PPV and PPV-derived compounds in cancer.

Natural Radiosensitizers in Radiotherapy: Cancer Treatment by Combining Ionizing Radiation with Resveratrol.

Conventional cancer treatment is mainly based on the surgical removal of the tumor followed by radiotherapy and/or chemotherapy. When surgical removal is not possible, radiotherapy and, less often, chemotherapy is the only way to treat patients. However, despite significant progress in understanding the molecular mechanisms of carcinogenesis and developments in modern radiotherapy techniques, radiotherapy (alone or in combination) does not always guarantee treatment success. One of the main causes is the radioresistance of cancer cells. Increasing the radiosensitivity of cancer cells improves the processes leading to their elimination during radiotherapy and prolonging the survival of cancer patients. In order to enhance the effect of radiotherapy in the treatment of radioresistant neoplasms, radiosensitizers are used. In clinical practice, synthetic radiosensitizers are commonly applied, but scientists have recently focused on using natural products (phytocompounds) as adjuvants in radiotherapy. In this review article, we only discuss naturally occurring radiosensitizers currently in clinical trials (paclitaxel, curcumin, genistein, and papaverine) and those whose radiation sensitizing effects, such as resveratrol, have been repeatedly confirmed by many independent studies.

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).

In Vitro Effects of Papaverine on Cell Migration and Vascular Endothelial Growth Factor in Cancer Cell Lines.

Papaverine (PPV) is a benzylisoquinoline alkaloid isolated from Papaver somniferum that exerts antiproliferative activity. However, several questions remain regarding the biochemical pathways affected by PPV in tumourigenic cells. In this study, the influence of PPV on cell migration (light microscopy), expression of vascular endothelial growth factor (VEGF) B, VEGF R1, VEGF R2, and phosphorylated focal adhesion kinase (pFAK) were investigated using spectrophotometry in MDA-MB-231-, A549- and DU145 cell lines. The migration assay revealed that, after 48 h, PPV (100 µM) reduced cell migration to 81%, 91%, and 71% in MDA-MB-231-, A549-, and DU145 cells, respectively. VEGF B expression was reduced to 0.79-, 0.71-, and 0.73-fold after 48 h of exposure to PPV in MDA-MB-231-, A549- and DU145 cells, while PPV exposure of 48 h increased VEGF R1 expression in MDA-MB-231- and DU145 cells to 1.38 and 1.46. A fold decrease in VEGF R1 expression was observed in A549 cells to 0.90 after exposure to 150 µM. No statistically significant effects were observed on VEGF R2- and FAK expression after exposure to PPV. This study contributes to the understanding of the effects of a phytomedicinal alkaloid compound in cancer cells and may provide novel approaches to the application of non-addictive alkaloids.

GC-MS Analysis and In Vivo and Ex Vivo Antidiarrheal and Antispasmodic Effects of the Methanolic Extract of Acacia nilotica.

This present study evaluated and rationalized the medicinal use of the fruit part of Acacia nilotica methanolic extract. The phytochemicals were detected using gas chromatography−mass spectrometry (GC−MS) while the in vivo antidiarrheal test was done using Swiss albino mice. To determine the details of the mechanism(s) involved in the antispasmodic effect, isolated rat ileum was chosen using different ex vivo assays by maintaining a physiological environment. GC−MS results showed that A. nilotica contained pyrogallol as the major polyphenol present (64.04%) in addition to polysaccharides, polyphenol, amino acid, steroids, fatty acid esters, and triterpenoids. In the antidiarrheal experiment, A. nilotica inhibited diarrheal episodes in mice significantly (p < 0.05) by 40% protection of mice at 200 mg/kg, while 80% protection was observed at 400 mg/kg by the orally administered extract. The highest antidiarrheal effect was observed with loperamide (p < 0.01), used as a control drug. In the ex vivo experiments, A. nilotica inhibited completely in increasing concentrations (0.3 to 10 mg/mL) the carbachol (CCh; 1 µM) and high K+ (80 mM)-evoked spasms in ileum tissues at equal potencies (p > 0.05), similar to papaverine, a dual inhibitor of the phosphodiesterase enzyme (PDE) and Ca++ channels. The dual inhibitory-like effects of A. nilotica on PDE and Ca++ were further validated when A. nilotica extract (1 and 3 mg/mL)-pre-incubated ileum tissues potentiated and shifted isoprenaline relaxation curves towards lower doses (leftward), similar to papaverine, thus confirming the PDE inhibitory-like mechanism whereas its CCB-like effect of the extract was confirmed at 3 and 5 mg/mL by non-specific inhibition of CaCl2-mediated concentration response curves towards the right with suppression of the maximum peaks, similar to verapamil, used as standard CCB. Thus, this study characterized the chemical composition and provides mechanistic support for medicinal use of A. nilotica in diarrheal and hyperactive gut motility disorders.

Effect of Papaverine on Renal Artery Blood Flow during Robot-Assisted Partial Nephrectomy: A Randomized Controlled Study.

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 m2 versus 85.9 ± 15.8 mL/min/1.73 m2, 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.

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.

Grainyhead 1 acts as a drug-inducible conserved transcriptional regulator linked to insulin signaling and lifespan.

Aging is impacted by interventions across species, often converging on metabolic pathways. Transcription factors regulate longevity yet approaches for their pharmacological modulation to exert geroprotection remain sparse. We show that increased expression of the transcription factor Grainyhead 1 (GRH-1) promotes lifespan and pathogen resistance in Caenorhabditis elegans. A compound screen identifies FDA-approved drugs able to activate human GRHL1 and promote nematodal GRH-1-dependent longevity. GRHL1 activity is regulated by post-translational lysine methylation and the phosphoinositide (PI) 3-kinase C2A. Consistently, nematodal longevity following impairment of the PI 3-kinase or insulin/IGF-1 receptor requires grh-1. In BXD mice, Grhl1 expression is positively correlated with lifespan and insulin sensitivity. In humans, GRHL1 expression positively correlates with insulin receptor signaling and also with lifespan. Fasting blood glucose levels, including in individuals with type 2 diabetes, are negatively correlated with GRHL1 expression. Thereby, GRH-1/GRHL1 is identified as a pharmacologically malleable transcription factor impacting insulin signaling and lifespan.

Assessment of encrustation and physicochemical properties of poly(lactide-glycolide) - Papaverine hydrochloride coating on ureteral double-J stents after long-term flow of artificial urine.

Implantation of ureteral stents is associated with inconvenience for the patient, which is related to the natural ability of the ureter to contract. The most frequently used solution is the systemic administration of a diastolic drug, which has a relaxing effect on smooth muscle cells and decreases inconvenience. Current interdisciplinary research aimed at reducing the complications after the implantation of ureteral stents used in the treatment of upper urinary tracts with regard to infection, initiation of encrustation, and fragmentation of stents, and patient pain has not been resolved. This study presents the results of research regarding the impact of a biodegradable coating with the active substance on the physical and chemical properties of ureteral stents used in the treatment of the upper urinary tract. The surface of polyurethane double-J stents was coated with poly(lactide-glycolide) (PLGA) 85/15 loaded with papaverine hydrochloride (PAP) with diastolic properties. The coating for ureteral stents has been designed for short-term implantation. The effect of the coating on the process of encrustation and PAP release by the dynamic in vitro model with artificial urine (AU) up to 30 days was evaluated. The influence of AU on the physical and chemical properties of ureteral stents was determined. As part of the study, surface structure and topography researches; chemical composition analyses using X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, and wetting; and surface roughness studies of both PUR stents and coated stents were carried out. The proposed biodegradable PLGA+PAP coating is characterized by controlled drug release, while optimal physicochemical properties does not increase the encrustation process.

Specific phosphodiesterase type-10 inhibitor, papaverine, added after the cooling period improves canine sperm quality.

The use of chilled semen has gained increasing interest in canine reproductive services. The addition of phosphodiesterase (PDE) inhibitors that increase the intracellular cyclic adenosine monophosphate levels may improve sperm motility. The purpose of this study was to examine the quality of sperm under the effect of the specific PDE-10 inhibitor (papaverine) added after storage for 1, 2, and 3 days at 5 °C. The ejaculates were obtained from 5 healthy Beagle dogs by digital manipulation. After collection, ejaculates were pooled, extended and cooled at 5 °C during 3 days. Sperm parameters were tested 30 min after the addition of different papaverine (PA) concentrations: 0, 5, 10 and 20 µM. Sperm motility (CASA), viability (PI/FITC-PNA) and capacitation status (chlortetracycline assay) were evaluated. The results showed that the addition of PA has no effect on sperm samples at day 0. However, concentrations of 5 and 10 µM increased (p < .05) sperm motility kinetics and viability significantly compared to the control at day 1, day 2 and day 3 of cooling. The addition of 20 µM PA decreased (p < .05) sperm quality parameters significantly and increased the percentage of capacitated/acrosome-reacted spermatozoa. In conclusion, the addition of 5 and 10 µM PA concentrations after cooled storage improved canine sperm quality.

The Efficacy of Hydrodilatation for the Prevention of Vasospasm following Microsurgical Anastomosis.

BACKGROUND: Vasospasm is a major problem following microsurgical reconstruction which can result in the partial or complete loss of the flap tissue. The aim of this study was to investigate the efficiency of hydrodilatation for the prevention of vasospasm. METHODS: Thirty male Wistar rats were used for this experimental study. Femoral arteries of were exposed, photographed, and transected. In group 1, group 2, and group 3 papaverine solution, hydrodilatation, and minimal mechanical dilatation (control group) was performed, respectively. The anastomosis was completed and the arteries were photographed again 10 minutes after completion of the anastomosis. Following 7-day period samples for transmission electron microscopy (TEM) and light microscopy were obtained. RESULTS: The mean vessel diameters prior to transection were 0.43, 0.45, and 0.52 mm in the papaverine, hydrodilatation, and control groups, respectively. The mean vessel diameter 10 minutes following the completion of anastomosis was 0.76, 0.75, and 0.51 mm in the papaverine, hydrodilatation, and control groups, respectively. Median score for papaverine group regarding histological parameters of regular endothelial lining and lumen, neutrophil infiltration, vascular congestion, and edema in tunica adventitia was 2, 3, 2, and 3 positive, respectively. Median score for the papaverine group regarding histological parameters of regular endothelial lining and lumen, neutrophil infiltration, vascular congestion, and edema in tunica adventitia was 3, 3, 3, and 3 positive, respectively. All the histological scores were negative in the control group. The difference between the control group and the experiment groups 1 and 2 was significant regarding all four histological parameters (p < 0.05). CONCLUSION: Hydrodilatation and papaverine application were both effective in preventing vasospasm following microsurgical intervention but papaverine caused slightly less damage to the endothelial lining and less edema in the tunica adventitia when compared with the hydrodilatation. Hydrodilatation group showed a vasodilatory effect that was statistically similar to that of papaverine, which has a proven efficacy.