Association between Postoperative Adjuvant Vasodilator Therapy and In-Hospital Mortality for Non-Occlusive Mesenteric Ischemia: A Nationwide Observational Study.

BACKGROUND: Although several clinical guidelines recommend vasodilator therapy for non-occlusive mesenteric ischemia (NOMI) and immediate surgery when bowel necrosis is suspected, these recommendations are based on limited evidence. METHODS: In this retrospective nationwide observational study, we used information from the Japanese Diagnosis Procedure Combination inpatient database from July 2010 to March 2018 to identify patients with NOMI who underwent abdominal surgeries on the day of admission. We compared patients who received postoperative vasodilator therapy (vasodilator group) with those who did not (control group). Vasodilator therapy was defined as venous and/or arterial administration of papaverine and/or prostaglandin E1 within 2 days of admission. The primary outcome was in-hospital mortality. Secondary outcomes included the prevalence of additional abdominal surgery performed ≥3 days after admission and short bowel syndrome. RESULTS: We identified 928 eligible patients (149 in the vasodilator group and 779 in the control group). One-to-four propensity score matching yielded 149 and 596 patients for the vasodilator and control groups, respectively. There was no significant difference in in-hospital mortality between the groups (control vs. vasodilator, 27.5% vs. 30.9%; risk difference, 3.4%; 95% confidence interval, -4.9 to 11.6; p=0.42) and no significant difference in the prevalences of abdominal surgery, bowel resection ≥3 days after admission, and short bowel syndrome. CONCLUSIONS: Postoperative vasodilator use was not significantly associated with a reduction in in-hospital mortality or additional abdominal surgery performed ≥3 days after admission in surgically treated NOMI patients.

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.

A comprehensive history of injection therapy for erectile dysfunction, 1982-2023.

INTRODUCTION: Although oral phosphodiesterase 5 inhibitors represent a first choice and long-term option for about half of all patients with erectile dysfunction (ED), self-injection therapy with vasoactive drugs remains a viable alternative for all those who are not reacting or cannot tolerate oral drug therapy. This current injection therapy has an interesting history beginning in 1982. OBJECTIVES: To provide a comprehensive history of self-injection therapy from the very beginnings in 1982 by contemporary witnesses and some members of the International Society for Sexual Medicine's History Committee, a complete history of injection therapy is prepared from eyewitness accounts and review of the published literature on the subject, as well as an update of the current status of self-injection therapy. METHODS: Published data on injection therapy, as a diagnostic and therapeutic tool for ED, were reviewed thoroughly by PubMed and Medline research from 1982 until June 2023. Early pioneers and witnesses added firsthand details to this historical review. Therapeutic reports of injection therapy were reviewed, and results of side effects and complications were thoroughly reviewed. RESULTS: The pioneers of the first hours were Ronal Virag (1982) for papaverine, Giles Brindley (1983) for cavernosal alpha-blockade (phentolamine and phenoxybenzamine), Adrian Zorgniotti (1985) for papaverine/phentolamine, and Ganesan Adaikan and N. Ishii (1986) for prostaglandin E1. Moxisylyte (thymoxamine) was originally marketed but later withdrawn. The most common side effect is priapism, with the greatest risk of this from papaverine, which has modified its use for therapy. Currently, prostaglandin E1 and trimixes continue to be the agents of choice for diagnostic and therapeutic use in ED. A recent agent is a mixture of a vasoactive intestinal polypeptide (aviptadil) and phentolamine. CONCLUSIONS: After 40 years, self-injection therapy represents the medication with the highest efficacy and reliability rates and remains a viable option for many couples with ED. The history of this therapy is rich.

Delineating patient errors in an intracavernosal injection program.

BACKGROUND: Intracavernosal injection therapy (ICI) is a well-established therapeutic strategy for men with erectile dysfunction. Complications are often related to patient error when performong ICI. AIM: The objective of this study was to examine patient errors in an established patient training program for performing ICI and identify factors that could predict major errors. METHODS: Patients enrolled in our ICI program are trained on technical aspects, and dose titration is begun. Patients are given explicit instructions during training, both verbally and in written form. Records were reviewed for men using ICI for ≥6 months. Multivariable analysis was used to define predictors of major errors. OUTCOMES: Errors were listed as minor (zero-response injection, penile bruising, expired medication) and major (errors potentially leading to priapism: dose self-titration, double injecting). RESULTS: Overall, 1368 patients met the inclusion criteria and were included in the analysis. The mean patient age was 66 ± 22 (range 29-91) years. Regarding education, 41% of patients had graduate-level education, 48% had college education, and 11% high school education. Mean follow-up was 3.2 ± 7.6 (range 0.5-12) years. The agents used were trimix (62%), bimix (35%), papaverine (2%), and prostaglandin E1 monotherapy (1%). At least 1 error occurred during self-administration in 42% of patients during their time in the program. Errors included zero response to medication due to technical error (8% of patients), penile bruising (34%), use of an expired bottle (18%), self-titration (5%), and double injecting (4% of patients); 12% of men committed ≥1 error during their time in the program. On multivariable analysis, independent predictors of the occurrence of a major error included: young age, graduate-level education, and <12 months of injection use. CLINICAL IMPLICATIONS: To the best of our knowledge, this is the first reported study to investigate ICI errors and risk factors. The identification of factors predictive of major errors allows for more tailored and intensive training in this subset of patients. STRENGTHS AND LIMITATIONS: Strengths of this study include a large patient population (1386 men) with a considerable follow-up time. Additionally, the rigorous training, education, and monitoring of the participants, as well as the use of formal definitions, enhances the accuracy and reliability of the results. Despite the strengths of the study, recall bias may be a limitation concern. CONCLUSION: The majority of patients were error free, and the majority of the errors were minor in nature. Major errors occurred in <10% of patients. Younger age, graduate-level education, and less experience with ICI were independent predictors of major errors.

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.

Ocular Distribution of Papaverine Using Non-aqueous Vehicles.

Papaverine, a poorly soluble opium alkaloid, has recently been shown to reduce retinal inflammation due to which it may have therapeutic application in the management of Leber's hereditary optic neuropathy. In this study, papaverine eyedrops based on medium chain triglycerides were prepared and the effect of diethyl glycol monoethyl ether (DGME) on their ocular distribution was evaluated using an ex vivo porcine eye model. The route of drug penetration was also studied by orienting the eye to expose either only the cornea or the sclera to the formulation. Furthermore, in vivo studies were performed to confirm ocular tolerability and evaluate ocular drug distribution. Our results showed increased papaverine concentrations in the cornea and sclera in the presence of DGME but with a slight reduction in the retina-choroid (RC) drug concentration when administered via the corneal route, suggesting that DGME enhances drug accumulation in the anterior ocular tissues but with little effect on posterior drug delivery. In vivo, the papaverine eyedrop with DGME showed good ocular tolerability with the highest drug concentration being observed in the cornea (1.53 ± 0.28 µg/g of tissue), followed by the conjunctiva (0.74 ± 0.18 µg/g) and sclera (0.25 ± 0.06 µg/g), respectively. However, no drug was detected in the RC, vitreous humor or plasma. Overall, this study highlighted that DGME influences ocular distribution and accumulation of papaverine. Moreover, results suggest that for hydrophobic drugs dissolved in hydrophobic non-aqueous vehicles, transcorneal penetration via the transuveal pathway may be the predominant route for drug penetration to posterior ocular tissues. Graphical abstract.

Independent Predictive Factors for Occurrence of Ischemic Priapism after Papaverine Injection.

PURPOSE: To analyze the predictive factors causing ischemic priapism following penile doppler ultrasonography (PDU) with intracavernosal papaverine injection   Materials and methods: Medical records of 467 patients who underwent PDU examination following intracavernosal papaverine injection for erectile dysfunction (ED) between 2009 and 2017 were retrospectively reviewed. Patients with hematological disease anamnesis, patients taking phosphodiesterase-5 inhibitor, patients with intracavernosal injection therapy anamnesis and patients who underwent PDU with other intracavernosal vasodilator drugs other than papaverine were excluded from the study. The remaining 268 patients were divided into two groups as priapism (38 patients) and non-priapism (230 patients). The groups were compared in terms of demographic data, American Society of Anesthesiologists (ASA) score, comorbidities, international index of erectile dysfunction (IIEF) score and PDU results. The significant parameters were analyzed with binary logistic regression analysis. The receiver operating analysis was used to obtain cut-off, sensitivity and specificity values for the independent predictive factors.    Results: The age, ASA score, diabetes mellitus, IIEF score, duration of ED, peak arterial and peak end diastolic venous flow values in the 20th minute were significantly different in the two groups (p<0.001). Binary logistic regression analysis found age, duration of erectile dysfunction, IIEF score, peak arterial flow and venous flow rate in the 20th minute were predictive variables for the occurrence of priapism.   Conclusions: Young patients, patients with good IIEF score, patients with ED for a short time, and patients with normal peak arterial and venous flows are more prone to developing post-papaverine ischemic priapism.

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.

Combined effect of left stellate ganglion blockade and topical administration of papaverine on left internal thoracic artery blood flow in patients undergoing coronary revascularization.

Background: Left stellate ganglion blockade (LSGB) may have additive effect to topical administration of papaverine on prevention of vasospasm of left internal thoracic artery (LITA). Aims: This study aims to compare LITA blood flow with topical application of papaverine alone or in combination with LSGB. Setting: Tertiary care hospital. Design: Prospective randomized controlled study. Materials and Methods: A total of 100 patients operated for coronary revascularization were randomly and equally allocated into two groups. In control Group-C, papaverine was applied topically during the dissection of LITA. In Group-S, the additional LSGB was performed. Blood flow was measured from cut end of the LITA for 15 s. Primary objectives of the evaluation were to observe differences in the LITA blood flow. Observing incidence of radial-femoral arterial pressure difference after cardiopulmonary bypass (CPB) was secondary objective. Statistical Analysis: Student's unpaired t-test and Fisher's exact test to find out a significant difference between the groups. Results: LITA flow in Group-S was insignificantly more (49.28 ± 7.88 ml/min) than Group-C (47.12 ± 7.24 ml/min), (P = 0.15). Radio-femoral arterial pressure difference remained low for 40 min after termination of CPB in the Group-S compared to the Group-C (-0.99 ± 1.85 vs. -1.92 ± 2.26). Conclusion: Combining LSGB with papaverine does not increase the LITA blood flow compared to when the papaverine is used alone. However, ganglion blockade reduces radial-femoral arterial pressure difference after CPB. Blockade can be achieved successfully under the ultrasound guidance without any complications.

Ultrasonography after pharmacological stimulation of erection for the diagnosis and therapeutic follow-up of erectile dysfunction due to cavernovenous leakage.

The goal of this work was to demonstrate that Doppler ultrasound (DUS) after pharmacological stimulation of erection (PSE) can be used to evaluate the presence and intensity of a cavernovenous leak (CVL) suspected in erectile dysfunction (ED) patients. The study was built around 50 DUS-PSE exams of penile arteries and veins, which were carried out 3, 5, 10 and 20minutes after pharmacological stimulation. Measured parameters were end diastolic velocity of the cavernous arteries and mean velocity of the deep penile vein and/or penile superficial veins. A score from 0 to 3 was attributed to each according to the recorded velocities. A final score from 0 to 9 was established by adding the three values: patients quoting 0 and 1 were classified as "no leak" (n=8); from 2 to 9 (n=42) as "leaking". Penile computed tomography (CT-scan) under identical pharmacological stimulation identified the cavernovenous leak to be compared with the DUS-PSE results, which were valid in 47 cases (94%), with 97.6% sensitivity and 77.7% specificity. The kappa correlation coefficient for CT-scan diagnosis of suspected CVL was 0.7875 (P<0.001). In addition, we found that end diastolic velocity in the cavernous artery, considered up until now as the gold standard in cases of suspected CVL was insufficient (negative predictive value=47%). In addition to its well-known diagnostic value regarding ED of arterial origin, DUS-PSE is an excellent screening test for CVL, especially in young patients without vascular risk factors who are resistant to medical treatments. For those with well-established CVL, confirmation by CT-scan to discuss possible surgery should be the next step. Moreover, DUS-PSE is useful in postoperative monitoring.

Effect of QTU prolongation on hyperemic instantaneous wave-free ratio value: a prospective single-center study.

We hypothesized that in patients with QT prolongation, resistance might not decrease in the wave-free period, because QTU prolongation cannot be detected by instantaneous wave-free ratio (iFR) analysis software. We investigated whether corrected QTU (QTUc) prolongation affects the hyperemic iFR value. Forty-two consecutive patients with intermediate stenosis (≥ 50%) in the left anterior descending coronary artery (LAD) were analyzed. Fractional flow reserve (FFR) and hyperemic iFR were simultaneously and continuously recorded with intravenous adenosine triphosphate (ATP) and papaverine infusions. In 17 patients with stenosis in the proximal LAD, coronary flow was measured. Patients were divided into two groups according to the median absolute deviation of the QTUc by ATP administration/QTUc by papaverine administration. FFR, hyperemic iFR, and flow data were compared between each stimulus and group. Moreover, influences of pressure and electrocardiogram parameters on differences in iFR values under ATP and papaverine administration were compared between the following two groups (group 1: the absolute difference of hyperemic iFR values between ATP and papaverine administration is ≤ 0.05; group 2: that is > 0.05). The paired t test and t test were used in analysis. Hyperemic iFR values of patients under the use of papaverine were lower than those of patients under the use of ATP when QTUc was more prolonged by papaverine administration than by ATP administration (ATP 0.74 ± 0.14, papaverine 0.71 ± 0.15, P = 0.025). No significant differences were observed in the FFR value and flow data between the groups. Regarding QTU, QTUc, and QTUc by ATP/QTUc by papaverine, significant differences were observed between group 1 and group 2. Pressure parameters did not induce significant differences. QTUc prolongation induced by papaverine was associated with lower hyperemic iFR values. An iFR-based assessment might lead to inappropriate treatment of patients with QTUc prolongation.

Confirmation of maximal hyperemia by the incremental dose of intracoronary papaverine.

We investigated the effect of the papaverine dose increment method to confirm maximal hyperemia for fractional flow reserve (FFR) measurements. We evaluated 115 consecutive patients involving 200 lesions. FFR was measured after intracoronary papaverine injection into the left (12 mg) and right (8 mg) coronary arteries as standard doses. Except for 2 patients who had ventricular tachyarrythmia (VTA), we administered a higher papaverine dose (2 mg added to the standard dose). We compared the FFR values after using different papaverine doses. VTA incidence and electrocardiogram parameters were compared according to the papaverine doses used. The QTU interval and corrected QTU were significantly prolonged after using a higher dose compared with a standard dose. VTA occurred in one patient (0.9%) at the higher dose. There was no significant difference with a strong correlation between the FFR values in the 2 doses (r = 0.963, P < 0.001). Maximal hyperemia was achieved in most patients at the standard papaverine dose. However, 19 lesions changed ischemic diagnosis at the higher dose (12 lesions changed from ischemia negative to positive, and 7 lesions changed from positive to negative). Therefore, to confirm the appropriate ischemia diagnosis for borderline FFR values, it may be favorable to perform another FFR measurement at an incremental papaverine dose.

The Impact of Intra-Arterial Papaverine-Hydrochloride on Cerebral Metabolism and Oxygenation for Treatment of Delayed-Onset Post-Subarachnoid Hemorrhage Vasospasm.

BACKGROUND: Delayed posthemorrhagic vasospasm remains among the major complications after aneurysmal subarachnoid hemorrhage (SAH) and can result in devastating ischemic strokes. As rescue therapy, neurointerventional procedures are used for selective vasodilatation. OBJECTIVE: To investigate the effects of intra-arterial papaverine-hydrochloride on cerebral metabolism and oxygenation. METHODS: A total of 10 consecutive patients, suffering from severe aneurysmal SAH were prospectively included. Patients were under continuous multimodality neuromonitoring and required intra-arterial papaverine-hydrochloride for vasospasm unresponsive to hypertensive therapy. Cerebral metabolism (microdialysis), brain tissue oxygen tension (ptiO2), intracranial pressure (ICP), and cerebral perfusion pressure (CPP) were analyzed for a period of 12 h following intervention. RESULTS: A median dose of 125 mg papaverine-hydrochloride was administered ipsilateral to the multimodality probe. Angiographic improvement of cerebral vasospasm was observed in 80% of patients. During intervention, a significant elevation of ICP (13.7 ± 5.2 mmHg) and the lactate-pyruvate ratio (LPR) (54.2 ± 15.5) was observed, whereas a decrease in cerebral glucose (0.9 ± 0.5 mmol/L) occurred. Within an hour, an increase of cerebral lactate (5.0 ± 2.0 mmol/L) and glycerol (104.4 ± 89.8 µmol/L) as well as a decrease of glucose (0.9 ± 0.4 mmol/L) were measured. In 2 to 5 h after treatment, the LPR significantly decreased (pretreatment: 39.3 ± 15.3, to lowest 30.5 ± 6.7). Cerebral pyruvate levels increased in 1 to 10 h (pretreatment: 100.1 ± 33.1 µmol/L, to highest 141.4 ± 33.7 µmol/L) after intervention. No significant changes in ptiO2 or CPP occurred. CONCLUSION: The initial detrimental effects of the endovascular procedure itself were outweighed by an improved cerebral metabolism within 10 h thereafter. As the effect was very limited, repeated interventions or continuous application should be considered.

Effectiveness and safety of intracoronary papaverine, alprostadil, and high dosages of nicorandil and adenosine triphosphate for measurement of the index of coronary microcirculatory resistance in a pig model.

BACKGROUND: Papaverine is used to induce maximal hyperemia for index of coronary microcirculatory resistance (IMR) measurement in animal experiments, although it can lead to polymorphic ventricular tachycardia and ventricular fibrillation. OBJECTIVES: This study investigated the effect of an intracoronary (IC) bolus of high adenosine triphosphate (ATP) and nicorandil doses for IMR measurement and explored the possibility of inducing maximal hyperemia with an IC alprostadil bolus. MATERIAL AND METHODS: Index of coronary microcirculatory resistance was measured in a hyperemic state induced by 7 experimental conditions in 21 pigs (IC bolus of papaverine (18 mg), ATP (40 µg, 80 µg, 160 µg, and 240 µg), and nicorandil (2 mg and 4 mg)). The 7 conditions were induced sequentially, and the average IMR was calculated. Because of the long-term hyperemic condition in the pilot experiments, the IMR was measured 1, 3, 5, 8, and 10 min after an IC bolus of alprostadil (10 µg) in another 7 pigs. RESULTS: The IMR induced by 240 µg of ATP or 4 mg of nicorandil was not significantly different from that induced by 18 mg of papaverine (both p > 0.05). A strong linear correlation was observed between IMRs with papaverine (18 mg) and nicorandil (4 mg) (R2 = 0.936, p < 0.001) and with papaverine (18 mg) and ATP (240 µg) (R2 = 0.838, p < 0.05). The IC bolus of nicorandil (4 mg) produced the smallest changes, whereas papaverine caused the most significant changes in mean blood pressure and heart rate (p < 0.05). Tachypnea and transient ST depression were more common with increasing ATP dosages (especially 240 µg). Alprostadil (5 min) yielded a significant hyperemic response but reduced baseline blood pressure by almost 40% for a long time. CONCLUSIONS: Intracoronary bolus administration of 4 mg of nicorandil was better than 18 mg of papaverine or 240 µg of ATP for induction of maximal hyperemia and IMR measurement in a pig model, whereas alprostadil was not suitable for IMR measurement.

Effect of local papaverine on arteriovenous fistula maturation in patients with end-stage renal disease.

BACKGROUND: Arteriovenous fistula (AVF) maturation is one of the main concerns in patients with end-stage renal disease (ESRD) and finding a strategy for increasing success rate and accelerating fistula maturation is valuable. The aim of this study was to evaluate the effects of papaverine injection on AVF maturation and success rate. METHOD: This study was a randomized clinical trial that involved 110 patients with ESRD that were referred for AVF construction. Patients were allocated in papaverine group and control group with block randomization according to age and sex. In the case group, papaverine (0.1 or 0.2 cc) was injected locally within the subadventitia of artery and vein after proximal and distal control during AVF construction and in the control group, AVF construction was done routinely without papaverine injection. RESULTS: Maturation time in case and control groups was 37.94 ± 11.49 and 44.23 ± 9.57 days, respectively (p=0.004). Hematoma was not seen in the case group but occurred in one patient in the control group. One patient of the case group developed venous hypertension. Four functional fistulas, 1 (1.8%) in the case group and 3 (5.5%) in the control group, failed to mature (p=0.618). Maturation rate did not differ between the two groups statistically (p=0.101). CONCLUSION: Local papaverine injection increased vessel diameter and blood flow, increasing shearing stress in both arterial and venous segment of recently created AVF. In this way, papaverine probably can decrease AVF maturation time without an increase in complications.

Effect of local papaverine on arteriovenous fistula maturation in patients with end-stage renal disease / Efeito da papaverina local na maturação de fístulas arteriovenosas em pacientes com doença renal terminal

Abstract Background: Arteriovenous fistula (AVF) maturation is one of the main concerns in patients with end-stage renal disease (ESRD) and finding a strategy for increasing success rate and accelerating fistula maturation is valuable. The aim of this study was to evaluate the effects of papaverine injection on AVF maturation and success rate. Method: This study was a randomized clinical trial that involved 110 patients with ESRD that were referred for AVF construction. Patients were allocated in papaverine group and control group with block randomization according to age and sex. In the case group, papaverine (0.1 or 0.2 cc) was injected locally within the subadventitia of artery and vein after proximal and distal control during AVF construction and in the control group, AVF construction was done routinely without papaverine injection. Results: Maturation time in case and control groups was 37.94 ± 11.49 and 44.23 ± 9.57 days, respectively (p=0.004). Hematoma was not seen in the case group but occurred in one patient in the control group. One patient of the case group developed venous hypertension. Four functional fistulas, 1 (1.8%) in the case group and 3 (5.5%) in the control group, failed to mature (p=0.618). Maturation rate did not differ between the two groups statistically (p=0.101). Conclusion: Local papaverine injection increased vessel diameter and blood flow, increasing shearing stress in both arterial and venous segment of recently created AVF. In this way, papaverine probably can decrease AVF maturation time without an increase in complications.

Resumo Introdução: A maturação da fístula arteriovenosa (FAV) é uma das principais preocupações em pacientes com doença renal terminal (DRT). Assim, é importante identificar estratégias para aumentar as taxas de sucesso e acelerar a maturação da fístula. O objetivo do presente estudo foi avaliar os efeitos da infiltração de papaverina sobre a maturação da FAV e suas taxas de sucesso. Método: O presente ensaio clínico randomizado incluiu 110 pacientes com DRT encaminhados para colocação de FAV. Os pacientes foram randomizados em bloco em função de idade e sexo e alocados nos grupos caso ou controle. Os indivíduos no grupo caso receberam infiltração local de papaverina (0,1 ou 0,2 ml) no plano da sub-adventícia da artéria e veia após o controle proximal e distal durante a construção da FAV. No grupo controle, a construção da FAV foi realizada rotineiramente sem infiltração de papaverina. Resultados: Os tempos de maturação dos grupos caso e controle foram 37,94 ± 11,49 e 44,23 ± 9,57 dias, respectivamente (p = 0,004). Foi observado hematoma em apenas um paciente do grupo controle. Um paciente do grupo caso desenvolveu hipertensão venosa. Quatro fístulas funcionais, uma (1,8%) no grupo caso e três (5,5%) no grupo controle, não amadureceram (p = 0,618). A taxa de maturação não diferiu estatisticamente entre os dois grupos (p = 0,101). Conclusão: A infiltração local de papaverina aumentou o diâmetro do vaso e o fluxo sanguíneo, elevando a tensão de cisalhamento nos segmentos arterial e venoso da FAV recentemente criada. Desta forma, a papaverina provavelmente consegue reduzir o tempo de maturação da FAV sem aumentar as complicações.

Vasodilatory efficacy and impact of papaverine on endothelium in radial artery predilatation for cabg surgery: in search for optimal concentration

Abstract Objective: The aim of this study was to compare the efficacy of two different papaverine concentrations (0.5 mg/ml and 2 mg/ml) for vasospasm prevention and their impact on endothelium integrity. Methods: We have studied distal segments of radial arteries obtained by no-touch technique from coronary artery bypass graft (CABG) patients (n=10). The vasodilatory effect of papaverine (concentrations of 0.5 mg/ml and 2 mg/ml) was assessed in vitro, in isometric tension studies using ex vivo myography (organ bath technique) and arterial rings precontracted with potassium chloride (KCl) and phenylephrine. The impact of papaverine on endothelial integrity was studied by measurement of the percentage of vessel's circumference revealing CD34 endothelial marker. Results: 2 mg/ml papaverine concentration showed stronger vasodilatatory effect than 0.5 mg/ml, but it caused significantly higher endothelial damage. Response to KCl was 7.35±3.33 mN for vessels protected with papaverine 0.5 mg/ml and 2.66±1.96 mN when papaverine in concentration of 2 mg/ml was used. The histological examination revealed a significant difference in the presence of undamaged endothelium between vessels incubated in papaverine 0.5 mg/ml (72.86±9.3%) and 2 mg/ml (50.23±13.42%), P=0.002. Conclusion: Papaverine 2 mg/ml caused the higher endothelial damage. Concentration of 0.5 mg/ml caused better preservation of the endothelial lining.

Papaverine hydrochloride containing nanostructured lyotropic liquid crystal formulation as a potential drug delivery system for the treatment of erectile dysfunction.

PURPOSE: Papaverine hydrochloride (PaHCl) is an old, well-known drug with spasmolytic activity but it has therapeutic effect in erectile dysfunction, too. As an intracavernous injection, it is not used in urologic clinics today because the side effects of the injection are pain, scarring or priapism. Our aim was to develop and test a topical semi-solid preparation containing PaHCl that would provide an alternative administration option by eliminating the undesirable side effects of the injection. MATERIALS AND METHODS: Lyotropic liquid crystal (LLC) systems were formulated as a semi-solid preparation with different concentrations of PaHCl. The characterization of the LLC structure was performed by polarization microscopy using a Leica image analyzer and rheological measurements. The drug diffusion and penetration tests were performed with in vitro synthetic membrane and an ex vivo human epidermis, using Franz diffusion cell to test the skin penetration of PaHCl. Human skin was investigated by Raman microscope to visualize the Active Pharmaceutical Ingredient (API) in different skin layers. RESULTS: The results of diffusion and penetration showed reverse concentration dependency. The in vitro and ex vivo studies correlated with each other and the results of Raman microscopy. The LLC structure influenced the penetration results, the lower viscosity and lamellar structure increased penetration through the skin. CONCLUSION: Based on our results, a PaHCl containing topically used LLC formulation may be a suitable and effective alternative to the injectable formulation.