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.

Effects of caffeine on fractional flow reserve values measured using intravenous adenosine triphosphate.

We investigated the effects of caffeine intake on fractional flow reserve (FFR) values measured using intravenous adenosine triphosphate (ATP) before cardiac catheterization. Caffeine is a competitive antagonist for adenosine receptors; however, it is unclear whether this antagonism affects FFR values. Patients were evenly randomized into 2 groups preceding the FFR study. In the caffeine group (n = 15), participants were given coffee containing 222 mg of caffeine 2 h before the catheterization. In the non-caffeine group (n = 15), participants were instructed not to take any caffeine-containing drinks or foods for at least 12 h before the catheterization. FFR was performed in patients with more than intermediate coronary stenosis using the intravenous infusion of ATP at 140 µg/kg/min (normal dose) and 170 µg/kg/min (high dose), and the intracoronary infusion of papaverine. FFR was followed for 30 s after maximal hyperemia. In the non-caffeine group, the FFR values measured with ATP infusion were not significantly different from those measured with papaverine infusion. However, in the caffeine group, the FFR values were significantly higher after ATP infusion than after papaverine infusion (P = 0.002 and P = 0.007, at normal and high dose ATP vs. papaverine, respectively). FFR values with ATP infusion were significantly increased 30 s after maximal hyperemia (P = 0.001 and P < 0.001 for normal and high dose ATP, respectively). The stability of the FFR values using papaverine showed no significant difference between the 2 groups. Caffeine intake before the FFR study affected FFR values and their stability. These effects could not be reversed by an increased ATP dose.

[Nutricional support in the complex treatment of a patient with esophageal spasm].

In the presented clinical case the theme of the need for an integrated therapeutic intervention has been disclosed, including nutritional support on the various links of the pathogenesis of esophagospasm to the effectiveness of the patient's treatment.

Treatment of loin pain suspected to be renal colic with papaverine hydrochloride: a prospective double-blind randomised study.

OBJECTIVE: • To assess the efficacy of papaverine hydrochloride combined with a diclofenac sodium suppository to relieve renal colic compared with diclofenac suppository monotherapy, as the effect of phosphodiesterase inhibitors on ureteric muscles might reduce the pain of renal colic. PATIENTS AND METHODS: • A prospective, double-blind clinical study was performed. • In all, 550 patients aged 17-55 years with acute renal colic were randomised to two groups. Patients in one group (group A) received a diclofenac suppository (100 mg) plus saline 0.9% (placebo) and the other group (group B) received a diclofenac suppository (100 mg) plus intravenous (i.v.) papaverine hydrochloride (1.5 mg/kg up to 120 mg). • Pain intensity was assessed using a visual analogue scale (VAS) at 0, 20 and 40 min after treatment. Further analgesia was provided at the patients' request (25 mg pethidine intramuscularly). RESULTS: • Baseline characteristics (sex, age, past history of similar pains) were similar in the two groups. • There were significant differences in VAS pain scores between 0 and 20 min and 0 and 40 min in both groups (P < 0.001). • At the end of study, 71.1% of patients in group A and 90.9% of patients in group B reported pain relief and did not require pethidine, respectively. • Significantly more patients in group A required further analgesia. CONCLUSIONS: • According to our results, i.v. papaverine hydrochloride plus a diclofenac suppository were more effective than the diclofenac suppository alone for treating acute renal colic. • Therefore, i.v. papaverine hydrochloride is a beneficial supplemental therapy to relieve renal colic pain, particularly combined with non-steroidal anti-inflammatory drugs.

A multi-institutional experience of isolated limb infusion: defining response and toxicity in the US.

BACKGROUND: Isolated limb infusion (ILI) is a minimally invasive approach for treating in-transit extremity melanoma, with only two US single-center studies reported. Establishing response and toxicity to ILI as compared with hyperthermic isolated limb perfusion is important for optimizing future regional chemotherapeutic strategies in melanoma. STUDY DESIGN: Patient characteristics and procedural variables were collected retrospectively from 162 ILIs performed at 8 institutions (2001 to 2008) and compared using chi-square and Student's t-test. ILIs were performed for 30 minutes in patients with in-transit melanoma. Melphalan dose was corrected for ideal body weight (IBW) in 42% (n = 68) of procedures. Response was determined at 3 months by Response Evaluation Criteria in Solid Tumors; toxicity was assessed using the Wieberdink Limb Toxicity Scale. RESULTS: In 128 evaluable patients, complete response rate was 31%, partial response rate was 33%, and there was no response in 36% of patients. For all patients (n = 162), 36% had Wieberdink toxicity grade >or=3 with one toxicity-related amputation. On multivariate analysis, smaller limb volumes were associated with better overall response (p = 0.021). Use of papaverine in the circuit to achieve cutaneous vasodilation was associated with better response (p < 0.001) but higher risk of grade >or=3 toxicity (p = 0.001). Correction of melphalan dose for ideal body weight did not alter complete response (p = 0.345), but did lead to marked reduction in toxicity (p < 0.001). CONCLUSIONS: In the first multi-institutional analysis of ILI, a complete response rate of 31% was achieved with acceptable toxicity demonstrating this procedure to be a reasonable alternative to hyperthermic isolated limb perfusion in the management of advanced extremity melanoma.

Interactions between symptoms and motor and visceral sensory responses of irritable bowel syndrome patients to spasmolytics (antispasmodics).

AIM: to evaluate and correlate the symptomatic, motor and sensory responses to two widely used categories of spasmolytic agents in irritable bowel syndrome (IBS). METHODS: 118 patients with IBS, diagnosed by Rome II criteria and 45 healthy individuals were studied. In the IBS subjects, pain severity, as well as the sensory response to rectal balloon distention and rectal and sigmoid motility, were studied at baseline and after two weeks therapy with either oral buscopan (20 mg three times a day, n=37), a buscopan suppository (30 mg once daily, n=21), oral drotaverine (80 mg three times a day, n=30), calcium gluconate tablets (one three times a day, n=16) as a control for oral agents, or calendula suppository (once daily, n=14) as a control for those who received a suppository. RESULTS: Buscopan, whether administered as a tablet or a suppository, produced a significant reduction in pain scores among IBS patients with predominant diarrhea. No significant differences were evident among other IBS subgroups or in response to drotaverine. None of the interventions had any effect on any of the parameters of rectal or sigmoid motility studied. However, both buscopan and drotaverine led to a significant augmentation of the rectal threshold for discomfort/pain among IBS subjects with predominant diarrhea [21.78 + or - 2.8 vs 39.60 + or - 2.4 (p<0.05), 20.5 + or - 2,8 vs 36.84 + or - 3.8 (p<0.05) and 22.18 + or - 2.8 vs 36.9 + or - 2.42 (p<0.05) for oral buscopan, rectal buscopan and oral drotaverine, respectively]. CONCLUSION: We conclude that the clinical benefits of supposed spasmolytic (anti-spasmodic) agents may relate more to effects on visceral sensation than motility.

[Role of coil embolization and arterial injection in elderly subarachnoid hemorrhage patients: preliminary report].

With the recent advanced aging seen in society, the number of elderly patients with aneurismal subarachnoid hemorrhage (SAH) is increasing. We focused on current management of SAH in patients who were over 75 years old. From January 1st, 2004 to the end of June, 2007, we had treated 170 SAH patients including 39 who were over 75 years old. We divided the patients into three groups : Coiling Group, Clipping Group, and conservative treatment group (Conservative Group). We analyzed the Hunt-Kosnik grade (H-K), the rate of symptomatic vasospasm, the rate of shunting operation, the Glasgow Outcome Scale (GOS) at 30 days after the onset of SAH, bed rest periods and rate of shunt operation retrospectively. The Conservative Group included many H-K poor grade cases. Symptomatic vasospasm occurred significantly less in the Coiling Group. Rates of shunting operation did not have any significant change. GOS of the Coiling Group and Clipping Group had no significant change, due to the effectiveness of arterial injection for vasospasm. Patients in the Coiling Group started walking significantly earlier than members of other groups. Twenty-five percent of the Clipping Group needed a shunt operation but no patients of the Coiling Group needed a shunt. For elderly SAH patients, we recommend doing coil embolization or clipping and maintaining the patients' activity in daily life. Interventional treatment is necessary to improve results for elderly SAH patients.

Effects of transanal pelvic plexus stimulation on penile erection: clinical implications.

OBJECTIVE: To determine the ability of transanal pelvic plexus stimulation (TPPS) in inducing penile tumescence in patients with non-neurogenic erectile dysfunction (ED) and to compare the erection degree with papaverine-induced erection. PATIENTS AND METHODS: The cavernous electrical activity (CEA) in 21 men with non-neurogenic erectile dysfunction was measured during TPPS by electromyography of corpus cavernosum and the erection degree of penis (flaccid, semi-rigid, rigid) was noted. The stimulation amplitude was increased from 20 to 100 mA. All patients also underwent intracavernous papaverine injection and further CEA recordings were obtained. RESULTS: Twelve and nine patients were diagnosed with vasculogenic (VED) and non-vasculogenic ED (NVED), respectively. TPSS led to a penile erectile response in 12 patients (57%), whereas papaverine injection caused erection in 16 (76.2%) patients. The mean baseline CEA (16.9 +/- 9.1 mV) did not change with TPPS, but papaverine significantly decreased the mean CEA to 12.3 +/- 4.9 mV (P < 0.001). CEA recordings of 16 (76.2%) patients revealed a significant decrease after papaverine injection, however seven (33.3%) patients showed significant CEA decrease in response to TPPS. Both TPPS and papaverine were observed to have a higher effect in patients with NVED in terms of inducing penile erection and decreasing CEA compared to their effects in patients with VED. CONCLUSION: TPPS induces penile erection and decreases CEA for some extent, but to a lesser degree compared to papaverine. As further improvements are achieved in the methodology of TPPS, it may be a valuable method in the evaluation patients with erectile dysfunction.

Periarterial application of papaverine during laparoscopic donor nephrectomy improves early graft function after kidney transplantation in pigs.

BACKGROUND: Laparoscopic donor nephrectomy (LDN) increases incentives to donation by subjects who might refuse an open operation. However, the incidence of delayed graft function is higher after LDN than after open operation. This may be caused by the reduction of renal perfusion as a result of the raised intraabdominal pressure and mechanically induced renal angiospasm during the operation. We conducted experiments to find out whether the application of papaverine around the renal artery during LDN could improve early graft function after transplantation. METHODS: Renal function was studied in 10 male pigs (weight approximately 25 kg). The left kidney was harvested laparoscopically (intraabdominal pressure 8 mmHg). Five animals were randomly selected to have perivascular application of 50 mg papaverine (treatment group) before preparation of the vessels. In controls no papaverine was used. After LDN and open right nephrectomy the left kidney was autotransplanted. The main outcome measures were volume of urine produced and creatinine clearance during the first 20 h after the transplant. RESULTS: The groups were comparable in respect of body weight, hemodynamic values, amount of infusions, warm and cold ischemia time, and duration of anastomosis. Urine output and creatinine clearance were significantly higher in pigs treated with papaverine than in controls. CONCLUSIONS: Papaverine substantially improved early graft function in pigs when applied around the renal artery during LDN. Whether this is applicable to procurement of human kidneys remains to be evaluated.

The effect of papaverine on acute opiate withdrawal in guinea pig ileum.

In the present work the effect of papaverine, a non specific smooth muscle relaxant, was investigated on the naloxone-precipitated withdrawal contracture of the acute morphine-dependent guinea-pig ileum in vitro. Furthermore, the effect of papaverine was also considered on DAGO (highly selective mu -agonist) and U50-488H (highly selective k-agonist) withdrawal to test whether the possible interaction of papaverine on opioid withdrawal involves mu - and/or k-opioid receptors. Following a 4 min in vitro exposure to opioid agonist, the guinea-pig isolated ileum exhibited a strong contracture after the addition of naloxone. Papaverine treatment (1 x 10(-7) - 5 x 10(-7) - 1 x 10(-6) M) before or after the opioid agonists was able of both preventing and reversing the naloxone-induced contracture after exposure to mu (morphine and DAGO) or k (U50-488H) opiate agonists in a concentration-dependent fascion. Both acetylcholine response and electrical stimulation were not affected by papaverine treatment whereas the final opiate withdrawal was still reduced. The results of the present study indicate that papaverine was able to produce significative influence on the opiate withdrawal in vitro and papaverine was able to exert its effect both at mu and k opioid agonists.

The influence of periarterial papaverine application on intraoperative renal function and blood flow during laparoscopic donor nephrectomy in a pig model.

BACKGROUND: The transplantation of live donor kidneys harvested laparoscopically is associated with a higher incidence of delayed graft function than the transplantation of grafts harvested via the open technique. The delay is believed to be due to a decrease in renal blood flow during laparoscopic donor nephrectomy (LDN). The aim of this study was to evaluate whether renal function and blood perfusion can be enhanced by the periarterial application of papaverine during LDN. METHODS: Renal function and blood flow were studied in a porcine model that included a total of 24 pigs (20-30 kg). In 12 of the pigs, urine output and creatinine clearance were determined as measures of renal function. In the other 12 pigs, renal blood flow was determined using fluorescent-labeled microspheres. In each group, the pigs were randomized into two subgroups, one with and one without a perivascular injection of 50 mg papaverine. RESULTS: As compared to the controls, the animals receiving papaverine had a significantly higher urine output (3.1 +/- 1.6 vs 0.9 +/- 0.45 ml/h/kg; p = 0.02), superior creatinine clearance (2.22 +/- 0.5 vs 0.95 +/- 0.1 ml/min/kg; p = 0.038), and enhanced renal blood flow (4.9 +/- 2.2 vs 2.1 +/- 0.8 ml/min/g; p = 0.008). CONCLUSIONS: When applied to the tissue surrounding the renal artery, papaverine substantially improves renal function and blood flow during laparoscopic live kidney donation. Whether graft optimization during kidney procurement also translates into improved posttransplantation function remains to be established.

Magnesium: a useful adjunct in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage.

UNLABELLED: Despite recent advances in the management of aneurysmal subarachnoid haemorrhage delayed ischaemic deficits from cerebral vasospasm remains a major cause of morbidity and mortality. As magnesium is a potent cerebral vasodilator we have introduced routine supplementation in patients presented with subarachnoid haemorrhage to determine whether there has been a reduction in the incidence of cerebral vasospasm. METHOD: All patients presented with aneurysmal subarachnoid haemorrhage from February 1997 were included except those who presented after day 5 following bleed. Identical management protocol was used except intravenous magnesium supplementation which was introduced to all patients from May 1999. Incidence of cerebral vasospasm on angiograms among the two groups was analysed. RESULTS: Seven out of 10 patients who did not receive magnesium supplement developed vasospasm requiring intra-arterial papaverine compared with 2 of 13 patients among the treated group (P<0.008). CONCLUSIONS: From our pilot study it appears that magnesium supplement has a beneficial role in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. Further studies would seem justified.

Treatment of erectile dysfunction by an external ischiocavernous muscle stimulator.

OBJECTIVE: The aim of the present study was to evaluate the therapeutic potency of an electrotherapy of striated ischiocavernous muscles in patients with erectile dysfunction. PATIENTS AND METHODS: Transcutaneous electrostimulation of striated ischiocavernous muscles by self-adhesive penile or perineal skin electrodes was performed in 48 patients with erectile dysfunction. 6/48 patients (R) responded to intracavernous pharmacotherapy while 42/48 (NR) did not show significant penile rigidity even to intracavernous papaverine/phentolamine/PGE1 triple drug medication. RESULTS: Within the observation time of 3 months, 10/48 patients dropped out. 22/38 patients reported a penile rigidity for sufficient sexual intercourse whereby 3/22 NR required additional intracavernous pharmacotherapy. Penile rigidity could be objectivated by triple drug medicaton in 12/14 NR after ischiocavernous muscle stimulation (EIS) therapy. 5/6 R were treated successfully for premature erection loss. During EIS treatment neither discomfort nor complications could be observed. CONCLUSION: Transcutaneous electrostimulation of ischiocavernous muscles is a new, noninvasive therapy for the improvement of penile rigidity. The clinical results underline the importance of the striated ischiocavernous muscles for penile rigidity.

[The sequential use of local vacuum magnetotherapy and papaverine electrophoresis with sinusoidal modulated currents in impotence]. / Posledovatel'noe primenenie lokal'noi vakuummagnitoterapii i élektroforeza sinusoidal'nymi modulirovannymi tokami papaverina pri impotentsii.

105 patients with chronic nonspecific prostatitis were examined and treated with papaverin electrophoresis using sinusoidal modulated currents (SMC) and local vacuum magnetotherapy (LVMT). Papaverin SMC electrophoresis and LVMT stimulated cavernous circulation. The highest stimulation was achieved at successive use of LVMT and the electrophoresis. LVMT followed by the electrophoresis maintained good cavernous circulation for 5-6 hours after the procedure in the course of which several spontaneous erections were observed.

Chronic penile denervation in the rat: effect on cavernous tissue morphology and function.

We evaluated the effects of chronic penile denervation on cavernous tissue morphology and function in 36 Sprague-Dawley rats. At age seven weeks, 18 animals underwent bilateral cavernous nerve neurectomy: 18 animals underwent sham operation as a control. A functional, biochemical and morphological assessment of the rats' penises was performed at 4 months. In denervated rats, intracavernous pressure failed to rise with electrostimulation of the pelvic plexus. However, a normal rise in pressure was found with direct intracavernous injection of sodium nitroprusside and papaverine. Sodium dodecylsulfate polyacrylamide (SDS) gel electrophoresis of the penile homogenate showed subtle differences between denervated and control animals. Based upon the histological findings there was no difference in staining of the cavernous tissue for acetylcholinesterase- and catecholamine-positive nerve fibers between experimental and control animals, since the innervation density was not quantified and the number of fibers was not counted. We conclude that chronic cavernous nerve neurectomy does not cause significant morphological or functional changes to the penile erectile tissue of rats.

Intra-arterial infusion of papaverine combined with intravenous administration of high-dose nicardipine for cerebral vasospasm.

The clinical effect of combination therapy with high doses of intravenous nicardipine and intra-arterial infusion of papaverine on symptomatic vasospasm after subarachnoid haemorrhage (SAH) was analysed retrospectively. In 66 of 122 patients who underwent early aneurysm surgery between 1990 and 1993, the intracranial haemodynamics were documented by transcranial Doppler (TCD) ultrasonography. 33 of these 66 patients received high dose nicardipine intravenously (Group I); the other 33 patients were not treated with calcium antagonists (Group II). Symptomatic vasospasm occurred in 6 Group I patients (18%) and in 13 (39%) in Group II patients. All 19 symptomatic patients received an intra-arterial infusion of papaverine; 15 patients (79%) responded well to this therapy and the symptoms were reversed quickly. Although the mean flow velocity (MFV) was not different between the two groups, it was reduced significantly after papverine infusion. Our retrospective analysis suggests that symptomatic vasospasm can be treated effectively with the combination of intravenous high dose nicardipine and intra-arterial infusion of papaverine, and that the correct timing of the infusions is crucial.

In vitro evaluation of papaverine hydrochloride incompatibilities: a simulation of intraarterial infusion for cerebral vasospasm.

PURPOSE: To elucidate, in light of reports of complications associated with intraarterial infusion of papaverine hydrochloride, the known propensity of papaverine hydrochloride to form precipitate in combination with other solutions or pharmaceuticals. METHODS: Initially simulating a situation experienced during an intraarterial papaverine infusion for cerebral vasospasm, we mixed various concentrations of papaverine with serum, nonheparinized and heparinized saline, and nonionic contrast material. RESULTS: Papaverine in concentrations of 0.3% (300 mg/100 mL of normal saline) or greater formed a precipitate when mixed with human serum (blood). The precipitate crystals were 50 to 100 microns in size and could be returned to solution simply by the addition of more serum. CONCLUSION: Crystal emboli are a possible transient cause of complications experienced during treatment of vasospasm with its attendant altered flow dynamics.