Papaverine Hydrochloride Research Articles

Stability of papaverine hydrochloride and phentolamine mesylate in injectable mixtures

The stability of papaverine hydrochloride and phentolamine mesylate combined in a single vial was studied. Injectable mixtures (10 mL) of papaverine hydrochloride 300 mg and phentolamine mesylate 5 mg (from two sources) were prepared by adding the contents of one vial of lyophilized phentolamine mesylate to the contents of one vial of papaverine hydrochloride injection. The vials were stored at 5 degrees C and 25 degrees C. Duplicate aliquots of the mixtures were obtained, and the concentrations of papaverine hydrochloride and phentolamine mesylate remaining at time 0 and after 1, 2, 5, 10, 20, and 30 days were determined in triplicate by a stability-indicating high-performance liquid chromatographic assay. The concentration of papaverine hydrochloride stored in the vials remained constant (less than 1% loss) over the 30-day period at both 5 degrees C and 25 degrees C. Phentolamine mesylate was less stable than papaverine but still retained more than 97% of its original concentration after 30 days at 5 degrees C and more than 95% of its original concentration at 25 degrees C. Papaverine hydrochloride and phentolamine mesylate are stable in injectable mixtures when stored for up to 30 days at 5 degrees C or 25 degrees C.

Spongiosolysis: A New Surgical Treatment of Impotence Caused by Distal Venous Leakage

Until recently ligation of the dorsal veins of the penis had been the only effective surgical treatment in cases of erectile dysfunction caused by venous insufficiency of the corpora cavernosa. Failure of this operation can be owing to persistent distal venous leakage consisting of venous shunts between the distal corpora cavernosa and corpus spongiosum, which can be demonstrated by cavernosography. These shunts can be closed successfully by spongiosolysis, that is by dissecting the distal half of the corpus spongiosum and by isolating the tips of the corpora cavernosa. Of 5 patients who underwent spongiosolysis after previous ligation of the dorsal vein of the penis 4 regained erectile ability with the help of intracavernous injection of a vasoactive drug mixture (15mg. per ml. papaverine hydrochloride plus 0.5mg. per ml. phentolamine mesylate, 0.5 to 2ml. per injection), which was necessary because of concomitant arterial lesions demonstrated by arteriography. The only failure proved to be persistent venous insufficiency of the deep dorsal vein of the penis. Since none of the patients had any serious complication spongiosolysis seems to be a safe procedure in the treatment of distal venous leakage.

Superiority of intracoronary papaverine to radiographic contrast for measuring coronary flow reserve in patients with ischemic heart disease

Measurement of coronary flow reserve has been suggested as an adjunct to anatomic assessment of coronary stenoses in patients with ischemic heart disease. We compared papaverine hydrochloride and radiographic contrast to determine which agent was superior for the determination of coronary flow reserve. Coronary flow reserve was determined during cardiac catheterization by means of digital coronary angiography and parametric imaging. Two groups of patients were studied. Among patients in group 1, coronary flow reserve was determined by means of both papaverine and contrast. In group 1 patients with normal coronary arteries, papaverine-induced flow reserve was greater than contrast-induced reserve in all but one vascular region (n = 9, 4.98 ± 1.15 vs 3.56 ± 0.89; p = 0.29). Group 1 patients with coronary disease also demonstrated significantly greater flow reserve with papaverine (n = 25, 2.57 ± 0.20 vs 1.83 ± 0.11, p < 0.01). Group 2 included patients with single-vessel coronary artery stenoses. These patients were studied by means of either papaverine or contrast to determine coronary flow reserve for both the stenotic “ischemic” region and an adjacent nonstenotic, “nonischemic” region. Those patients in group 2 who wers studied by means of contrast had a modest difference between flow reserve values in the nonischemic and those in the ischemic regions (n = 15, 1.78 ± 0.10 vs 1.26 ± 0.09; p < .0001) with considerable overlap. Patients studied by means of papaverine had a much greater separation in flow reserve between nonischemic and ischemic regions (n = 22, 2.78 ± 0.19 vs 1.46 ± 0.14; p < 0.0001). We conclude that papaverine is superior to radiographic contrast for measuring coronary flow reserve in patients with ischemic heart disease, because of the greater degree of induced hyperemia and the ability to more accurately differentiate nonischemic from ischemic vascular regions in individual patients.

In vivo measurements of intra- and extracellular Na+ and water in the brain and muscle by nuclear magnetic resonance spectroscopy with shift reagent

The introduction of new paramagnetic shift reagents in the nuclear magnetic resonance (NMR) method has made it possible to distinguish intra- and extracellular ions in tissues or organs in vitro. We measured the intra- and extracellular 23Na and 1H in vivo in the gerbil brain and skeletal muscle by NMR spectroscopy employing the shift reagent, dysprosium triethylenetetraminehexaacetate (Dy[TTHA]3-). Without Dy(TTHA)3-, the 23Na and 1H signals were seen only as single peaks, but gradual intravenous infusion of Dy(TTHA)3- separated these signals into two peaks, respectively. The unshifted peaks reflected the intracellular 23Na and 1H signals, while the shifted peaks reflected the extracellular signals. In the brain spectra, an additional small peak, which represented intravascular signals, was detected and its intensity increased after injection of papaverine hydrochloride. The present method is advantageous over the microelectrode technique because of its nondestructiveness and its capability for obtaining intra- and extracellular volume information from measurements of the 1H spectra, the peaks of which reflect the intra- and extracellular water amounts. The intracellular Na+ increase associating with increased cellular volume after ouabain in the muscle was clearly visualized by this method. The technique is clearly of use for physiological and pathophysiological studies of organs.

Microvascular pressures measured by micropuncture in lungs of newborn rabbits.

The purpose of this study was to determine the pattern of vascular pressure drop in newborn lungs and to define the contribution of active vasomotor tone to this longitudinal pressure profile. We isolated and perfused with blood the lungs from 22 rabbit pups, 5-19 days old. We inflated the lungs to a constant airway pressure of 7 cmH2O, and at constant blood flow, we maintained outflow pressure in the circulation greater than airway pressure at the level of micropuncture (zone 3). By the use of glass micropipettes and a servo-nulling device, we measured pressures in small (20-60 micron diam) subpleural arterioles and venules in the lungs of 13 newborn rabbits. We found that 60% of the pressure drop was in arteries, 31% in microvessels of less than 20-60 micron diam, and 9% in veins. In the lungs of an additional nine rabbit pups we measured microvascular pressures before and after the addition to the perfusate of the vasodilator, papaverine hydrochloride. We found that removal of vasomotor tone resulted in a 33% reduction in total lung vascular resistance, which resulted from a decrease in pressure in arterial vessels, with no change in microvascular pressure. These findings indicate that arteries of greater than 60 micron diam constitute the major source of vascular resistance in isolated perfused newborn rabbit lungs.

Vasoactive Intracavernous Pharmacotherapy for the Treatment of Erectile Impotence in Men with Spinal Cord Injury

A total of 66 spinal cord injury patients with erectile dysfunction entered a protocol of penile intracavernous pharmacotherapy with papaverine hydrochloride (30mg. per ml.) or a combination of papaverine (25mg. per ml.) and phentolamine mesylate (0.83mg. per ml.) in an attempt to restore erectile function. Of the patients 52 completed the protocol and all achieved transient functional penile erections after administration of the drug. Of the 52 responders 71 per cent currently practice self-injection as a method to restore erectile function. Sustained erections that required irrigation of the cavernous bodies with alpha-adrenergic agents developed in 4 patients and 1 suffered localized intracorporeal induration.If the long-term followup shows that complications remain relatively minor, undoubtedly vasoactive intracavernous pharmacotherapy will have a major role in the restoration of erectile function in the motivated man with spinal cord injury. However, in view of the unknown long-term effects and potential dangers of this approach it is important that patients adhere to a strict drug injection protocol under the supervision of qualified urologists who are familiar with the potential risks and complications. (J. Urol., 138: 539–542, 1987)

Intracavernosal injection in the treatment of impotence: A prospective study of sexual, psychological, and marital functioning

This study assessed the sexual, psychosocial, and medical impact of intracavernosal injection of papaverine hydrochloride and phentolamine mesylate in the treatment of impotence. Ninety-six percent of patients initially achieved satisfactory erections with injections. Common side effects of self-injections included bruising (26%), nodule development (21%), abnormal liver function tests (7%), and pain (5%). No nodules resulted in penile bending or pain, and no patient discontinued treatment due to nodule development. Dropout rate to date was 35%. Self-injection treatment was associated with increases in erection quality, intercourse frequency, and sexual satisfaction, and decreases in masturbation frequency for patients. Partners also reported increases in intercourse frequency, coital arousal, and satisfaction. Decreases in general psychiatric symptomatology and increases in relationship satisfaction and self-esteem were apparent for patients, but not for partners.

Clinical experience with vasoactive intracavernous pharmacotherapy for treatment of impotence

A total of 336 patients with organic impotence completed a testing protocol of penile vasoactive intracavernous pharmacotherapy (VIP) using papaverine hydrochloride (30 mg/ml) or a combination of papaverine (25 mg/ml) and phentolamine mesylate (0.83 mg/ml). Transient functional erections were achieved in 97.2% of patients with neurogenic impotence, 81.6% of those with vascular impotence, 90.7% of those with undetermined organic impotence, and 100% of patients with psychogenic and hormonal impotence. Of the responders, 273 elected to practice VIP as a method to restore erectile function and completed a training session on self- or partner-assisted injection. After an average follow-up of 9.2±6.7 months, 170 patients were still administering self-injections at home, 16 were lost to follow-up, and 87 discontinued the protocol. The average follow-up of patients actively practicing VIP was 11.6±6.5 months. Significant complications were few and included dizziness, sustained erections, and intracorporal hardening and fibrosis. Vasoactive intracavernous pharmacotherapy is a powerful tool in the management of impotence. Careful analysis of the risks and benefits and accurate definition of the long-term complications and their incidence are necessary to establish the role of VIP among other treatment options for impotence.

Fibrosis of Tunica Albuginea: Complication of Long-Term Intracavernous Pharmacological Self-Injection

We report 3 cases of penile curvature deformity and fibrosis of the tunica albuginea after longterm self-injection with papaverine hydrochloride and phentolamine mesylate. To our knowledge this complication has not been reported previously. The clinical presentation and possible etiology are discussed.

New methods in the diagnosis of impotence: RigiScan� penile tumescence and rigidity monitoring and diagnostic papaverine hydrochloride injection

In 26 patients with erectile impotence and 8 healthy volunteers the value of continuous monitoring of penile tumescence and rigidity by means of the RigiScan was tested. Based on history and routine screening tests the patients were divided into 3 groups of preliminary diagnosis: psychogenic (5 patients), organic (10 patients), mixed (11 patients). Real-time measurements of tumescence and rigidity were performed during direct visual stimulation and after intracorporeal injection of 80 mg papaverine hydrochloride according to a specific protocol. A total of 21 patients were monitored during sleep studies for 2 or 3 consecutive nights. The rigidity figures of the volunteers correlated well with their subjective interpretation of the erection. Evaluation of the recordings of the impotent patients enabled reclassification of the mixed group into 3 patients with mainly organic and 8 patients with mainly psychogenic impotence. RigiScan recording of penile tumescence and rigidity appears to be of great value in the diagnosis of impotent patients. Real-time monitoring during direct visual stimulation and after papaverine injection can generally replace nocturnal measurements. If the patient shows a positive response on visual sexual stimulation (VSS) alone, then his impotence is of psychogenic origin. Failing rigidity during VSS after injection indicates vascular impotence. In patients who show negative results during VSS alone, and positive response after injection or during subsequent VSS, nocturnal monitoring will differentiate between psychogenic and neurogenic impotence.

Intracavernosal pharmacotherapy: the pharmacologic erection program

Intracavernosal pharmacotherapy to facilitate tumescence is possible utilizing agents that induce corporal lacunar and helicine arteriolar smooth muscle relaxation. The patient experience in our pharmacologic erection program (P.E.P.) is presented herein. A total of 201 patients, aged 18–79 years, have entered the program over the 46 months since it was initiated and have been followed for a mean of 26 months. A mixture of papaverine hydrochloride (22.5 mg/ml) and phentolamine mesylate (1.25 mg/ml) has been utilized. The patients with “failure to initiate” neurogenic impotence (21%) required smaller doses and responded more rapidly and for a longer duration than patients with either vasculogenic impotence (65%) or patients with diabetes mellitus (13.5%). All patients who failed to enter the program because of inadequate erectile response to high doses of intracavernosal pharmacotherapy (13%) had “failure to store” corporal leakage syndrome as diagnosed by dynamic infusion cavernosometry and cavernosography (DICC). The drop-out rate of patients having successfully entered the program was 21%. Complications experienced were few and included corporal fibrosis (1.5%), prolonged erections (greater than 2 h) requiring intracavernosal adrenergic injection or irrigation therapy (1.5%), papaverine-related hepatic dysfunction (LFT) (1.5%), and tachyphylaxis (2%). Pharmacologic erection therapy is efficacious and safe, but requires careful and continuous physician/nurse monitoring. It is applicable as therapy in failure to initiate, failure to fill and failure to store erectile dysfunction. The incidence of long-term complications, particularly that of corporsal fibrosis, will require longer follow-up. Further research with the combination agents presently in use and newer single agents is encouraged.

Pharmacological Erection: Diagnosis and Treatment Applications in 69 Patients

Pharmacological erection is becoming an accepted form of treatment in the impotent patient. We report on our experience in 69 men with organic and psychogenic etiologies using intracorporeal injection with a mixture of papaverine hydrochloride and phentolamine mesylate. A good response was achieved in all patients except those with severe arterial or venous insufficiency. Although it was used primarily in cases of organic impotence, we found intracorporeal injection to be valuable in the patient with psychogenic impotence as an adjunct to sex therapy. Auto-injection was practiced by 74 per cent of our patients with a good response and 50 per cent noticed subjective improvement in the ability to obtain natural erections. Priapism was the most significant complication and occurred in 8.7 per cent of the patients. However, most patients have expressed satisfaction with this alternative to penile implantation.

Studies on Intracavernosal VIP Levels during Pharmacologically Induced Penile Erections

Intracavernosal and peripheral venous vasoactive intestinal polypeptide (VIP) levels were measured in men with predominantly organic or predominantly psychogenic impotence. The measurements were taken at intervals up to 30 min following intracavernosal injections of saline, papaverine hydrochloride and papaverine hydrochloride and phentolamine. Levels were also measured after tactile and visual sexual stimulation and following an intravenous injection of papaverine and phentolamine. A penile erection occurred in all men receiving intracavernosal vasoactive compounds. The mean VIP concentration did not alter significantly in either cavernosal or peripheral venous blood during the erection. Mean VIP concentrations were significantly greater in the neurogenic (all diabetic) group than in the other groups studied. Mean cavernosal and peripheral VIP concentrations did not alter following tactile or visual sexual stimulation and no significant alteration in mean peripheral venous VIP concentration occurred following injection of papaverine and phentolamine. The putative role of VIP in the induction of penile erection has not been elucidated in these studies.

HPLC determination of papaveraldine and papaverinol in papaverine injection

A simple, specific, and sensitive high-performance liquid chromatographic method for the determination of papaveraldine and papaverinol in papaverine hydrochloride injection has been developed. The compounds were chromatographed on a reversed-phase C-18 column using a water-methanol-acetonitrile solvent system containing sodium lauryl sulphate ion-pair reagent.

Mechanism of penile erection in the dog. Pressure-flow study combined with morphological observation of vascular casts.

A pressure-flow study of the corpus cavernosum penis in the dog was performed during the flaccid, tumescent, erect and rigid stages. Perfusion was selectively made into the penile deep artery. The erect stage was induced with the local administration of papaverine hydrochloride, and the rigid stage by electrostimulation of the ischiocavernous muscle during the erect stage. Concurrently, vascular casts of the penis at each stage of erection were observed under a scanning electron microscope for the anatomical analysis of the mechanisms controlling cavernous pressure. In the pressure-flow study, it was demonstrated that a combination of decreased arterial resistance and restricted venous outflow was essential to both cause and maintain the erect state. The rigid stage was generated by contraction of the ischiocavernous muscle tightly compressing the crus penis. In the rigid stage, the cavernous pressure was elevated as high as five times the perfusion pressure; nevertheless, no backflow from the cavernous sinus to the deep artery was recognized. By use of the casts, it was confirmed that venous outflow restriction in the erect and rigid stages was due to compression of the postcavernous venules and penetrating veins in the tunica albuginea. The deep artery was occluded in the tunica albuginea in the casts made during the rigid stage, suggesting that the backflow from the corpus cavernosum penis to the deep artery was prevented by this occlusion. Therefore, in the rigid stage, the arterial and venous occlusion isolated the cavernous sinus from the systemic circulation; this mechanism seems to account for the maintenance of the extremely high cavernous pressure.

Microvascular pressures measured by micropuncture in isolated perfused lamb lungs.

To investigate the influence of vasomotor tone and vessel compliance on pulmonary segmental vascular resistance, we determined the longitudinal distribution of vascular pressures in 15 isolated blood perfused lungs of newborn lambs. We measured pulmonary arterial and left atrial pressures and by micropuncture the pressures in 20- to 80-micron-diam subpleural arterioles and venules, both before and after paralyzing the vasculature with papaverine hydrochloride. In five lungs we also determined the microvascular pressure profile during reverse perfusion. In lungs with baseline vasomotor tone, approximately 32% of the total pressure drop was in arteries, approximately 32% in microvessels, and approximately 36% in veins. With elimination of vasomotor tone, arterial and venous resistances decreased to one-fifth and one-half of base-line values, respectively, indicating that vasomotor tone contributed mainly toward arterial resistance. During reverse perfusion, the pressure drop in veins was similar to that in arteries during forward perfusion, suggesting that the compliance of arteries and veins is comparable. We conclude that vascular tone and compliance are important factors that determine the distribution of segmental vascular resistance in lungs of the newborn.

Papaverine Biotransformation bySilene albaCell Suspension

Silene alba cell suspensions were supplied with papaverine hydrochloride. Seven biotransformation compounds were obtained of which four were alkaloidal. The two most important compounds are regioselective demethylation products: 6-monodemethylpapaverine and 4′-monodemethylpapaverine.

Spectrophotometric determination of papaverine hydrochloride by using a membrane filter preconcentration technique with 2,4,5,7-tetrachlorofluorescein and palladium(II).

Spectrophotometric determination of papaverine hydrochloride by using a membrane filter preconcentration technique with 2,4,5,7-tetrachlorofluorescein and palladium(II).

Papaverine therapy in atopic dermatitis

Papaverine hydrochloride taken by mouth in doses of 100 mg four to six times daily or in 150-mg timed-release capsules two or three times daily is often effective in significantly decreasing itching in patients with atopic dermatitis. When used orally, as described here, it does not appear to have beneficial effects in other itchy dermatoses. It should be used as adjuvant treatment in combination with other accepted forms of therapy, since it alone cannot reverse the chronic skin changes brought about by months or years of scratching and rubbing.

Quantification of the characteristics of antagonists exhibiting both competitive antagonism and functional interaction.

Null equations have been derived which, when applied to log10 concentration-tissue state curves for an agonist determined in the presence and absence of a competitive antagonist which also exhibits functional interaction, allow quantitation of the characteristics of the competitive and functional interactant effects. Both the affinity constant of the antagonist for its receptors and numerical values characterizing the functional interaction can be obtained. The null equations have been tested in a model system by using a mixture of papaverine hydrochloride (either 5 or 20 microM) and methyl atropine bromide (10 nM) to mimic a competitive antagonist which also shows functional interaction. Agreement between values derived directly and indirectly from the model is good and validates the use of the null equations.