Are alpha-blockers involved in lower urinary tract dysfunction in multiple system atrophy? A comparison of prazosin and moxisylyte.

Lower urinary tract dysfunction is a major cause of morbidity in patients with multiple system atrophy (MSA). alpha1-Adrenergic receptors are present in the proximal urethra where impaired relaxation may be responsible for voiding difficulty and a large amount of residual urine. An open study was designed to evaluate whether the blockade of these receptors by prazosin (a nonselective alpha1 blocker) and moxisylyte (an alpha1A-selective blocker) would improve bladder emptying in patients with MSA. Post-micturition residual volumes and clinical symptoms of 49 patients with MSA were evaluated at trial entry and after 4 weeks (prazosin; n=21 and moxisylyte; n=28). The respective means for the prazosin and moxisylyte groups were 38.1% and 35.2% reductions in residual urine volume (P<0.05), and there was lessening of urinary symptoms. Side effects due to orthostatic hypotension were seen in 23.8% of the prazosin group but in only 10.7% of the moxisylyte group. These effects were common in patients with postural hypotension of more than -30 mmHg at trial entry (P<0.05). Modulation of alpha1-receptors may function in the management of lower urinary tract dysfunction in MSA.

[Reduction of endothelial cell number by cataract operation with intraocular thymoxamine administration. A randomized, double-blind study]. / Endothelzellzahlreduktion durch Kataraktoperation bei intraokularer Anwendung von Thymoxamin. Randomisierte doppelt maskierte Studie.

BACKGROUND: Thymoxamine, an alpha-1-receptor blocker, considerably enhances miosis when given intraocularly in combination with acetylcholine. We investigated whether intraocular use of thymoxamine 0.02% reduced the number of endothelial cells. PATIENTS AND METHODS: After phacoemulsification of 59 eyes, either thymoxamine 0.02%, acetylcholine 1.0% or buffered saline solution was given intraocularly. With a contact specular microscope, corneal endothelial cell photographs were taken on the day before treatment and 3 days and 6 weeks after surgery. RESULTS: There were no statistically significant differences between endothelial cell counts of eyes treated with thymoxamine (-7.2%), acetylcholine (-10.2%) or BSS (-9.4%). CONCLUSION: This study shows for the first time that thymoxamine, when given in the anterior chamber after phacoemulsification, does not cause a greater loss of endothelial cells than acetylcholine or buffered saline solution.

Intracavernous pharmacotherapy: comparison of Moxisylyte and prostaglandin E1.

We report in this retrospective study the results obtained with the first two drugs proposed to reduce the relatively high rates of priapism and fibrosis bound to the papaverine intracavernous injections, i.e. the alpha-blocking agent Moxisylyte (Mox), and prostaglandin E1 (PGE1). Each drug was used for auto-injections in 130 patients with a comparable mean follow up (14.8 months with Mox compared to 14.6 with PGE1). PGE1 proved to be significantly more efficacious (good results in 71% of the patients vs 50% with Mox), especially in the arteriogenic patients (respectively 96% vs 46%). Conversely PGE1 induced prolonged erections in significantly more patients (11 vs 1 with Mox), including 2 priapisms, and also induced pain in more patients (12 vs 1 with Mox). The rate of fibrotic nodules and plaques was low (2 and 3 patients). Despite the better tolerance of Mox, its continuation rate was significantly lower than that of PGE1, PGE1 can be the first choice agent in most cases. Mox is mainly indicated in the patients with supersensitivity to the injections and in those with significant pain following PGE1.

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous infusion and intracavernous administration with and without a penile tourniquet.

The concentration-time profiles of metabolites of moxisylyte (or thymoxamine), an alpha-blocking agent, were investigated in 18 healthy volunteers after intravenous (i.v.) and intracavernous (i.c.) administrations with and without a tourniquet. Four metabolites, unconjugated desacetylmoxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulfates, were found in plasma and urine. For all metabolites, tmax was significantly increased after i.c. administrations and Cmax was significantly decreased. Maximum plasma level of unconjugated DAM was lower after i.c. administration with (1.81-fold) and without (1.26-fold) a tourniquet than after i.v. administration (43.6 +/- 19.6 ng/ml). The elimination half-life of each metabolite showed no change between the three treatments. The difference of 19 min between the mean residence times of unconjugated DAM after i.c. administration with and without a tourniquet may be compared with the difference between the mean duration of the intumescence, that is, 19 min (73 and 54 min with and without a tourniquet, respectively). Total percentages of metabolites recovered in urine were 66.2 +/- 20.9, 61.4 +/- 12.2, and 58.7 +/- 9.1% after i.v. and i.c. administrations with and without a tourniquet, respectively. In conclusion, tourniquet placed before i.c. administration increased the mean residence time of unconjugated DAM of approximately 25% and seemed to increase the efficacy of the drug in healthy volunteers.

Pharmacokinetics of moxisylyte in healthy volunteers after intracavernous injection of increasing doses.

OBJECTIVE: The concentration-time profiles of specific metabolites of moxisylyte, an alpha-adrenoceptor blocking agent, in the plasma and urine from 18 healthy volunteers were investigated after intracavernous (IC) administrations at three dose levels (10, 20 and 30 mg). RESULTS: Four metabolites, unconjugated desacetyl-moxisylyte (DAM), DAM glucuronide, and DAM and monodesmethylated DAM (MDAM) sulphates were found in plasma and urine. For all metabolites, t1/2 elimination was independent of the administered dose (1.19 h for unconjugated DAM; 1.51 h for DAM glucuronide; 1.51 h for DAM sulphate; and 2.17 h for MDAM sulphate). Cmax and AUC increased in direct proportion to dose, except for the inactive DAM glucuronide. Any the differences detected were small and equivalence of the three doses can be accepted. CONCLUSION: The pharmacokinetics of moxisylyte in humans following intracavernous administration were linear in the dose range 10 to 30 mg.

[Prolonged use of moxisylyte chlorhydrate (Icavex) by intracavernous self-injections in the treatment of impotence. Evaluation of long-term tolerance]. / Utilisation prolongée de chlorhydrate de moxisylyte (Icavex) en auto-injections intra-caverneuses dans le traitement de l'impuissance. Evaluation de la tolérance à long terme.

Moxisylyte chlorhydrate is a selective alpha-blocker of the post-synaptic alpha 1-adrenoreceptors. It has been used since 1992 for self-injections to induce erection. Tolerance has been studied in open trials in 143 men using 20 mg per intracavernous injection. Among these subjects, 104 were followed for 11 months. Self-administration was performed 7,509 times, i.e. 49.1 injections per subject over a mean period of 307 days. No severe side effects were observed. A total of 1,041 undesirable effects were reported by 90 subjects (75.1%), including mechanical disorders (28.2%) such as pain and burning sensation at injection, hematomas and ecchymoses. Nodules developed in 0.08% of these cases but always regressed. In 71.8% of the cases, the undesirable events was imputable to moxisylyte: dry mouth (2.73%), somnolence (1.9%), sinus congestion (0.71%). No case of priapism was reported. Long-term evaluation showed a reduction in the main undesirable effects with time. This fall off in the mechanical events could be explained by the subjects become for familiar with the technique. Pharmacological effects remain to be analysed. Added to the good tolerance, this result suggests that self-injection can be proposed as a first intention treatment for impotency.

[Effectiveness of and tolerance to intracavernous injection of moxisylyte in patients with erectile dysfunction: effect/dose relationship versus placebo]. / Efficacité et tolérance du moxisylyte en injection intracaverneuse chez le patient présentant un dysfonctionnement érectile: relation effet/dose versus placebo.

The authors investigated the optima dose (efficacy and safety) of moxisylyte, an alpha-blocking agent, in a double-blind placebo-controlled crossover study in 30 patients. The origin of the erectile dysfunction was predominantly psychological in 14 patients and neurological in 16 patients. Each patient received 4 intracavernous injections in a randomized order (placebo, 10, 20, 30 mg of moxisylyte) at 7-day intervals. Regardless of the dose, moxisylyte induced significantly greater penile responses than placebo on all erection criteria. The frequency of responses allowing sexual intercourse appeared to be dose-dependent in the two aetiological groups. The erectile responses most frequently obtained were complete rigidity in the "neurological" group and tumescence in the "psychological" group. The safety was excellent for 95.6% of injections and no case of priapism was observed. One patient (neurological patient) experienced two prolonged erections after the dose of 20 mg and another patient (psychological patient) reported 2 headaches after the dose of 30 mg. No pain was experienced on injection. Moxisylyte is very well tolerated and is able to induce an erectile response from the dose of 10 mg. This dose appears to be sufficient in patients with central neurological erectile dysfunction; a dose of 20 mg tends to improve the quality of response in patients with a predominantly psychological disorder, although the differences observed between the doses were not statistically significant in this number limited of patients.

[Changes in urethral pressure after intravenous injection of moxisylyte hydrochloride in urethral instability in women. Preliminary results]. / Evolution des pressions urétrales après injection intraveineuse de chlorhydrate de Moxisylyte dans l'instabilité urétrale de la femme. Résultats préliminaires.

OBJECTIVE: To study the action of an alpha blocker, Moxisylyte hydrochloride, during an intravenous test on the course of urethral pressure in women with urethral instability associated with urethral hypertonia. METHODS: The population consisted of 20 women with a mean age of 38 years, presenting with a clinical disorder of micturition (urinary incontinence: 15 cases, urgency: 17 cases, frequency, 17 cases) present for an average of 4 years and associated with resting urethral pressure variations ranging from 22 to 88 cm H2O (mean: 44.8 cm H2O) and static urethral pressures ranging 72 to 150 cm H2O (mean: 102.5 cm H2O). An urodynamic assessment was performed before and after intravenous injection of Moxisylyte hydrochloride at the dose of 0.5 mg/kg. RESULTS: Moxisylyte hydrochloride induced a significant reduction of urethral pressure variations, ranging from 8 to 42 cm H2O (mean: 21.9 cm H2O) and static urethral pressures, ranging from 47 to 102 cm H2O (mean: 68.8 cm H2O). Treatment was well tolerated in every case. CONCLUSION: These preliminary results need to be completed by a randomized placebo-controlled study to confirm a statistically significant effect of Moxisylyte hydrochloride on urethral pressure stability in women presenting with urethral instability.

The antimigraine effect of ergotamine: a role for alpha-adrenergic blockade?

The hypothesis that alpha-adrenergic receptor blockade accounts for the ability of ergotamine to stop migraine attacks was tested, in migraine patients, in an experimental migraine model based on nitroderivative- induced attacks. In a preliminary single blind, placebo controlled study, thymoxamine, a prevalently post-synaptic alpha adrenergic receptor antagonist, was able to abort migraine attack in 9 out of 10 patients, as opposed to 2 out of 10 by placebo (p < 0.005 Fisher's exact test). In a subsequent randomized, crossover, placebo controlled double blind study, the ability of a selective alpha-1 adrenergic receptor agonist, methoxamine, to block ergotamine antimigraine effect was studied. In 26 patients migraine was induced in two separate tests and then ergotamine was administered once after methoxamine pretreatment and once after placebo; methoxamine was significantly more effective than placebo in blocking antimigraine effect of ergotamine (p = 0.0055 Fisher's exact test). These results support the hypothesis that ergotamine alpha-1 adrenolytic properties may account for its antimigraine effect suggesting that this action takes place outside the blood-brain barrier, since methoxamine can cross it very poorly. Ergotamine target structure could be the trigeminal innervation of the extracranial and/or dural vessels.

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and intracavernous administration.

The concentration-time profiles of metabolites of moxisylyte, an alpha-adrenergic receptor blocking agent, in the plasma of 12 healthy volunteers were investigated after intravenous (iv) and intracavernous (ic) administrations. The study was conducted in open, randomized, Latin Squares. Plasma levels of moxisylyte and its biotransformation products were assayed by a specific high-performance liquid chromatography method with fluorescence detection. Three metabolites, unconjugated desacetylmoxisylyte (DAM), conjugated DAM, and conjugated monodesmethylated DAM (MDAM), were found in plasma. After iv administration, unconjugated DAM appeared in plasma in < 5 min; the formation of this metabolite is slightly lower after ic administration (half-life, 6.08 +/- 2.33 min). Maximum plasma levels (57.2 +/- 29.4 ng/mL) and area under the curve of concentration versus time (43.3 +/- 11.4 micrograms.h/L) were significantly lower after ic administration than after iv administration (352.8 +/- 287.6 ng/mL and 152.6 +/- 0.247 micrograms.h/L, respectively). For conjugated DAM, the time to reach the maximum concentration is significantly increased after ic administration (0.9 h instead of 0.46 h) and the maximum concentration is significantly decreased (163.5 ng/mL instead of 203.4 ng/mL). The other pharmacokinetic parameters show no change between the two routes of administration. The pharmacokinetic parameters computed for MDAM are in the same range after iv and ic administrations, and there are no significant statistical differences.

Dose-related effect of moxisylyte on maximal urethral closing pressure in patients with spinal cord injuries.

The effects of single intravenous doses of 0.25, 0.50, and 0.75 mg/kg moxisylyte on maximum urethral closure pressure were evaluated in a placebo-controlled double-blind experiment in 20 patients with spinal cord injuries. Pharmacodynamic testing was performed until 30 minutes, and blood pressure was assessed until 60 minutes. Our findings showed a dose-dependent decrease in maximum urethral closure pressure. At each individual time point, the three doses differed significantly from placebo. Ten minutes after dose administration the maximum effect (48% decrease) was obtained with 0.75 mg/kg. A significant difference in favor of the highest dose was shown from 15 to 20 minutes after administration. According to these findings and because 0.75 mg/kg was as well tolerated as the two other doses, such a drop in pressure indicates that the alpha-blocking agent moxisylyte may be an effective means of decreasing urethral resistance, with obvious implications for the management of urinary obstruction.

Efficiency and side effects of intracavernous injections of moxisylyte in impotent patients: a dose-finding study versus placebo.

We assessed the efficiency and tolerance of the alpha-blocking agent moxisylyte in 2 double-blind studies versus placebo performed in 12 neurogenic patients with spinal cord lesions and in 61 patients presenting with either psychogenic impotence (30) or erectile dysfunction that was predominantly neither psychogenic, hormonal nor neurogenic (31). In each etiological group patients were randomized (according to latin square method) to receive 3 single doses (10, 20 and 30 mg.) of moxisylyte and a placebo. The erectile response was determined 5, 10, 15, 20 and 30 minutes after each injection. Whatever etiology of impotence and dosage tested, the erectile response induced by moxisylyte was significantly higher than the placebo-induced response. No difference occurred among the 3 doses. In 93% of the patients moxisylyte induced an erectile response, including tumescence in 6, partial rigidity in 16 and complete rigidity in 46. Thus, in 62 of 73 patients (85%) the drug allowed initiation of erection adequate for intercourse. Placebo induced such erection in only 25% of the cases and in 55% there was no response. Tolerance was good and no priapism occurred. Only 4 patients (5%) reported mild pain during injection but erections were never painful, 1 presented with moderate and transient hypotension at the 20 mg. dose and a painless prolonged erection was observed in 1 case after the lowest dose. Drugs such as moxisylyte should be given before less well tolerated drugs.

Pharmacokinetics of moxisylyte in healthy volunteers after intravenous and oral administration.

The concentration-time profiles of metabolites of moxisylyte, an alpha-blocking agent, in the plasma and urine of 12 healthy volunteers were investigated after intravenous (iv) and oral (two formulations) administration. The study was conducted with an open, randomized Latin squares design. Plasma and urine levels of moxisylyte and its biotransformation products were assayed by a specific HPLC method with fluorescence detection. Plasma levels declined in a monophasic or biphasic pattern depending on the subject. Two metabolites, conjugated desacetylmoxisylyte (DAM) and conjugated monodesmethylated DAM (MDAM), were found in plasma and urine. Unconjugated DAM was found in plasma only after iv administration. The apparent elimination half-lives of unconjugated DAM, conjugated DAM, and MDAM were 0.86, 1.7, and 3 h, respectively. The total amounts of metabolites (expressed as the equivalent of DAM) excreted in the urine were 75% after i.v. administration and 68 and 69% after oral administration of the two formulations. Oral absorption appeared to be complete for the two treatments. There was no statistical difference between the two oral formulations studied.