Intracavernous Injections in Spinal Cord Injured Men With Erectile Dysfunction, a Systematic Review and Meta-Analysis.

INTRODUCTION: Despite improvements in the care of patients after spinal cord injury (SCI), permanent impairment of locomotion, sensation, and autonomic function remains a major hurdle. After the acute stage of injury, recovering sexual function is a high priority. AIM: To review the efficacy of intracavernous injections (ICIs) in men with SCI and to identify prognostic factors affecting the efficacy of ICIs in this population. METHODS: Systematic review of the literature was conducted using the PubMed-Medline, Embase, EBSCO, Web of Science, and Cochrane Library databases. The literature search was restricted to articles published in English, French, and Spanish up to November 2014 using the key words alprostadil, papaverine, moxisylite, alpha-blocking agent, phentolamine, intracavernous injection, spinal cord injuries, paraplegia, quadriplegia, and erectile dysfunction. Studies involving patients with SCI and erectile dysfunction treated with ICIs of alprostadil, papaverine, and α-blocking agents, including retrospective and prospective cohorts, population studies, and randomized controlled trials, were included. MAIN OUTCOME MEASURE: Overall response rate to ICI for erectile dysfunction in patients with SCI. RESULTS: Of 283 studies identified, 23 involved 713 patients with SCI. ICIs resulted in successful erections in 88% of patients (n = 713, 95% CI = 83%-92%). Erections were obtained in 93% of patients (n = 101, 95% CI = 83%-99%) with the combination of papaverine and phentolamine, in 91% (n = 274, 95% CI = 78%-97%) with papaverine alone, and in 80% (n = 119, 95% CI = 64%-90%) with alprostadil. Type of injected drug, doses, level of injury (complete or incomplete), extent of injury, age, time since injury, and persistence or transience of erections were evaluated, but statistical analysis could not identify specific factors predictive of a response to ICI. CONCLUSION: ICIs are an effective treatment of erectile dysfunction in men with SCI. No predictive factor for efficacy could be identified. Studies comparing the response to ICI in upper vs lower motor neuron lesions could improve our understanding of ICI failure.

Noradrenergic control of arginine vasopressin release from the ewe hypothalamus in vitro: sensitivity to oestradiol.

The present study aims at ascertaining the influence of alpha(1)-adrenoreceptors on arginine vasopressin (AVP) release in vitro and determine whether E(2) modulates the alpha(1)-adrenoreceptor and AVP interaction. Ten minutes after ewe killing, sagittal midline hypothalamic slices (from the anterior preoptic area to the mediobasal hypothalamus with the median eminence, 2 mm thick, 2 per sheep) were dissected, placed in oxygenated minimum essential media-alpha (MEM-alpha) at 4 degrees C and within 2 h were singly perifused at 37 degrees C with oxygenated MEM-alpha (pH 7.4; flow rate 0.15 ml/min), either with or without E(2) (24 pg/ml). After 4 h equilibration, 10 min fractions were collected for 4 h interposed with 10 min exposure at 60 min to a specific alpha(1)-adrenoreceptor agonist or antagonist at various doses (0.1-10 mm). At the end of all perifusions, slices responded to KCl (100 mm) with AVP efflux (p < 0.05). Release of AVP was enhanced (p < 0.05) by the alpha(1)-adrenoreceptor agonist (methoxamine 10 mm; no E(2), n = 7 perifusion chambers: from 14.3 +/- 2.7 to 20.9 +/- 3.9, with E(2), n = 10: from 10.7 +/- 1.2 to 18.4 +/- 3.4 pg/ml) or the antagonist (thymoxamine 10 mm; no E(2), n = 5: from 9.5 +/- 3.1 to 30.4 +/- 6.0, with E(2), n = 10: from 10.8 +/- 0.9 to 39.1 +/- 6.3 pg/ml). With the agonist, the response occurred only at 80 min (p < 0.05) both in the presence and absence of E(2). Whereas, after the antagonist, values were higher (p < 0.05) throughout the post-treatment period (80-170 min) without E(2), but declined by 150 min in the presence of E(2). Furthermore, the response to the alpha(1)-adrenoreceptor antagonist was greater (p < 0.05; 90-140 min) than the agonist only in the presence of E(2). In conclusion, these results reveal direct alpha(1)-adrenoreceptor-mediated control of the hypothalamic AVP neuronal system which is modulated by E(2).

[Intracavernous injections in the treatment of erectile dysfunction in spinal cord injured patients: experience with 36 patients]. / Utilisation des injections intracaverneuses dans les dysfonctionnements érectiles du blessé médullaire : à propos d'une expérience sur 36 patients.

OBJECTIVES: To confirm the efficiency of intracavernous injections in the treatment of erectile dysfunction in spinal cord injured (SCI) patients and to determine the mean necessary dose to obtain functional erection. MATERIALS: This prospective study concerns 36 spinal cord injured men. None of them had erectile dysfunction before the neurologic impairement. Sixty four intracavernous injections were performed. METHOD: The first injection was done with the usually recommended starting dose. The injections were then repeated with increasing dosage to archive a rigid erection. The erection was evaluated with Schramek grading. A grade 4 or 5 erection was considered as functional. RESULTS: Nine tetraplegics and 27 paraplegics were included. Twenty two were grade A in ASIA classification. The mean age was 31 years. Twenty for patients had a level above T10, 11 between T11 and L2, one below L2. Twenty seven patients obtained an erection of grade 4 or 5. Alprostadil was used 51 times, moxisylite nine times and papaverine four times. The average dose necessary to obtain a grade 4 or 5 functional erection adequate for coitus was 12.3 +/- 4.8 microgram with alprostadil and 14 +/- 5.4 mg with moxisylite. No side effects were noted. The nine left patients did not archive satisfying erection during this study. No clinical differences were noted in this population, compared with the 27 other patients. CONCLUSION: The findings confirm the efficiency of intracavernous injections in the management of erectile dysfunction in SCI. The average doses required to obtain a functional erection was 12.3 (+/- 4.8) microgram with alprostadil and 14 (+/- 5.4) mg with moxisylyte.

Comparative pupil dilation using phenylephrine alone or in combination with tropicamide.

OBJECTIVE: A prevalence survey of actinic and other eye diseases was conducted in Nambour, Queensland, Australia, in 1992. Pupils were dilated with phenylephrine alone for cataract identification because there were concerns that patient discomfort, due to cycloplegia occurring with the usual dilating agents of tropicamide and phenylephrine, may influence future compliance in an associated intervention study. This validation study was undertaken to measure the possible underestimation of cataract prevalence in this community study, which may have occurred because of inadequate dilation from phenylephrine alone. DESIGN: The study design was a repeated measures experimental design. PARTICIPANTS: Forty-seven normal subjects participated in the study. Both eyes were tested. INTERVENTION: Pupil diameter after dilation with three drops of 10% phenylephrine alone was compared with pupil diameter after dilation with three drops of 10% phenylephrine together with three drops of 1% tropicamide. The two regimens were given to the same subjects 1 week apart. Reversal was attempted with thymoxamine hydrochloride 0.5%. MAIN OUTCOME MEASURES: Pupil diameter was assessed using a Neitz cataract camera, and accommodation reserve also was measured. Subjects' subjective appreciation of return of ocular function was assessed by a questionnaire. Repeated measures analysis of variance, paired t test, McNemar's test, and Wilcoxon signed rank test were used to analyze outcomes. RESULTS: Mean maximum pupil size with 10% phenylephrine and 1% tropicamide was significantly larger than pupil size after the use of 10% phenylephrine alone (F1,19 = 18.99, P = 0.0003). However, there was no significant difference between the two dilation regimens when comparing the proportion of subjects who dilated to 6 mm or more (McNemar's X(2)1 = 2.7, P > 0.1). Compared with 10% phenylephrine and 1% tropicamide, pupil diameters were significantly smaller (t46 = 16.77, P = 0.0001), and accommodation reserve greater (t46 = 4.14, P = 0.0001), 40 minutes after reversal with thymoxamine in the group dilated with 10% phenylephrine alone. CONCLUSION: Pupil dilation with 10% phenylephrine alone, if allowed at least 40 minutes to act, will be as satisfactory for the identification of cataracts in a normal population as 10% phenylephrine and 1% tropicamide and is more acceptable because of reduced problems with glare and accommodation.

Metabolism of 14C-moxisylyte after percutaneous application in hairless rat.

The pharmacokinetics of 14C-thymoxamine (4-(2-dimethylaminoethoxy)-5-isopropyl-2-methyl phenyl acetate, CAS 54-32-0, moxisylyte, Carlytène) were studied in female hairless rats following different administration routes: oral, intravenous or percutaneous. After percutaneous administration, the half-life of elimination of 14C-thymoxamine and its metabolites was longer (t 1/2 = 15 h) than after oral or intravenous administration (t 1/2 = 9 h). The penetration/resorption phenomenon of thymoxamine base mainly located in the horny layer could explain the high value of the pseudo half-life of elimination observed after percutaneous administration. Due to the absorption slower than elimination, this special pharmacokinetics had to be considered as a flip-flop model. The type and proportions of thymoxamine metabolites recovered in plasma varied according to the route of administration. The unconjugated metabolites, desacetyl-thymoxamine (DAT) + desacetyl-desmethyl-thymoxamine (DMAT), were observed only after intravenous or percutaneous administration, they represented 12% and 15%, respectively. They were never observed after oral administration suggesting the existence of a hepatic first-pass metabolism. The other metabolites observed were sulphate conjugates and glucuronides of DAT + DMAT. The values of sulfoconjugates were constant with each administration route (21%), whereas glucuronides increased with oral administration. In conclusion, the pharmacokinetics of percutaneous thymoxamine presented two main features: the drug absorption was high and durable (t 1/2 = 15 h); the cutaneous application allowed to avoid the hepatic first-pass metabolism.

[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.

[Efficacy and tolerance of intracavernous injection of moxisylyte in patients with erectile dysfunction: double-blind placebo-controlled study]. / Efficacité et tolérance du moxisylyte en injections intracaverneuses chez des patients ayant une dysérection: étude en double aveugle contrôlée par placebo.

OBJECTIVE: To evaluate the efficacy of intracavernous moxisylyle versus placebo in patients with erectile dysfunction of various origins. To assess the local tolerance and systemic safety of moxisylyte by self-administered injection. METHODS: Multicentre study, comprising two treatment phases: The first, double-blind phase, was conducted in two parallel groups of randomized patients, over a 1-month period (1 injection per week) in the investigator's office; the second phase was conducted under open conditions in the patient's home, over a period of 3 to 11 months. Self-administered injections (1 to 2 per week) were performed using a prefilled syringe containing 10 mg of moxisylyte. RESULTS: Out of 307 patients evaluated during the first phase, the qualitative and quantitative superiority of erectile response induced by moxisylyte compared to placebo was confirmed (p < 0.0001). The stability of the response to moxisylyte was also confirmed on 4 injections, and the frequency of responses compatible with sexual intercourse ranged from 48% to 52% from one injection to another. This efficacy was also maintained during the open phase, as 92% of the 4,487 self-administered injections generated positive erectile responses. The quality of these responses was considered sufficient to allow sexual intercourse after 62% of injections. The local tolerance was considered to be excellent for more than 95% of injections, without any major adverse effects, and a very low risk of prolonged erection and fibrotic reaction. The systemic safety was also considered to be excellent for more than 98% of erections. CONCLUSION: This study confirms the possibility of obtaining an erectile response by intracavernous injection of 10 mg of moxisylyte with a very low incidence of local and systemic adverse effects. It also tends to confirm the superior efficacy of moxisylyte by self-administered injections at home than by injection in the doctor's office.

[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.

Pharmacokinetics study of 14C-moxisylyte after percutaneous application to hairless rat.

The percutaneous pharmacokinetic parameters of 14C-thymoxamine (4-(2-dimethylaminoethoxy)-5-isopropyl-2-methyl phenyl acetate, moxisylyte, Carlytène) were studied on female hairless rats. Animals received 30.3 mg/kg of thymoxamine-base (CAS 54-32-0) percutaneously (dorsal skin). The decrease of the radiolabelled compound on the skin surface (drug penetration) and the appearance of the total radioactivity in plasma (drug absorption) were measured. The time-course study of the total radioactivity measured on the skin surface indicates a biphasic profile with a rapid decrease during the first h (t1/2 from 0 to 4 h = 1.4 h) and then a less rapid one (t1/2 after 4 h approximately 29 h). Plasma data demonstrated that 14C-thymoxamine was rapidly and almost entirely absorbed (91%) after percutaneous application. The values of absorption parameters suggest that thymoxamine is a compound with a high absorption process using this route of administration. The t(max) value was about 2 h and the half-life of absorption was 0.70 h. Compared to the apparent half-life of elimination observed after oral or i.v. administration (t1/2 = 9 h),the elimination phase of thymoxamine was relatively rapid after percutaneous administration (t1/2 = 15 h). The penetration /absorption phenomenon of thymoxamine base mainly located in the horny layer could explain the higher value of the half-life of elimination observed after percutaneous administration.

[Treatment of erectile insufficiency]. / Traitement de l'insuffisance érectile.

Impotency, or impaired erectile function, affects approximately 10% of the adult males in France. The psychological consequences can have a major impact not only on the subject's sexual life but also his familial and professional relationships. The task facing the urologists is to carefully evaluate the patient's request for care and adapt treatment not only to the physiological situation but also the patient's psychological and social context. Several approaches have been developed. Search for an aetiology, excepting exceptional cases with a recognized organic origin, is often unsatisfactory due to the multifactor processes involved and the self-sustaining inter-relationship between the psychological impact and the physiological disorder. Sex therapy is aimed at reducing anxiety and helping the couple better understand their sexual relationship. Such behavioural counselling is particularly indicated in absence of organic disorders or as complementary therapy combined with medical or surgical treatment. The pharmacological approach relies on alphablockers or certain psychotropic drugs which have a moderate but real effect when taken orally. Local non-invasive applications of protaglandin E1 can also improve erectile function. The mechanism of intrapenial injections is to release the erectile smooth muscles. The most widely used drugs in France are papaverine, phentolamine and moxisylite as well as prostaglandin E1. Self-injections may be required in certain cases but are abandoned by about half of the patients after one or two months. Vacuum with a mechanical pump can produce a non-physiological erection but is rarely used in France. Surgical repair of arterial or venous disorders can also provide excellent, particularly long-term, results in carefully selected patients. Despite undeniable progress, the treatment of impotency remains a difficult therapeutic challenge, basically due to the large number of casual factors and their complex interactions.

[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.

Metabolism of 14C-moxisylyte in hairless rat. Comparison between intravenous and oral route.

The pharmacokinetics of 14C-thymoxamine (4-(2-dimethylaminoethoxy)-5- isopropyl-2-methyl phenyl acetate hydrochloride) (moxisylyte, Carlytène) was studied on female hairless rats. Animals received 5 mg/kg of thymoxamine-HCl (CAS 964-52-3) intravenously or orally. 14C-thymoxamine was both rapidly and entirely absorbed after oral administration, Tmax value was observed at 0.25 h. The decrease of the total radioactivity followed a biexponential mode. After intravenous and oral administration, the apparent half-live of distribution were 0.20 and 0.31 h, respectively, whereas the apparent half-live of elimination were 9.6 (i.v.) and 8 h (p.o.). The nature and proportions of thymoxamine metabolites recovered in the plasma varied according to the route of administration. After intravenous administration, desacetyl-thymoxamine (DAT) + desacetyl-desmethyl-thymoxamine (DMAT), sulphate conjugates and glucuronides of DAT + DMAT represented 12, 21 and 63%, respectively. After oral administration, the values were 0, 21 and 79%, respectively. These results underlined the importance of the hepatic first-past effect which induced the disappearance of DAT and DMAT, and increased the levels of glucuronides when thymoxamine was orally administered. The level of sulphate conjugates for DAT and DMAT seems always constant.

Intraocular thymoxamine or acetylcholine for the reversal of mydriasis.

In a placebo-controlled prospective study, thymoxamine 0.02% or acetylcholine 1.0% or thymoxamine 0.01% plus acetylcholine 0.5% were used intraocularly to reverse mydriasis during cataract surgery. Prior to surgery, pupils were dilated with scopolamine 0.25%, tropicamide 1%, and phenylephrine 10%. At the end of surgery, 228 eyes were randomly assigned to 1 of 4 different treatments: 57 eyes each received intracamerally thymoxamine 0.02%, acetylcholine 1%, a combination of both drugs, or placebo. At 5 min posttreatment, there was a significant mean pupillary constriction of 1.86 +/- 0.67 mm following acetylcholine administration and 1.53 +/- 0.80 mm following thymoxamine application as compared with the placebo group, in which the pupillary diameter remained almost constant. For the combination of acetylcholine plus thymoxamine the effect was fully additive, with a pupillary constriction of 3.42 +/- 0.98 and 4.04 +/- 1.02 mm being observed at 5 and 10 min posttreatment, respectively. No drug-related side effect was detected. We conclude that thymoxamine can be useful during surgery as an intraocular miotic to reverse mydriasis and can considerably enhance miosis when given in combination with acetylcholine.

Pharmacokinetics of thymoxamine in rabbits after ophthalmic and intravenous administration.

The pharmacokinetics of thymoxamine hydrochloride were studied in rabbits by the assessment of its ocular and systemic absorption after instillation of thymoxamine hydrochloride 0.5% eye drops. Plasma levels were compared with those observed after i.v. bolus administration of thymoxamine hydrochloride at 2.5 mg/kg. Deacetylthymoxamine is the main metabolite of thymoxamine, generated by esterase hydrolysis. It was evaluated, as an indication of the parent drug, in aqueous humor and plasma by an HPLC method with fluorescence detection (detection limit = 5 ng/ml). Thymoxamine was found to permeate the cornea and to be hydrolysed very quickly, showing very good absorption with a maximum aqueous humor concentration of deacetylthymoxamine of 2329 ng/ml 15 min after eye drop instillation. The study of the systemic absorption of thymoxamine allowed the exclusion of the possibility of systemic side effects following ocular treatment. In fact, considering the detection limit of the method, the plasma levels of deacetylthymoxamine are certainly more than 100-times lower than those observed with intravenous treatment.

Multiple-dose pharmacokinetics of moxisylyte after oral administration to healthy volunteers.

The pharmacokinetics of moxisylyte in plasma and urine was investigated after oral administration. Twelve subjects were treated orally, twice daily with 240 mg of the drug for 6 days; on day 7, the subjects received a last dose of 240 mg of moxisylyte. Moxisylyte was assayed in plasma and urine by a specific HPLC method with fluorimetric detection. Moxisylyte was absorbed rapidly and changed to its metabolites immediately after drug administration; unchanged moxisylyte was not found in plasma. Two metabolites were found in plasma and urine: conjugated desacetylmoxisylyte (DAM) and the conjugate of desmethylated DAM (MDAM). The pharmacokinetic parameters determined after the first oral administration were not modified on multiple dosing. The apparent elimination half-lives of conjugated DAM and MDAM were 2.3 and 3.5 h, respectively. Elimination of these two metabolites in urine averaged 50 and 10%, respectively.