Interet diagnostique d’une injection intracaverneuse de 20 μg de Prostaglandine E1 dans l’impuissance

Intracavernous injection of 20 μg of prostaglandin E1 (PGE1) was carried out in 130 impotent patients. The erectile response was compared to the results of arteriological investigations including nocturnal penile tumescence and rigidity monitoring (NPTR) in 59 patients. The response of 60 patients positively categorized as exclusively psychogenic or vasculogenic was also compared to the pattern of the response to 80 mg of papaverine observed in a previous study by the same authors. The PGE1 test may not discriminate psychogenic from wholly organic patients since its results are not correlated to those of NPTR. It helps for the screening of vasculogenic impotence. Lack of response or a partly rigid response is consistent with this actiology but is not specific for it. A fully response makes it unlikely. Compared to papaverine, PGE1 induces less non rigid responses in psychogenic patients (15% versus 35% with papaverine) and more fully rigid responses in vasculogenic patients (respectively 12% and 5 %). Consequently the specificity of the PGE1 test is higher but its sensitivity lower than that of papaverine so that there is no clear difference in the effectiveness of the tests. Nevertheless the PGE1 test should be preferred, because it is safer. Prolonged erections occured in only 5 patients, and all ceased spontaneously. However 4 presented severely painful erections.     

Les injections intracaverneuses de prostaglandine E1: un reel progres dans l’efficacite et la securite des injections intracaverneuses

Intracavernosal injections of vaso-active agents were a major breakthrough in the investigation and treatment of impotence. However the first generation agents (papaverine ± phentolamine, phenoxybenzamine) result in a too high rate of complications (prolonged erection, priapism, corporeal fibrosis,), what requires strict precautions, making their use cumbersome and even stressing. A tremendous development of the pharmacological research arises in order to find agents not resulting in those risks. This article reviews the litterature concerning one of them, Prostaglandin E1 (PGE1), and compares its effects in near 4000 patients to those of papaverine ±phentolamine in over 5000. Experimental data suggests that PGE1 might act in normal erection, and its local tolerance might be better than that of Papaverine, specially as regards the risk of fibrosis. The studies without intraindividual comparison done in men tend to confirm this better tolerance: during the workup period, PGE1 induces prolonged erection in 2.7% of men (requiring treatment in only 0.3%) compared to 9.5% with papaverine and 5.3 % with papaverine + phentolamine (p<0.001); during auto-intracavernosal therapy, the rate of prolonged erections is 0.8% with PGE1 compared to 8.7% with papaverine, and the rate of fibrosis is 0.4% versus 3.5 to 5.4% with papaverine (p<0.001). PGE1 induces slightly more erections compatible with penetration than papaverine ± phentolamine (77% vs 73 %). However it induces pain in 23% of the cases, either at the time of injection, or, more specifically, during erection. This pain is intense in only 3.9% of the cases. General tolerance is excellent. The studies with intra-individual comparison confirm the statistically significant reduction of the risk of prolonged erection requiring treatment (1.7% with PGE1 versus 4.3% with papaverine and 6% with the combination, p<0.05) and the increase in efficacy (75% versus 64% with the combination), though papaverine is superior to PGE1 in a minority of the cases. By reducing the risks, PGE1 allows directly using the effective dosage as regards the diagnostic injections. Its higher effectiveness reduces the false-negative rate in the psychogenic patients, and widens the possibilities of the intracavernosal therapy.     

Synthese de la table ronde: “Apport de la Prostaglandine E1 dans l’exploration et le traitement de l’impuissance”

Intracavernosal injections of prostaglandin E1 (PGE1) have induced positive erectile responses in 70% of subjects investigated. Mild pain was reported in 15% of cases, with only 5% describing the pain as annoying. Prolonged erections were uncommon and priapism extremely rare. No systemic or generalised complication has ever been reported in about 1500 subjects. Pharmaco-Döppler, using intracavernosal 10 μg PGE1 injections, and pharmacocavernosometry have been investigated. Self-administered injections are obviously of great interest due to the high prevalence of positive responses and absence of complications. Long-terme tolerance is excellent, far better than with other drugs. PGE1 has also been used, with favourable preliminary findings as a treatment for specific conditions, particularly venous leakage and intractable erectile failure with combined organic and psychogenic lesions. PGE1 is becoming progressively more important in the investigation and management of impotence, principally because of its reliability and innocuous nature.     

Impotence: treatment by autoinjection of vasoactive drugs.

One hundred and twenty five men with psychogenic or organic impotence used autoinjection of the penile corpora cavernosa with either papaverine or papaverine and phentolamine for a mean period of 10.5 months (range 1-24 months) to achieve penile erection for sexual intercourse. Prolonged (over four hours) painless erection resulted from 34 of the 3513 self administered injections. This seems to be a highly effective approach to treating impotence irrespective of the aetiology.     

Topical treatment of erectile dysfunction: randomised double blind placebo controlled trial of cream containing aminophylline,isosorbide dinitrate,and co-dergocrine mesylate.

OBJECTIVE--To examine the effectiveness in treating impotence to topically applied cream containing three vasodilators--aminophylline, isosorbide dinitrate, and co-dergocrine mesylate--which act by different mechanisms. DESIGN--Randomised double blinded placebo controlled crossover trial over two weeks. SUBJECTS--36 men with erectile dysfunction randomly allocated to two equal groups. INTERVENTIONS--Active cream containing aminophylline 3%, isosorbide dinitrate 0.25%, and co-dergocrine mesylate 0.05% for one week and placebo for another. MAIN OUTCOME MEASURES--Patients'' reported experience of penile responses and side effects of treatment in questionnaires. Penile tumescence and arterial flow in the laboratory. RESULTS--21 patients reported full erection and satisfactory intercourse with the active cream. Three men reported full erection and satisfactory intercourse with either cream. The active cream was more effective in psychogenic than organic impotence (eight out of nine men with psychogenic impotence achieved a full erection upsilon four out of eight with neurogenic impotence and two out of seven with arterial insufficiency). No major side effects were reported. In the laboratory the active cream increased penile arterial flow (0.19 (SD 0.08) m/s upsilon 0.02 (0.15) m/s with placebo) and induced tumescence in 24 patients. CONCLUSIONS--Topical treatment with a cream containing three different vasodilators might be considered before intracavernous injection of vasoactive agents, particularly in psychogenic impotence.     

Traitement des dysfonctions érectiles par auto-injections intracaverneuses: comparaison des résultats du moxisylyte et de la prostaglandine E1

We report in this retrospective study the results obtained with the 2 first drugs proposed to reduce the relatively high rates of priapism and fibrosis bound to the papaverine intracavernous injections, ie 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 versus 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.     

Succes des auto-injections intra-caverneuses de Prostaglandine E1 dans des cas d’impuissance par dysfonction veino-occlusive rebelles a la Papaverine

Erectile failure due to veno-occlusive dysfunction (venous incompetence) is generally thought to be resistant to auto-intra-cavernosal injection therapy. Because PGE1 recently emerged as a drug more potent than Papaverine, we tested it in 26 impotent patients presenting this condition. All of them had abnormal Nocturnal Penile Tumescence and Rigidity recording, a non rigid response to intracavernosal injection (ICI) of 80 mg papaverine, and abnormal pharmacocavernosometry (maintenance flow rate exceeding 30 ml/mn after 80 mg of papaverine). When tested with 20 μg of PGE1 and observed for 30 mn in our office, 16 out of 26 developped a rigidity seeming consistent with vaginal intromission, including full rigidity in 2. In several additional patients, partial or full rigidity was achieved after leaving the center. The patients who did not develop rigidity were retested with high dosages. Finally 19/26 developped a rigidity seeming consistent with vaginal intromission within 2 hours of an ICI of 20 to 60 μg of PGE1. Seven of those patients elected to try auto-ICI of 20 to 60 μg of PGE1. The treatment failed in 2. The 5 other ones were able to have intercourse after each ICI, but not without ICI. 2 achieved full rigidity, and 3 only partial rigidity. Papaverine failed in everyone. Until now they have performed about 250 ICI of PGE1, and the maximum follow-up is 18 months. No complications has been observed, including no priapism and no fibrotic nodule. PGE1 widens the possibilities of the auto-ICI therapy. It seems the first medical treatment effective in case of erectile failure due to severe veno-occlusive dysfunction, or at least the most powerful.     

Compartive behavioral effects of dibutyryl cyclic AMP and prostaglandin E1 in mice.

Three behavioral tests, spontaneous locomotor activity (SLMA), exploratory behavior (EB) and rotarod performance (RP), a measure of neuromuscular coordination, were used to stuey the interaction of PGE1 (1 mg/kg i.p., 10 min. pretreatment) with DBcAMP (25 mg/kg i.p., 25 min. pretreatment) in mice. A dose-response relationship of PGE1 (0.01-5.0 mg/kg) to SLMA was determined, with a significant decrease in SLMA produced by a dose of 0.1 mg/kg. decreases in SLMA were produced by PGE1 (79%), DBcAMP (41%) and DBcAMP-PGE1 combination (71%). Similar decreases in EB were observed. Although no significant difference between controls and DBcAMP was observed in RP, 52% of mice tested were RP failures following PGE1 and a 100% failure rate was induced by the combination. Mice were treated with a second injection of DBcAMP or PGE1 or the combination 24 hr following the first injection. Behavioral activity of these mice was observed 25 min (DBcAMP) or 10 min (PGE1) after the second dose was administered. A second injection of DBcAMP failed to decrease SLMA and EB from controls; moreover, SLMA began to return towards control levels as early as 2 hr between injections. The second injection of PGE1 or DBcAMP+PGE1 produced the same behavior as that produced by the first injection. On the basis of these results, the relationship of cyclic nucleotides and PGs to behavioral activity is discussed.     

Apport de l’injection intracaverneuse de Prostaglandine E1 lors de la premiere consultation de l’impuissant: à propos de 414 cas

The authors report their experience of 414 injections of prostaglandin E1 (prostine). The diagnostic orientation between functional or organic impotence was assessed through questionaires and more particularly on the presence or absence of nocturnal or morning erections. The prostine reconditioning and self injection use techniques are precised: 80% of positive responses with better results in the oldest patients, whatever their medical antecedents. No relation between positive response to prostaglandin E1 and normal nocturnal erections could be found. Patients still presenting erections can present good or bad responses. This confirms the results previously given only allow us to put in evidence the good functional and anatomic state of cavernous bodies, without any etiological orientation (not mentioning the cases in which these self-injections reveal the presence of deformation, bend or fibrosis). The acceptance of self injection is low (30%) as well as a regular and prolonged medical observance (only 15%). This work confirms the low rate of local complications after repeated injections and the low rate of prolonged erections or priapism during Test 1. However, these possibilities must incite to prudence as for the generalization of this kind of treatment, out of specialized centers.     

Characteristics of prostaglandin E1 potentiation of inflammatory activity of some agents

In rats pretreated with indomethacin, injection of PGE₁ (prostaglandin E₁) with carrageenan potentiated the carrageenan paw oedema. This effect of PGE₁, was maximal when it was injected together with carrageenan, there being a reduction in the action of PGE₁ if carrageenan injection was delayed after PGE₁ injection. PGE₁ induced potentiation of increase in plasma protein leakage induced by intradermal injections of bradykinin and histamine also depended on the injection of PGE₁ along with these agents. Thus oedema enhancement by PGE₁ differs from its action in pain, where PGs cause a long lasting sensitization of the injected area for the actions of other algesics. Since vasodilation may be a mechanism of oedema enhancement by PGs, the ability of adenosine and papaverine to mimic PGE₁ in paws and skins of rats were examined. Adenosine was active whereas papaverine was inactive in this respect. To clarify this difference, the vasodilatory properties of PGE₁, adenosine and papaverine were assessed by their ability to antagonize NA response in perfused rat mesenteric blood vessels. Only papaverine was effective in antagonising the NA response. Thus, PGE₁ and adenosine which potentiated the oedema inducing actions of other agents showed no vasodilatory properties and papaverine, a vasodilator, had no oedema potentiating actions.     

Serum FSH, LH and testosterone in the male rhesus following prostaglandin injection.

Adult male rhesus were treated with PGE2, PGF2 alpha or the 13,14-dihydro-15-keto metabolite of PGE2 in a randomized crossover design. Serum concentrations of FSH, LH and testosterone were determined and compared to the respective values in the same uninjected animals. No significant changes were noted in controls or following the metabolite injection. FSH increased gradually for 4 hours after metabolite treatment. In contrast, injection of PGF2 alpha was followed by an abrupt (within 15 minutes) increase in LH and testosterone. FSH increased gradually in 2 of 3 treated animals. Injection of PGE2 was followed by a similar abrupt increase in LH concentration. This was not always associated with a significant increase in testosterone or FSH. These results demonstrate that injections of PGE2 or PGF2 alpha can change serum gonadotropin and testosterone concentrations in male rhesus monkeys, and that the effects of these two prostaglandins are qualitatively different.     

Radioreceptor assay in checking serum concentration in long-term treatment with cis(z)-flupenthixol decanoate

24 patients have been treated with cis(z)-flupenthixol decanoate for 6-12 months. Intramuscular injections were given about every 3 weeks. Before treatment and on each day of injection the mental state was assessed by BPRS and registration of side effects was performed. Blood samples were taken 7 days after each injection and on the last day of the dosage interval. Neuroleptic activity was determined in serum by RRA and expressed in cis(z)-flupenthixol equivalents. The drug level was significantly correlated to the dose. No clear relationship between drug level and clinical results as well as side effects was found. Less pronounced variations of the drug level between subsequent injections resulted in a positive therapeutic response.     

Resultats preliminaires d’injections intracaverneuses d’un donneur d’oxyde d’azote (NO), la linsidomine,dans le traitement de l’impuissance

Recent experimental studies showed an important role of endothelium derived relaxing factor (EDRF) for cavernous smooth muscle relaxation. Since nitric oxide (NO) seems to account for the biological actions of EDRF, a study was done to examine a possible role of the NO-donor SIN-1 in the treatment of erectile dysfunction. To determine the therapeutic range, 0.1, 0.2, 0.5 and 1 mg SIN-1 were injected intracavernously in 2 patients with erectile dysfunction each. Then, 40 patients were injected 1 mg SIN-1 including 4 patients that had prolonged erections to minimal doses of papaverine-phentolamine and 4 patients that did not respond with a full erection to other pharmacologic agents. Intracavernous injection of SIN-1 induced a dose dependent erectile response by increasing the arterial inflow and relaxing cavernous smooth muscle. To 1 mg SIN-1, 19 patients had a full, 14 an almost full and 7 a moderate erection. There were no systemic or local side effects. In the patients with prolonged erections to papaverine-phentolamine, the mean duration of a full erection to SIN-1 was 68 minutes. Compared to a papaverine (15 mg/ml)-phentolamine (0.5 mg/ml) mixture, the erectile response to SIN-1 was superior in 8, comparable in 29 and inferior in 3 patients. Our preliminary data suggest a possible role of SIN-1 for the treatment of erectile dysfunction. The absence of prolonged erections by its spontaneous intracavernous decomposition, a maximal smooth muscle relaxation by a receptor independant action and its low cost indicate its potential to become a standard drug for intracavernous pharmacotherapy.     

Multidisciplinary survey of erectile impotence.

A study was done of 220 men referred principally by family physicians to a multidisciplinary erectile dysfunction study group to determine the factors causing or contributing to impotence that had persisted for more than 2 months and for which no cause was apparent. The men were aged 21 to 79 (mean 50.3) years, and the duration of impotence was a few months to 15 years (mean 2.65 years). The men were to be assessed from general medical, endocrinologic/metabolic, psychiatric and urogenital viewpoints. The significance of the causal or contributory factors detected was scored by application of defined criteria and a four-point scale. The degree of loss of potency and of libido as well as level of concern were also scored by each specialist. Impotence was complete in 60%, and an associated decline in libido was reported by 38%. The level of concern was high--that is, normal--in 81% and slightly reduced in 9%. Full investigation by all the specialists was precluded by the severity of other conditions in 16 patients, by the return of potency following relief of anxiety/depression or genitourinary tract infection in 16 and for logistic or other reasons in 34. Although the cause of the impotence could be attributed in 186 of the patients, only 154 were fully assessed. Among these patients general medical factors were contributory in 46%, endocrinologic/metabolic factors in 44%, psychogenic factors (primary or secondary) in 60% and urogenital factors in 49%. Multiple contributing factors were identified in 65%, which underscores the importance of a multidisciplinary approach to assessing many cases of impotence.     

Les traitements pharmacologiques de l'insuffisance érectile

About 10 to 20% of men are affected by erectile dysfunction in France. The prevalence of erectile dysfunction increases with age and has a multifactorial etiology in the great majority of cases. The recent availability of oral treatments has improved the medical approach to erectile dysfunction. After a clinical presentation of erectile dysfunction and its causes, this article deals with the general principle of medical therapy for erectile dysfunction. Oral therapy with sildenafil and other compounds and local therapy by intracavernous injections (papaverine, moxisylyte, prostaglandin E1) or intraurethral administration of PGE1 are reviewed.     

Prostaglandin E2, adenosine 3':5'-cyclic monophosphate and changes in endometrial vascular permeability in rat uteri sensitized for the decidual cell reaction

The possibility that prostaglandin E2 (PGE2) increases endometrial vascular permeability and initiates decidualization in sensitized rat uteri by stimulation of adenosine 3':5'-cyclic monophosphate (cAMP) synthesis was investigated. Immature rats, pretreated so that they were sensitized for the decidual cell reaction, were used. Following the unilateral intrauterine injection of 50 microliters phosphate-buffered saline containing gelatin (PBS-G), a deciduogenic stimulus, uterine concentrations of both PGE and cAMP were elevated as early as 1 min after the intrauterine treatment. To determine if uterine stimuli which increase endometrial vascular permeability also increase uterine cAMP concentrations, rats, treated with or without indomethacin, an inhibitor of PG synthesis, received unilateral intrauterine injections of 50 microliters PBS-G with and without 10 micrograms PGE2 and were killed 15 min later. Uterine cAMP concentrations were elevated in all injected horns except in those of indomethacin-treated rats receiving PBS-G intraluminally, thus paralleling the expected changes in endometrial vascular permeability. As indicated by radioactivity levels in the stimulated horn 15 min after the i.v. injection of 125I-labeled bovine serum albumin, the intrauterine injection of dibutyryl cAMP, with or without theophylline, did not increase endometrial vascular permeability in indomethacin-treated animals. In contrast, cholera toxin, an activator of adenylate cyclase activity, markedly elevated permeability and induced decidualization. Except for the lack of a permeability response to the cAMP analogue, these data are consistent with the hypothesis that the effect of PGE2 on endometrial vascular permeability is mediated by cAMP.     

Impaired febrile responses to immune challenge in mice deficient in microsomal prostaglandin E synthase-1

Fever is a common, centrally elicited sign of inflammatory and infectious processes and is known to be induced by the action of PGE2 on its specific receptors in the thermogenic region of the hypothalamus. In the present work, using genetically modified mice, we examined the role of the inducible terminal PGE2-synthesizing enzyme microsomal prostaglandin E synthase-1 (mPGES-1) for the generation of immune-elicited fever. Animals with a deletion of the Ptges gene, which encodes mPGES-1, or their wild-type littermates were given either a subcutaneous injection of turpentine--a model for aseptic cytokine-induced pyresis--or an intraperitoneal injection of interleukin-1beta. While both procedures resulted in typical febrile responses in wild-type animals, these responses were strongly impaired in the mPGES-1 mutant mice. In contrast, both genotypes showed psychogenic stress-induced hyperthermia and displayed normal diurnal temperature variations. Both wild-type and mPGES-1 mutant mice also showed strongly reduced motor activity following turpentine injection. Taken together with previous observations on mPGES-1 induction in the brain vasculature during various inflammatory conditions and its role in endotoxin-induced pyresis, the present findings indicate that central PGE2 synthesis by mPGES-1 is a general and critical mechanism for fever during infectious and inflammatory conditions that is distinct from the mechanism(s) underlying the circadian temperature regulation and stress-induced hyperthermia, as well as the inflammation-induced activity depression.     

A型肉毒毒素治疗偏侧面肌痉挛和头颈部肌张力障碍的疗效观察

为评估Ａ型肉毒毒素治疗偏侧面肌痉挛和头颈部肌张力障碍的疗效,本文对４２例偏侧面肌痉挛及３４例头颈部肌张力障碍（后者包括１８例眼睑痉挛,１２例Ｍｅｉｇｅ氏病、４例痉挛性斜颈）病人进行Ａ型肉毒毒素肌肉多点注射治疗,并治疗前后的病情分级对比。结果表明,Ａ型肉毒毒素治疗有效率为１００％,疗效持续８～２６周,可重复注射,并再次取得疗效。部分病人局部出现轻度肌无力,数周后均可恢复,无全身毒副作用。结论认为Ａ型肉毒毒素能治疗偏侧面肌痉挛和头颈部局限性肌张力障碍,不失为一种有效安全简便易行的治疗手段。     

Evaluation of papaverine in treatment of impotence]

The results of therapy of 52 male patients with impotence with papaverine are presented. The drug was injected by the intra-cavernous route. Recovery has been achieved in all of them with marked improvement of sexual functions in 73%.     

The involvement of oxytocin in ovulation and in the outputs of cyclo-oxygenase and 5-lipoxygenase products from isolated rat ovaries

The effects on ovulation of a specific anti-oxytocin rabbit serum (anti-OT) (50.0 microliters) given by intrabursal injection into the right ovaries of etherized adult female rats at proestrus, were explored by counting the number of ovulated ova present within the right oviducts. Left ovaries were not treated and served as control ovaries. Control rats were treated with male normal rabbit serum (NRS) (50.0 microliters) given by intrabursal injections into the right ovaries of animals at proestrus. Ovulation was induced by injection of human chorionic gonadotrophin (hCG). Anti-OT administered into the right ovarian bursae of proestrous rat ovaries evoked a significant 51% inhibition of ovulation in comparison with that observed in control non-injected left ovaries (p less than 0.01). Also, when the ovulation of right ovaries injected with anti-OT was compared with that of left ovaries injected with NRS, the number of ovulated ova in the right side was significantly smaller (30%) than on the contralateral side (p less than 0.02). However, in rats pre-treated with hCG the intrabursal injection of oxytocin (OT) (50.0 mU/ml) into right and left ovaries failed to alter the number of ovulated ova compared with that of rats receiving intrabursal injections of saline. The basal control and the OT-evoked synthesis and release of endogenous prostaglandin E2 (PGE2) and PGF2 alpha were explored in ovaries isolated from prepuberal rats injected with pregnant mare's serum gonadotrophin (PMSG), two days prior to sacrifice. OT augmented the basal release of PGF2 alpha but did not influence that of PGE2. Moreover, the conversion of exogenous 14C-arachidonic acid (14C-AA) into different prostanoids and into 5-HETE, in the presence and in the absence of added OT (50.0 mU/ml), was studied in rat ovaries isolated in proestrus. The challenge with OT augmented the basal synthesis and release of PGF2 alpha and of 5-HETE from 14C-AA, but failed to influence the formation of products generated via the cyclo-oxygenase pathway, namely 6-keto-PGF1 alpha, PGE2 and thromboxane B2 (TXB2). Therefore, the present results suggest that ovarian OT may play a role in the ovulatory process, via generation of PGF2 alpha to enhance contractions of ovarian smooth muscle and of 5-HETE to promote follicular collagenolysis.