Double-blind, placebo-controlled safety and ef cacy trial with yohimbine hydrochloride in the treatment of nonorganic erectile dysfunction

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1 International Journal of Impotence Research (1997) 9, 155±161 ß 1997 Stockton Press All rights reserved /97 $12.00 Double-blind, placebo-controlled safety and ef cacy trial with yohimbine hydrochloride in the treatment of nonorganic erectile dysfunction H-J Vogt 1, P Brandl 1, G. Kockott 2, JR Schmitz 2, MH Wiegand 2, J Schadrack 3 and M Gierend 3 1 Dermatologische Klinik und Poliklinik; 2 Psychiatrische Klinik und Poliklinik, Technische UniversitaÈt MuÈnchen, Munich, Germany; and 3 Medicomp Gesellschaft fuèr Versuchsplanung und Datenanalyse mbh, Ulm, Germany This double-blind, placebo-controlled clinical trial of yohimbine hydrochloride included 86 patients with erectile dysfunction and without clearly detectable organic or psychologic causes. The patient group ful lled all entry criteria; 85 of these could be considered for the Safetyrespectively 83 for the Intention-to-treat (ITT)-analysis. Yohimbine was administered orally in a dosage of 30mg a day (two 5mg tablets three times daily) for eight weeks. Patients were seen for follow-up after four weeks' treatment, and for a nal visit after eight weeks. Ef cacy evaluation was based on both subjective and objective criteria. Subjective criteria included improvement in sexual desire, sexual satisfaction, frequency of sexual contacts, and quality of erection (penile rigidity) during sexual contact/intercourse. Objective criteria of outcome were based on improvement in penile rigidity determined by use of polysomnography in the sleep laboratory. Overall Yohimbine was found signi cantly more effective than placebo in terms of response rate: 71 vs 45%. Yohimbine was well-tolerated: Only 7% of patients rated tolerability fair or poor, and most adverse experiences were mild. There was no serious adverse event. Keywords: yohimbine hydrochloride; erectile dysfunction; nocturnal penile tumescence (NPT); polysomnography; clinical trial Introduction Erectile dysfunction affects at least 1±2% of the male population and possibly up to 9%, according to Spector and Carey. 1 It is a serious problem for many patients and therapeutic options that are convenient, safe, and effective are desirable. Oral treatment of erectile dysfunction with yohimbine hydrochloride, an a 2 -adrenergic receptor blocker, has been the focus of persistent medical interest. Yohimbine is an indol alkaloid derived from the bark of Corynanthe johimbe, a tree indigenous to Central Africa. It has been used for more than a century in treatment of libido and erectile disorders. As a nonstandardized whole or bark extract, yohimbine was usually one ingredient in various compounds and preparations. Once yohimbine was identi ed as the main active constituent, puri ed and standardized drug became available. Borelli 2 considered it the prime aphrodisiac in terms of quality of medical documentation and clinical utility. Yohimbine is a selective competitive a 2 -adrener- Correspondence: Dr H-J Vogt. Received 18 December 1996; accepted 28 December 1996 gic receptor blocker with some loss of selectivity in higher doses. The drug has been used in numerous in vitro receptor binding studies. 3±5 Moreover a large number of in vivo pharmacology studies are available to identify three major sites of action: (1) central action in various regions of the central nervous system (CNS), where yohimbine blocks cerebral a 2 - adrenergic receptors, increasing norepinephrine release and turnover; (2) direct peripheral action through modulation of autonomic nervous system (ANS) tone via presynaptic autoinhibitory a 2 receptors; (3) direct action on penile tissues and vascular smooth muscle cells, blocking postsynaptic vasoconstrictor a 2 receptors. Although the mode of action of yohimbine suggests its effect may not be con ned to erections while awake, clear evidence to support this assumption is still lacking. It was among the aims of the present study to include NPT measurements as a possible additional indicator of the effect of yohimbine on erectile dysfunction. The clinical use of yohimbine has been documented by several open studies and anecdotal reports as well as by ve double-blind placebocontrolled trials 6±10 conducted between 1987 and Patients received daily oral doses of 16.2± 43.2mg for 4±10 weeks. While varied in design and

2 156 outcome, all of these studies consistently indicated a trend for improved erectile function with yohimbine [for a review see KoÈhler et al 11 ; for metaanalytic considerations see Carey and Johnson 12 ]. Given the above considerations, and since previous studies had focused on subjective aspects known to be exceedingly dependent on the patient's momentary suffering, the present clinical trial was designed to evaluate the ef cacy of yohimbine in terms of both objective and subjective variables. This study also aimed to establish the safety and tolerability pro le of daily dosing with yohimbine over an eight week period of therapy. Methods Subjects The target population consisted of men aged 18 and up suffering from erectile dysfunction. Criteria for exclusion were: absence of sexual partner; severe organic diseases such as severe heart disease, genital injury or serious intercurrent diseases; severe mental disease (for example depression); severe emotional disturbances such as severe partner discord or overwhelming fear of sexual incompetence; severe sleep disorder; known allergy or hypersensitivity to yohimbine; alcohol or drug abuse; participation in another clinical trial within the last 30 d; expected lack of cooperation and failure to give informed consent. A total of 309 patients presented with erection inadequacy at the Male Sexual Disorders Clinic of Dermatologische Klinik und Poliklinik, Technische UniversitaÈt MuÈ nchen, Munich, Germany, between 1993 and mid Out of the 309 patients 86 men were quali ed for the trial, 223 patients with erectile impotence were screened and excluded for various reasons (see Table 1). All patients gave informed consent in writing prior to study entry. The study received institutional approval by the Ethics' Review Board. Mean age of the study population was 53.9y for the yohimbine group and 51.3y for the placebo group (range, 28±71). The patients in the yohimbine group were slightly shorter (176.5 vs cm) and weighed slightly less (80.3 vs 82.3kg) than those of the placebo group. Other main characteristics of the study population are summarized in Table 2. Blood counts, blood glucose, erythrocyte sedimentation rate, [serum] creatinine, liver enzymes, urinalysis, and TPHA showed no deviations from normal. The testosterone assay showed slightly higher mean [serum] concentrations in the yohimbine group (14.88 nmol/l) than in the placebo group (12.81nmol/L). Mean baseline luteinizing hormone (LH) levels were essentially identical in the two groups. Nonetheless, all values including those determined for prolactin were within a normal range. Psychiatric/psychologic evaluation using a depressive disorder evaluation questionnaire 13 revealed evidence of mild paranoid or depressive ideation (yet without clinical signi cance) in three yohimbine-treated patients (7.3%) and in one patient assigned to the placebo group (2.4%), and evidence of a history of affective disorders (with no current signi cance) in two patients of the yohimbine group. In both groups the baseline mean scores of a Partnership Questionnaire 14 and Insecurity in Sociosexual Situations Questionnaire 15 showed no signi cant deviations from normal (Partnership Questionnaire: normal score, 64.9; yohimbine group, 59.6; placebo group, 59.0; Insecurity in Sociosexual Situations Questionnaire: normal score, 21.64; patients with sexual disorders due to psychogenic factors: 46.53; yohimbine group, 29.3; placebo group, 27.6). This con rms that no patients with disinterest in sexual partner/marital discord or clearly psychogenic sexual disorders had been included. Procedure After the screening interview, patients were provided with a diary to be completed and returned at the time of the entry visit. After a thorough history and physical examination, subjects underwent a Table 1 Reasons for exclusion from the trial Primary reason for exclusion No. of patients Poor Compliance (for example no interest, too much hassle) 34 (15.3%) Criterion for Exclusion (for example no sexual partner, already takes yohimbine, 35 (15.7%) participates in another trial, currently receives psychotherapy) Disinterest in sexual partner/marital discord 19 (8.5%) Erectile dysfunction due to mental disorder 42 (18.8%) Erectile dysfunction due to organic cause (for example anorchism, prolactinoma, prostate cancer) 38 (17.1%) Severe serious concomitant disease or need for unacceptable comedication 55 (24.6%) Total exclusions (223 of 309 patients) 223 (100.0%)

3 Table 2 Baseline demographics/population characteristics 157 Yohimbine hydrochloride (n ˆ 41) Placebo (n ˆ 42) Impotence Loss of erection 41 (100.0%) 42 (100.0%) Loss of desire 3 (7.3%) 2 (4.8%) Absence of orgasm 1 (2.4%) 1 (2.4%) Absence of emission Ð 4 (9.5%) Prior treatment for erectile inadequacy None 32 (78.0%) 27 (64.3%) Androgens 4 (9.8%) 4 (9.5%) Vitamin E Ð 1 (2.4%) Yohimbine 2 (4.9%) 3 (7.1%) Cavernous body auto-injection therapy Ð 1 (2.4%) Suppositories 1 (2.4%) Ð Unknown 2 (4.9%) 5 (11.9%) Patients with prior psychotherapy 4 (9.8%) 6 (14.3%) Patients with concomitant diseases 16 (39.0%) 14 (33.3%) Patients with concomitant medications 11 (26.8%) 11 (26.2%) Smokers/exsmokers 23 (56.1%) 23 (54.8%) Sexual partner Spouse 35 (85.4%) 30 (71.4%) Other partner 6 (14.6%) 12 (28.6%) Partner's age (y) Mean s.d cavernous body injection test using 5±10 mg of prostaglandine (PGE-1) followed by penile artery Doppler ultrasonography. Hormonal and serious organic causes were ruled out by a variety of laboratory tests. A complete psychiatric/psychologic evaluation, including an interview/discussion of the information provided in the completed diary, Partnership Questionnaire, 14 and Insecurity in Sociosexual Situations Questionnaire 15 was also performed. Sleep was polysomnographically recorded during two consecutive nights at baseline and after eight weeks of treatment. In addition to routine sleep parameters, spontaneous nocturnal erections were monitored using a RigiScan device (Dacomed Corp., Minneapolis, MN, USA). This device allows continuous recording of both penile tumescence and rigidity without interfering with sleep recordings. At the four-week follow-up visit the following variables were recorded: compliance (by counting returned tablets), comedication changes, adverse events, overall and physical well-being, sexual desire, and best erection. Patients then received another four weeks' supply of their study medication, along with a new diary. After eight weeks' treatment, patients underwent follow-up sleep laboratory studies including measurements of nocturnal penile tumescence/rigidity during two consecutive nights. Other nal visit activities included a psychiatric/psychologic follow-up evaluation, as well as recording of co-medication changes and any adverse reports. Treatment of concomitant diseases that were not criteria for exclusion was acceptable unless it interfered with erectile function or speci c study procedures (for example sleep quality). Unacceptable comedications included aphrodisiacs, male sex hormones, and other drugs affecting sexual function; beta-blockers and antihypertensive drugs; sleeping drugs, tranquillizers, and any other psychoactive drugs. All comedication was to be recorded in the Case Report Form (CRF), including nature, dosage, duration, and indication. Existing acceptable comedications were not to be changed during the trial as far as possible. The sample size calculation for this trial was based on assumptions set forth in the study protocol, which were derived from reference to previous clinical trials of yohimbine. 6±10 These studies used 5.4mg of yohimbine (instead of 5.0 mg) per tablet, but the current state of medical knowledge and the nature of the criteria used for ef cacy evaluation in this trial suggest this minor difference in tablet strength was insigni cant. The following assumptions were used in calculating sample size: two independent groups, testing for statistically signi cant between-group difference, same number of patients in both groups, a ˆ 5%, b ˆ 20%, one-tailed test, and difference in response between yohimbine and placebo after eight weeks: yohimbine response rate placebo response rate 30% (in absolute terms). Based on the above assumptions, the calculated sample size ranged from 64±80 evaluable patients as a function of assumed placebo response rate (10±50%). A 30% difference (in absolute terms) in response rate in favor of yohimbine was assumed to be a clinically signi cant result. The basis for response de nition was a combina-

4 158 tion of objective and subjective criteria of outcome. The objective end-point was based solely on the rigidity measured at the base of the penis, rating the quality of erection on a scale from 0±3 (0 ˆ 0% rigidity, 1 ˆ 1±40% rigidity, 2 ˆ 41±70% rigidity, 3 ˆ 71±100% rigidity). Erections of nights 1 and 2 (baseline recordings) and those of nights 3 and 4 (end-of-study recordings) were pooled for erection quality analysis, using the best rigidity level maintained for at least 15 minutes for the baseline versus end-of-study night comparison (objective endpoint). The subjective end-point re ected changes in four variables, namely `sexual desire', `sexual satisfaction', `best erection during sexual contact/intercourse', and `frequency of sexual contacts'. These variables were determined from the information provided in the diaries and obtained during the patient interviews. To calculate subjective response the values of the 14d diary maintained by patients prior to initial entry into the study and the eightweeks follow up diaries were used as well as the interview values. In order to calibrate response rate for these values in an equal manner, qualitative diary values were averaged (sexual desire, sexual satisfaction, best erection during sexual contact) and added to the proper interview value, using the arithmetic mean for analysis. The quantitative diary values (frequency of sexual contact) were summarized and added to the proper interview value, again using the arithmetic mean for analysis. Response was de ned as a best rigidity improvement of at least 1 point in the two end-of-study nights versus the two baseline nights and/or an improvement in at least 2 of the 4 subjective criteria of outcome by at least 0.5 points (sexual desire, sexual satisfaction, best erection during sexual contact) of a 5-point scale or at least one more sexual contact over a two-week period. The between-group difference in response rate (primary end-point) was analyzed and interpreted con rmatively by Fisher's exact test at the a ˆ 5% level, one-tailed. All other ef cacy and safety variables were presented descriptively and interpreted exploratively. Results Of the 86 randomized patients, 85 were evaluated for safety/tolerability (n ˆ 43 in the yohimbine hydrochloride group, n ˆ 42 in the placebo group) and 83 for ef cacy (n ˆ 41 in the yohimbine group, n ˆ 42 in the placebo group). Eighty-one patients (n ˆ 41 in the yohimbine group, n ˆ 40 in the placebo group) completed eight weeks of treatment as scheduled for the trial. Two patients in the yohimbine group and three patients in the placebo group were withdrawn or dropped out before completing the full eight week treatment period and/or all of the nal visit activities. The primary reasons for termination were non-compliance and adverse events such as sleep disturbances. The mean baseline values calculated for `sexual desire' were slightly better in the yohimbine group than in the placebo group (2.61 vs 2.43), whereas baseline `best erection during sexual contact', `frequency of sexual contacts', and `sexual satisfaction' were essentially identical in the two groups. The reported current mean monthly frequency of intercourse/sexual contacts was 1.8 (yohimbine) or 2.5 (placebo). All variables indicated considerable variation in both groups. Response After eight weeks of treatment 24 out of 41 patients (59%) were responders according to the subjective response de nition in the yohimbine group compared to 16 out of 41 (39%) in the placebo group. This difference is associated with a P-value of The NPT recordings re ected a treatment response according to the objective response de nition in 13 out of 41 patients (32%) receiving yohimbine; in contrast, only 6 out of 42 patients (14%) receiving placebo exhibited a response according to the criteria described above. This difference, however, did not reach statistical signi cance either (P-value of ). Using the primary target, namely the overall response de nition, 29 out of 41 patients of the yohimbine group (70.7%) versus 19 out of 42 patients of the placebo group (45.2%) were responders at the end of therapy (Table 3). This difference in response rates was statistically signi cant in Fisher's exact test at a ˆ 5%, one-tailed (P ˆ ). The 95% con dence interval of the likelihood of response after eight weeks' treatment was 54.5± 83.8% in the yohimbine group vs 29.9±61.3% in the placebo group (Figure 1). The statistical power was 70% at the a ˆ 5% level and 81% at the a ˆ 10% level. There was a weak relationship between the outcome of NPT recordings and subjective response criteria, with only eight patients receiving yohimbine (20%) classi ed as responders according to both subjective and objective criteria. In the placebo group, only three patients (7%) ful lled both criteria. There was no signi cant difference between yohimbine and placebo regarding this relationship. Safety and tolerance Adverse events (AEs) were reported in 13 patients of the yohimbine group (30.2%) vs four in the placebo

5 Table 3 Response rates after eight weeks of treatment 159 Type of response group Overall response Subjective response Objective response Yohimbine Yohimbine hydrochloride Placebo * Hydrochloride Placebo Yohimbine Hydrochloride Placebo a Response 29 (71%) 19 (45%) 24 (59%) 16 (39%) 13 (32%) 6 (14%) Non-response 12 (29%) 23 (55%) 17 (41%) 25 (61%) 28 (68%) 36 (86%) P-value * ** ** * Exact P-values from Fisher's exact test (one-tailed). ** P-values were calculated using Fisher's exact test (two-tailed) and are double the respective one-tailed P-value. a No subjective response evaluation was available for one patient of the placebo group. Figure 1 95% con dence intervals (95% CI) for overall response rates and respective mean values after eight week treatment with Yohimbine versus Placebo. The upper and lower bars indicate the upper and lower limit of the 95% CI, respectively. The middle (mean) bar indicates the study population mean. group (9.5%). This difference was statistically signi cant in Fisher's exact test. Two of the 43 patients of the yohimbine group and one of the 42 patients of the placebo group stopped treatment prematurely for adverse experiences. There were no serious AEs in the yohimbine group. Two AEs experienced by patients of the placebo group were considered serious (per study protocol de nition): one patient required hospitalization for intercurrent depression and was withdrawn, but the investigator considered the relationship of this AE with the study medication questionable. Another placebo-treated patient underwent an appendectomy during the trial, but this event had no signi cant impact on the course of the trial and a causal relationship with the study medication was ruled out. Discussion The report of Morales et al 16 on the successful treatment of impotence in diabetes with yohimbine helped lead to intensive investigation of this substance. Besides the effect on erectile functions, Yohimbine often shows additional improvement in sexual appetite/desire. Apart from this, the improvement in erections may exert a positive in uence on the patient's emotional condition and thus support overall success of the treatment. Although subjective improvement in sexual experience tends to be a prime concern for men with erectile impotence, and perhaps for their sexual partners as well 6 medical scientists also must concern themselves with measuring and quantifying this subjective experience for objective veri cation. This is why in our study subjective as well as objective criteria were to be evaluated. This double-blind, placebo-controlled clinical trial of yohimbine hydrochloride was carried out in patients with erectile dysfunctions with or without reduced sexual desire/libido. Strict exclusion criteria were applied to ensure valid conclusions, with the result that only 86 of the 309 screened patients could be included in this study. The mean age of the study population (53y) is that of the typical patient with erectile impotence seen by the GPs, andrologists and urologists. Most clinical studies used the patients' (subjective) response to rate the therapeutic ef cacy, relaying, primarily on the patients, as well as on their partners to a lesser extent (Morales et al 6, Reid et al 7 ). Patients were asked to rate their erectile capability (Morales et al 6,17, Sonda et al 9, Susset et al 10 ). Additional ratings referred to orgasmic response (Riley et al 8 ) or sexual desire (mostly in older reports). In several previous studies three rating categories were used: `un-changed', `partial improvement' or `no further erection problems' (Morales et al 6, Reid et al 7 ). This study used three qualitative parameters (sexual desire, sexual satisfaction, and best erection during sexual contact/ intercourse) and one quantitative variable (frequency of sexual contacts) for subjective response evaluation. To obtain more complete information the patients were interviewed using a semi-structured schedule, and additionally were asked to keep a speci c daily diary for two weeks before the start medication (baseline) until the end of the study. Data from these two sources were given equal statistical weight in the nal analyses.

6 160 We used NPT recording as an additional objective response criterion to evaluate the ef cacy of yohimbine. We considered it essential to perform the NPT measurements in the sleep laboratory concurrently with polysomnographic recordings during sleep at night in order to allow differentiation of spontaneous erection while asleep and erections while lying awake. NPT being rather closely linked to REM sleep, NPT frequency and duration can be properly assessed only when the frequency and duration of REM phases are known. REM sleep deprivation may be caused by many different factors including unfamiliar surroundings, sleep fragmentation due to external or internal causes, drugs, and alcohol. Moreover, certain sleep disorders such as severe sleep apnea are known to compromise erectile function. The measurement of nocturnal penile tumescence (NPT) is by no means a standard procedure in this kind of study. While the merits of this method in the differential diagnosis of erectile impotence are noncontroversial, 18 its utility and reliability for documentation of ef cacy of drugs used in treatment of this sexual disorder are not. Jovanovic 19 used NPT measurements in a clinical trial of a yohimbine product and observed pronounced effects that correlated closely with subjective improvement. Morales et al 6, on the other hand, found signi cant discrepancies between NPT measurements and subjective perception of clinical outcome among patients and their partners. As subjective response appeared more valid from a clinical standpoint, the authors decided not to use the NPT recordings as an outcome measurement. 20 Other workers performed polysomnographic measurements including NPT but only used these to establish the differential diagnosis and not as part of the response criterion. 21 NPT measurements result a variety of parameters including extent and duration of penile tumescence, extent and duration of penile rigidity, number of erections, and temporal stability of an erection. There is no consensus in the literature on which of these variables are useful for the assessment of spontaneous nocturnal erectile functions (for example in the differential diagnosis of erectile dysfunction) or which most reliably mirror drug effects. We decided to focus on penile rigidity measurements at the penis base, and to de ne `objective' response as an improvement in this parameter. However, when `response' is de ned using absolute rigidity measurements and percentages of improvement from baseline, a serious methodological problem arises: in the present sample, a large percentage of patients had such favorable NPT measures at baseline as to leave very little, if any, room for potential improvement attributable to treatment. In these patients, minor improvements are not adequately mirrored in the perceptual changes. Conversely, even minute changes are re ected as disproportionally great improvement in patients with extremely low baseline activity. This led us to choose a response criterion which takes account of the `ceiling effects' and other possible kinds of distortions. Based on studies using a similar design, 22,23 we used a four class ordinal scale for rigidity classi cation, response being de ned as an improvement by at least one rigidity class. Additionally, we required that rigidity of a given class should be maintained for at least 15 minutes. We are aware that by doing so, some of the potential statistical power of the analyses is lost, but elimination of cluster-effects and bias were the main arguments leading to our decision. Yohimbine tended to be better than placebo in terms of subjective response criteria and the objective response criteria looked at these two categories separately (Table 3), but it is not statistically signi cant. It was not possible to sum up both groups, because some patients from the subjective response group responded in the objective response group as well. The combined set of objective responders and subjective responders (namely the overall response set of patients achieving objective and/or subjective response), revealed a statistically signi cant superiority of yohimbine to placebo. Using all due caution, this result can be interpreted as indicating that the threshold of a subjective or objective response shows great between-patient variability. In other words, some patients experienced subjective improvement while objective response remained below the `limit of detection', whereas others achieved objective response while subjective response was not detectable with the rating scales used for sexual function assessment in our trial. Unlike Morales 6 and Condra 20 we found no substantial discrepancy between subjective perception and NPT recordings. However, a couple of important differences between these studies deserve special mention. Morales 6 studied only patients with organic erectile dysfunction, while these patients were excluded from our trial. Moreover, changes in penile circumference (tumescence) may have less clinical signi cance than do changes in penile rigidity. Consequently, we used an instrument that allows continuous rigidity measurements (RigiScan), and based our assessment on rigidity only. Another variable used by Morales 6 was the number of nocturnal erections. As this parameter correlates with the number of REM phases, all events producing REM sleep deprivation are also liable to reduce the number of erections. Based on this consideration, we believe this variable to be an unreliable indicator of erectile function. The relationship between `subjective' and `objective' response criteria merits particular attention. It is still a matter of debate whether, and to what extent, there is a relationship between nocturnal

7 spontaneous erections/nocturnal penile tumescence and sexual performance in erotic situations. While certainly not identical, the underlying neurophysiologic mechanisms are likely to overlap at least in some respects. The following conclusions can be drawn from our results regarding this relationship: The intersection of the set of objective responders and the set of subjective responders is a small one but shows a marked difference between the two treatment groups, suggesting a rather loose link between the two criteria. Neither criterion is prerequisite or suf cient for the other to occur. The higher incidence of adverse experiences with yohimbine than with placebo is not surprising. As yohimbine acts on both the central and autonomic nervous systems, side effects on both are likely. Placebo produced only psychosomatic reactions while yohimbine also caused reactions to the drug itself. However, as these adverse reactions were typically mild, they were either acceptable or made acceptable by dose reduction. Acknowledgements This study was supported by Glenwood GmbH, Starnberg, Germany, Yohimbine-HCl (Yocon-Glenwood 1 ) was provided by Glenwood GmbH, Starnberg, Germany. References 1 Spector JP, Carey M. Incidence and prevalence of the sexual dysfunctions: a critical review of the empirical literature. Arch Sex Behav 1990; 19: 389± Borelli S. Die Aphrodisiaka. In: Jadassohn J (Hrsg). Handbuch der Haut- und Geschlechtskrankheiten. ErgaÈnzungswerk Band VI , 737± Borowski E, Starke K, Ehrl H, Endo T. A comparison of preand postsynaptic effects of the alpha-adrenolytic drugs in the pulmonary artery of the rabbit. Neuroscience 1977; 2: 285± Starke K, Borowski E, Endo T. Preferential blockade of presynaptic alpha-adrenoceptor by yohimbine. Eur J Pharmacol 1975; 34: 385± Weitzell R, Tanaka T, Starke K. Pre- and postsynaptic effects of yohimbine stereo-isomers on noradrenic transmission in the pulmonary artery of the rabbit. Naunyn Schmiedebergs Arch Pharmacol 1979; 308: 127± Morales A et al. Is yohimbine effective in the treatment of organic impotence? Results of a controlled trial. J Urol 1987; 137: 1168± Reid K et al. Double-blind trial of yohimbine in treatment of psychogenic impotence. Lancet 1987; 2: 421± Riley AJ, Goodman RE, Kellett JM, Orr R. Double blind trial of yohimbine hydrochloride in the treatment of erection inadequacy. J Sex Marital Ther 1989; 15: 17±26. 9 Sonda LP, Chancellor MB, Mazo R. Treatment of erectile impotence with yohimbine; prospective double blind trial and review of experience in 215 patients. J Sex Marital Ther 1990; 16: 15± Susset JG et al. Effect of yohimbine hydrochloride on erectile impotence; a double-blind study. J Urol 1989; 141: 1360± KoÈhler LD, Borelli S, Vogt HJ. Yohimbin-HCl in der Behandlung von ErektionsstoÈrungen. Sexuologie 1995; 3 (2): 209± Carey MP, Johnson BT. Effectiveness of Yohimbine in the Treatment of Erectile Disorders: Four Meta-Analytic Integrations. Arch Sex Behav 1996; 25: 341± Zerssen D von. Paranoid-DepressivitaÈts-Skala. DepressivitaÈts- Skala. PD-S Manual Beltz-Verlag, Weinheim, Hahlweg K. Partnerschaftliche Interaktion; Partnerschaftsfragebogen. G. RoÈttgerVerlag, MuÈ nchen, Fahrner EM. Fragebogen zur Unsicherheit in soziosexuellen Situationen (FUSS). In: Fahrner EM (ed). Psychologische Behandlung von SexualstoÈrrungen bei maènnlichen AlkoholabhaÈngigen. G. RoÈttger-Verlag; MuÈ nchen, Morales A, Surridge DHC, Marshall PG. Yohimbine for treatment of impotence in diabetes. N Engl J Med 1981; 305: Morales A, Surridge DHC, Marshall PG, Fenemore J. Nonhormonal Pharmacological Treatment of organic impotence. J Urol 1982; 128: 45± Schiavi RC. Nocturnal penile tumescence in the evaluation of erectile disorders: a critical review. J Sex Marital Ther 1988; 14: 83± Jovanovic UJ. Hormonfrei gegen Impotenz. Sexualmedizin 1980; 9: 453± Condra M et al. The unreliability of nocturnal penile tumescence recording as an outcome measurement in the treatment of organic impotence. J Urol 1986; 135: 280± Montorsi F et al. Effect of yohimbine-trazodone on psychogenic impotence: a randomized, double-blind, placebo-controlled study. Urology 1994; 44: 732± Mann K et al. Effects of yohimbine on sexual experience and nocturnal penile tumescence and rigidity in erectile dysfunction. Arch Sex Behav 1996; 25: 1± Warner P, Bancroft J. Assessment of erectile dysfunction: consideration of the research issues. Poster presented at the 20th Annual Conference of the International Academy of Sex 161