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

Adel Gomaa, Mohamed Shalaby, Mohamed Osman, Mohamed Eissa, Alaa Eizat, Mostafy Mahmoud, Nabiel Mikhail

Abstract induce or facilitate erection. These agents have variable Objective-To examine the effectiveness in ability in penetrating the cutaneous tissues, though they treating impotence of topically applied cream are absorbed topically and reach the systemic circulation containing three vasodilators-aminophylline, in small quantities.2023We investigated their effectiveness in isosorbide dinitrate, and co-dergocrine facilitating erection when given topically in a double blind mesylate-which act by different mechanisms. placebo controlled trial. Design-Randomised double blinded placebo controlled crossover trial over two weeks. Subjects-36 men with erectile dysfunction ran- Subjects and methods domly allocated to two equal groups. Patients whose chiefcomplaint was erectile dysfunction Interventions-Active cream containing amino- were invited to participate in the present study. Their phylline 3%, isosorbide dinitrate 0.25%, and median age was 48 (range 31-65). The median duration of co-dergocrine mesylate 0.05% for one week and erectile dysfunction was 39 months (range 5-72). The placebo for another. cause of the dysfunction was determined after the initial Main outcome measures-Patients' reported evaluation and consultation, which included serum testo- experience of penile responses and side effects of sterone determination, neurological and psychiatric evalu- treatment in questionnaires. Penile tumescence ation, penile blood flow assessment by colour duplex and arterial flow in the laboratory. ultrasonography, and a papaverine test.24 25 Medical Results-21 patients reported full erection and history associated with erectile dysfunction was variable satisfactory intercourse with the active cream. (diabetes mellitus, hypertension, anxiety, depression, and Three men reported full erection and satisfactory surgery). No patient with hypotension or glaucoma was intercourse with either cream. The active cream enrolled in this study. was more effective in psychogenic than organic Two weeks after the papaverine test each patient was impotence (eight out of nine men with psycho- informed that he would be asked to determine which of genic imnpotence achieved a full erection v four out two different treatments was the more useful. One ofeight with neurogenic impotence and two out of cream contained a combination of aminophylline 3%, seven with arterial insufficiency). No major side co-dergocrine mesylate 0.05%, and isosorbide dinitrate effects were reported. In the laboratory the active 0.25% (active cream) and the other lubricating gel (pla- cream increased penile arterial flow (0.19 (SD cebo). The two creams were prepared in the hospital's 0.08) mIs v 0.02 (0.15) mIs with placebo) and pharmacology department for research purposes. induced tumescence in 24 patients. Patients attended the urology outpatients clinic at the Conclusions-Topical treatment with a cream hospital and gave their informed consent to participate containing three different vasodilators might be in the study. They were classified into two strata accord- considered before intracavernous injection of ing to age. They were randomly allocated to two groups vasoactive agents, particularly in psychogenic im- by means of a stratified systematic random technique, potence. the first patient in each stratum who attended the clinic being in group I, the next in group II, and so on, until Introduction each group contained 18 patients. Each group received Current pharmacological treatment for most types of the active and placebo creams alternately, one prepara- Departments of erectile dysfunction is based on the intracorporeal tion each week. In the first week group I received the Pharmacology, Urology, injection of vasoactive agents. These agents either treatment cream and group II the placebo. In the Neurology, and induce erection-for example, papaverine, phenoxyben- second week group I received placebo cream and group Community Medicine, zamine, and prostaglandin El'-5-or facilitate it-for II the treatment cream. Investigators were blind to Faculty ofMedicine, example, thymoxamine, phentolamine, nicergoline, which cream was being used by means of coded labels. Assiut University, Assiut, dihydroergocryptine, and vasoactive intestinal The two preparations looked similar and had identical Egypt Adel Gomaa, professor of peptide.6 7 Both types of agent need to be injected packaging. Each patient was given seven divided doses pharmacology intracavernously at each use and become less effective of 2 g of cream (on the basis of one dose daily). Mohamed Shalaby, professor with time.8 In addition, self injection is painful and Penile tumescence and arterial flow were measured in ofurology stressful and may cause haematoma and infections. the laboratory before and after each week's trial of a Mohamed Osman, associate Furthermore, intracorporeal fibrosis, priapism, and sys- cream. No erotic stimulation was used during these professor in urology temic cardiovascular side effects may develop.9'" laboratory measurements. Before the trial patients were Mohamed Eissa, associate Topically acting vasodilating drugs seem an attractive advised to apply a thin layer of cream on the glans penis professor in neurology option in treating erectile dysfunction, but few studies and on the penile shaft 15 minutes before erotic stimu- Alaa Eizat, assistant lecturer in have investigated the management of impotence by lation and intercourse at home. Patients with venous urology Mostafy Mahmnoud, assistant topically effective agents. Most of these reports have leakage were advised to use a tourniquet at the base of lecturer in pharmacology described the use of glyceryl trinitrate or minoxidil in the penis. Cream was applied to the glans penis as well Nabiel Mikhail, statistician the management of erectile dysfunction."-6 Some of as the shaft to enhance transcutaneous absorption 'of them showed a high rate of success17; most found that active ingredients."6 Correspondence to: glyceryl trinitrate was not useful clinically'8 19 and that it Patients reported their experience after each week in Professor Gomaa. induced headache at all concentrations used."2-9 a questionnaire. The questionnaire investigated three To our knowledge, topical aminophylline, co-dergocrine main areas: erectile response, patient's satisfaction, and BMJ 1996;312:1512-5 mesylate, or isosorbide dinitrate have not been used to side effects. Each patient described all his experiences

1512 BMJ VOLUME 312 15 JUNE 1996 Table 1-Penile response after topical application of placebo and active creams in 36 (SD 0.02) m/s before application and 0.25 (0.10) m/s patients with erectile dysfunction. Values are numbers of patients after application (P<0.001), compared with 0.06 (0.02) m/s before and 0.08 (0.07) m/s after application of pla- Response cebo (P>0.05) Moreover, the active treatment caused tumescence in 24 patients, the tumescence being com- Full Partial No plete in seven and partial in 17. No tumescence was Aetiology erection erection Tumescence response achieved in 12 patients. Placebo cream Analysis of data from the questionnaires showed that Psychogenic (n =9) 3 6 the active cream induced a greater erectile response Neurogenic (n = 8) 8 than did placebo (21 v 3, P<0.00 1). The response after Arterial insufficiency (n = 7) 7 the active cream was significantly different from that Venous leakage (n = 4) 4 before application (21 v 0, P<0.001 by McNemar's Mixed* (n = 8) 8 Total (n = 36) 3 33 test), while the response after placebo was no different Active cream from that before application (3 v 0, P = 0.25 by Psychogenic (n = 9) 8 1 McNemar's test). Neurogenic (n=8) 4 1 1 2 The penile response after placebo and active treatment Arterial insufficiency (n = 7) 2 1 1 3 is shown in table 1. Twenty five patients reported sponta- Venous leakage (n =4) 1 3 Mixed* (n =8) 6 2 neous erections during the week of active treatment. The Total (n = 36) 21 2 2 11 quality and duration of erection varied. Twenty one patients reported a full erection with successful inter- *Psychogenic with minor organic disorder. course, orgasm, and ejaculation. Eight of them had a full erection after the first application, while six, four, and three patients respectively reported a full erection after two, over the week, but the best response during the week three, and five days of using the cream once daily. Other was used in the statistical analyses. Erectile response respondents were dissatisfied; two had a partial erection and patient's satisfaction were measured on seven point that was insufficient for successful intercourse and two had semantic scales.8 Erectile response was graded as full tumescence without sufficient rigidity for intercourse. erection, which implies successful intercourse; partial erection, in which penetration but not intercourse is possible; tumescence, in which penetration is not possi- ble; and no response. Statistical analysis included Student's t test (peak flow velocity) and X2 test (erectile response) for comparison of the two groups (unpaired data), and it included paired t tests (peak flow velocity) and McNemar's test (erectile response) for analysis of data in each group (paired data). McNemar's test was used to compare the proportions of men with full erections.

Results During laboratory testing active treatment was highly effective in increasing penile arterial flow (figs 1 and 2). Mean arterial flow with active treatment was 0.06

Fig 2-Duplex ultrasonogram showing a weak response in Fig 1 Duplex ultrasonogram showing good peak flow veloc- peak flow velocity with placebo (0.09 mls) and active cream ity (0.34 mls) after application of active cream in patient with (0.22 mls) in diabetic patient with arterial, neurogenic, and arterial impotence psychogenic impotence over previous five years

BMJ VOLUME 312 15 juNE 1996 1513 Erectile dysfunction of psychogenic origin or of mixed causes (mostly minor neurological or arterial in Key messages addition to psychogenic disorders) was most success- fully treated by the active cream. Only one of the four * Impotence is almost routinely treated by vaso- patients with venous leakage had a good response, and active drugs given by intracavernous injections, he used a tourniquet 20 minutes after applying the which may be stressful for patients and have cream. The active cream was more effective in unpleasant side effects neurogenic impotence (four out of eight patients had a * In this study a topical cream containing three full erection) than in arterial impotence (two out of vasodilators with different mechanisms of action seven patients had a full erection) (table 1). was tested in a double blind placebo controlled Three of the nine patients with psychogenic crossover trial in 36 impotent men impotence described a full erection and satisfactory intercourse with both types of cream. Neither cream * The active cream increased penile arterial flow produced a noticeable response in 11 patients (table 1). and induced tumescence in the laboratory, and 21 None of the patients had prolonged erection or pria- patients reported full erection and intercourse after pism. None of them reported clinically significant a week's treatment cardiovascular side effects (such as postural dizziness), * The cream was most effective in psychogenic headache, or pain at site of application. None of them impotence, success rates being lower when the reported complaints from their partner. impotence had organic causes * This topical treatment should be used before Discussion intracavernous agents, especially in psychogenic The active cream acts locally on penile tissue. If the impotence topical application of cream precedes sexual inter- course, the release of neurotransmitters prompted by erotic stimulation will enhance further the action of the pharmacological agents and result in a better erection.24 tumescence in 66% of patients. Tumescence under For these reasons none ofthe 36 patients achieved a full laboratory conditions may be an index of erection on erection in our laboratory, whereas 21 ofthem had a full erotic stimulation during sexual activity. We can draw erection during sexual intercourse. The greatest effect several conclusions from the laboratory data and the was seen in psychogenic impotence with or without a data obtained after erotic stimulation at home. A neurogenic disorder and the lowest in vascular combination of aminophylline, co-dergocrine, and impotence. This may be because the agents in the active isosorbide dinitrate, even in the small doses ofour active treatment are primarily vasodilators and penile vascula- cream, was as effective in treating impotence as the ture is healthy in psychogenic impotence but compro- reported intracavernous injection ofvasoactive agents.` mised in vascular impotence. The cream had no clinically significant side effects. Headache was not reported by any patient because the PHARMACODYNAMICS OF AGENTS IN ACTIVE CREAM dose of isosorbide dinitrate in the cream was smaller Papaverine works better when it is injected in combi- than the usual systemic dose. nation with phentolamine to induce erection.38 10 The Even though more studies are needed, topical two drugs act by different mechanisms, so we combined treatment ofimpotence with a cream containing amino- three agents with different mechanisms of action in our phylline, isosorbide dinitrate, and co-dergocrine active cream. mesylate might be considered before the intracavernous Aminophylline releases theophylline after crossing injection of vasoactive drugs. the skin. Theophylline induces erection on intracavern- Funding: No additional funding. ous injection26 and acts similarly to papaverine. It inhib- Conflict of interest: None. its the action of phosphodiesterase, thus preventing the breakdown of cyclic AMP to 5-AMP and subsequently 1 Brindley GS. Cavernosal alpha blockade: a new technique for investigating causing sinusoidal smooth muscle relaxation and and treating erectile impotence. BrJ Psychiatry 1983;143:332-63. erection." 2 Virag R, Frydman D, Legmen M, Virag H. Intra-cavernous injection of papaverine: on a diagnostic and therapeutic method in erectile failure. Agents such as isosorbide dinitrate are absorbed topi- Angiology 1984;35:79-84. cally and generate nitric oxide either spontaneously or 3 Gasser TC, Roach RM, Larsen EH, Madson PO, Bruskewitz RC. Intracav- ernous self-injection with phentolamine and papaverine for treatment of after metabolism in smooth muscle. Nitric oxide impotence.J Urol 1987;137:678-83. activates guanylate cyclase and the formation of cyclic 4 Sidi AA, Cameron JS, Duffy LM, Lange PH. Intracavernous drug-induced GMP (guanosine monophosphate), causing local erection in the management of male erectile dysfunction:experience with 100 patients.J Urol 1986;135:704-11. relaxation of corporeal smooth muscle. This results in 5 Gerber G, Levine L. Pharmacological erection program using prostaglan- increased filling of the corpus cavernosum with blood din E-l.I Urol 1991;146:786-9. 6 Buvat J, Buvat-Herbaut M, Lemaire A, Marcolin G. Applications diagnos- and consequently impairment of venous outflow, tiques et therapeutiques des injections intracaverneuses (ic) de drogues thereby causing penile erection..4 2728 vasoactives dans l'impuissance. Plaidoyer pour l'utilisation des drogues Current data suggest that selective blockade of a facilitatrices. I. Pharmacologie, classification et complications des drogues actives. J Urol (Paris) 1989;95:33-7. adrenergic nerve impulses within the corpus caverno- 7 Buvat J, Buvat-Herbout M, Lemaire A, Marcolin G. Applications diagnos- sum in men will erection. Erection tiques et therapeutiques des injections intracaverneuses (ic) de drogues impotent promote vasoactive dans l'impuissance. Plaidoyer pour 1' utilisation des drogues was produced by intracavernous injection of phenoxy- facilitatrices. II. Applications diagnostiques et therapeutiques. J Urol benzamine in six out of 11 impotent men,' while lower (Paris) 1989;95:89-92. 8 Girdley RM, Bruskewitz RC, Jan Feyzi, Graversen PH, Gassert TC. Intra- activity was reported with phentolamine.29 However, cavernous self-injection for impotence: a long-term therapeutic option? dihydroergocryptine (one component of co-dergocrine) Experience in 78 patients.J Urol 1988;140:972-9. 9 Abozeid M, Juenemann K.P, Luo JA, Lue TF, Yen TS, Tanagho EA. was effective only as a facilitator of erection.6 7In a pre- Chronic papaverine treatment; the effect of repeated injections on the vious study co-dergocrine cream elicited full erection in simian erectile response and penile tissue. Urol 1987;138: 1263-9. 22% of impotent men after erotic stimulation.'0 10 Walters GR, Keogh ZS, Thliloch AGS, Lord DG. Prolonged erection following intracorporeal injection of medications to overcome impotence. Go-dergocrine has blocking activity at a receptors and BrJ Urol 1988;62:143-6. also has central actions,3' which may contribute to its 11 Krane R, Goldstein I, Saenz de Tejada I. Impotence. N Engl Jf Med 1989;321:1648-59. valuable effect on erectile dysfunction. 12 Class H , Baert L. Transcutaneous nitroglycerin therapy in the treatment of impotence. UrollInt 1989;44:309-12. CONCLUSIONS 13 Owen JA, Saunders F, Harris C. Topical nitroglycerin: a potential treat- ment for impotence. Jf Urol 1989;141:546-8. During laboratory testing the active cream signifi- 14 Negeleve S. Topical nitroglycerin: a potential treatment for impotence. cantly increased penile arterial flow and induced Jf Urol 1990;143:586-8.

1514 BMJ VOLUME 312 15 juNE 1996 15 Heaton JPW, Morales A,Owen J. Topical glyceryltrinitrate causes 23 Gomaa AA. Percutaneous absorption of co-dergocrine mesilate in rats and measurable penile arterial dilatation in impotent men. J Urol 1990; guinea pigs. Yournal of the Egyptian Academy of Scientific Research 143:729-32. 1994;145:150. 16 Cavallini G. Minoxidil versus nitroglycerin: a prospective double-blind 24 Lue TF, Tanagho EA. Physiology oferection and pharmacological manage- controlled trial in transcutaneus erection facilitation for organic ment of impotence.Y Urol 1987;137:829-36. impotence.J Urol 1991;146:50-3. 25 Aboseif SR, Breza J, Lue TF, Tanagho EA. Penile venous drainage in erec- 17 Morales A, Condra M, Owen JA. Oral and transcutaneous pharmacologic tile dysfunction, anatomical, radiological and functional consideration. Br agents for treatment of impotence. In:Tanagho E, Lue TF, MeClure DR, J Urol 1989;64:183-9. eds. Contemporary management ofimpotence and infertility. Baltimore: Wil- 26 Hashmat Al, Rehman J. Priapism. In: Hashmat Al, Das S, eds. The penis. liams andWilkins, 1988:178-85. Philadelphia: Lea and Febiger, 1993:222. 18 Meyhoff H, Rosenkilde H, Bodker A. Non-invasive management of impo- 27 Donatucci GF, Lue TF. Physiology of penile tumescence. In: Hashmat Al, tence with transcutaneous nitroglycerin. BrJ Urol 1992;69:88-90. Das S, eds. The Penis. Philadelphia: Lea and Febiger, 1993:20. 19 Kirby RS, Eardly I. Medical treatment oferectile dysfunction. In: Kirby RS, 28 Buch PA, AronsonWJ, Buga GM, Ignarro U. Nitric oxide is a potent relax- Carson CC,Webster GD, eds. Impotence: diagnosis and management ofmale ant ofhuman and rabbit corpus cavernosum. Y Urol 1992;147:1650-5. erectile dysfunction.Oxford: Butterworth-Heinemann, 1991: 149-52. 29 Blum MD, Bahnson RR, Porter TN, Carter MF. Effect of local alpha 20 Conner DP, Almirez RG, Rhyne P, Zamani K, Bolden BJ, Peck CC. Trans- adrenergic blockade on human penile erection. J Urol 1985;134:479-81. cutaneous collection of theophylline: constancy and linearity of skin per- 30 Gomaa AA, Shalaby MA, Ahmed HN, Osman ME, Abdel-Menam AE, meability. Skin Pharmacol 1989;2:153-6. Abdellah MM. Treatment of impotence by Eroderm cream. Eur J Clin 21 Cartwright RG, Cartlidge PET, Rutter G, Davis SS. Transdermal delivery Pharmacol 1994;47:A1O1. of theophylline to premature infants using a hydrogen disc system. Br.J 31 Gilman AG, Rail TW, Nies AS, Taylor P. The pharmacological basis of thera- Clin Pharmacol 1990;29:533-54. peutics. 8th ed. NewYork: Pergamon, 1990: 939, 947. 22 Handler CE. Double-blind randomised crossover trial comparing isosorb- ide dinitrate cream and oral sustained release tablet, in patients with angina pectoris. J Cardiol 1985;7:149-53. (Accepted 6 March 1996)

Certification of cause of death in patients dying soon after proximal femoral fracture

S J Calder, G H Anderson, P J Gregg

Certification of cause of death has been a legal Comment obligation for medical practitioners since 1874' and has In most patients who die within 28 days of admission been central to our knowledge of the incidence of fatal for hip fracture the fracture contributes significantly to diseases. To assess whether certified cause of death death-for example, through problems related to reflects the well documented high mortality after immobility-even though the direct cause may be a fracture of the proximal femur,2 we reviewed the medical problem such as bronchopneumonia. This certification of cause of death in patients who died judgment was the initial reason for choosing 28 days as soon after such injuries. If a fracture is mentioned the cut offpoint for this study and was supported by the on the death certificate as contributory to death coroner's finding in every case in which an inquest was the registrar of deaths has a duty to report it to held that the fracture had been contributory. There is the coroner and the coroner must hold an inquest. no specified interval for the reporting of trauma related We suspected that the need for an inquest might act deaths to the coroner, but junior hospital staff often use as a barrier to doctors recording fractures on the death 28 days or four weeks as a rule of thumb. certificate. Twenty three per cent may seem a high proportion of proximal femoral fractures to necessitate an inquest, but these deaths are early in the period after injury. Deaths Patients, methods, and results occurring later, when the importance of the fracture We collected data prospectively in 1991-2 on patients becomes less, will rarely involve the coroner, and the admitted to Leicester Royal Infirmary with proximal overall proportion will therefore be much lower. The femoral fractures who died within 28 days of admission inquest is a formality necessitated by the mention of the to see what was recorded on their death certificate and fracture on the death certificate and is in addition to the whether or not a coroner's inquest was held. No calcu- coroner's post mortem examination. lation of sample size was performed because we had no The practice of not mentioning the fracture on the idea of expected differences. death certificate to avoid an inquest may lead to consid- University Department of Ninety four of 1274 consecutive patients with erable under certification of proximal femoral fracture Orthopaedic Surgery, fractures died within 28 days; the cause of death on the as a predisposing cause of death-75% of cases were Glenfield General unreported in our series. This has been recognised Hospital, Leicester death certificate was obtained for 92 of these patients LE3 9QP (98% follow up). An inquest was held in 22 of the 92 before, and true mortality figures have to be estimated S J Calder, research registrar cases (23%); every case was checked with hospital data in an unsatisfactory empirical fashion.3 A legal facility to P J Gregg, professor sources and referenced to the death certificate and mention age related proximal femoral fractures on the information from the coroner's office. In each of these death certificate without the mandatory need for an Department of 22 cases the fracture was recorded on the death certifi- inquest may improve the accuracy of mortality figures. Orthopaedic Surgery, cate as a contributory factor. In only one out of the 70 Funding: Collection of data for this study was aided by fund- Leicester Royal Infirmary, cases where an inquest was not held, however, was the ing from the Wishbone Trust. Leicester LE1 SWW Conflict of interest: None. G H Anderson, senior fracture recorded on the death certificate (and in that registrar case an inquest was not indicated because it was a pathological fracture). No certificate recorded the frac- 1 Rights and responsibilities ofdoctors. London: BMJ Publishing, 1992:79-80. Correspondence to: ture as being the direct cause of death. The difference 2 Wood DJ, Ions GK, Quinby JM, Gale DW, Stevens J. Factors which influ- 12 two in fracture on the ence mortality after subcapital hip fracture. J Bone joint Surg 1992;74B: Mr Calder, Park Lane, between the groups hip appearing 199-202. Leeds LS8 2EU. death certificate was highly significant (P<0.001 by x2 3 Parker MJ, Anand JK. What is the true mortality after hip fracture? Public test with Yates's correction; 95% confidence interval Health 1991;105:443-6. BMJ 1996;312:1515 0.00 to 0.01). (Accepted 2 February 1996)

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