Yohimbine: a clinical review

Pharmacology & Therapeutics 91 (2001) 215 – 243 Yohimbine: a clinical review S. William Tama,*, Manuel Worcela, Michael Wyllieb a b NitroMed, Inc., 12 Oak Park Drive, Bedford, MA 01730, USA URODOC, Maryland, Ridgeway Road, Herne Bay, Kent CT6 7LN, UK Abstract Although yohimbine (YOH) has been available for the treatment of male erectile dysfunction (ED) for longer than Viagra1, there is a perception that little is known about the clinical performance of the drug. This review attempts, by comprehensive analysis of the literature, to cover the clinical, pharmacological, and therapeutic profiles of YOH, relevant to its potential utility in the management of patients with ED. Relatively few well-designed studies have been completed. From these, however, it can be concluded that YOH as monotherapy possesses only modest efficacy in ED patients. In acute and chronic (long-term) studies, YOH has been found to be relatively free of side effects over the dose range predicted to be effective in ED. At much higher doses, the most frequently observed effects, consistent with the primary pharmacological action of the drug, are elevation of blood pressure, a slight anxiogenic action, and increased frequency of urination. These side effects are all easily reversible on termination of YOH therapy. There is increasing evidence that the erectogenic action of YOH can be augmented by concomitant administration of agents that augment the release and/or action of nitric oxide in the corpus cavernosum. YOH has yet to be studied in female sexual dysfunction. Overall, the benefit risk profile of YOH would indicate that it has potential, more probably as part of a combination strategy, e.g., with a drug that enhances the nitric oxide pathway, in the treatment of ED. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Yohimbine; Erectile dysfunction; Sexual dysfunction; Concomitant administration; Blood pressure; a-Adrenoceptors; Combination therapy Abbreviations: AD, Alzheimer’s disease; AR, adrenoceptor; AUC, area under the curve; BMI, body mass index; BP, blood pressure; CGI, Clinical Global Impression; cGMP, cyclic GMP; CSF, cerebral spinal fluid; DBP, diastolic blood pressure; ED, erectile dysfunction; EPI, epinephrine; Fm theta, frontal midline theta activity; HR, heart rate; HVA, homovanillic acid; L-dopa, L-3,4-dihydroxyphenylalanine; MAP, mean arterial blood pressure; MHPG, 3-methoxy-4-hydroxyphenylglycol; NANC, nonadrenergic, noncholinergic; NE, norepinephrine; NEFA, non-esterified fatty acid; NO, nitric oxide; 10-OH-YOH, 10-hydroxyyohimbine; 11-OH-YOH, 11-hydroxyyohimbine; PET, Positron Emission Tomography; PTSD, posttraumatic stress disorder; SBP, systolic blood pressure; SSRI, selective serotonin uptake inhibitor; VAS, visual analogue scale; VSS, visual sexual stimulation; YOH, yohimbine. Contents 1. 2. 3. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . Clinical pharmacology . . . . . . . . . . . . . . . . . . . . . 3.1. Haemodynamics, side effects, and overall tolerability . 3.1.1. Oral administration to healthy subjects . . . . 3.1.2. Intravenous administration to healthy subjects 3.2. Effect on memory . . . . . . . . . . . . . . . . . . . 3.3. Effects on semen . . . . . . . . . . . . . . . . . . . . 3.4. Effects on platelets . . . . . . . . . . . . . . . . . . . 3.5. Metabolic effects . . . . . . . . . . . . . . . . . . . . 3.6. Endocrine effects . . . . . . . . . . . . . . . . . . . . 3.7. Effect on sleep . . . . . . . . . . . . . . . . . . . . . 3.8. Effects on salivary secretion . . . . . . . . . . . . . . * Corresponding author. Tel.: 781-685-9748; fax: 781-275-2282. E-mail address: [email protected] (S.W. Tam). 0163-7258/01/$ – see front matter D 2001 Elsevier Science Inc. All rights reserved. PII: S 0 1 6 3 - 7 2 5 8 ( 0 1 ) 0 0 1 5 6 - 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 218 219 219 219 224 225 225 225 225 226 226 226 216 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 4. 5. 6. 3.9. Effects on analgesia . . . . . . . . . . . . . . . 3.10. Antidote for clonidine overdose . . . . . . . . . Therapeutic profile of yohimbine . . . . . . . . . . . . . 4.1. Patients with erectile dysfunction. . . . . . . . . 4.1.1. Monotherapy . . . . . . . . . . . . . . 4.1.2. Yohimbine in iatogenic impotence . . . 4.1.3. Yohimbine combination clinical studies . 4.2. Women with hypoactive sexual desire . . . . . . 4.3. Obese patients . . . . . . . . . . . . . . . . . . 4.4. Alcoholics . . . . . . . . . . . . . . . . . . . . 4.5. Diabetic patients . . . . . . . . . . . . . . . . . 4.6. Drug addicts . . . . . . . . . . . . . . . . . . . 4.7. Patients with autonomic dysfunction . . . . . . . 4.8. Hypertensive patients . . . . . . . . . . . . . . . 4.9. Patients with orthostatic hypotension . . . . . . . 4.10. Patient with Parkinson’s disease . . . . . . . . . 4.11. Patients with Alzheimer’s disease . . . . . . . . 4.12. Patients with depression . . . . . . . . . . . . . 4.13. Patients with generalized anxiety disorders. . . . 4.14. Patients with panic disorder . . . . . . . . . . . 4.15. Patients with posttraumatic stress disorder . . . . 4.16. Patients with narcolepsy . . . . . . . . . . . . . 4.17. Patients with sensorineural impairment. . . . . . Overdose . . . . . . . . . . . . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction Yohimbine (17a-hydroxyyohimban-16a-carboxylic acid methylester, YOH) (Fig. 1), an indole alkaloid found in a variety of botanical sources such as the Rauwolfia root, is the principal alkaloid extracted from the bark of the Pausinystalia yohimbe tree. It has also been called quebrachine, aphrodine, corynine, and hydroaerogotocin. YOH is a potent selective a2-adrenoceptor (AR) antagonist with weaker Fig. 1. The chemical structure of YOH. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 227 227 227 227 232 232 233 233 234 234 234 234 234 235 235 235 236 236 237 237 238 238 238 239 239 a1-antagonist activity, as demonstrated by radioreceptor ligand binding assays and by pharmacological studies (for a review, see Goldberg & Robertson, 1983). The predominant use of YOH has been as a pharmacological tool to study the involvement of a2-ARs in the regulation of autonomic function and for the treatment of impotence in males. Animal studies confirm the enhancing effect of YOH on sexual behaviour. In male rats, YOH decreases the latencies of intromission, mounting, and ejaculation (Smith et al., 1978a); increases the frequency of penile erection (Smith et al., 1978b); increases sexual motivation (Clark et al., 1984); induces mating behaviour during sexual exhaustion (Rodrı́guez-Manzo and Fernández-Guasti, 1994); and induces copulatory behaviour in sexually inactive rats (Clark et al., 1984). At low doses, YOH also enhances the ejaculatory response (Yonezawa et al., 1991). The mechanism by which YOH could enhance sexual function is not fully understood. It has been postulated that a2-ARs play a modulatory role in the resting and stimulated noradrenergic nervous system outflow (sympathetic tone) from the brain. Activation of a2-ARs located in the CNS results in inhibition of sympathetic tone and decrease of blood pressure (BP). Conversely, inhibition of central a2-ARs by antagonists such as YOH results in an increase in sympathetic tone (outflow) and an increase in BP. It is well documented that the erectile response is driven largely by the nonadrenergic, noncholinergic (NANC) system with the cavernosal tissue, and the degree of erection or erectile dysfunction (ED) is determined by S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 the balance between the nitric oxide (NO) stimulus originating from the NANC nerves and the counterbalancing effect of the sympathetic noradrenergic nerves (for a review, see Traish et al., 1999) (Fig. 2). The flaccid state of the human penis is primarily maintained by the action of norepinephrine (NE) on the a1A- and a1D-ARs in the corpus cavernosum (Traish et al., 1994, 1995; Dausse et al., 1998), although a role for the small population of a1B-ARs in the same tissue cannot be ruled out. Overall, therefore, penile erection is a complex haemodynamic event invol- 217 ving a delicate balance between corpus cavernosum smooth muscle constrictor and relaxant mediators that are controlled by the central and peripheral nervous systems and the penis. A complex interaction of adrenergic, cholinergic, and NANC mechanisms are involved in erectile response. Expression of a2a-, a2b-, and a2c-ARs in human corpus cavernosum and expression of a2a- and a2c-ARs in cultured trabecular smooth muscle cells have been demonstrated (Traish et al., 1997). The physiological function of these postsynaptic a2-ARs in human and rabbit Fig. 2. Schematic presentation of the pathways involved in the regulation of penile smooth muscle tone and the mechanism of action of YOH in its regulation. YOH antagonizes the stimulation of a2-ARs by NE released from adrenergic nerve terminals, resulting in decreased intracellular Ca2+ and increased relaxation of penile smooth muscles. YOH also antagonizes the presynaptic inhibition of the NANC nerves and increases the release of NO, which stimulates soluble guanylate cyclase to synthesize cGMP, which, in turn, decreases intracellular Ca2+ and relaxes penile smooth muscles. AC, adenylate cyclase; ACh, acetylcholine; Arach. acid, arachidonic acid; EP R, prostaglandin E receptor; GC, guanylate cyclase; IP3, inositol triphosphate; L-Arg, L-arginine; MR, muscarinic receptor; NOS, NO synthase; PDE, phosphodiesterase; PGE2, prostaglandin E2; PLC, phospholipase C; VIP, vasoactive intestinal polypeptide; VIP R, vasoactive intestinal polypeptide receptor. Modified from Traish et al. (1999). 218 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 corpus cavernosum is demonstrated by the concentrationdependent contractile response to the a2-selective agonist UK14304 in vitro, its attenuation by YOH (Gupta et al., 1998; Sáenz de Tejada et al., 1999), and by the concentration-dependent antagonism of NE-induced contraction of human corpus cavernosum by YOH in vitro (Steers et al., 1984). At least part of the mechanism of YOHinduced erectile response should include the antagonism of presynaptic and postsynaptic a2-ARs. The blocking of presynaptic a2-ARs by YOH activates noradrenergic neurons to release NE (see Section 3.1.1), which, in turn, may activate a-ARs in the endothelium to mediate the release of NO and prostanoids. These released NO and prostanoids should elevate intracellular cyclic GMP (cGMP) and cyclic CMP, respectively, and should result in relaxation of the penile smooth muscles (Fig. 2). Simonsen et al. (1997) demonstrated that stimulation of prejunctional a2-ARs inhibits the release of a NANC neurotransmitter, NO, in horse penile resistance arteries. Blocking of these prejunctional a2-ARs by YOH should enhance the release of NO to stimulate soluble guanylate cyclase and should increase cGMP levels, leading to relaxation of the corpus cavernosal smooth muscles. A recent study suggests that concomitant stimulation of the NO pathway and blockade of a-ARs by YOH with the introduction of a NO-donor group into a new analogue of YOH produces a synergistic effect on relaxation of rabbit corpus cavernosum in vitro and enhancement of rabbit penile erection in vivo (Sáenz de Tejada et al., 1999). Therefore, combination of YOH with agents that enhance the release of NO should enhance the therapeutic effect on ED. (Owen et al., 1987; Guthrie et al., 1990; Le Verge et al., 1992; Grasing et al., 1996; Sturgill et al., 1997; Le Corre et al., 1999). The pharmacokinetic parameters of these studies are summarized in Table 1. The average absorption half-life is 0.17 ± 0.11 hr, and absorption of YOH from the gut is generally complete in 45– 60 min (Owen et al., 1987). Data resulting from oral YOH generally fit a onecompartment pharmacokinetic model. A dose-dependent relationship for C max and the area under the curve (AUC) has been demonstrated (Sturgill et al., 1997). Oral bioavailability is low and quite variable between subjects with a mean of 22.3%, 30%, and 33%, as was shown in 3 studies (Le Corre et al., 1999; Le Verge et al., 1992; Guthrie et al., 1990). Grasing et al. (1996) demonstrated that a high-fat meal increased Tmax from 0.28 ± 0.24 hr to 0.70 ± 0.53 hr without affecting elimination half-life. The high-fat meal also decreased the AUC by 30%, suggesting that a high-fat meal decreased the absorption of YOH. Clearance is primarily by hepatic metabolism, as very little YOH (
1%) is eliminated by urinary excretion (Owen et al., 1987; Hedner et al., 1992; Le Verge et al., 1992). Hepatic metabolism produces two hydroxylated metabolites (Le Verge et al., 1992). The major metabolite, 11-hydroxy-YOH (11-OH-YOH), and the minor metabolite, 10-OH-YOH, are excreted into urine, but only 11-OH-YOH is detected in large amounts in the plasma. The extent of YOH and its 2 metabolites bound to plasma proteins is different: 82%, 43%, and 32% for YOH, 11-OH-YOH, and 10-OH-YOH, respectively (Berlan et al., 1993). The order of binding affinity to a2-ARs in human platelet and adipocyte membranes is YOH > 11-OH-YOH > 10-OH-YOH. However, in the presence of 5% albumin, the binding affinity of YOH is decreased to that of 11-OH-YOH (Berlan et al., 1993). 11-OH-YOH is an active metabolite with a similar a2-AR antagonist potency to YOH in inhibiting UK14304-induced antilipolysis in human adipocytes and is slightly less potent than YOH in inhibiting adrenaline-induced platelet aggregation (Berlan et al., 2. Pharmacokinetics Single-dose pharmacokinetic studies with oral YOH HCl demonstrated that YOH is rapidly absorbed and eliminated (both mean Tmax and elimination T1/2 < 1 hr) Table 1 Single-dose pharmacokinetic parameters of YOH HCl in fasted healthy subjects Subject Dose (mg) 11 Healthy young adults 12 Healthy subjects 7 Healthy men (21 – 36 years old) 8 Healthy young men 32 Healthy men (30 – 55 years old) 8 8 10 32 Healthy men (30 – 49 years old) 10 5.4 10.8 16.2 5.4 10.8 10.81 16.2 21.6 Tmax (hr) 1.1 ± 0.60 Cmax (ng/mL) AUC (ng/hr/mL) 37.3 ± 51.5 55.7 ± 68.2 0.17 – 0.75 0.75 – 1.0 0.43 ± 0.31 0.45 ± 0.13 0.39 ± 0.21 0.43 ± 0.36 0.28 ± 0.24 0.70 ± 0.53 0.56 ± 0.14 0.56 ± 0.20 134 ± 231 50.9 ± 46.1 154 ± 107 400 ± 314 Data represent mean ± SD. 1 Subjects received a high fat meal before YOH administration. 30.8 ± 14.9 119 ± 72.5 376 ± 374 T1/2 (hr) Oral bioavailability (%) Reference 1.3 ± 1.2 0.92 0.68 22.3 ± 21.5 30 33 Le Corre et al., 1999 Le Verge et al., 1992 Guthrie et al., 1990 0.60 0.29 0.21 0.34 0.51 0.30 0.53 0.39 0.50 ± ± ± ± ± ± ± ± ± 0.26 0.19 0.06 0.09 0.44 0.23 0.40 0.10 0.17 Owen et al., 1987 Sturgill et al., 1997 Grasing et al., 1996 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 1993). 11-OH-YOH has a longer elimination half-life than YOH (6.0 hr vs. 0.92 hr, respectively). According to Le Verge et al. (1992), these results may explain the discrepancy between the pharmacokinetic data and the duration of therapeutic effects, and may support the hypothesis of a first-pass effect and subsequent low oral bioavailability after hepatic oxidative metabolism. 3. Clinical pharmacology 3.1. Haemodynamics, side effects, and overall tolerability A majority of clinical studies indicate that YOH, administered orally or intravenously, can induce a dose-dependent transient moderate increase in BP without affecting heart rate (HR), as would be expected for a selective a2-AR antagonist. However BP elevation is dependent on the dose and the initial haemodynamic baseline. The results of representative studies of the effects of YOH on haemodynamics in normotensive and hypertensive subjects are summarized in Table 2. Thus, at oral doses of 4 –16.2 mg administered as a single dose or t.i.d., YOH generally had no effect on BP and HR in normotensive men and women. At higher oral doses of 20 –30 mg, YOH either had no significant effect or caused moderate increases in BP, without affecting HR. At doses of 45.5 mg or higher, YOH occasionally increased mean arterial BP (MAP), with less frequent increases in HR. When observed, these haemodynamic changes usually peaked at 60 –90 min, and then gradually decreased back to baseline in several hours. Thus, there appears to be a good pharmacokinetic/pharmacodynamic relationship. Both young and older adults tolerated YOH well. An oral dose of YOH (10 mg) had no effect on BP and HR in hypertensive patients; a high dose (21.6 mg) produced only a moderate increase (maximum mean increase of 5 mm Hg) in hypertensive patients, without affecting HR. Information on the haemodynamic effects of YOH in patients with ED (usually a high percentage of diabetic and hypertensive patients) or other diseases can be found in Section 4.1. It is likely that the overall haemodynamic profile of YOH reflects both central and peripheral actions on a2-ARs. Over the dose range likely to be effective in ED, there would appear to be reflex adaptation to any tendency to increase vasomotor drive. Only at much higher doses can uncompensated, occasional elevation of BP occur. There is no evidence of an exaggerated response to patients with hypertension (Section 4.8) or a propensity for orthostatic hypotension (Section 4.9). 3.1.1. Oral administration to healthy subjects 3.1.1.1. Resting. Galitzky et al. (1990) evaluated the effects of 14 days of treatment with oral YOH (4 mg t.i.d., 12 mg/day) in 10 healthy male subjects. The treatment increased plasma NE, but did not affect BP or HR. 219 Sturgill et al. (1997) reported on the safety and haemodynamic response of single- and multiple-doses of YOH HCl in a randomised, double-blind, placebo-controlled, repeat-dose escalation study design. Thirty-two healthy human subjects received YOH for 6 days [5.4 mg t.i.d. (16.2 mg/day), 10.8 mg t.i.d. (32.4 mg/day), 16.2 mg t.i.d. (48.6 mg/day), or 21.6 mg b.i.d. (43.2 mg/day)]. Plasma catecholamine levels increased significantly in relationship to both average YOH AUC and Cmax, but there were no significant effects on HR, BP, or anxiety/ mood-inventory scores. YOH HCl administered as single oral doses of 5.4, 10.8, 16.2, and 21.6 mg to healthy human male volunteers (30 – 55 years old, 8 different subjects per dose) was well tolerated (Grasing et al., 1996). No significant changes in BP, HR, respiratory rate, or psychometric data [mood was assessed by visual analogue scale (VAS), the Profile of Mood States, and the Spielberger State Anxiety Index] were observed between groups treated with different doses of YOH or placebo. However, increases in BP, respiratory rate, plasma catecholamine levels, and total VAS scores were observed in some subjects with elevated AUC values. The effects of 3 oral doses of YOH (10, 15, and 20 mg) were tested in 8 healthy human subjects (4 male, 39 ± 14 years old; 4 female, 36 ± 6 years old), and all 3 doses significantly increased the free NE metabolite 3-methoxy4-hydroxyphenylethylglycol (MHPG) in plasma (Charney et al., 1982). YOH had no significant effect on HR, systolic BP (SBP), and diastolic BP (DBP) between drug groups and placebo when all time points were included. However, compared with their respective baselines, significant increases in sitting SBP (mm Hg) measured at 1, 2, 3, and 4 hr were observed at the following time points: 15 mg, + 10 at 2 hr and + 7 at 3 hr; 20 mg, + 9 at 1 hr and + 12 at 4 hr. At the 10-mg dose, YOH did not affect sitting SBP. Only the 15-mg and 20-mg doses induced autonomic symptoms, such as piloerection (15 mg and 20 mg) and rhinorrhea (20 mg only). Ninety minutes following the 20-mg dose of YOH, there was a small, but significant, increase in self-reported anxiety compared with placebo. Orally administered YOH (0.2 mg/kg) in fasting nonobese women [body mass index (BMI), 20.2 ± 0.5, 35.5 ± 2.7 years old] had no significant effect on HR or BP during the course of the experiment (4 hr) (Berlan et al., 1991). Plasma NE levels, but not epinephrine (EPI) levels, were increased 100% after oral YOH administration. A high oral dose of YOH (20 mg) was administered to 10 healthy human subjects (33.2 ± 3.6 years old) for 5 days, during which, medication effects on mood and anxiety states, physiologic indices, plasma cortisol levels, and plasma levels of MHPG were assessed (Krystal et al., 1992). YOH increased plasma MHPG and plasma cortisol. YOH significantly increased SBP from baseline. However, the peak YOH increase (16.5 ± 3.1 mm Hg) was not significantly greater than placebo. There was no significant 220 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 Table 2 Haemodynamic effects of YOH on normotensive and hypertensive human subjects Reference Subject YOH Route Cardiovascular effects of YOH Goldberg et al., 1983 7 Normal males 0.016 – 0.125 mg/kg (total 0.25 mg/kg) i.v. 5 Normal males, double-blind study 0.125 mg/kg bolus + 0.001 mg/kg/min i.v. Grossman et al., 1991 7 Normal, mean age 28 years 0.125 mg/kg bolus + 0.001 mg/kg/min i.v. Goldstein et al., 1991 19 Normal and 19 essential hypertensive 0.125 mg/kg bolus + 0.001 mg/kg/min for 15 min i.v. Galitzky et al., 1990 10 Normal males, mean age 27.7 years 25 Normal (16 males and 9 females) and 29 sex- and age-matched unmedicated hypertensives 4 mg t.i.d. for 14 days p.o. 10 mg p.o. 32 Normal, 30 – 55 years, double-blind, placebo-controlled, repeat-dose escalation 32 Normal males, 30 – 55 years 6 Days of 5.4, 10.8, 16.2 mg (all t.i.d.) or 21 mg b.i.d. 5.4, 10.8, 16.2, or 21.6 mg p.o. Dose-dependent increase in MAP, SBP, and DBP; plateaued at 10 – 15 min. Maximum dose increased MAP, SBP, and DBP by 14 ± 1, 28 ± 3, and 8 ± 1 mm Hg, respectively. BP returned to baseline within 1 – 2 hr after last dose. No change in HR. Significant increase in supine MAP by YOH, with a maximum increase of 10 mm Hg at 15 min. No change in MAP at standing. No change in HR. From baseline, significant increase in MAP from 86 to 100 mm Hg, mean SBP from 118 to 143 mm Hg, mean DBP from 70 to 79 mm Hg. Significant increase in mean MAP from 88 ± 2 to 101 ± 3 mm Hg in normals vs. 106 ± 4 to 127 ± 5 mm Hg in hypertensives. No significant effect on HR in either group. Cardiac output was significantly increased: 7.5 ± 0.4 to 7.7 ± 2 L/min in normals vs. 7.2 ± 0.5 to 8.7 ± 0.7 L/min in hypertensives. No effect on SBP, DBP, and HR (time of measurement not specified). Measurements made 80 min after dosing. No significant effect on SBP, DBP, and HR in the normals in either supine or upright positions compared with placebo. No effect on SBP and HR in the hypertensives in either supine or upright positions compared with placebo. Significant increase of 5 mm Hg in DBP in the upright position only. No significant effect on BP and HR (time of measurement not specified). p.o. Charney et al., 1982 8 Normal (4 males, 4 females, mean age 38 years) 10, 15, or 20 mg p.o. Berlan et al., 1991 Fasting non-obese (35.5 ± 2.7 years old) and obese women (37 ± 3.6 years old) 20 Normal (11 females, 43 ± 7 years old; 9 males, 34 ± 8 years old) 0.2 mg/kg p.o. 20 mg p.o. 20 mg p.o. Musso et al., 1995 Sturgill et al., 1997 Grasing et al., 1996 Charney et al., 1987 Krystal et al., 1992 10 Normal (33.2 ± 3.6 years old) No significant effect on BP and HR (time of measurement not specified). No significant effect on HR, SBP, and DBP between YOH groups and placebo when all time points were included. YOH (10 mg) had no effect. Significant increases in sitting SBP from baseline (mm Hg) measured at up to 4 hr were observed with 15 mg (+ 10 at 2 hr and + 7 at 3 hr) and 20 mg (+ 9 at 1 hr and + 12 at 4 hr). No significant effect on HR or BP in both non-obese and obese women during the first 4 hr after dosing. Significant YOH-placebo differences (5 – 7 mm Hg) in increases from baseline in sitting SBP (1, 2, and 3 hr post-dose), in standing SBP (1, 1.5, and 3 hr post-dose), and in standing DBP (1.5, 2, 3, and 4 hr post-dose). Significant increase in SBP from baseline, but the peak increase (16.5 ± 3.1 mm Hg) was not significantly different from placebo. No significant effect on DBP and HR. (continued on next page) S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 221 Table 2 (continued ) Reference Subject YOH Route Cardiovascular effects of YOH Rasmussen et al., 1987 12 Normal (11 female and 1 male, 43 ± 7 years old) 32 Normal males (30 – 49 years old) 20 mg p.o. No significant effect on BP and HR compared with placebo controls. 5.4 – 21.6 mg p.o. Grossman et al., 1993 25 Unmedicated hypertensive patients (17 males, 8 females) 21.6 mg p.o. Morley et al., 1991 8 Normal males (19 – 23 years) 17 Normal young males, placebo-controlled 22 mg p.o. SBP was significantly increased at 2 hr, but not at 1 or 4 hr, after YOH only in the highest AUC group. No dose-dependent relationship on HR. Significant increase in SBP from 144 ± 4 (baseline) to 150 ± 5 mm Hg at 1 hr and 151 ± 4 mm Hg at 2 hr. DBP was significantly increased from a baseline value of 83 ± 3 to 86 ± 3 mm Hg at 1 hr and 87 ± 3 mm Hg at 2 hr, and MAP was significantly increased from a baseline value of 103 ± 3 to 107 ± 3 mm Hg at 1 hr and 108 ± 3 mm Hg at 2 hr post-dose. No effect on HR. No significant effect on BP and HR. 20 or 40 mg p.o. Adler et al., 1994 7 Normal (5 males, 2 females, 21 – 35 years old) 0.4 mg/kg p.o. Charney et al., 1983 10 Normal (6 males, 4 females, mean age 38 years) 30 mg p.o. Charney et al., 1986a 8 Normal (4 males, 28 ± 4 years old, 4 females, 35 ± 6 years old) 18 Normal males (26 ± 1 years old) and 5 healthy elderly males (74 ± 1 years old) 30 mg p.o. 0.65 mg/kg p.o. Peskind et al., 1995 18 Normal males (26.4 ± 0.9 years old) and 10 elderly normals (6 male and 4 female, 71.2 ± 1.1 years old) 0.65 mg/kg p.o. Peskind et al., 1989 7 Normal males (23 – 32 years old) 0.65 mg/kg p.o. Peskind et al., 1998 54 Normal young subjects, 42 normal elderly subjects, 74 AD patients 0.65 mg/kg p.o. Lucchini et al., 1989 8 Normal 60 mg p.o. Grasing et al., 1996 Murburg et al., 1991 Petrie et al., 2000 YOH (20 mg) had no significant effect on SBP, DBP, MAP, and HR compared with placebo. YOH (40 mg) produced no significant effect on SBP, a 10% increase in DBP, a 7% increase in MAP, and an 11% increase in HR. Only significant effect was an increase in SBP from a baseline value of 100.9 – 113.1 mm Hg 30 min after dosing. No effect on SBP at 1 and 2 hr. No effect on DBP and HR. Significant increases in sitting and standing SBP compared with placebo. Mean increases in standing SBP (mm Hg) was + 17 (1 hr), + 14 (2 hr), + 6 (3 hr), and + 6 (4 hr). No significant effect on HR or DBP. No significant effect on standing SBP compared with placebo. Increased MAP by 9 and 14 mm Hg in young and elderly subjects, respectively, at 30 – 90 min. Mean HR increased significantly by 4 and 9 beats/min in young and elderly subjects, respectively, but no difference between the 2 groups. Significant increase in MAP in both groups, with mean increases of 5 and 6 mm Hg in young and elderly subjects, respectively, 90 min after dosing. HR increased significantly by 6 beats/min in young subjects. No significant effect on MAP compared with placebo. Significant increase in HR (70 ± 5 vs. 61 ± 3 beats/min at baseline) at 120 min, but not at 90 min or earlier. No effect on BP in young subjects. Significant increase in SBP (16 mm Hg) and DBP (12 mm Hg) in elderly normal subjects. Significant increase in SBP (25 mm Hg) in AD patients. No significant effect on BP. (continued on next page) 222 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 Table 2 (continued ) Reference Subject YOH Route Cardiovascular effects of YOH Kenney et al., 1994 5 Normal young males before and after exercise 16.2 mg/day for 3.5 – 4.5 days + additional 5.4 mg immediately before exercise test p.o. At rest, MAP after 30 min (99 ± 2 mm Hg) was significantly increased vs. control (no placebo) (88 ± 2 mm Hg). HR was significantly increased from 58 ± 5 beats/min in controls to 71 ± 6 beats/min in YOH group. Exercise began 30 min after YOH, and the ambient temperature was increased from 25 to 36C. MAP (mm Hg) was significantly increased by YOH when measured at 15, 30, and 45 min during exercise; control (no placebo) was 89 ± 5, 87 ± 4, and 85 ± 4 mm Hg; YOH group was 98 ± 4, 96 ± 4, and 93 ± 5 mm Hg, respectively. No significant difference in HR between control and YOH during exercise. effect on DBP and HR. YOH had no significant effect on the Panic Attack Symptom Scale scores compared with placebo. YOH HCl (22 mg) administered orally to 8 healthy male volunteers (19 – 23 years) had no significant effect on BP, HR, and mood state (alertness, contentedness, and calmness) compared with placebo when measured 3 hr after receiving the drug (Morley et al., 1991). YOH produced a small, but significant, increase in resting pupil diameter (YOH, 7.4 ± 0.2 mm; placebo, 7.1 ± 0.2 mm) when measured at 3 hr post-dose. The response of sweat glands activated by different doses of carbachol was not affected by YOH. YOH has a dose-dependent effect on haemodynamics and an increase in plasma NE. Placebo (n = 6) or YOH (20 mg, n = 5; 40 mg, n = 6) was administered orally to healthy young men. Subjects receiving placebo or YOH (20 mg) had no significant effect on SBP, DBP, MAP, or HR (Murburg et al., 1991). There is a nonsignificant trend towards increasing plasma NE in the 20-mg YOH group. The 40-mg YOH group showed no significant change in SBP, a 10% increase in DBP, a 7% increase in MAP, and an 11% increase in HR over that produced by placebo. Charney et al. (1987) studied the effect of oral YOH (20 mg) on 20 healthy subjects (11 females, 43 ± 7 years old; 9 males, 34 ± 8 years old). There were significant YOH-placebo differences (5 –7 mm Hg) in the increases from baseline in sitting SBP, 1, 2, and 3 hr after the dose; in standing SBP, 1, 1.5, and 3 hr post-dose; and in standing SBP, 1.5, 2, 3, and 4 hr after the dose. Rasmussen et al. (1987) reported that oral YOH (20 mg) had no significant effect on BP and HR in 12 healthy subjects (11 females and 1 male, 43 ± 7 years old). YOH induced a significant increase in MHPG at 2, 3, and 4 hr compared with placebo controls. Behavioural observation up to 4 hr after YOH administration indicated a significant YOH-placebo increase in ratings of nervousness at 1, 1.5, and 2 hr. YOH did not appear to alter somatic function. There were no recorded instances of nausea, urinary frequency, perspiration, palpitation, restlessness, anorexia, tremulousness, piloerection, hot and cold flashes, lacrimation, rhinorrhea, and muscle aches. Significant YOH-placebo differences were found for rating scores of piloerection at 1 and 1.5 hr after administration. The effects of placebo or oral YOH (20 mg) on orthostatic tolerance to cardiovascular stress in 10 untrained, healthy human subjects (9 male and 1 female, 22– 46 years old) were studied. YOH was well tolerated (Farrow et al., 1990). Compared with placebo, YOH significantly increased forearm blood flow at rest (1.80 ± 0.25 vs. 2.66 ± 0.31 mL/ 100 mL/min) and during 40 mm Hg of lower body negative pressure (1.36 ± 0.25 vs. 1.91 ± 0.28 mL/100 mL/min). YOH administered orally at 0.4 mg/kg to 7 healthy subjects (5 male and 2 female, 21– 35 years old) produced a moderate significant increase in SBP from baseline (100.9 mm Hg) to 113.1 mm Hg 30 min post-dose, and no significant change was observed at 1 and 2 hr (Adler et al., 1994). There was no significant change in DBP or HR at any time. YOH, but not placebo, caused a significant, but transient, decrease in P50 auditory gating in these subjects when each subject was used as his own control. The decrease in P50 auditory gating may reflect increased central catecholamine activity. For example, the cold pressor test, which has been associated with increasing NE neuronal transmission, has been shown to cause a transient impairment in P50 auditory sensory gating in normal control subjects (Johnson & Adler, 1993). The appearance of a distinct EEG theta rhythm, frontal midline theta activity (Fm theta), in the frontal midline area during performance of a mental task indicates relief from anxiety in humans. The effects of oral clonidine (0.15 mg) and YOH (15 mg) on anxiety and arousal in 24 male university students (12 with Fm theta, low anxiety, and 12 without Fm theta, high anxiety) were studied in a placebocontrolled, double-blind crossover trial (Mizuki et al., 1996). Blood samples were obtained, state-trait anxiety inventory scores were determined, and EEGs were recorded before and during the performance of an arithmetic addition task. The test was repeated before and 1 hr after drug administration. Clonidine reduced while YOH increased S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 MHPG in both groups. In the Fm theta group, clonidine reduced the appearance time of Fm theta and the number of task performance, but did not affect the state anxiety scores. YOH had no effect on Fm theta or the state anxiety, but increased the task performance. In the non-Fm theta group, YOH reduced Fm theta, but increased the state anxiety, the task performance, and the number of errors; clonidine increased the amount of Fm theta and reduced the state anxiety score, but did not affect task performance. Thus, YOH predominantly increased the arousal level in lowanxiety subjects and increased both anxiety and arousal levels in high-anxiety subjects. YOH did not induce panic attacks in any of the subjects. A high oral dose of YOH (30 mg) administered to 10 healthy subjects (6 male, 38 ± 13 years old, and 4 female, 37 ± 6 years old) produced significant increases in sitting and standing SBP compared with placebo. Mean increases in standing SBP (mm Hg) were + 17 (1 hr), + 14 (2 hr), + 6 (3 hr), and + 6 (4 hr) after YOH treatment. YOH had no significant effect on HR or DBP (Charney et al., 1983). YOH induced a significant, but mild, increase in anxiety, but no other mood changes. Both diazepam and clonidine significantly antagonized YOH-induced anxiety, but only clonidine significantly attenuated the YOH-induced increase in plasma MHPG, BP, and autonomic symptoms (Charney et al., 1983). A high oral dose of YOH (30 mg) administered to 8 healthy human subjects (4 male, 28 ± 4 years old, and 4 female, 35 ± 6 years old) had no significant effect on standing SBP, plasma cortisol, or subjective ratings to evaluate the change in 10 different mood states (happy, sad, drowsy, anxious, irritable, energetic, calm, fearful, high, and mellow) when compared with placebo (Charney et al., 1986a). YOH-induced increase in noradrenergic turnover was suggested by a significant increase in plasma-free MHPG. Concomitant YOH administration antagonized the alprazolam (1.5 mg)-induced decrease in BP and attenuated both the alprazolam-induced decrease in plasma cortisol and increase in subjective rates of drowsiness and mellow (Charney et al., 1986a). A high oral dose of YOH (0.65 mg/kg) administered to 18 normal young men (26.4 ± 0.9 years old) and 10 elderly normal subjects (6 male and 4 female, 71.2 ± 1.1 years old) significantly increased the concentrations of NE in both plasma and cerebrospinal fluid in both groups compared with the placebo group (Peskind et al., 1995). MAP was significantly increased in both groups, with mean increases of 5 and 6 mm Hg for young subjects and elderly subjects, respectively, 90 min after dose administration. HR increased significantly by 6 beats/min in the young subjects. Ratings of tension, excitement, and anxiety were significantly higher in both groups compared with the placebo group. In a similar study, plasma NE increases, but not plasma EPI increases, were greater in 5 elderly men (74 ± 1 years old) than in 18 healthy young men (26 ± 1 years old) after a high dose of YOH (0.65 mg/kg) (Petrie et al., 2000). MAP was 223 increased by 9 and 14 mm Hg for young and old subjects, respectively, between 30 – 90 min. Mean HR significantly increased by 4 and 9 beats/min in young and old subjects, respectively, over the same period, and there was no difference between the 2 groups. YOH administered to 7 young normal male subjects (23 – 32 years old) at a high oral dose of 0.65 mg/kg produced no significant difference in MAP compared with placebo (Peskind et al., 1989). A significant moderate increase in HR (70 ± 5 beats/min vs. 61 ± 3 beats/min at baseline) was observed with YOH treatment at 120 min, but the effect was not significant at 90 min or earlier, which was probably due to the small sample size. A very high oral dose of YOH (0.8 mg/kg) was administered to 16 healthy young adults in a placebo-controlled, double-blind and crossover study with 10-mg/kg caffeine (Mattila et al., 1988). YOH increased SBP and plasma prolactin concentrations, and induced drowsiness and passiveness. Both YOH and caffeine treatments produced anxiety, muzziness, clumsiness, tremor, chills, and nausea in some subjects. Clonidine (200 mg) antagonized the YOH effect on BP and sedation, but not the effect on prolactin. The changes in plasma aldosterone during an angiotensin II infusion at doses of 1, 2, 5, and 10 ng/kg/min or after 0.25 mg corticotrophin infusion in 8 normal human subjects before and after treatment with YOH (maximal dosage, 60 mg daily) was studied by Lucchini et al. (1989). YOH did not modify BP, body weight, the supine levels of angiotensin II, renin and aldosterone, the pressor response to angiotensin II, and the correlation relating plasma aldosterone to plasma angiotensin II obtained during infusion studies. 3.1.1.2. Exercising. The effects of YOH on haemodynamic measures were studied in 5 healthy young men. YOH was first administered orally to test subjects 36 hr before the test, and the subjects received 16.2-mg YOH/day, plus an additional 5.4 mg immediately before exercise on a cycle ergometer (Kenney et al., 1994). YOH significantly increased MAP (99 ± 2 mm Hg) from baseline (88 ± 2 mmHg) at resting condition, and HR (beat/min) was also significantly increased from 58 ± 5 in controls to 71 ± 6 in the YOH group. Exercise began 30 min after taking YOH, and the ambient temperature was increased from 25C to 36C. MAP (mm Hg) was significantly increased by YOH when measured at 15, 30, and 45 min during exercise [control (no placebo), 89 ± 5, 87 ± 4, and 85 ± 4, respectively; YOH group, 98 ± 4, 96 ± 4, and 93 ± 5, respectively]. There were no significant differences in HR between control and YOH during exercise. In another study, the effect of oral YOH (15 mg) or placebo on ventilation and subjective measures of breathlessness in normal subjects during steady-state exercise was studied in 10 normal male subjects 20 –44 years old in a double-blind crossover fashion (Clark et al., 1997). Plasma NE was significantly higher following YOH administration after 6 min of exercise, but not at resting, standing, or at 4 min of exercise. HR was 224 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 significantly higher following YOH at 3 min (146.9 ± 4.0 vs. 156.7 ± 5.3) and 6 min (167.4 ± 4.9 vs. 175.6 ± 5.7) of exercise, suggesting an adrenergic effect of YOH. The lactate levels were not changed by YOH. There was no difference between pre-exercise and baseline (end of 2-min warm-up) values for any metabolic gas exchange variables between the 2 groups. Oxygen consumption was unchanged, but ventilation and the sensation of exertion was significantly greater with YOH during exercise. 3.1.1.3. During alcohol consumption. The effects of oral administration of ethanol, intravenous administration of YOH, and the combination of ethanol and YOH on subjective measures of intoxication and anxiety, plasma MHPG and cortisol, and cardiovascular indices were studied in 12 healthy subjects (7 men and 5 women, 22 –49 years old) using a double-blind, placebo-controlled design (McDougle et al., 1995). Acute ethanol administration (1.1 mL 95% ethanol/kg) significantly increased the subjective measure of intoxication and anxiety, plasma MHPG and cortisol, and BP relative to placebo. Intravenous YOH HCl (0.4 mg/kg) significantly increased subjective measures of intoxication and anxiety, plasma MHPG and cortisol, and BP relative to placebo. The combination of YOH and ethanol increased the subjective measure of intoxication and plasma MHPG more than either ethanol or YOH alone, and the increase was less than additive. McDougle et al. (1995) also studied the effects of oral administration of ethanol, intravenous administration of YOH, and the combination of ethanol and YOH on subjective measures of intoxication and anxiety, plasma MHPG and cortisol, and cardiovascular indices in 12 healthy subjects (7 men and 5 women, 22– 49 years old) using a double-blind, placebo-controlled design. Acute ethanol administration (1.1 mL 95% ethanol/kg) significantly increased the subjective measure of intoxication and anxiety, plasma MHPG and cortisol, and BP relative to placebo. Intravenous YOH HCl (0.4 mg/kg) significantly increased subjective measures of intoxication and anxiety, plasma MHPG and cortisol, and BP relative to placebo. The combination of YOH and ethanol increased the subjective measure of intoxication and plasma MHPG more than either ethanol or YOH alone, and the increase was less than additive. 3.1.2. Intravenous administration to healthy subjects As anticipated, the intravenous doses of YOH required to produce haemodynamic changes were lower than the oral doses producing equivalent changes. The overall magnitude of the change that was produced was similar for either route. Human veins have both a1- and a2-ARs. Not surprisingly, therefore, in the absence of an exogenous stimulus, YOH, as a selective a2-AR antagonist, had no effect on venous tone in the dorsal hand veins of healthy human volunteers during in vivo infusion of 15.5-mg YOH/min (Blochl-Daum et al., 1991). The mean diameter of a hand vein during YOH infusion was 103 ± 8% of baseline (n = 4). YOH dose-dependently antagonized the venoconstriction induced by the a-AR agonists NE, methoxamine, phenylephrine, clonidine, and azepexole. Under similar conditions, selective a1-AR antagonists such as prazosin are known to affect basal venous tone, reflecting the greater dependence of vascular resistance vessels on a1-ARs (Amann et al., 1981; Harada et al., 1996). The effects of intravenous YOH on BP and HR were investigated by Goldberg et al. (1983) in a dose-ranging study followed by a double-blind, placebo-controlled study in 7 normal human male volunteers (21 – 39 years old). YOH administered intravenously (0.016 – 0.125 mg/kg, total dose of 0.25 mg/kg i.v.) resulted in a maximum significant increase in MAP, SBP, and DBP of 14 ± 1 mm Hg, 28 ± 3 mm Hg, and 8 ± 1 mm Hg, respectively. After termination of the study, the subjects’ BP returned to baseline within 1– 2 hr. There was no change in HR. In a doubleblind study, 5 of these 7 patients received saline or YOH (0.125 mg/kg i.v. and 0.001 mg/kg/min), and there was a significant increase in supine MAP by YOH compared with saline placebo (at 0, 15, and 45 min, the saline group was 79 ± 4, 78 ± 4, and 82 ± 5 mm Hg, respectively, and the YOH group was 83 ± 4, 93 ± 4, 92 ± 5 mm Hg, respectively). The maximum increase of MAP from baseline after YOH was 10 mm Hg. YOH did not change MAP at the standing position. There was no change in HR at either supine or standing positions. Side effects reported during the dose-ranging and double-blind study were restlessness (7), cold sweaty hands (5), urge to void (4), sexual arousal (3), erection (1), nervousness (1), piloerection (2), stuffy nose (2), and unusual taste or smell (3). During the doubleblind studies, 3 of 5 subjects correctly guessed the YOH day in retrospect; 2 were unable to differentiate YOH from saline, even in retrospect. Intravenous administration of YOH (0.125 mg/kg bolus + 0.001 mg/kg/min infusion) to 7 healthy male volunteers (mean age 28, range 21 – 39 years) increased MAP by 16%, HR by 8%, and forearm vascular resistance by 67% (Grossman et al., 1991). From baseline, YOH significantly increased MAP from 86 to 100 mm Hg, mean SBP from 118 to 143, and mean DBP from 70 to 79 mm Hg. NE spill over into arterial blood was increased by 125%. Goldberg et al. (1983) reported in a dose-ranging study that intravenously administered YOH HCl (0.016 – 0.125 mg/kg) elicited doserelated increases in MAP, SBP, and DBP. At the maximum dose used (0.125 mg/kg), increases in MAP, SBP, and DBP were 14 ± 1, 28 ± 3, and 8 ± 1 mm Hg, respectively. Intravenous YOH (0.4 mg/kg), administered over 10 min to 10 normal subjects (7 white, and 3 black, 44.1 ± 2.5 years old), did not increase anxiety or panic symptoms (Bremner et al., 1997). Positron Emission Tomography (PET) measurements of these healthy subjects indicated that there was an increase in global cerebral metabolism, with significant increases in the orbitofrontal cortex, prefrontal cortex, and cerebellum. S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 YOH (0.4 mg/kg i.v.) administered to 7 male healthy subjects (29 ± 4 years old) in a randomised, double-blind, placebo-controlled study significantly increased acoustic startle reflex amplitude for signals above 90 dB (Morgan et al., 1993). An increase in plasma MHPG was observed, which supports the relationship between increased noradrenergic function and anxiety states. In a different study, YOH (0.4 mg/kg i.v.) increased the probability that a 90-dB stimulus produced a startle response in 13 male healthy subjects (Krystal et al., 1997). YOH also increased startle magnitudes and reduced startle latencies relative to placebo in the healthy subjects and in 22 male patients (39.3 ± 1.7 years old), meeting DSM-III-R criteria for alcohol dependence. 3.2. Effect on memory O’Carroll et al. (1999) studied the effect of enhancement and blockade of the noradrenergic system on recall and recognition of emotional material in 36 health young adults in a randomised, placebo-controlled study. Subjects were randomised to receive either oral placebo, YOH (18 mg) to stimulate central noradrenergic activity, or metoprolol (50 mg) to block noradrenergic activity 90 min before watching a narrated 11-slide show describing a boy involved in an accident. One week later, memory for the slide show was tested in a surprise test. The YOH-treated subjects recalled significantly more, while the metoprololtreated subjects recalled fewer slides as compared with placebo subjects. YOH treatment also improved multiplechoice recognition memory scores. Thus, stimulation of the central noradrenergic system by YOH resulted in improved memory for emotional material. 3.3. Effects on semen Homonnai et al. (1978) studied the semen quality of 786 sub-fertile men who received hormone treatment. Most of the patients’ semen was characterized as idiopathic oligo- or asthenozospermia. No cases of hypothalamohypopitituitaryhypogonadism were included in this study. The parameters for improvement of sperm quality were motility, concentration, morphology, and vitality. Groups of patients received either one hormone or combinations of two hormones or hormone with drugs. Two hundred and seventy men received androgen for 20 –60 days: 61% had improvement in semen quality, mainly in motility and morphology, and 24 pregnancies were recorded among 58 couples (41%). Forty men received androgen, YOH (3 mg/day), and strychnine (0.1 mg/day) treatment for improvement in sexual potency for 30– 60 days: 65% showed a significant improvement in semen quality and 4 pregnancies were recorded among 15 couples (27%). Although the improvement in semen quality cannot be attributed to YOH alone due to administration of multiple compounds, it can be concluded that YOH, at 3 mg/day for 60 days, did not decrease semen 225 quality and did not prevent hormonal improvement of semen quality in sub-fertile men. 3.4. Effects on platelets The effects of orally administered 4-, 8-, and 12-mg YOH on platelet aggregation were studied in healthy male volunteers (20 –33 years old) by Berlin et al. (1991). YOH selectively antagonized EPI-induced, but not collagen-, arachidonic acid-, or ADP-induced, ex vivo platelet aggregation. The lowest oral dose of YOH that significantly inhibited EPI-induced platelet aggregation ex vivo was 8 mg. The YOH inhibition of EPI-induced, but not ADPinduced, ex vivo platelet aggregation was dose-dependent upon intravenous administration (0.032 – 0.125 mg/kg) (Goldberg et al., 1983). Andrews et al. (1999) demonstrated that oral YOH (20 mg) had antithrombotic activity in 11 healthy subjects (5 women and 6 men, 34 ± 3 years old). The YOH dose that blocked systemic a2-ARs was shown to inhibit the increase of platelet aggregation associated with the assumption of upright posture (orthostatic increase) by 63 ± 11%, but exercise-induced increase in aggregation was not affected by YOH in these normal subjects. There was no difference in platelet count and haematocrit between the control and YOH groups taken in supine or standing positions and during exercise at various times. Galitzky et al. (1990) found that 14 days of treatment with oral YOH (4 mg t.i.d.) in healthy volunteers did not result in any change in platelet a2-ARs. 3.5. Metabolic effects Lipid mobilization is accelerated during the earlier part of energy restriction or fasting. Insulin is a potent antilipolytic hormone (Cahill et al., 1966). Reduction in plasma thyroid hormone (Suda et al., 1978) and a decrease in sympathetic activity (Landsberg & Young, 1978) also have antilipolytic actions. b2-AR agonists have been found to have lipolytic activities by directly stimulating b-ARs on fat cells (Ricks et al., 1984). YOH, being an a2-AR antagonist, is able to acutely enhance lipid mobilization with increases in nonesterified fatty acid (NEFA) in fasting normal human subjects (Galitzky et al., 1988, 1990) and obese women (Berlan et al., 1991) by blockade of the antilipolytic a2-ARs on fat cell membranes (Arner & Ostman, 1976). The acute lipidmobilizing action of YOH in men was reinforced during physical exercise, completely suppressed after a meal, and partially blocked by propranolol (Galitzky et al., 1988). In fasting non-obese (BMI, 20.2 ± 0.5; 35.5 ± 2.7 years old) and obese women (BMI, 36.4 ± 2.1; 37 ± 3.6 years old), oral YOH (0.2 mg/kg) increased acute lipid mobilization (increase in NEFA), without significantly affecting plasma glucose, insulin levels, HR, or BP during the course of the study (4 hr) (Berlan et al., 1991). The plasma NE levels were increased to about the same level as the non-obese subjects. In fasting non-obese (BMI, 20.2 ± 0.5; 35.5 ± 2.7 226 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 years old) and obese women (BMI, 36.4 ± 2.1; 37 ± 3.6 years old), oral YOH (0.2 mg/kg) increased acute lipid mobilization (increase in NEFA), without significantly affecting plasma glucose, insulin levels, HR, or BP during the course of the study (4 hr) (Berlan et al., 1991). The plasma NE levels were increased to about the same level as the non-obese subjects. However, sub-chronic (14 days) YOH treatment (4 mg t.i.d.) in healthy men had no effect on lipid-mobilization, BP, HR, blood glucose, insulin, urea, creatinine, SGTP, cholesterol, and triglycerides (Galitzky et al., 1990). The lack of effect of YOH (peak dose, 43 mg/ day) on fat distribution in healthy men upon chronic administration was confirmed by Sax (1991) in a 6-month randomised, double-blind, placebo-controlled trial. YOH had no effect on body weight and BMI, total cholesterol and high-density lipoprotein, body fat, and fat distribution, as measured by both waist-to-hip ratio and CT scan. YOH does not induce hyperglycaemia in humans (Galitzky et al., 1990; Berlan et al., 1991) or dogs (Valet et al., 1989). Intravenous YOH (0.4 mg/kg) administered over 10 min to 10 normal subjects (7 white and 3 black, 44.1 ± 2.5 years old) tended to increase global cerebral metabolism, with significant increases in metabolism in orbitofrontal cortex, prefrontal cortex, and cerebellum by PET measurements (Bremner et al., 1997). administration of YOH (0.125 mg/kg) in a double-blind study increased plasma NE by 2- to 3-fold, but had no effect on plasma EPI or plasma renin activity (Goldberg et al., 1983). In a placebo-controlled, double-blind, crossover study with 10 mg/kg caffeine, Mattila et al. (1988) showed that a high oral dose of YOH (0.8 mg/kg) increased plasma prolactin and that caffeine increased plasma cortisol. Clonidine (200 mg) antagonized the YOH effect on BP, but not the effect on prolactin, suggesting that the high dose of YOH may have pharmacological effects, in addition to antagonizing a2-ARs. The growth hormone response to apomorphine (0.5 mg s.c.) in normal men was not blocked by YOH (16 mg p.o.) (Lal et al., 1996). 3.6. Endocrine effects 3.8. Effects on salivary secretion In animal studies, an extremely high intravenous dose of YOH HCl (3.3 mg/kg) acutely and rapidly increased secretion of insulin and somatostatin, and increased glucagon secretion more gradually (Ribes et al., 1989). These stimulatory effects were suppressed by propranolol, implicating b-adrenergic mechanisms. The increase in insulin was accompanied by a decrease in blood glucose levels. In humans, YOH, at an oral dose of 12 mg/day for 14 days, had no effect on plasma insulin or blood glucose (Galitzky et al., 1990), but plasma insulin was significantly increased in a separate study using a higher oral dose of YOH (20 mg), without inducing hypoglycaemia (Farrow et al., 1990). YOH (20 mg p.o.) had no effect on the plasma cortisol of 12 healthy subjects compared with placebo controls when measured up to 4 hr after administration. In 12 obsessive-compulsive patients, the same dose of YOH significantly increased the plasma cortisol levels compared with placebo (Rasmussen et al., 1987). A higher oral dose of YOH (30 mg), administered to 6 normal men during insulininduced hypoglycaemic stress, did not change basal or stimulated plasma adrenocorticotropic hormone, cortisol, arginine, vasopressin, or prolactin (Cuneo et al., 1987). A high intravenous dose of YOH (0.4 mg/kg) has also been reported to increase plasma prolactin and cortisol in recently detoxified alcoholics and healthy human subjects (Krystal et al., 1996) and plasma neuropeptide Y in normal men (Rasmusson et al., 1998), but not plasma and cerebral spinal fluid (CSF) arginine vasopressin in normal men (Peskind et al., 1989). Intravenous YOH (0.5 mg/kg i.v.) significantly increased salivary secretion for a period of 45 min in anaesthetised dogs (Montastruc et al., 1989). The mechanism by which YOH increases submaxillary secretion appears to involve inhibition of presynaptic a2-ARs located on the chorda tympani, which inhibit cholinergic transmission (Montastruc et al., 1989; Bagheri et al., 1995). The release of kallikrein into saliva observed after YOH administration is the consequence rather than the cause of the increase in salivary secretion (Bagheri et al., 1992a). Oral YOH (14 mg) also significantly increased salivary secretion in healthy human subjects from 60 to 180 min after administration (Chatelut et al., 1989). In another study with oral YOH (4 mg t.i.d.) treatment for 3 weeks, YOH increased salivary volume within 1 hr in normal subjects and in depressed patients treated with tricyclic antidepressants, who exhibited a reduced salivary flow (Bagheri et al., 1992b). A single lower dose of oral YOH (4 mg) also induced salivary secretion for 3 hr without any side effects in patients treated with tricyclic antidepressants, but did not induce salivary secretion in healthy volunteers (Bagheri et al., 1994). A high dose of YOH (10 mg) increased salivary secretion for 4 hr in these depressed patients, who had been treated with tricyclic antidepressants. In a randomised, double-blind, crossover study, 10 depressed patients treated with psychotropic drugs and suffering from xerostomia received orally for 5 days YOH (6 mg t.i.d.) or anetholtrithione (25 mg t.i.d.), a reference drug in the treatment of dry mouth (Bagheri 3.7. Effect on sleep YOH (5.4 mg/kg) was shown to have no apparent effect on sleep in 8 healthy men (mean age 35 ± 8 years) in a sleep laboratory in a placebo-controlled, randomised, double-blind, crossover study with placebo and clonidine (0.1 mg) (Gentili et al., 1996). Each arm of the study was conducted at 3-week intervals. Clonidine, in contrast, completely suppressed rapid eye movement sleep in one subject and decreased rapid eye movement sleep in all of the other subjects. S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 et al., 1997). Salivary secretion was estimated under resting conditions before any YOH or anetholtrithione, and then on day 6, 1 hr after the ingestion of drug. YOH increased salivary flow over basal secretion significantly more than after anetholtrithione. YOH and other a2-AR antagonists may be potentially useful in the treatment of dry mouth. 3.9. Effects on analgesia Oral YOH (5.4 mg t.i.d.), preoperatively administered for 3 days and immediately before dental surgery, enhanced the analgesia produced by postoperatively administered morphine (8 mg, i.v.) (Gear et al., 1995). Placebo had no effect on morphine-induced analgesia. YOH by itself did not produce analgesic effects. Oral YOH (16 mg) reversed the sedation induced by extradural clonidine, and shortened the duration of analgesia induced by clonidine, but it did not reduce the clonidine-induced hypotension and bradycardia (Liu et al., 1993). These results suggest that the haemodynamic effects of extradural clonidine are not mediated by stimulation of supraspinal a2-ARs. 3.10. Antidote for clonidine overdose A 20-year-old woman who overdosed on clonidine was admitted to the emergency room with complaints of drowsiness, dizziness, nausea, and four episodes of ‘‘blackouts.’’ She had severe hypotension and low HR, and was treated unsuccessfully with naloxone and naltrexone. Her condition returned to normal 1 hr after she received oral YOH (5.4 mg). 4. Therapeutic profile of yohimbine 4.1. Patients with erectile dysfunction 4.1.1. Monotherapy A meta-analysis of YOH treatment for ED in 7 randomised, placebo-controlled, double-blind clinical trials suggested that YOH is clinically more effective than placebo (Ernst & Pittler, 1998). This meta-analysis excluded other YOH trials that did not meet its inclusion criteria of randomised, placebo-controlled, double-blind design and adequate statistical evaluation. Trial reports were excluded if they scored less than 3 (maximum 5) points on the Jadad scale assessing methodological quality. Carey and Johnson (1996) performed four independent, yet convergent, metaanalyses and observed a consistent tendency for YOH to enhance erectile function relative to placebo. Although many other YOH trials for the treatment of ED have been performed, they were poorly designed and uncontrolled, and, thus, it is difficult to draw conclusions from these trials. Equally, although there are also trials of YOH in combination with other drugs, these are almost impossible to interpret, due to the lack of appropriate control and/or 227 baseline data. No trials have been completed using validated questionnaires such as the International Index of Erectile Function (Rosen et al., 1997). The overall clinical performance of YOH in all 11 placebo-controlled studies is summarized in Table 3, and the relevant features of individual studies are described below. It can be concluded that doses of YOH up to and including 100 mg/day are generally well-tolerated. However, it is also obvious that the efficacy of the drug as monotherapy for ED is somewhat limited, even when evaluated in clinical subpopulations such as patients with psychogenic ED. Twenty-two patients with organic ED (age between 28 and 69 years; mean = 58 years) were treated in a blind design for 30 days with placebo, followed by 30 days with a daily high single-oral dose of YOH HCl (100 mg) (Teloken et al., 1998). Although this high YOH dose showed a trend toward increasing the erectile response, the difference was not significant. Of the 22 patients who received placebo, only 1 (4.5%) had complete erectile response, 9 (40.9%) had partial response, and 11 (50%) had no response. When treated with YOH, 3 patients (13.6%) had complete response, 12 (54.5%) had partial response, 4 (18%) had no response, and 3 (13.6%) were worse. The side effects of this very high-dose YOH and placebo were increased urinary frequency (7 with YOH vs. 2 with placebo), tachycardia (6 with YOH), anxiety (4 with YOH), headache (3 with YOH vs. 1 with placebo), vertigo (3 with YOH vs. 1 with placebo), increased arterial BP (2 with YOH), facial redness (2 with YOH), urticaria (1 with YOH), inferior limbs paraesthesia and epigastralgia (1 with YOH), anorexia (1 with YOH), flatulence (1 with YOH), perspiration (1 with YOH), weight gain (2 with placebo), and allergy (1 with placebo). Importantly, this study shows that patients tolerated this heroic dose of YOH over the 30-day study period without severe side effects, and none of the patients withdrew from the study. Forty-eight patients with psychogenic impotence were studied in a 10-week placebo-controlled, double-blind, partial crossover trial of oral YOH (6 mg t.i.d.) (Reid et al., 1987). At the end of the first arm of the trial, 62% of patients taking YOH produced some improvement in sexual function, which was significantly better than the 16% equivalent improvement in the placebo group. However, most patients who were crossed over from placebo to the active treatment did not notice any further benefit, with only 21% showing any additional improvement. YOH was reported to be safe and well-tolerated by the patients. No serious adverse events were noted. Riley et al. (1989) conducted a double-blind, placebocontrolled, partial crossover, multicenter trial with 61 men (18– 70 years old), who had secondary ED for at least 6 months prior to inclusion. Patients with psychiatric diseases, treated hypertension, and renal or hepatic insufficiency were excluded. Patients received oral YOH (5.4 mg t.i.d.) or placebo for 8 weeks, and then all patients 228 Table 3 Therapeutic and adverse effects of oral YOH in the treatment of ED YOH treatment (# of days) Number and type of patients Morales et al., 1987 5.4 mg t.i.d. 70 100 Organic ED Double-blind, randomised, placebo-controlled, partial crossover Reid et al., 1987 6 mg t.i.d. 70 48 Psychogenic ED Placebo-controlled, double-blind, partial crossover Riley et al., 1989 5.4 mg t.i.d. 56 61 Chronic ED; mixed etiology; excluded psychiatric and hypertensive diseases Double-blind, placebo-controlled, partial crossover Susset et al., 1989 5.4 mg q.i.d. increased to 10.8 mg q.i.d. 30 days at 43.2 mg/day 82 ED, any kind Double-blind, partial crossover Ashton, 1994 Initial 5.4 mg t.i.d, some About 21 days 8 ED, 7 had major psychiatric disorders Open label Study design Therapeutic effect on erection Type of adverse effects Severity of adverse effects Frequency of adverse effects In the first phase, complete response: YOH (21.4%), placebo (13.8%); partial response: YOH (21.3%), placebo (13.8%); no response: YOH (57.4%), placebo (72.4%). In the second phase, placebo crossover to YOH: complete response 18.2%), partial response (27.3%), no response (54.5%) In the first phase, YOH response (62%) significantly better than placebo response (16%). In the second phase, placebo crossover to YOH had no significant effect (21%) In first phase, YOH response (36.7%) better than placebo (12.9%) ( P < 0.05). In the second phase, placebo crossover to YOH had significant improvement (41.9%) ( P < 0.02) Complete response (14%); partial response (20%); no improvement (65%) None None reported None reported No serious undesirable effects None reported None reported Hypertension, loss of antiepileptic action of phenytoin, rash One withdrawal because of adverse effects YOH group, 10%: placebo group, 5% Anxiety, dizziness, increased frequency of urination, chills, headache Four withdrawals due to adverse effects, but all adverse effects disappeared after withdrawal and none was severe None reported YOH group, 21%; placebo group, 16% Marked improvement (37.5%); mild improvement (25%); No intolerable increases in anxiety None reported S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 Maximum dose Reference increased to 10.8 mg t.i.d 15 mg/day 49 31 Organic or nonorganic ED Double-blind, placebo-controlled, randomised after a 1-week placebo run-in Sonda et al., 1990 5.4 mg t.i.d. 28 40 Organic ED Placebo-controlled, double-blind, crossover 5.4 mg t.i.d. 42 Open label 5.4 mg q.i.d. up to 330 215 ED, 66%, diabetic 33%, hypertensive 25% alcoholic 46 ED of the above 215 who were nonresponsive to 5.4 mg t.i.d. Vogt et al., 1997 10 mg t.i.d. 56 85 ED without clear detectable cause Placebo-controlled Rowland et al., 1997 5 mg t.i.d. for 2 weeks, then 10 mg t.i.d. for 2 weeks 28 11 ED, mean ED duration, 3.8 years Double-blind, placebo-controlled, crossover Kunelius et al., 1997 32.4 mg/day 25 29 Mixed-type ED with no neurologic or organic disease; excluded pure organic or psychogenic ED. Randomised, double-blind, placebo-controlled, crossover Open label Response rate significantly more effective than placebo in subjective and objective measures: 71 vs. 45% Sexual arousal and erections significantly stronger under YOH for masturbation ( P = 0.016), but not for intercourse. In clinic audio-VSS test at the end of each drug period indicated YOH not different from placebo Gastrointestinal disturbances (1 placebo, 2 YOH); sweating (2 YOH); agitation (1 placebo, 1 YOH), headache (2 placebo), anxiety (1 YOH), tachycardia (1 placebo) One withdrawal because of pathological changes in EEG under placebo treatment YOH group, 19%; placebo group, 16% One case of hypertension exacerbation (placebo), 5 cases of mild side effects (placebo) One withdrawal due to hypertension exacerbation while on placebo Drug group, 0%; placebo group, 15% No serious undesirable effects reported Not reported Not reported Mild and reversible: headache (3), gastric distress (3), insomnia (2), hypertension (2), nervousness, anorexia, or nausea (2) Well-tolerated, 7% patients rated tolerability fair or poor. Most side effects are mild No serious adverse effects YOH group, 3% No serious adverse effects YOH group, 30%; placebo group, 10% No effect on BP, slight diarrhea (1), frequent urination, and lack of energy (1) No serious adverse effects YOH group, 27% This high dose was tolerated moderately well One case of hypertensive crisis and 1 case of severe palpitation YOH group, 7% 229 (continued on next page) S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 Mann et al., 1996 no improvement (37.5%). Five patients elected to continue YOH beyond the trial. CGI improvement scores: YOH better than placebo in nonorganic patients ( P < 0.05); no significant difference in organic patients. Response rate: nonorganic patients, YOH (86%), placebo (33%); organic patients, YOH (38%), placebo (44%). Subjective improvement: YOH alone (33%); placebo alone (15%); both (15%); neither (36%). P = 0.07 between YOH and placebo groups. Complete subjective improvement (5%); partial improvement (33%); no improvement (62%) Subjective improvement (52%) 230 Reference Teloken et al., 1998 Maximum dose YOH treatment (# of days) Number and type of patients Study design Therapeutic effect on erection Type of adverse effects Severity of adverse effects Frequency of adverse effects 100 mg/day 30 22 Organic ED Patient blinded, not aware of placebo treatment: 1-month placebo followed by 1-month YOH NO significant difference. YOH showed a trend toward increasing complete and partial response. YOH: complete response (13.6%); partial response (54.5%); no response (18%); worsening (13.6%). Placebo: complete response (4.5%); partial response (40.9%); no response (50%). Increased urinary frequency (7 YOH, 2 placebo), tachycardia (6 YOH), anxiety (4 YOH), headache (3 YOH, 1 placebo), vertigo (3 YOH, 1 placebo), increase arterial pressure (2 YOH), facial redness (2 YOH), urticaria (1 YOH), inferior limb paresthesia and epigastralgia (1 YOH), anorexia (1 YOH), flatulence (1 YOH), perspiration (1 YOH), weight gain (2 placebo), and allergy (1 placebo) No serious side effects YOH group, 145%; placebo group, 32% S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 Table 3 (continued ) S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 were crossed over to the active drug treatment arm for 8 weeks. At 4-week intervals, the quality and frequency of erections were assessed by patient self-report. After the first 8 weeks, 36.7% of the drug group and 12.9% of the placebo group ( P < 0.05) reported good stimulated (by vibration or erotic stimulus) erections. In the placebo group, the percent reporting improvements rose to 41.9% after crossing over to drug ( P < 0.02). Other parameters, for example, morning erections and spontaneous erection, were not affected. One hundred patients with organic impotence were evaluated in a randomised, double-blind, placebo-controlled study with partial crossover of placebo to YOH (5.4 mg t.i.d. orally) (Morales et al., 1987). The overall response rate of YOH in the two arms was 43.5%, which showed a trend toward statistical significance from placebo. YOH was reported to be a safe treatment in this study, but no details on side effects were given. Forty patients participated in a double-blind, crossover study of oral YOH (16.2 mg) vs. placebo for 4 weeks during each phase, with a 1-week washout in between (Sonda et al., 1990). Eleven of 33 patients (33%) who completed the study had subjective improvement of erection while taking YOH alone, 5 of 33 (15%) responded while taking YOH and placebo, 5 of 33 (15%) responded to placebo alone, and 12 of 33 (36%) responded to neither. A positive response was defined as subjective improvement in degree of erection sufficient for vaginal penetration. No dropouts were attributed to YOH. No hypertension or other side effects were associated with YOH. Five of the 33 patients complained of mild side effects while taking placebo. Two hundred and fifteen patients (age 26 – 78 years; mean = 56 years) with ED were treated with oral YOH (16.2 mg) daily for 6 weeks (Sonda et al., 1990). Sixty-six percent of the patients had diabetes, 33% had hypertension, and 25% were alcoholics. Sixty-two percent of the patients had no improvement, 33% had partial subjective improvement, and 10% had complete subjective improvement. The author did not report any YOH-associated side effects from this group. Forty-six patients with either no or partial improvement of erection were administered a higher dose of YOH (21.6 mg/day) for up to 11 months. Fifty-two percent of these patients reported further subjective improvement. Only 3% of these patients had mild and reversible side effects: headache in 3, gastric distress in 3, insomnia in 2, elevated BP in 2, nervousness, anorexia, or nausea in 2. Vogt et al. (1997) performed an 8-week, double-blind, placebo-controlled trial of YOH (10 mg t.i.d.) on 85 patients with ED without clearly detectable organic or psychological causes. Patients were evaluated at 4 and 8 weeks of treatment, with efficacy evaluation based on both subjective and objective criteria. The subjective criteria included improvement in sexual desire, sexual satisfaction, frequency of sexual contacts, and quality of erection during sexual contact/intercourse. The objective criteria were based on improvement of penile rigidity determined by polysomnography in a sleep laboratory. The response rate of YOH was significantly better 231 than placebo, with 71 vs. 45%. YOH was found to be well tolerated, and no serious adverse event occurred. In a double-blind, placebo-controlled crossover study on 11 patients with ED and a sexually functional control group, the effect of oral YOH (up to 30 mg/day) was assessed on a number of objective and subjective measures of erectile response through the use of daily logs and psychophysiological laboratory procedures involving response to visual sexual stimulation (VSS) (Rowland et al., 1997). Patients received placebo or YOH (15 mg) each day for the first 2 weeks, the dose was increased to 30 mg/day for the last 2 weeks, and then the patients crossed over to YOH or placebo. During VSS, patients treated with YOH found it significantly easier to get an erection, reported stronger feelings in their penis, and rated their erections as somewhat stronger. Blind global investigator evaluations of combined objective and subjective measures of the 11 patients showed 3 with an overall strong effect, 5 with a partial effect, and 3 with no effect. In contrast, one subject showed very weak improvement during the placebo phase. At the doses used, YOH did not significantly increase BP. Among the normal controls, the most prevalent side effects were disturbed sleep (9) and lower sexual desire (4). Two patients noted YOH side effects, and these were minimal [slight diarrhoea (1), frequent urination, and lack of energy (1)]. Thirty-one male patients (42.7 ± 11.4 years old) with organic or nonorganic ED were studied in a double-blind, placebo-controlled trial with YOH HCl (5 mg t.i.d.) (Mann et al., 1996). After a 1-week placebo run-in period, patients were randomised to a placebo or a drug group for a treatment period of 7 weeks. The Clinical Global Impression (CGI) scale was used as the primary efficacy parameter. Additionally, nocturnal penile tumescence and rigidity were measured. Based on the CGI scores, the percentage of responders of all patients was 40% for placebo and 60% for YOH, which was not significant. After differentiation of the patients according to aetiology, the organic patients revealed similar response rates of 44% for placebo and 38% for YOH. In contrast, the response rate nonorganic patients for YOH (86%) was significantly higher than placebo (33%). The side effects were gastrointestinal disturbances (1 placebo, 2 YOH), sweating (2 YOH), agitation (1 placebo, 1 YOH), headache (2 placebo), anxiety (1 YOH), and tachycardia (1 placebo). Twenty-nine patients with ED were entered into a doubleblind, placebo-controlled, crossover study with a high oral dose of YOH HCl (36 mg/day) (Kunelius et al., 1997). Patients were on YOH or placebo for 25 days, with a 14-day washout in between. No significant improvement was observed with YOH compared with placebo. YOH was tolerated moderately well, but two patients had to be withdrawn due to side effects: a hypertensive crisis in one and severe palpitation in another. Eight patients with ED initially were treated with YOH (5.4 mg t.i.d.) for several weeks, and the dose was increased to 10.8 mg t.i.d. for those who did not respond (Ashton, 232 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 1994). Seven of these patients had another major psychiatric illness, including posttraumatic stress disorder (PTSD), major depression, bipolar disorder, and obsessive-compulsive disorder. YOH produced marked improvement in 37.5% of patients, mild improvement in 25%, and no improvement in 37.5%. No intolerable increases in anxiety were observed. Five patients elected to continue YOH beyond the trial. A case study report described a 59-year-old patient with ED developed pain and discomfort above both eyes, which he described as being like ‘a thick head cold,’ after taking YOH (5.4 mg t.i.d.) for 3 days. There were no other symptoms to suggest sinus problems, influenza, or an anxiety state, and the symptoms resolved within 24 hr after YOH was stopped (Wylie, 1996). Of the numerous patients who had been taking YOH, apparently only one case of agranulocytosis was reported (Siddiqui et al., 1996). A 69-year-old man, who had suffered a stroke syndrome previously and had long-standing idiopathic impotence during 5 years of oral YOH therapy (5.4 mg t.i.d.), was admitted to a hospital with a 3-week history of ataxia, frequent falls, increasing spastic gait, and onset of fever. He was taking no other medication than YOH at the time. Laboratory test revealed profound neutropaenia, but erythrocytes, platelets, haemoglobin, liver function, and other tests were within normal limits. The neutropaenia resolved in 4 days after discontinuation of YOH and empiric antibiotic therapy. The cause of the transient fever was attributed to transient bacteremia. The neutropaenia was causally linked to YOH therapy. However, since there was no follow up on whether the patient continued to take YOH after discharge from the hospital and whether the neutropaenia returned upon continuation of YOH therapy, a clear link between the sudden onset of neutropaenia and YOH following 5 years of daily use cannot be established. 4.1.2. Yohimbine in iatogenic impotence YOH has been claimed to be of value in the treatment of antidepressant-induced sexual dysfunction in patients with depression, including those affected by selective serotonin uptake inhibitors (SSRIs) and tricyclic antidepressants. Fluoxetine-induced anorgasmia was successfully treated with YOH (Segraves, 1993). Price and Grunhaus (1990) reported in a placebo-controlled, double-blind, crossover study that the clomipramine-induced anorgasmia of a patient with major depression and obsessive-compulsive symptoms was restored with YOH (10 mg) taken 90 min before intercourse. Buproprion-induced sexual dysfunction (low libido and anorgasmia) in a woman with major depression was successfully treated with 2.7 mg/day of YOH (Pollack & Hammerness, 1993). The patient experienced marked improvement after 5 days of treatment, and elected to stay on YOH for over 16 months. In another study, 6 cases of sertraline-induced anorgasmia (2 men, 4 women) and 4 cases of paroxetine-induced anorgasmia (3 men, 1 woman) were successfully treated with oral YOH (5.4 mg) taken  1– 2 hr prior to planned coitus (Segraves, 1994). No adverse reaction to YOH was reported in the above studies, with the exception of mild headache in the clomipraminetreated patient, and it disappeared after receiving several doses (Price & Grunhaus, 1990). Eight out of 9 fluoxetineinduced sexual dysfunctional patients (2 women and 7 men) with unipolar depression (6), bipolar II disorder (2), and bipolar I disorder (1) had complete or partial response to treatment with oral YOH (5.4 mg t.i.d.), and 5 patients reported side effects, including nausea, anxiety, insomnia, and urinary frequency (Jacobsen, 1992). YOH (2.7 – 16.2 mg/ day) was found to be an effective treatment for SSRI-induced sexual dysfunction (low libido, anorgasmia, delayed ejaculation in male) in 5 of 6 patients (3 men, 2 women) (Hollander & McCarley, 1992). In a retrospective case review, YOH was found to be safe and significantly more effective than amantadine or cyproheptadine in reversing SSRI-induced sexual dysfunction (Keller Ashton et al., 1997). YOH resulted in 71% of the patients with much improvement, 10% with some improvement, and 19% with no change or worse. The most frequent side effect reported with YOH was agitation, which contributed to discontinued use in three patients. Sixty-three patients with psychogenic impotence were entered into a randomised, double-blind, placebo-controlled, partial crossover study comparing placebo with oral YOH (5 mg t.i.d., 15 mg/day) plus trazodone (50 mg once a day orally) for 8 weeks for each of the two arms of the study (Montorsi et al., 1994). Complete (47%) and partial responses (25%) (total 71%) to the YOH plus trazodone treatment was significantly better than placebo (22% rate). Positive improvements were maintained in 58% and 56% of the patients at 3- and 6-month follow-ups, respectively. Minor drug-related adverse effects occurred in 11% of the patients in the drug group and 4% in the placebo group. 4.1.3. Yohimbine combination clinical studies Twenty patients with arterial insufficiency and cavernous venous leakage were treated with YOH (5.4 mg t.i.d.) plus isoxsuprine (10 mg) for 4 months (Knoll et al., 1996). The overall subjective partial response rate was 50%, and there was no complete response. Side effects were minimal, with two patients experiencing insomnia. YOH (5.4 mg t.i.d.) in combination with pentoxifylline (400 mg t.i.d.) was used for 10 weeks to treat impotence in 10 male patients (aged 40 – 63 years) with anxiety and mild to moderate penile arteriosclerosis (Nessel, 1994), and 7 patients reported return of erection adequate for intercourse and continued the medication. Sonograms, Doppler studies, penile/brachial ratios, and nocturnal erections all showed signs of improvement within a normal range. The remaining three patients improved, but were unable to sustain adequate erections. No placebo was used in this study, and no patients experienced any significant side effects. The efficacy of Afrodex1, which consists of YOH HCl (5 mg), methyltestosterone (5 mg), and nux vomica (5 mg) (the plant extract source of strychnine) for each capsule, was S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 studied in 22 impotent patients ranging from 29 to 62 years old in a double-blind, placebo-controlled, crossover study (Miller, 1968). Afrodex1 was found to be 1.7 –5.4 times more effective than placebo in increasing the number of erections and orgasms. Sobotka (1969) found a similar therapeutic effect of Afrodex1 in a double-blind, placebocontrolled, crossover study of 50 impotent patients ranging from 26 to 73 years old. Patients initially received Afrodex1 or placebo for 4 weeks, with a washout period of 4 weeks, and then were crossed over to the other treatment arm. Afrodex1 was found to be significantly more effective (3– 4.3 times) than placebo in relieving impotence. A large multipractitioner open-label study of Afrodex1 (1 capsule t.i.d.) for 10 weeks in 10,000 impotent men has shown a time-dependent beneficial effect, with relatively few and mild side effects (Margolis et al., 1971). Over 1000 physicians from throughout the United States had prepared case reports on these impotent patients. The majority of the patients were in the age range of 41– 60, with an overall range of 20 –87. Patients were instructed to evaluate their responses weekly in the first 6 weeks and then biweekly in the last 4 weeks. Not all patients reported weekly or biweekly as instructed. There was a steady improvement from the first week to the tenth, and maximal effectiveness was reached after 2– 3 weeks of therapy. The summary of treatment responses is listed in Table 4. The incidence of side effects was 6.86% in all patients, and ranged from 4.5 to 7.6% in different age groups. Of the 10,000 Afrodex1 cases, 686 incidences of side effects were reported, and were all relatively mild. The side effects and number of incidences include nervousness, irritability, insomnia (269); anorexia, nausea, gastric distress, diarrhoea (177); headache (36); palpitations or tachycardia (29); flushing (25); dysuria (17); pain (11); vomiting (11); increased BP (8); and miscellaneous (199). Most of the side effects were so mild or transient in nature that they caused little difficulty, and others were corrected by adjusting the dosage. Gastric irritation and nausea were much less when the capsules were taken on a full stomach. Where insomnia was reported, it could be corrected in many cases by eliminating the bedtime dosage. Since this was not a placebo-controlled Table 4 Afrodex1 cases: number of impotent patients reporting each week and the percent in each response category1 Week Reporting Excellent Good Fair None 1 2 3 4 5 6 8 10 8651 8339 7869 7324 5879 5398 4522 4102 9% 12% 17% 19% 23% 27% 34% 40% 20% 27% 35% 43% 47% 49% 46% 43% 28% 33% 33% 29% 24% 19% 16% 13% 43% 28% 15% 9% 6% 5% 4% 4% 1 Total number of patients reporting was 10,000; no placebo controls. 233 study, the incidence of side effects of placebo for a comparable treatment period was not determined. 4.2. Women with hypoactive sexual desire Eleven women with hypoactive sexual desire (41.1 ± 1.0 years old) were enrolled in a study with oral YOH (5.4 mg t.i.d.) treatment for 3 months (Piletz et al., 1998). YOH had no significant effect on improving sexual desire in these subjects. YOH increased plasma MHPG to a level similar to that seen in men. One patient was withdrawn because of depression during placebo treatment. One patient on YOH was withdrawn because of the following side effects: nervousness, insomnia, palpitations, hyperventilation, and mild tremors. The 9 patients who completed this study tolerated the drug well. 4.3. Obese patients In fasting obese women (BMI, 36.4 ± 2.1; 37 ± 3.6 years old), orally administered YOH (0.2 mg/kg) provoked an increase in plasma NEFA levels, which was not markedly different from that observed in non-obese subjects. It had no significant effect on plasma glucose, insulin levels, HR, or BP in the obese women. The plasma NE levels were increased to about the same level as the non-obese subjects. A study was performed to compare the haemodynamic effect of a standard hypocaloric diet with ephedrine (2  25 mg) and caffeine (2  200 mg) versus the same diet with ephedrine, caffeine, and YOH (2  5 mg) (n = 9/ group) in obese women after 10 days of treatment (Waluga et al., 1998). Caffeine and ephedrine had no haemodynamic effect in resting patients, but caused an increase in ejection fraction during cycloergometer exercise. Addition of YOH to this diet and drugs increased DBP and HR, but decreased ejection fraction and stroke index, during rest. Only a decrease in ejection fraction during handgrip and an increase in cardiac load during cycloergometer exercise were induced by YOH in this diet and drug supplement. A 6-month study of the effect of YOH on body weight and body fat distribution was evaluated in moderately obese men between the ages of 23 and 55 with more than 20% over ideal body weight and weighing less than 270 lb (Sax, 1991). There were 18 subjects in the YOH group and 15 subjects in the placebo group. The YOH group began with 5.4 t.i.d. and increased the total daily dose to 21.6 mg/day and then to 27 mg/day over the first 6 weeks of the study. At the 3-month point, the dosage was increased to 32.4 mg/day for 1 month; then to 37.8 mg/day for 1 month; and finally, to 43.2 mg/day for the last month. YOH had no effect on body weight or fat distribution. The incidence of adverse effects was low in both groups. At exit interview, the majority of the subjects in both groups thought they were taking the placebo. Adverse reaction reported in the placebo 234 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 group was impaired sleep (1) and that in the YOH group were impaired sleep (3), ‘nervous’ (1), and headache (1). 4.4. Alcoholics The effects of a high i.v. dose of YOH (0.4 mg/kg) were studied in 22 recently detoxified male (21 –54 years old) alcoholics, who were abstinent for 12 – 26 days, and 13 male healthy subjects (Krystal et al., 1996). YOH infusion significantly increased BP, plasma cortisol, prolactin, MHPG, and nervousness in both groups; and anxiety was significantly increased in the YOH group only. Placebo also significantly increased BP, but the increase was less than by YOH. The increases in plasma cortisol and prolactin were significantly greater in the patients than in the healthy controls. No group differences on BP, plasma MHPG, and nervousness in control versus alcoholics were observed after YOH infusion. 4.5. Diabetic patients A 72-year-old woman with severe orthostatic hypotension due to diabetic polyneuropathy was successfully treated with YOH (Brodde et al., 1983). The patient demonstrated hypersensitivity of a1- and a2-ARs. Treatment with oral YOH (12.5 mg daily for 6 months) resulted in a steady increase in BP, which allowed the patient to recover a considerable degree of mobility. Four of 6 impotent diabetics who reported incapacitating paraesthesia of the lower limbs received prompt relief after the use of oral YOH (6 mg t.i.d.) (Morales et al., 1981). Interruption of treatment after 8 weeks resulted in recurrence of the paraesthesia, which again disappeared after reinitiation of YOH therapy. No side effects were reported. In addition to these two reports, many patients with sexual dysfunction described in Section 5.2 were diabetic. For example, Sonda et al. (1990) treated 215 patients with YOH (5.4 mg t.i.d.) for ED, and 66% of these patients were diabetics (142 diabetics). These patients tolerated YOH treatment generally well. 4.6. Drug addicts Twelve methadone-maintained patients were randomised into a controlled crossover study with placebo and oral YOH [20 mg once a day (n = 4), 5 mg t.i.d. (n = 4), or 10 mg t.i.d. (n = 4) for 7 days] to evaluate the effects of YOH on naloxone-precipitated opiate withdrawal (Hameedi et al., 1997). YOH at 20 mg once a day induced significant withdrawal-like symptoms in 2 out of 4 subjects. The other 2 subjects experienced a moderate increase in anxiety and a decreased baseline MAP by 6 mm Hg (128 vs. 134 mm Hg), without changes in HR. The 20-mg YOH treatment increased naloxone-precipitated subjective withdrawal symptoms on a 0 – 100 mm VAS by 35 (56 vs. 21 mm), and increased net SBP during naloxone-precipitated opiate withdrawal by 40 mm Hg, without changes in HR. The subjects who were administered YOH at 20 mg once a day were maintained on a comparatively higher mean dose of methadone (80 mg vs. 29 mg and 39 mg, respectively), and this could account for the more severe opiate withdrawal symptoms. In the YOH (5 mg t.i.d.) group, all 4 subjects tolerated the drug well, with no change in mean baseline HR, but mean baseline SBP decreased by 7 mm Hg (126 vs. 133 mm Hg) after 7 days of YOH treatment. This YOH treatment decreased the naloxone-precipitated withdrawal rating by 7 mm (69 vs. 62 mm) on the VAS. During naloxoneprecipitated withdrawal, YOH treatment increased net mean SBP by 7 mm Hg and decreased HR by 4 beats/min. In the YOH (10 mg t.i.d.) group, all 4 subjects tolerated the drug well. With this dose, YOH decreased mean baseline HR by 4 beats/min (70 vs. 66 beats/min) and increased mean baseline SBP by 6 mm Hg (118 vs. 112 mm Hg). This dose reduced naloxone-precipitated withdrawal symptoms on the VAS by n  30% (37.5 vs. 55). This YOH treatment increased peak HR by 8 beats/min during naloxone-precipitated withdrawal without affecting SBP. The results of this study suggest further studies to investigate whether the development of opiate dependence can be prevented or modified by YOH at 10 mg t.i.d. 4.7. Patients with autonomic dysfunction The effects of YOH and clonidine on BP, HR, and plasma catecholamines were studied in 12 patients with autonomic dysfunction (Robertson et al., 1986). YOH (4– 64 mg/kg i.v. bolus) dose-dependently increased plasma NE and BP in 6 patients. YOH also dose-dependently and significantly attenuated the hypotensive response to headup tilt of patients with degenerative autonomic dysfunction. Clonidine decreased BP in six patients and raised BP in the other six. 4.8. Hypertensive patients The pressor response to YOH is more sensitive in hypertensive patients than in normal subjects. YOH administered orally at 0.2 mg/kg produced a pressor response in hypertensive patients, but not in normotensive subjects, and a lesser increase in plasma NE in hypertensive patients ( + 67%) than in normotensive subjects ( + 178%) (DamaseMichel et al., 1993). Grossman et al. (1993) reported that YOH (21.6 mg) administered orally to 25 unmedicated hypertensive patients (17 male and 8 female, 36 ± 2 years old) resulted in significant, but small, increases in SBP, DBP, and MAP from baseline at 1 and 2 hr post-dose, but had no effect on HR. SBP (mm Hg) increased from a baseline value of 144 ± 4 to 150 ± 5 at 1 hr and 151 ± 4 at 2 hr after YOH administration. DBP (mm Hg) was increased from a baseline value of 83 ± 3 to 86 ± 3 at 1 hr and 87 ± 3 at 2 hr post-dose. MAP (mm Hg) was increased from a baseline value of 103 ± 3 to 107 ± 3 at 1 hr and to 108 ± 3 at 2 hr post-dose. Plasma NE levels were signifi- S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 235 cantly increased by 66%. Musso et al. (1995) reported the results of a study comparing the effects of placebo or YOH (10 mg) administered orally to 25 healthy volunteers and 29 sex- and age-matched untreated hypertensive patients. Volunteers and patients were studied twice in random order, before and 80 min after placebo or YOH, in supine and upright positions. YOH did not have a significant effect on SBP, DBP, and HR in the normal subjects or SBP and HR in the hypertensive patients in either supine or upright position when compared with placebo treatment. YOH had no effect on DBP in the hypertensive patients in the supine position, but induced a small significant increase in DBP from a mean of 95 mm Hg to a mean of 100 mm Hg in the upright position only. Plasma NE was increased significantly in both YOH-treated groups. Goldstein et al. (1991) studied the haemodynamic response to intravenous YOH (0.125 mg/kg i.v. bolus, followed by 0.001 mg/kg/min infusion for 15 min) in 19 patients with essential hypertension and 19 normotensive control subjects. YOH significantly increased MAP by 13 ± 2% in normal subjects and 17 ± 2% in hypertensive subjects. YOH had no significant effect on HR in either group. YOH increased arterial NE in all subjects. Patients with large haemodynamic and NE responses to YOH typically reported a history of anxiety, depression, or other psychopathology, and had marked pressor or tachycardic episodes during emotional stress. The addition of YOH could be useful in the treatment of Parkinson’s disease in combination with L-3,4-dihydroxyphenylalanine (L-dopa). In an open study, oral YOH (12 mg/ day) significantly improved both orthostatic hypotension and stamping in 18 L-dopa-treated Parkinsonian patients (6 male and 12 female, 48 –81 years old) (Montastruc et al., 1981). Furthermore, YOH, as well as other selective a2-AR antagonists (rauwolscine and idazoxan), have been demonstrated to reduce L-dopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primate model of Parkinson’s disease (Henry et al., 1999). Orally administered YOH (0.2 mg/kg) did not modify the BP or HR of 6 control subjects, 9 patients with multiple system atrophy plus orthostatic hypotension, and 20 Parkinsonian patients with (n = 9) or without orthostatic hypotension (n = 11) (Senard et al., 1993a). In a doubleblind, placebo-controlled crossover trial, 17 patients (69 ± 5 years old) with Parkinson’s disease suffering from nondrug-induced orthostatic hypotension received 6 mg/day of oral YOH (2 mg t.i.d.) for 4 weeks. At the end of the 4 weeks, there was no significant difference in the mean SBP, DBP, HR, BP variability (coefficient of variation of the mean) and the nychtemeral rhythm between baseline, YOH, and placebo periods for both daytime and nighttime measurements (Senard et al., 1993b). 4.9. Patients with orthostatic hypotension 4.11. Patients with Alzheimer’s disease YOH may offer a therapeutic option in autonomic dysfunction, even for those with severe sympathetic deprivation. Preliminary studies suggest that the effectiveness of YOH in autonomic failure can be enhanced with monoamine oxidase inhibitors (Biaggioni et al., 1994). YOH (5 mg), administered orally to 8 patients with autonomic failure characterized by profound orthostatic hypotension, significantly elevated the mean SBP and DBP and the mean HR (Onrot et al., 1987). Plasma NE, but not EPI, was increased significantly. In 5 patients administered YOH (2.5 mg) orally, there was a trend toward increases in BP, HR, and plasma NE. YOH pretreatment of patients with neurally mediated syncope increased the sympathetic reflex response to tilt, precluded the development of hypotension, and prevented syncope in 7 out of 8 patients (5 females and 3 males; 34 ± 2 years old) susceptible to tilt-induced syncope (Mosqueda-Garcia et al., 1998). Oldenburg et al. (1999) treated a 71-year-old man with treatment-resistant orthostatic hypotension, and later diagnosed with Shy-Drager syndrome, with YOH. YOH treatment allowed the wheelchair-bound patient to be able to stand and to walk for a few minutes. The positive effect of YOH on orthostatic hypotension was confirmed in a new model of neurogenic orthostatic hypotension obtained by sinoaortic denervation in chloralose-anaesthetised dogs using an a2-AR-selective dose (0.05 mg/kg, i.v.) to delay the fall in BP elicited by head-up tilting (Verwaerde et al., 1997). A high oral dose of YOH (0.65 mg/kg) administered to 10 patients with Alzheimer’s disease (AD) (7 male and 3 female, 69.5 ± 2.5 years old) significantly increased the concentrations of NE in both plasma and cerebrospinal fluid compared with the placebo group (Peskind et al., 1995). MAP and HR significantly increased with a mean rise of 15 mm Hg and 7 beats/min, respectively, in AD patients 90 min after dose administration. Ratings of tension, excitement, and anxiety were significantly higher compared with the placebo group. In the absence of drug, these ratings in AD patients were significantly higher than those in the agematched control subjects. The increased agitation in patients with AD after YOH may be explained by increased central adrenergic activity. Peskind et al. (1998) demonstrated in a single-blind, placebo-controlled study involving 74 AD patients, 42 cognitively normal elderly subjects, and 54 healthy young subjects that resting CSF EPI was higher in patients with AD than in elderly or young subjects and that oral YOH (0.65 mg/kg) increased CSF EPI in people with AD and elderly subjects, but not in young subjects. YOH significantly increased SBP and DBP in elderly subjects, SBP in AD patients, and had no effect on BP in young subjects. Raskind et al. (1999) found that both CSF and plasma dihydroxyphenylacetic acid, the precursor of NE, following oral YOH (0.59 mg/kg) was higher in the elderly (6 men and 4 women, 70 ± 8 years old) and people with 4.10. Patient with Parkinson’s disease 236 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 AD (7 men and 3 women, 70 ± 8 years old) subjects, than in young subjects (11 men, 27 ± 5 years old). CSF dihydroxyphenylacetic acid following YOH was also higher in elderly healthy subjects than in young subjects. CSF 3,5-dihydroxyphenylglycine was not different between the three groups. These results suggest the partial loss of central noradrenergic neurons in AD patients and elderly subjects, with compensatory activation of remaining CNS noradrenergic neurons. Average MAP was significantly higher after YOH (0.59 mg/kg) treatment in people with AD (109 vs. 94 mm Hg), elderly subjects (111 vs. 95 mm Hg), and the young (95 vs. 88 mm Hg). In a pharmacokinetic study, 10 overnight-fasted AD patients (7 males and 3 female, mean age of 69.5 years) received a single oral dose of YOH (0.65 mg/kg), and no side effects were reported (Le Corre et al., 1997). Ten patients with AD (6 female and 4 male, 69 ± 7 years old) were treated with placebo for 5 days, followed by physostigmine (2 mg every 2 hr while awake) for 7 days (Bierer et al., 1993). During each of these treatment periods, YOH challenges were administered at oral doses of 10 mg and 20 mg in a placebo-controlled manner. Nine patients tolerated the protocol with no clinically significant changes in BP, HR, or ECG and no cardiovascular, gastrointestinal, or autonomic toxicity. One 75-year-old female patient tolerated the protocol well until day 10. She tolerated YOH at doses of 10 mg and 20 mg with physostigmine placebo without any side effects. She was then administered YOH while taking physostigmine. Before the YOH dose, her BP and HR were 119/74 mm Hg and 78 beats/min supine and 128/82 mm Hg and 105 beats/min standing. Two hours after YOH, her BP and HR increased to 127/65 mm Hg and 100 beats/min supine and 149/83 mm Hg and 123 beats/min standing. Shortly thereafter she complained of generalized discomfort and diffuse chest pain without nausea or diaphoresis. An ECG showed a t-wave inversion in lead V2. All medications were discontinued. Three hours later she was comfortable; her tachycardia had resolved and her ECG had reverted to baseline. Serial ECG tracings and cardiac enzymes during the next several days showed no evidence of myocardial injury. 4.12. Patients with depression A number of clinical reports have suggested that YOH, combined with antidepressant treatment, may increase efficacy. Sachs et al. (1986) reported dramatic improvement in three patients pretreated with YOH before electroconvulsive therapy. Pollack and Hammerness (1993) described a patient with chronic depression and ongoing buproprion therapy who experienced marked improvements with the addition of oral YOH (2.7 mg/day). Cappiello et al. (1995) reported significant improvement in 9 patients (5 male and 4 female, 24 –63 years old) with major depression and refractoriness to multiple antidepressant trials when treated with YOH (mean dosage, 27 ± 8 mg/day t.i.d. or q.i.d.) in addition to fluvoxamine, with 3 patients meeting criteria for clinically significant categorical improvement. The YOH + fluvoxamine treatment was generally well-tolerated, and the principal side effects were initial insomnia and anxiety. Price et al. (1984) reported that a single oral dose of YOH (10 –20 mg) induced transient elevated mood and brightened affect when administered to three depressed patients with a bipolar diathesis. However, Charney et al. (1986b) did not observe enhanced efficacy when YOH was combined with desipramine early in treatment (starting from 4 to 7 days after the onset of active desipramine treatment for a subsequent 10-day treatment) in a placebo-controlled study. Antidepressants have been reported to induce sexual dysfunction in patients with depression, irrespective of gender. YOH was reported to benefit antidepressant-induced sexual dysfunctions in some depressed patients (see Section 5.1.2. for details). Heninger et al. (1988) studied the effects of oral YOH (20 mg) in 45 patients (28 female and 17 male, 41 ± 13 years old) with major depression and 20 healthy control subjects (11 females and 9 males, mean age of 39 years). YOH increased plasma MHPG by 25% in both patients and controls. Subjective mood changes were reported: YOH produced small, but significant, increases in ratings of nervousness in both patients and controls and provided significant minor improvement in depression and sadness in the depressed patients. Somatic symptoms of nausea, perspiration, increased urinary frequency, palpitation, restlessness, tremors, piloerection, hot and cold flashes, and muscle aches were reported by patients. Controls reported increased urinary frequency, anorexia, rhinorrhea, and piloerection. YOH had no consistent effect on HR in the patients, but it produced transient increases in SBP in both patients and controls. YOH has been used successfully to treat tricyclic antidepressant-induced orthostatic hypotension. A double-blind, crossover, placebo-controlled study in 12 patients with depression with clomipramine-induced orthostatic hypotension demonstrated that low doses (4 mg, t.i.d.) of YOH had a favourable effect in orthostatic hypotension and induced a significant increase in BP (Lacomblez et al., 1989). In another study, a 54-year-old female patient with major depression with melancholia, experiencing severe desipramine-induced orthostatic hypotension that could not be ameliorated by switching to nortriptyline, was successfully treated with oral YOH (7.5 mg t.i.d.) (Seibyl et al., 1989). The patient tolerated this dose with minimal side effects (tremor and mild anxiety) while taking nortriptyline (100 mg/day). YOH was discontinued after 6 weeks, and the patient remained on nortriptyline, with no further episodes of hypotension. 4.13. Patients with generalized anxiety disorders The effects of oral YOH (20 mg) were studied in 20 patients (12 females and 8 males, 36 ± 6 years old) with generalized anxiety disorder and in 20 age- and sexmatched healthy control subjects (Charney et al., 1989). S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 The behavioural, biochemical, and cardiovascular responses to YOH were generally similar in the control and generalized anxiety disorder groups, except that there was a trend for a smaller increase in plasma MHPG in the patient group. There was a small, but significant, increase in ratings of nervousness in the control group only at 60 min, and there was no significant increase in ratings of nervousness and anxiety over baseline after YOH administration. These findings contrast with studies of the effects of YOH in panic disorder patients (Charney et al., 1992; Gurguis et al., 1997), and suggest a neurobiological distinction between these two disorders. 4.14. Patients with panic disorder Patients with panic disorder are more sensitive than normal subjects to the induction of anxiety by YOH. A high intravenous dose of YOH (0.4 mg/kg) was administered to 15 healthy volunteers and 38 patients with panic disorder (Charney et al., 1992) in order to evaluate possible abnormal noradrenergic neuronal functional regulation in patients with panic disorder. In the healthy subjects, there was a trend towards a significant increase in anxiety compared with placebo at 15 min. In the panic disorder patients, there was a significant increase in anxiety rating compared with placebo at 15 and 30 min. A subgroup of 24 out of 38 panic disorder patients were observed to experience YOH-induced panic attacks and had higher YOHinduced increases in plasma MHPG than healthy subjects and other panic disorder patients. Yeragani et al. (1992) studied the effects of oral YOH (20 mg) in 13 normal controls (8 female and 5 male, 27.1 ± 1.4 years old) and 13 panic disorder patients (5 female and 8 male, aged 31.2 ± 2 years), and they found no significant effect on the State Anxiety Inventory or Panic Description Scale scores in either the controls or the panic disorder patients. However, there was a trend toward significance for Panic Description scores to be higher in the patients after YOH. The controls reported no heart pounding, tremulousness, general nervousness, or subjective experience of a panic attack after YOH administration. YOH produced no change in HR and standing SBP in either patients or controls, but supine SBP was moderately increased by an average of 6 mm Hg in both groups. YOH caused a significant increase in supine and standing DBP in both groups, with an average increase of  4 mm Hg over baseline. The effects of oral YOH or placebo on plasma homovanillic acid (HVA), an indicator of dopamine turnover, were studied in 11 patients with panic disorder and 6 normal controls (Gurguis & Uhde, 1990). Panic disorder patients had similar HVA values at baseline compared with normal controls, and YOH had no significant effect on plasma HVA in both groups. YOH (20 mg) was administered to 20 healthy subjects and 39 drug-free patients with agoraphobia and panic attacks. YOH produced significantly greater increases in 237 patient-rated anxiety, nervousness, palpitations, hot and cold flashes, restlessness, tremors, piloerection, and sitting SBP in the patient group compared with healthy subjects (Charney et al., 1984). Patients experiencing frequent panic attacks had a significantly greater plasma MHPG response to YOH than the healthy subjects and to patients having less frequent panic attacks. In a similar study, oral YOH (20 mg) produced panic attacks in 37 of the 68 patients with agoraphobia and panic attacks and only 1 of 20 healthy subjects (Charney et al., 1987). In the healthy subjects, there was no significant change in the visual analogue rating of anxiety between the YOH- and placebo-induced changes from baseline at any time. In the total group of panic disorder patients, a significant Drug by Time interaction was found for the anxiety ratings. The patients reporting YOH-induced panic attacks had significantly larger increases in plasma MHPG, cortisol, SBP, and HR than the healthy subjects. The effects of YOH and placebo were studied in 7 healthy controls and 11 patients diagnosed with agoraphobia with panic attacks. YOH induced a panic episode in 6 panic disorder patients, but not in control subjects (Gurguis et al., 1997). YOH significantly raised SBP, plasma NE, and cortisol levels, but had no effect on EPI levels. Despite similar increases in plasma NE levels between panic disorder patients and healthy controls, panic disorder patients had greater anxiogenic, cardiovascular, and cortisol responses to YOH. Enhanced postsynaptic AR sensitivity may explain the noradrenergic dysregulation found in panic disorder. 4.15. Patients with posttraumatic stress disorder Intravenous YOH (0.4 mg/kg) administered over 10 min resulted in a significant increase in anxiety in Vietnam combat veterans with combat-related PTSD (all white, 46.7 ± 0.54 years old), but not in healthy, aged-matched control subjects (n = 10/group) in a randomised, placebocontrolled, double-blind study (Bremner et al., 1997). PET and the use of [18F]fludeoxyglucose indicated a significant difference in brain metabolic response to YOH in patients with PTSD compared with healthy subjects in prefrontal, temporal, parietal, and orbitofrontal cortices. YOH tended to decrease brain metabolism in patients with PTSD and to increase metabolism in healthy subjects. The YOH-induced increase in anxiety in patients with PTSD was not correlated with the decrease in regional brain metabolism. The behavioural and cardiovascular effects of 26 patients with PTSD and 14 healthy subjects, who each received an intravenous infusion of saline, YOH HCl (0.4 mg/kg), or meta-chlorophenylpiperazine (1 mg/kg) on 3 separate days in a randomised balanced and double-blind fashion, were studied (Southwick et al., 1997). Eleven (42%) of the patients with PTSD experienced YOH-induced panic attacks and had significantly greater increases in anxiety, panic, and PTSD symptoms as compared with controls. There was no difference in changes in BP and HR between the patient and 238 S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 control groups over time following YOH. Another study supported the relationship between increased noradrenergic function and exaggerated startle symptomatology of PTSD (Morgan et al., 1995). The effects of intravenous YOH (0.4 mg/kg) or saline placebo on acoustic startle reflex were studied in 18 patients with PTSD and 11 healthy combat controls on 2 separate days in a randomised, double-blind, placebo-controlled design. YOH significantly increased the amplitude, magnitude, and probability of the acoustic startle reflex in combat veterans with PTSD, but did not do so in combat controls. 4.16. Patients with narcolepsy Eight patients who met polysomnographic and multiple sleep latency test-verified narcolepsy were started with oral YOH at 2.7 –5.4 mg b.i.d., and were allowed up to 16 mg/ day (Wooten, 1994). Some patients were treated for 18 months. All patients had an initial response to YOH, and were able to stay awake during a normal 8-hr work period and travel to and from work. Most patients responded to 8.1– 10.8 mg daily in divided doses. Side effects were tolerable and transient, and included insomnia (1), dyspepsia (1), diarrhoea (2), tremor (1), flushing (1), and dizziness (1). 4.17. Patients with sensorineural impairment Fourteen sensorineurally impaired subjects (9 male and 5 female, 45– 74 years old) were treated with placebo or oral YOH (10 mg) in a double-blind study (Hughes et al., 1988). Mild, significant improvement was observed in one of the hearing components, ‘‘attenuation,’’ and an adverse effect was noted on ‘‘distortion’’ owing to noise. Auditory brainstem response was improved significantly. Eight of the patients had one or more of the following symptoms: a warm feeling, a flush, tenseness and anxiety, gastrointestinal queasiness, sweating, nervousness, unsteadiness, salivation, and metallic taste. The other six patients were without symptoms. 5. Overdose Apparently, only three cases of YOH overdose have been published in the literature. The overdosed subjects, who took 200 mg,  250 mg, and 350 mg, respectively, of YOH, all had transient hypertension, increased HR, and other symptoms. All symptoms resolved spontaneously in 1 –2 days. Friesen et al. (1993) reported that a 62-year-old white male with Type II diabetes mellitus treated with glyburide ingested 100 2.0-mg YOH tablets (200 mg total) and 4 – 5 oz. of vodka  90 – 120 min before he presented to the emergency room. His only complaint was light-headedness when standing. He denied palpitations, gastrointestinal upset, and hallucinations, but noted that his feet were tingling, which he attributed to prolonged standing and diabetes. The patient was anxious, but alert and oriented, and did not appear to be in any physical distress. His HR was 106 beats/min, and his supine BP was 174/94 mm Hg with a standing BP of 168/88 mm Hg. His pupils were midsized and reactive, and there was no diaphoresis or facial flushing. Except for an occasional twitching motion of his extremities and a slight decreased sensation to pinprick in his feet, his neurological status was normal. His ECG, blood urea nitrogen, creatine, and liver function tests were normal. He was administered 50 g of activated charcoal in sorbitol shortly after admission, and this dose was repeated 6 hr later. He was observed for a total of 19 hr. During this time, his HR returned to 80 beats/min and his BP decreased to 128/60 mm Hg. His only complaints were of some nausea and diarrhoea, which the doctor attributed to the result of the charcoal and cathartic therapy. Linden et al. (1985) reported that a 16-year-old girl ingested an estimated 250-mg YOH at 10 p.m. Twenty minutes following ingestion, she experienced weakness; generalized parasthesia; loss of coordination; severe, squeezing headache associated with tremors; and a dissociative state. Four hours after ingestion, the patient noted severe pressure-like substernal chest pain, which awakened her from a brief period of sleep, and there were no other symptoms except for continued anxiety, shakiness, and weakness. The chest pain resolved spontaneous after 2 hr, and the patient went back to sleep. The next morning, the patient still felt weak and shaky, and noted decreased hearing in her right ear. She subsequently developed nausea, diaphoresis, and intermittent palpitations. The squeezing headache returned and was not relieved by taking two aspirin tablets. Upon physical examination more than 16 hr after ingestion of YOH, the patient was pale, anxious, slightly diaphoretic, and had fine tremors of the extremities. A raised, blotchy, erythematous rash was present over the upper back and a submucosal haemorrhage was seen in the right tympanic membrane. The physical examination was unremarkable, except tachypnea and tachycardia were noted. Her vital signs were BP, 150/80 mm Hg; HR, 116; respiration, 24; and temperature, 37.2C. The patient was administered oxygen, and an ECG revealed sinus tachycardia. By the next morning, the patient was asymptomatic, except for decreased auditory acuity on the right side. Her BP was 112/74 mm Hg, HR was 64 beat/min, and respirations were 14. No further symptoms were observed, and the patient was discharged. Varkey (1992) reported that a 38-year-old man with insulin-dependent diabetes and depression was admitted to a hospital 2 hr after taking 350 mg of YOH. Upon admission, he was alert and oriented with BP of 130/80 mm Hg and HR of 88 beats/min. Six hours after admission, he discharged himself. He was readmitted 17 hr later (25 hr after taking YOH) in a drowsy and confused state. He was having rigors and complained of retrosternal pain. His rectal S.W. Tam et al. / Pharmacology & Therapeutics 91 (2001) 215–243 temperature was 35.5C and his BP was 135/85 mm Hg. His hands and feet were warm and well perfused. Blood urea concentration was 12.8 mmol/L, serum creatinine was 175 mmol/L, and blood glucose was 16.7 mmol/L. An ECG showed atrial fibrillation, with a ventricular rate of 150 beats/min. The day after admission, an ECG showed sinus rhythm, and no further cardiac symptoms were reported on subsequent days. Retrograde amnesia for the preceding 24 hr persisted for 4 days. No explanation could be given for the 25-hr delay between the patient taking the drug and his developing atrial fibrillation, drowsiness, and confusion and suffering a drop in body temperature, because YOH should be completely absorbed within 1 hr and essentially eliminated in 8 hr (Guthrie et al., 1990; Sturgill et al., 1997; Grasing et al., 1996) and the active metabolite 11-hydroxyyohimbine (11-OH-YOH) was formed very rapidly, with an elimination half-life of 6 hr (Le Verge et al., 1992). The patient claimed that he had not taken any other drugs. It is likely that the physiological changes at these extremely high doses reflect only an extension of the primary pharmacological properties of YOH. 6. Summary There has been a long history of use of YOH in patients, mainly for the treatment of sexual dysfunction. Patients generally have received oral doses between 5.4 and 10 mg YOH t.i.d., but some have received as much as 100 mg/day. Doses of 5.4 – 10 mg t.i.d. are well-tolerated, and the response rate ranges from 34 to 86% in placebo-controlled, double-blind trials in patients with ED. However, perhaps due to the relatively high placebo rate, YOH was significantly better than placebo in only a minority of the trials. The efficacy of YOH as monotherapy in open-label studies is likewise equivocal. There appears little clinical evidence to suggest that YOH will be particularly effective in a clinically defined subpopulation such as psychogenic ED. In the management of a non-life-threatening condition such as ED benefit risk is of particular concern, with a particular emphasis on cardiovascular safety. The side effects of YOH are clearly dose-dependent, are generally apparent at doses much higher than the claimed therapeutic doses, and reflect an extension of the primary pharmacological action as an a2-AR antagonist. Doses of 10 mg t.i.d. or lower generally are well-tolerated without side effects. Doses at 20– 40 mg occasionally cause small increases in BP and doses at 45.5 mg or higher sometimes increase HR in normotensive subjects. As a reflection of this relatively bland haemodynamic profile, the most consistently reported side effects reported (anxiety and increased urinary frequency) are not cardiovascular ones. Thus, at the projected therapeutic dose range, YOH appears to be safe in normal subjects and in patients with various diseases. Importantly, all reported side effects of YOH, including a dose as high as 350 mg in a diabetic patient, are reversible 239 and resolve spontaneously within a relatively short time after termination of the drug therapy. Although well-tolerated and safe, even when greatly exceeding the likely therapeutic range, it is obvious that the efficacy of YOH as monotherapy in the general ED population is likely to be modest. However, should the efficacy of YOH be augmented by concomitant use with other drugs, it may represent another option in the front-line management of ED. Given our understanding of the pathophysiology of ED, an intriguing option would be to combine YOH with a drug that enhances the NO pathway in the corpus cavernosum. References Adler, L. E., Hoffer, L., Nagamoto, H. T., Waldo, M. C., Kisley, M. A., & Giffith, J. M. (1994). Yohimbine impairs P50 auditory sensory gating in normal subjects. Neuropsycopharmacology 10, 249 – 257. Amann, F. 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