Efficacy and safety of guanabenz acetate treatment for non-alcoholic fatty liver disease: a study protocol for a randomised investigator-initiated phase IIa study.

INTRODUCTION: Non-alcoholic fatty liver disease (NAFLD) is a metabolic syndrome phenotype in the liver and thus obviously associated with metabolic abnormalities, including insulin resistance-related to hyperglycaemic and hyperlipidaemia. The prevalence of NAFLD is increasing worldwide. However, currently, there is no consensus regarding the efficacy and safety of drugs used to treat patients with NAFLD/non-alcoholic steatohepatitis (NASH). Guanabenz acetate, a selective α2-adrenoceptor stimulator used in the treatment of hypertension, binds at a high-affinity constant to a nuclear transcriptional coregulator, helicase with zinc finger 2 (Helz2) and inhibits Helz2-medaited steatosis in the liver; chronic oral administration of guanabenz acetate produces a dose-dependent inhibition of lipid accumulation by inhibiting lipogenesis and activating fatty acid Β-oxidation in the liver of obese mice, resulting in improvement of insulin resistance and hyperlipidaemia. Taken all together, guanabenz acetate has a potentially effective in improving the development of NAFLD/NASH and metabolic abnormalities. In this randomised, open label, parallel-group, phase IIa study, we made attempts to conduct a proof-of-concept assessment by evaluating the efficacy and safety of guanabenz acetate treatment in patients with NAFLD/NASH. METHODS AND ANALYSIS: A total of 28 adult patients with NAFLD or NASH and hypertension complications meeting the inclusion/exclusion criteria will be enrolled. Patients will be randomised to receive either 4 or 8 mg guanabenz acetate (n=14 per group). Blood tests and MRI will be performed 16 weeks after commencement of treatment. The primary endpoint will be the percentage reduction in hepatic fat content (%) measured using MRI-proton density fat fraction from baseline by at least 3.46% at week 16 after treatment initiation. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee of Yokohama City University Hospital before participant enrolment (YCU021001). The results of this study will be submitted for publication in international peer-reviewed journals, and the key findings will be presented at international scientific conferences. Participants wishing to know the results of this study will be contacted directly on data publication. TRIAL REGISTRATION NUMBER: This trial is registered with ClinicalTrials.gov (number: NCT05084404). PROTOCOL VERSION: V.1.1, 19 August 2021.

Guanabenz-an old drug with a potential to decrease obesity.

The aim of this study was to determine, in the diet-induced obesity model in rats, the potential of Guanabenz to reduce body weight and ameliorate some metabolic disturbances. Obesity was induced in rats by a high-fat diet. After 10 weeks, rats were treated intraperitoneally with Guanabenz at the two doses: 2 or 5 mg/kg b.w./day, once daily for 25 days. The spontaneous activity of rats was measured for 24 h on the 1st and 24th day of the Guanabenz treatment with a special radio-frequency identification system. Gastric emptying was measured in intragastric phenol red-treated mice by measuring the color of the stomach homogenate 30 min after phenol red administration. Intraperitoneal administration of Guanabenz for 25 days to obese rats resulted in a significant decrease in body weight compared to the baseline values (about 11% at a dose of 5 mg/kg). Both body weight and the amount of adipose tissue in the groups receiving Guanabenz decreased to the levels observed in the control rats fed only standard feed. The anorectic effect occurred in parallel with a reduction in plasma triglyceride levels. We also confirmed the beneficial effect of Guanabenz on plasma glucose level. The present study demonstrates that the administration of Guanabenz strongly inhibits gastric emptying (about 80% at a dose of 5 mg/kg). Guanabenz can successfully and simultaneously attenuate all the disorders and risk factors of metabolic syndrome: hypertension, hyperglycemia, obesity, and dyslipidemia. However, the exact cellular mechanisms of its action require further research.

Therapeutic effects of evening administration of guanabenz and clonidine on morning hypertension: evaluation using home-based blood pressure measurements.

OBJECTIVE: To clarify the effects of bedtime administration of the centrally acting alpha(2)-agonists, guanabenz and clonidine, on morning hypertension. METHODS: Patients with morning hypertension were assigned to receive once-daily evening administration of guanabenz (2 mg/day, n = 81; 4 mg/day, n = 2) or clonidine (75 microg/day, n = 40; 150 microg/day, n = 10) for 4 weeks, and the blood pressure (BP)-lowering effects of these drugs in the morning and evening were evaluated by assessing self-monitored BP in the home environment. The subjects were then subdivided into different groups according to their evening BP, and the effects of guanabenz and clonidine on evening BP were evaluated further for each group. In addition, as a substitute for the trough/peak ratio, the evening/morning (E/M) ratio was calculated to assess the duration of action of the two alpha(2)-agonists. RESULTS: Evening dosing with guanabenz or clonidine lowered morning BP significantly. Both drugs decreased evening BP in the subgroup of subjects with a high evening BP, but not in those with a normal evening BP. The individual E/M ratios for guanabenz, but not for clonidine, were significantly greater in those with a high evening BP than in those with a normal evening BP. In the early treatment period, treatment with guanabenz resulted in a higher diastolic E/M ratio in those subjects with a high evening diastolic BP than did treatment with clonidine. CONCLUSION: The results suggest that evening administration of the central alpha(2)-agonists guanabenz and clonidine effectively suppresses the morning BP elevation in treated hypertensive patients.

Non-adrenergic exploratory behavior induced by moxonidine at mildly hypotensive doses.

Moxonidine is a centrally-active imidazoline compound with preferential affinity for imidazoline receptors (IR) over alpha(2)-adrenoceptors (alpha(2)AR). Clinically, moxonidine has proven advantageous for treating hypertension over pure alpha(2)-adrenergic agonists (i.e., guanabenz) due to its lowered incidence of sedative side effects. The present experiments reveal divergent behavioral effects of low doses of moxonidine and guanabenz in C57Bl/6 mice in an exploratory arena. Low-dose moxonidine (0.05 mg kg(-1) i.p.) elicited an increase in novel object contacts (+36%) and more movement into central space (+56%; P<0.01) compared to saline-injected controls; whereas guanabenz induced only dose-responsive sedative-like behaviors in the same paradigm. Yet, the two agonists were indistinguishable in terms of blood pressure changes over a similar dose range (0.025-0.1 mg kg(-1) i.p.) in consciously free-moving mice (Delta mean+/-S.E.M.=-12.3+/-3.2 mm Hg for moxonidine versus -13.5+/-1.9 mm Hg for guanabenz). As expected of alpha(2)AR involvement, the sedative-like effects of guanabenz were completely blocked by pretreatment with the non-imidazoline alpha(2)AR-antagonist, SKF86466 (0.5 or 1.0 mg kg(-1) i.p.). However, the pro-exploratory effects of low doses of moxonidine (0.05 or 0.1 mg kg(-1)) were not antagonized by SKF86466. These results suggest that moxonidine acts preferentially through a non-adrenergic mechanism, possibly IR-mediated, to elicit pro-exploratory behavior.

Guanabenz combination therapy inhibits sympathetic nerve activity and regresses left ventricular hypertrophy.

The cardiovascular and sympatholytic effects of combination therapy with guanabenz were examined in 26 patients (48 +/- 13 years old [mean +/- SD]) with stage 2 and 3 hypertension. Included in the study were patients under treatment with conventional antihypertensive drugs whose systolic and diastolic blood pressure was above 140 and 90 mmHg, respectively. Blood pressure, heart rate, and sympathetic parameters such as plasma concentration of norepinephrine and muscle sympathetic nerve activity at rest as well as during ambulatory conditions, 24-hour urinary excretion of norepinephrine, and low frequency (LF: 0.04-0.15 Hz)/high frequency (HF: 0.15-0.4 Hz) power ratio as a marker of cardiac sympathetic activity during 24 hours were examined before and after guanabenz (4-8 mg/d) combination therapy with first-line antihypertensive drugs such as diuretics. Left ventricular mass index (LVMI) was also calculated by conventional echocardiography. After 32 weeks of guanabenz combination therapy, systolic and diastolic blood pressure, heart rate, plasma and urinary excretion of norepinephrine, muscle sympathetic nerve activity, and LF/HF power ratio were significantly decreased, while neither LF nor HF power was changed. LVMI was also significantly decreased (270 +/- 81 vs. 236 +/- 83 g/m2, p < 0.005). These results indicate that guanabenz combination therapy inhibits sympathetic nerve activity under resting conditions as well as during ambulatory conditions and may accelerate regression of left ventricular hypertrophy in patients with moderate to severe hypertension.

Comparison of the effects of guanabenz and hydrochlorothiazide on plasma lipids.

The effects of hydrochlorothiazide (HCTZ) and guanabenz monotherapy on blood pressure and serum lipoprotein levels were compared in a 14-week, randomized, parallel, double-blind multicenter study of 218 outpatients with mild hypertension. Mean supine blood pressure decreased 13/9 mm Hg in the guanabenz group and 17/11 mm Hg in the HCTZ group, changes that were significantly (p less than 0.01) different from baseline but not significantly different between the two treatment groups. Significant (p less than 0.01) mean decreases in total cholesterol and low-density lipoprotein (LDL) cholesterol levels (of 9 mg/dl and 4 mg/dl from baseline values) occurred during guanabenz treatment; HDL cholesterol levels fell by an average of 4 mg/dl. In the HCTZ group, triglyceride levels were significantly (p less than 0.01) increased by 13 mg/dl, and HDL cholesterol levels fell by 2 mg/dl. The change in LDL cholesterol levels, but not HDL cholesterol levels, was significantly different between guanabenz and HCTZ periods. The results show that guanabez, although providing effective blood pressure control that is comparable to that of HCTZ, has more favorable effects on lipoproteins.

Sinoatrial and atrioventricular dysfunction associated with the use of guanabenz acetate.

Guanabenz acetate is an antihypertensive drug that is closely related to clonidine hydrochloride. Clonidine is well known to potentiate atrioventricular (AV) node conduction disturbances, but to date that effect has not been attributed to guanabenz. A case of electrocardiographic and electrophysiologic studies in a patient with both sinus and AV node conduction disturbances associated with the use of guanabenz acetate is reported. The sinus cycle length was increased by 50% after guanabenz and the sinus node recovery time was prolonged by 42%. AV block occurred proximal to the His bundle and His-ventricular prolongation of 42% also occurred. This drug should be used cautiously in patients with evidence of sinus or AV node dysfunction.

Guanfacine as monotherapy for systemic hypertension.

Three clinical studies examined the effects of guanfacine as monotherapy. Study 1 was a double-blind, randomized, parallel trial with a placebo control with 26 patients with mild essential hypertension treated with 1-mg guanfacine or matching placebo daily at bedtime for 8 weeks. Pretreatment and posttreatment determinations of plasma volume, plasma aldosterone and blood pressure (BP) were made in all 26 patients. There were no significant differences between guanfacine and placebo with regard to changes in plasma volume or plasma aldosterone, but a significant decrease (p = 0.001) in both diastolic and mean BPs was seen with the active drug. No side effects were reported. From this study, it was concluded that guanfacine monotherapy is an effective and well-tolerated initial treatment for mild essential hypertension with no effect on either plasma volume or plasma aldosterone. Study 2 was a double-blind, randomized, parallel clinical study with placebo control with 42 patients with mild essential hypertension treated with either guanfacine (1 mg/day) or matching placebo at bedtime for 8 weeks. Pretreatment and posttreatment evaluations of serum cholesterol, triglycerides, low density lipoproteins, very low density lipoproteins and high density lipoproteins revealed no significant differences between the treatment and the placebo groups. A statistically significant (p less than 0.0001) decrease in diastolic BP was seen in the guanfacine group compared with those patients who received placebo. Guanfacine monotherapy was again shown to be an effective initial treatment for mild essential hypertension with no adverse influence on serum lipids.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-response relationship of single oral doses of guanabenz in hypertensive patients.

A single-blind, placebo-controlled study was conducted to determine the dose-response relationship of guanabenz, administered as single oral doses to patients with mild or moderate hypertension. Twelve hypertensive patients received ascending oral doses of 2, 4, 8, 16, 24, and 32 mg of guanabenz. Dose-response relationships were evaluated for the nine patients who received placebo and all six guanabenz doses. The greatest maximum response (40/24 mm Hg) was seen for the 16 mg guanabenz dose. Since eight of the nine patients had mild hypertension, they may have responded maximally to the lower guanabenz doses, precluding larger decreases with the 24 and 32 mg doses. The mean onset of satisfactory blood pressure reduction decreased from 4 to 2 h and the mean duration increased from 6 to 22 h as the oral dose was increased from 2 to 32 mg. In eight patients, the responses to 16 mg of guanabenz administered sublingually and orally were compared. The sublingual and oral routes produced similar mean (20/13 mm Hg) and maximum (33/24 mm Hg) blood pressure decreases as well as mean onset (2 h) and duration (16.5 h) of satisfactory response. Additional studies involving patients with more severe hypertension are needed to further characterize the dose-response relationship of oral guanabenz and to establish a dose-response relationship for sublingual guanabenz.

Pharmacokinetics of guanabenz in patients with impaired liver function.

The disposition of guanabenz, a centrally acting antihypertensive agent, was compared in 10 normotensive patients (eight males and two females) with chronic hepatic disease secondary to alcohol abuse and 10 healthy male volunteers after a 16 mg oral dose. Mean plasma concentrations of guanabenz were higher in patients with liver disease than in healthy subjects at every sampling time through 72 h after drug administration (p less than 0.05). In liver disease patients, the mean oral-dose clearance (2 L/h/kg) and terminal-phase volume of distribution (20 L/kg) were lower (p less than 0.001) than the respective values of 11 L/h/kg and 71 L/kg of healthy volunteers. The mean plasma half-life of patients with liver disease (6.4 h) was not significantly longer than that of healthy subjects (4.3 h). The mean fraction of unbound drug in the plasma was higher (p less than 0.01) in patients with liver disease (12.7%) than in healthy volunteers (10.5%). As guanabenz is eliminated predominantly via hepatic biotransformation and undergoes significant presystemic elimination after oral administration, the changes in guanabenz disposition in liver disease are not unexpected. They may be explained by enhanced oral bioavailability, owing to portosystemic shunting and/or reduced intrinsic clearance, combined with decreased hepatic clearance of guanabenz in liver disease. Individual dosage titration may be required when guanabenz is used for antihypertensive therapy of patients with chronic liver disease.

Endocrinologic effects of antihypertensive therapy with guanabenz or hydrochlorothiazide.

The effect of antihypertensive therapy with guanabenz or hydrochlorothiazide (HCTZ) on the secretion of growth hormone, prolactin, insulin, and glucagon was evaluated in double-blind fashion in 45 patients. Fifteen patients were treated with HCTZ, 50 mg twice daily, and 30 patients were treated with twice-daily dosages of guanabenz ranging from 4 to 32 mg. Blood samples for hormone analysis were collected during maintenance therapy when blood pressure was controlled as well as 1 week after the withdrawal of the antihypertensive medications. Serum levels of growth hormone and prolactin were within the normal ranges and were unchanged during treatment with HCTZ or guanabenz at any dose level. Interpatient variability in insulin levels was high, although within-subject insulin levels generally were consistent. No treatment effects were seen for insulin levels among guanabenz- or HCTZ-treated patients. Glucagon levels generally were above the expected range for fasting patients and were lower in patients receiving 4 or 8 mg of guanabenz twice daily than in those receiving 16 mg twice daily (p less than 0.05) and in those treated with HCTZ (p less than 0.01). However, analysis of paired data revealed no changes in glucagon levels upon withdrawal of guanabenz, whereas glucagon levels were higher during HCTZ treatment than after drug withdrawal (p = 0.012). Since guanabenz treatment did not affect the secretion of pancreatic or pituitary hormones, it may be preferable to other centrally acting agents and thiazide diuretics for hypertensive patients who are elderly, overweight, or diabetic.

Effects of guanabenz in adolescent hypertension.

Fourteen adolescent patients, aged 12 to 21 years, with essential hypertension were treated on an open basis with guanabenz, a centrally acting antihypertensive agent. Guanabenz doses of 3-24 mg/day (0.08-0.20 mg/kg/day) given twice daily for 2 months effectively lowered mean supine blood pressure (p less than 0.05), standing blood pressure (p less than 0.01), and supine pulse rate (p less than 0.01). Body weight and standing pulse rate were unaffected. Adverse effects were mild, usually short lived, and did not interfere with therapy. No adverse effects were noted in laboratory test results or physical examinations. Baseline funduscopic photography revealed numerous but minor changes, including altered arteriovenous ratios and crossing changes. Prestudy echocardiograms revealed changes consistent with early hypertensive changes. Poststudy echocardiograms obtained in nine of the 14 subjects after 4-6 weeks of guanabenz therapy suggested that cardiac hypertrophy had regressed, but these changes did not reach statistical significance. These preliminary results suggest that guanabenz can be a safe and effective treatment for hypertensive children, that early hypertensive changes can be seen in the fundi and echocardiograms of mildly hypertensive adolescents, and that some echocardiographic changes may be reversed even after relatively short-term guanabenz therapy.

Antihypertensive therapy with guanabenz in patients with chronic obstructive pulmonary diseases.

The management of hypertension in patients with chronic obstructive pulmonary disease (COPD) may be complicated by the adverse effects of several antihypertensive agents on pulmonary function. The safety and antihypertensive efficacy of guanabenz, a centrally acting alpha-adrenergic agonist, were evaluated in 42 patients with asthma and 24 patients with other forms of COPD. Among the 64 patients with data evaluated for efficacy, pretreatment supine diastolic blood pressures (SDBP) were between 90 and 121 mm Hg (mean, 100 mm Hg). The patients were treated for 6 months with guanabenz as sole antihypertensive therapy in doses ranging from 8 to 64 mg/day (mean final dosage, 28 mg/day). At the end of the treatment period, a mean decrease in SDBP of 10 mm Hg was observed (p less than 0.001). Excellent or satisfactory blood pressure responses were obtained for 65% of the asthmatic patients and 83% of the patients with other forms of COPD. Mean supine pulse rate decreased by 7 beats/min (p less than 0.001), and mean body weight decreased by 2 lb. (p less than 0.05). Only one patient discontinued guanabenz treatment because of an exacerbation of asthma thought to be due to airway dryness. Because beta-adrenergic blocking agents, including the cardioselective drugs, have been known to exacerbate COPD, guanabenz treatment may be preferable as antiadrenergic antihypertensive therapy in patients with asthma and other forms of COPD.

Hypertension in patients with diabetes mellitus: treatment with a centrally acting agent.

This retrospective study was undertaken to evaluate the effectiveness and clinical characteristics of guanabenz, a centrally acting agent, as monotherapy in hypertensive patients with coexisting diabetes mellitus. Of 113 patients with data available for analysis, 21 were receiving concurrent therapy with insulin, 31 were receiving oral hypoglycemic agents, and 61 were being treated by a diabetic diet alone. During treatment with guanabenz (4-64 mg daily) for up to 2 years (mean duration, 7 months), diastolic blood pressure (measured in the supine posture) decreased by an average of 10 mm Hg; the effects were similar among the three subgroups of patients receiving the different diabetic therapies. Clinically satisfactory treatment outcomes occurred in 52%, 77%, and 57% of patients, respectively. Body weight remained constant throughout the study. The antihypertensive efficacy of guanabenz in this study and the nature and frequency of side effects produced were similar to those reported previously in nondiabetic hypertensive patients. Neither plasma glucose concentrations nor the diabetic therapy requirements of the diabetic patients in this study were altered by guanabenz treatment. There also was a small decrease in serum total cholesterol concentration (mean decrease, 15 mg/dl, p less than 0.001) during the study. Thus, antihypertensive monotherapy with guanabenz is effective in the treatment of a majority of patients with coexisting diabetes mellitus. Since it does not appear to interfere with the concurrent treatment of diabetes or cause unwanted metabolic side effects, guanabenz may be a rational and safe agent for the management of hypertension in the diabetic patient.

Effect of guanabenz withdrawal on blood pressure and plasma catecholamines.

Previous studies provide conflicting conclusions concerning the consequences of abrupt withdrawal of guanabenz therapy for essential hypertension. In the present study, 10 patients were treated for mild to moderate essential hypertension for 12 weeks, following which the drug was abruptly withdrawn. Blood pressure, pulse rate, and plasma catecholamine levels were obtained before, at 4 and 12 weeks after starting therapy, and 48-96 h and 4 and 8 weeks post-therapy. At the end of 12 weeks of therapy, the mean dose of guanabenz was 22.2 +/- 4.4 mg/day (range, 16-48 mg/day) and supine blood pressure was 140 +/- 5.5/88 +/- 2.4 mm Hg. Two to 4 days after drug withdrawal, supine and standing diastolic blood pressure remained significantly reduced compared to control (p less than 0.01). Standing systolic blood pressure also remained significantly reduced compared to control (p less than 0.01). Mean plasma catecholamine level was less than baseline after 4 weeks of therapy, but the change was not significant. No increase in plasma catecholamine concentration was observed at any time during the withdrawal period. No patient had symptoms of sweating, nervousness, palpitations, or insomnia after guanabenz withdrawal. In one patient with pretreatment systolic pressure of 150 mm Hg, systolic pressure 48 h after drug withdrawal was 160 mm Hg. These studies, together with previous reports, suggest that guanabenz therapy for mild to moderate essential hypertension in doses of 32 mg/day or less can be safely withdrawn on an outpatient basis with a very low incidence of withdrawal phenomena.

Step-one antihypertensive therapy: a comparison of a centrally acting agent and a diuretic.

The safety and antihypertensive efficacy of guanabenz and hydrochlorothiazide (HCTZ) were compared in a 6-month multicenter, double-blind study involving 147 patients. Average daily dosages of guanabenz varied during the study period from 16 to 31 mg, and mean daily dosages of HCTZ varied from 50 to 75 mg. Mean supine diastolic blood pressure (SDBP) decreased from 100 to 85 mm Hg for 33 guanabenz-treated patients (p less than 0.001) and from 99 to 83 mm Hg for 41 HCTZ-treated patients (p less than 0.001) who completed 6 months of treatment. Clinically significant individual decreases in SDBP were observed for 85% of the patients in both treatment groups at 6 months. Mild side effects, which included dry mouth and drowsiness, were reported more frequently by guanabenz-treated patients than by HCTZ-treated patients (p less than 0.01). Among HCTZ-treated patients, statistically significant mean increases from baseline values were noted for uric acid, serum glutamic oxaloacetic transaminase, carbon dioxide, hemoglobin, and blood urea nitrogen levels, whereas mean decreases were observed for potassium and chloride levels. The only clinically significant change in mean laboratory values for the guanabenz group was a decrease of 16 mg/dl in total serum cholesterol (p less than 0.01). The electrolyte and metabolic disturbances associated with HCTZ treatment may lead to increased cardiovascular risk and thus negate or reduce the benefits of successful blood pressure control. A decrease in serum cholesterol levels and a reduction in blood pressure, however, are effects that have been associated with reduced cardiovascular risk. Thus guanabenz therapy may have a more beneficial effect on overall cardiovascular risk than HCTZ therapy.

Guanabenz for adolescent hypertension.

Guanabenz, a centrally acting antihypertensive agent that acts through stimulation of central alpha-adrenergic receptors, appears to produce neither sodium retention nor clinically significant renal, cardiac, hepatic, or metabolic abnormalities. This 2-month open, uncontrolled dose-finding and short-term safety and efficacy trial was conducted in 11 male outpatients (12 to 21 years old) to establish the potential use of guanabenz in treating children with hypertension. Doses of 3 to 12 mg/day (0.07 to 0.17 mg/kg/day) given twice daily effectively lowered blood pressure in all patients. Mean supine blood pressure was significantly (P less than 0.05) reduced from 135/91/81 mmHg (phase I/IV/V) at baseline to 124/80/66 mmHg after approximately 2 months of treatment. Mean supine pulse rate also was significantly (P less than 0.05) reduced (10 beats/minute), while standing pulse rate and body weight were unaffected by guanabenz therapy. Adverse effects, the most common being headache, dry mouth, and drowsiness, were generally mild and did not interfere with continued therapy. No abnormal findings were noted in laboratory test results or physical examinations. These preliminary results suggest that guanabenz is safe and effective for the treatment of childhood hypertension.

Guanabenz. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension.

Guanabenz is an orally active central alpha 2-adrenoceptor agonist. Its antihypertensive action is thought to result from a decrease in sympathetic outflow from the brain to the peripheral circulatory system as a result of stimulation of central alpha 2-adrenoceptors. In mild to moderate hypertension it is as effective as methyldopa and clonidine in lowering blood pressure when used as the sole treatment. As with these drugs, guanabenz may be combined with a diuretic to increase its blood pressure-lowering effect. The overall incidence of side effects seen with guanabenz was at least as high as with methyldopa or clonidine, and side effects such as drowsiness or dry mouth have been bothersome enough to lead to discontinuation of guanabenz therapy in some patients. However, particularly troublesome effects such as sodium retention, depression or sexual dysfunction which may occur with methyldopa or clonidine have not been reported with guanabenz.