VA Class:CN105

AHFS Class:

• Non-selective alpha-Adrenergic Blocking Agents 12:16.04.04

Generic Name(s):

• Ergoloid Mesylates

Ergoloid mesylates is an equiproportional mixture of the mesylate salts of the hydrogenated derivatives of 3 naturally occurring ergot alkaloids.

Dementia

Ergoloid mesylates has been used for the relief of signs and symptoms of idiopathic decline in mental capacity (e.g., mood, self-care, motivation, sociability, cognitive skills) in geriatric individuals.105 Approved for use in 1949, ergoloid mesylates was once widely used as a cerebral vasodilator to counteract cerebrovascular insufficiency and/or cerebral arteriosclerosis (“hardening of the arteries”), which were believed at the time to cause cognitive deficits consistent with current definitions of dementia.106,109,111 With the advent of more precise diagnostic criteria for dementia and mounting evidence supporting other etiologic hypotheses, however, ergoloid mesylates has been largely abandoned in favor of more effective agents (e.g., cholinesterase inhibitors).106,107,108,109,110,111

Efficacy of ergoloid mesylates is difficult to assess because individual studies use different signs and symptoms for evaluation, the etiology of these signs and symptoms is unknown, and the signs and symptoms are not specific for any disease or age. Results of several analyses of pooled data from randomized, controlled studies in patients with symptoms consistent with dementia indicate that ergoloid mesylates is more effective than placebo.106,107 However, the magnitude of improvement usually has been modest, particularly in patients with possible Alzheimer's disease,109 and the value of the drug has not been clearly established.106,107 In addition, specific traits or conditions, if any, that might predict the likelihood of response to therapy with ergoloid mesylates have not been clearly identified.105,106

There also is no convincing evidence that the drug alters sclerosis of cerebral arteries or improves the physical changes associated with aging. Efforts to improve nutrition along with psychological support to diminish feelings of loneliness and the psychological effects of idleness are the most valuable measures in the rehabilitation of the elderly.

Administration

Ergoloid mesylates is administered orally. The drug also has been administered sublingually, but a sublingual dosage form of the drug no longer is commercially available in the US.

Dosage

Dementia

The usual dosage of ergoloid mesylates is 1 mg 3 times daily.105 Therapeutic response to ergoloid mesylates is usually gradual, and beneficial effects may not be observed until after 3-4 weeks of therapy.105

The optimum dosage of ergoloid mesylates has not been established, but dosage has ranged from 1.5-12 mg daily.102 Some clinicians suggest a dosage of at least 6 mg daily and recommend a treatment period of 6 months to ensure an adequate trial of therapy with the drug.102 If treatment is considered beneficial and worth continuing, use of a lower dosage may be attempted; if no benefit is evident, the drug should be discontinued.102

Adverse Effects

Oral or sublingual (sublingual dosage form no longer commercially available in the US) administration of ergoloid mesylates has not produced any serious adverse reactions. Sublingual irritation, rashes, increased nasopharyngeal secretions or nasal stuffiness, blurred vision, orthostatic hypotension, flushing, sinus bradycardia, lightheadedness, anorexia, transient nausea and vomiting, or other mild GI disturbances have been reported infrequently.

Precautions and Contraindications

Patients should undergo careful diagnosis before ergoloid mesylates is administered to rule out the presence of potentially reversible and treatable underlying conditions .105 Particular care should be employed to rule out delirium and dementiform illness secondary to systemic disease, primary neurologic disease, or primary mood disturbance. The decision to use ergoloid mesylates therapy in the treatment of an individual with a symptomatic decline in mental capacity of unknown etiology should be continually assessed, since the patient's clinical presentation may subsequently evolve sufficiently to allow a specific diagnosis and alternative therapy. In addition, continued clinical evaluation is necessary to determine whether any initial benefit of ergoloid mesylates therapy persists with time.

Ergoloid mesylates is contraindicated in patients with acute or chronic psychosis regardless of etiology or with known hypersensitivity to the drug.105

Pharmacology

Ergoloid mesylates has some peripheral α-adrenergic blocking action, but has little or no vasoconstrictor activity and no oxytocic activity. The drug usually causes peripheral vasodilation primarily due to CNS depression of vasomotor nerve activity and may cause a slight decrease in blood pressure and heart rate. A few studies have shown that the drug may improve cerebral blood flow and EEG tracings, but other studies indicate that the drug does not significantly alter cerebral blood flow. It has been postulated that ergoloid mesylates may increase oxygen utilization in the brain via stabilization of ganglion cell metabolism, thus increasing cerebral blood flow indirectly rather than by direct dilation of cerebrovascular smooth muscle. There is no conclusive evidence that ergoloid mesylates affects cerebral arteriosclerosis or cerebrovascular insufficiency.

Pharmacokinetics

Absorption

Orally or sublingually (sublingual dosage form no longer commercially available in the US) administered ergoloid mesylates is rapidly absorbed. Although the metabolic fate is not completely known, ergoloid mesylates undergoes first-pass metabolism in the liver, and less than 50% of a dose reaches the systemic circulation unchanged. Following administration of a single 1-mg dose of radiolabeled ergoloid mesylates as an oral solution (no longer commercially available in the US) to fasting individuals in one study, peak plasma concentrations of total radioactivity were attained within 1.5-2.9 hours.100 Following administration of a single 4.5-mg dose as an oral solution (no longer commercially available in the US) to fasting individuals in a study which utilized a sensitive assay relatively specific for unchanged drug, peak plasma concentrations of unchanged drug averaged 576 pg/mL (range: 295-1100 pg/mL) and occurred after 35 minutes (range: 15-72 minutes); additional studies with IV administration of the drug indicated that the oral bioavailability averaged about 9% (range: 5-12%).101 Slightly higher peak plasma concentrations result when the drug is given orally compared with sublingual administration.

Elimination

Following a single oral dose of radiolabeled ergoloid mesylates in individuals with normal renal and hepatic function in one study, plasma concentrations of total radioactivity declined in a biphasic manner with an average half-life of 4.1 hours in the initial phase and 12 hours in the terminal phase.100 The elimination of unchanged drug is reportedly biphasic following oral administration in healthy individuals, with the half-life averaging 2.2 hours in the initial phase and 13.2 hours in the terminal phase.101

Following a single oral dose of ergoloid mesylates in individuals with normal renal and hepatic function in one study, only about 2% of the dose was excreted in urine within 96 hours; the remainder of the dose was presumably excreted in feces.100

Chemistry and Stability

Chemistry

Ergoloid mesylates is an equiproportional mixture of the mesylate salts of the hydrogenated derivatives of 3 naturally occurring ergot alkaloids. The derivatives are dihydroergocornine, dihydroergocristine, and dihydroergocryptine (dihydro-α-ergocryptine and dihydro-β-ergocryptine in the proportion of 2:1). The structures of dihydroergocornine and dihydroergocryptine differ from dihydroergocristine only in having an isopropyl or an isobutyl group, respectively, in place of the phenmethyl group on the polypeptide nucleus. Ergoloid mesylates occurs as a white to off-white, practically odorless, microcrystalline or amorphous powder and is slightly soluble in water and soluble in alcohol.

Stability

Ergoloid mesylates is unstable in the presence of light, moisture, or temperatures above 30°C. Ergoloid mesylates preparations should be stored in tight, light-resistant containers at 15-30°C.

Only references cited for selected revisions after 1984 are available electronically.

100. Aellig WH, Nüesch E. Comparative pharmacokinetic investigations with tritium-labeled ergot alkaloids after oral and intravenous administration in man. Int J Clin Pharmacol . 1977; 15:106-12.

101. Woodcock BG, Loh W, Habedank WD et al. Dihydroergotoxine kinetics in healthy men after intravenous and oral administration. Clin Pharmacol Ther . 1982; 32:622-7. [PubMed 7128002]

102. Hollister LE, Yesavage J. Ergoloid mesylates for senile dementias: unanswered questions. Ann Intern Med . 1984; 100:894-8. [PubMed 6372566]

103. van Loveren-Huyben CM, Engelaar HF, Hermans MB et al. Double-blind clinical and psychologic study of ergoloid mesylates (Hydergine^®) in subjects with senile mental deterioration. J Am Geriatr Soc . 1984; 32:584-8. [PubMed 6379022]

104. Spiegel R, Huber F, Köberle S. A controlled long-term study with ergoloid mesylates (Hydergine^®) in healthy, elderly volunteers: results after three years. J Am Geriatr Soc . 1983; 31:549-55. [PubMed 6886282]

105. Mutual Pharmaceutical Co., Ergoloid mesylates tablets prescribing information. Philadelphia, PA; 1998 Apr.

106. Schneider LS, Olin JT. Arch Neurol . 1994; 51:787-98.

107. Olin J, Schneider L, Novit A, Luczak S. Hydergine for dementia (Cochrane Review). In: The Cochrane Library . Issue 4, 2003. Chichester, UK: John Wiley & Sons, Ltd.

108. Doody RS, Stevens JC, Beck C et al. Practice parameter: management of dementia (an evidence-based review). Report of the quality standards subcommittee of the American Academy of Neurology. Neurology . 2001; 56:1154-66. [PubMed 11342679]

109. Thompson TL, Filley CM, Mitchell WD et al. Lack of efficacy of hydergine in patients with Alzheimer's disease. N Engl J Med . 1990; 323:445-8. [PubMed 2082953]

110. Shadlen MF, Larson EB. What's new in Alzheimer's disease treatment? Reasons for optimism about future pharmacologic options. Postgrad Med . 1999; 105:109-18. [PubMed 9924498]

111. Green RC. Ergoloid mesylates for dementia. From the medscape website. Posted to website 2003 Dec 12. Accessed 2004 Jan 2. [Web]