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Co-Dergocrine Mesylate

A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Use in Age-Related Cognitive Decline

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Abstract

Synopsis

Co-dergocrine mesylate is a combination of the mesylated forms of dihydroergocornine, di-hydroergocristine, dihydro-α-ergocryptine and dihydro-β-ergocryptine. In animal models and healthy elderly volunteers the compound improves indices of cognitive function such as memory and learning.

The mechanism(s) behind such action remains under investigation. Nonetheless, it has been proposed that co-dergocrine mesylate has a dual effect on central monoaminergic neurotransmitter systems, compensating for both hyperactivity and deficits of the adrenergic, serotoninergic and dopaminergic systems. The compound also appears to have a normalising effect on the power of electroencephalogram frequencies, and may improve cerebral metabolism.

Results from controlled studies of elderly patients with age-related cognitive decline have established that co-dergocrine mesylate is well tolerated and, in some studies, had statistically significant positive effects on symptoms of cognitive dysfunction. However, there is considerable controversy over the clinical relevance of these results as there was wide variability in the number and type of cognitive and neuropsychological assessments used in individual studies and there may have been considerable overlap in diagnosis of patients with varying degrees of dementia. In addition, the drug has not been compared with most other, more recently developed, centrally active agents. Thus, the specific place of co-dergocrine mesylate in the treatment of age-related cognitive decline remains undetermined, despite many years of clinical use.

Pharmacodynamic Properties

Co-dergocrine mesylate is a combination of the mesylated forms of the 4 dihydrogenated ergot alkaloid derivatives, dihydroergocornine, dihydroergocristine, dihydro-a-ergocryptine and dihydro-β-ergocryptine in the ratio 3: 3: 2: 1, and has direct action at α-adrenergic, dopamine and serotonin (5-HT) receptors. Although the mechanism of action of co-dergocrine mesylate has yet to be established conclusively, it appears to have a normalising effect on central monoaminergic neurotransmitter systems in elderly patients, compensating for under- and over-activity of the adrenergic, serotoninergic and dopaminergic systems. The compound has marked pre- and postsynaptic α-adrenoceptor antagonist activity, with higher affinity for α2- than α1-receptors, and has mixed agonist/antagonist effects at dopamine D1- and D2-receptors and at serotoninergic (5-HT1 and 5-HT2) receptors. Co-dergocrine mesylate also has a positive effect on cerebral metabolism and synaptic activity.

In animal models designed to evaluate parameters of learning and memory co-dergocrine mesylate administration has been associated with improved spatiotemporal performance, and enhanced habituation of exploratory activity and motor activity. In healthy elderly volunteers and elderly patients, co-dergocrine mesylate administration increased the power of electroence-phalographic (EEG) alpha and/or beta activity and decreased that of the lower delta and theta frequency bands. Improved availability of cognitive processing resources was also demonstrated by the augmentation of the P300 amplitude in elderly volunteers. However, long term co-dergocrine mesylate administration had no statistically significant effect on cognitive function of healthy volunteers.

Pharmacokinetic Properties

Approximately 25% of an orally administered co-dergocrine mesylate dose is absorbed in humans. Peak plasma concentrations of 0.5 to 1.2 μg/L are typically achieved within 0.5 to 2.3 hours of oral administration of doses of 1 to 6mg and plasma elimination half-life ranges between 1.5 and 4.1 hours. Co-dergocrine mesylate is eliminated mainly via biliary excretion although small amounts have been detected in the urine. In healthy elderly subjects total plasma clearance is reduced by approximately 30% compared with younger adults and there is a 2.5-fold increase in bioavailability, possibly as a result of a reduced extraction ratio.

Therapeutic Efficacy in Age-Related Cognitive Decline

Previous reviews of controlled studies have suggested that co-dergocrine mesylate 3 to 4.5 mg/day has a statistically significant and consistent effect on the symptoms of age-related cognitive decline although there has been some dispute over the clinical relevance of these findings.

Evidence from a meta-analysis of 49 placebo-controlled studies conducted over the past 3 decades confirms the findings of earlier reviews, although results suggest that in patients with dementia co-dergocrine mesylate has a greater effect on behaviour than cognitive performance. Findings from those placebo-controlled studies conducted over the past decade have been less consistent. Investigators have reported varying effects on the key symptoms of cognitive dysfunction (recent memory impairment, mental dullness, confusion, disorientation and lack of self care). Several investigators also noted statistically significant improvements in some symptoms of agitation/ irritability, mood depression, withdrawal and deterioration in health, although actual quantitative changes were small. These variations in results have done little to resolve the controversy over the effectiveness of co-dergocrine mesylate therapy in patients with age-related cognitive decline. Also confounding attempts to evaluate the efficacy of co-dergocrine mesylate have been: the lack of a generally accepted diagnosis of age-related cognitive decline during the period in which most of the studies were conducted; the similarity in symptoms of patients with age-related cognitive decline and those of patients with early signs of Alzheimer’s disease; and, the lack of comparisons with most other purportedly useful agents. While co-dergocrine mesylate has some statistically significant beneficial effects on the key symptoms of cognitive dysfunction in some patients with mild-to-moderate dementia, and it is possible that senile dementia of the Alzheimer type is a continuum of mild-to-moderate dementia, further research is required to determine whether the compound has a significant effect on cognitive function in patients with a diagnosis of senile dementia of the Alzheimer type.

Tolerability

Co-dergocrine mesylate has been well tolerated in clinical studies. Gastrointestinal disturbances (nausea, gastric upset, anorexia, abdominal pain and vomiting) were the most frequently reported unwanted effects. Dizziness, headache, nasal stuffiness, precordial discomfort, drowsiness, sleep disorders, and restlessness occurred in less than 3% of participants in nonblind studies. The frequency of reported adverse events decreases markedly during continued therapy.

Dosage and Administration

For long term therapy of mild-to-moderate symptoms of age-related cognitive decline the usual dosage of co-dergocrine mesylate (administered orally) ranges from 1 to 1.5mg 3 times daily, although daily dosages of up to 13.5mg have been administered in clinical studies.

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    Alison N. Wadworth & Paul Chrisp

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  1. Alison N. Wadworth
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Various sections of the manuscript reviewed by: J, Cummings, Laboratory of Neuroimaging, UCLA School of Medicine, Los Angeles, California, USA; M. Freedman, Baycrest Center for Geriatric Care, North York, Ontario, Canada; K. Ghose, Department of Pharmacology, University of Otago Medical School, Dunedin, New Zealand; M. Gordon, Baycrest Center for Geriatric Care, North York, Ontario, Canada; J.S. Meyer, Cerebrovascular Research Laboratories, Baylor College of Medicine, Houston, Texas, USA; B.J. Sahakian, Department of Experimental Psychiatry, University of Cambridge, Cambridge, England; B. Saletu, Division of Pharmacopsychiatry/ Sleep Laboratory, Psychiatric University Clinic of Vienna, Vienna, Austria; O.J. Thienhaus, Division of Geriatric Psychiatry, University of Cincinnati Medical Center, Cincinnati, Ohio, USA; Y. Wolmark, Hôpital Sainte Perine, Paris, France.

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Wadworth, A.N., Chrisp, P. Co-Dergocrine Mesylate. Drugs & Aging 2, 153–173 (1992). https://doi.org/10.2165/00002512-199202030-00002

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