Comparison of pramipexole with and without domperidone co‐administration on alertness, autonomic, and endocrine functions in healthy volunteers

• Published in: British journal of clinical pharmacology Vol. 64; no. 5; pp. 591 - 602
• Main Authors: Samuels, Ebony R., Hou, Ruihua H., Langley, Robert W., Szabadi, Elemer, Bradshaw, Christopher M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.11.2007; Blackwell Science; Blackwell Science Inc
• Subjects: Adolescent; Adult; alertness; Autonomic Nervous System - drug effects; Benzothiazoles - administration & dosage; Benzothiazoles - pharmacology; Biological and medical sciences; darkness reflex; domperidone; Domperidone - administration & dosage; Domperidone - pharmacology; Dopamine Antagonists - administration & dosage; Dopamine Antagonists - pharmacology; Dose-Response Relationship, Drug; Endocrine System - drug effects; Humans; light reflex; Male; Medical sciences; Neuropharmacology; Pharmacodynamics; Pharmacology. Drug treatments; pramipexole; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Psychophysiology; pupil; Pupil - drug effects; Reflex, Pupillary - drug effects; Treatment Outcome; Human; Reflex; Darkness; Agonist; Drug combination; Domperidone; Endocrine gland; Healthy subject; Dopamine antagonist; light reflex; Neuroprotective agent; Antiparkinson agent; Pramipexole; Endocrine secretion; Pupil; alertness; D2 Dopamine receptor; Autonomic nervous system; darkness reflex; Light; Dopamine agonist; Antiemetic; Comparative study
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/j.1365-2125.2007.02938.x

What is already known about this subject • It is known that the dopamine receptor agonist pramipexole, used for the treatment of Parkinson's disease, often causes nausea that can be treated in patients by the co‐administration of an antiemetic, for example domperidone. • In experimental studies of pramipexole it may be necessary to administer domperidone alongside pramipexole to alleviate nausea, and as such it is necessary to know how the co‐administration of domperidone may alter the observed effects of pramipexole. What this study adds • Results from our study indicate that the co‐administration of pramipexole and domperidone may reduce the likelihood of observing an effect that is present when pramipexole is administered alone. • Although domperidone is mainly a peripherally acting drug, it appears that a high enough concentration of the drug crosses the blood–brain barrier to partially antagonize some of the autonomic actions of pramipexole. • Therefore, this report provides a cautionary note to the use of domperidone alongside pramipexole where the results of interest are those from pramipexole alone. Aims To investigate the effects of the D2‐receptor agonist pramipexole with and without the co‐administration of the peripherally acting D2‐receptor antagonist domperidone on measures of alertness, autonomic and endocrine function. Methods Sixteen male volunteers participated in four weekly sessions of pramipexole 0.5 mg, domperidone 40 mg, their combination, and placebo administered according to a balanced, double‐blind design. Alertness (visual analogue scales (VAS), critical flicker fusion frequency, pupillographic sleepiness test), autonomic (pupil diameter, light and darkness reflexes, blood pressure, heart rate, salivation, temperature) and endocrine (prolactin, thyroid‐stimulating hormone (TSH), growth hormone (GH)) functions were assessed. Data were analyzed with anova with multiple comparisons. Results The pre‐post treatment changes in VAS alertness were reduced by pramipexole with and without domperidone (mean difference from placebo (95% confidence interval), mm): pramipexole −15.75 (−23.38, −8.13), combination −11.84 (−20.77, −2.91). Treatment condition significantly affected pupil diameter measured in different ways (resting pupil diameter (F3,45 = 8.39, P < 0.001), initial diameter of the light reflex response (F3,42 = 3.78, P < 0.05), and light (F3,45 = 5.21, P < 0.005) and dark (F3,45 = 3.36, P < 0.05) diameters of the darkness reflex response). Pramipexole without domperidone consistently increased pupil diameter on all measures (P < 0.05), whereas with domperidone only the increase in resting and dark diameters reached significance. Pramipexole reduced light reflex amplitude and increased latency, whereas the combination affected latency only. Concentrations of prolactin and TSH were increased by domperidone. Pramipexole reduced prolactin and increased GH concentrations. Conclusions The attenuation of the central pupillary effects of pramipexole by domperidone indicates that domperidone had access to some central D2‐receptors.