Restricted sedation and absence of cognitive impairments after administration of intranasal scopolamine.

INTRODUCTION: Space motion sickness in astronauts during spaceflight causes significant discomfort, which might impede their functionality. Pharmacological treatment has been mainly restricted to promethazine. Transdermal and oral scopolamine have also been used in space; however, their use was reduced due to unpredictable effectiveness and side effects. Recently, intranasal scopolamine administration has gained much interest, since this route ensures fast and reliable absorption with a decreased incidence of undesirable side effects. The aim of this study was to evaluate the effect of intranasal scopolamine on cognitive performance and to determine its side effects. METHODS: This double-blind, placebo controlled, repeated measures study evaluated vigilant attention, short-term memory, implicit memory and working memory. Side effects were reported on a 22-item questionnaire and sleepiness was assessed by the Karolinska, Stanford and Epworth Sleepiness Scales. RESULTS: Scopolamine had no effect on cognitive function. Only the Karolinska score was significantly increased for scopolamine compared to placebo. Participants reported a dry mouth and dizziness after receiving scopolamine. DISCUSSION: Results show that intranasal scopolamine did not impair cognitive performance. Intranasal scopolamine might be a good alternative to promethazine for the alleviation of space motion sickness, since the agent has minimal sedative effects and does not hamper cognitive performance.

Intranasal scopolamine affects the semicircular canals centrally and peripherally.

Space motion sickness (SMS), a condition caused by an intravestibular conflict, remains an important obstacle that astronauts encounter during the first days in space. Promethazine is currently the standard treatment of SMS, but scopolamine is used by some astronauts to prevent SMS. However, the oral and transdermal routes of administration of scopolamine are known to have substantial drawbacks. Intranasal administration of scopolamine ensures a fast absorption and rapid onset of therapeutic effect, which might prove to be suitable for use during spaceflights. The aim of this study was to evaluate the effects of intranasally administered scopolamine (0.4 mg) on the semicircular canals (SCCs) and the otoliths. This double-blind, placebo-controlled study was performed on 19 healthy male subjects. The function of the horizontal SCC and the vestibulo-ocular reflex, as well as the saccular function and utricular function, were evaluated. Scopolamine turned out to affect mainly the SCCs centrally and peripherally but also the utricles to a lesser extent. Centrally, the most probable site of action is the medial vestibular nucleus, where the highest density of muscarinic receptors has been demonstrated and afferent fibers from the SCCs and utricles synapse. Furthermore, our results suggest the presence of muscarinic receptors in the peripheral vestibular system on which scopolamine has a suppressive effect. Given the depressant actions on the SCCs, it is suggested that the pharmacodynamic effect of scopolamine may be attributed to the obliteration of intravestibular conflict that arises during (S)MS.

Space motion sickness countermeasures: a pharmacological double-blind, placebo-controlled study.

INTRODUCTION: Space motion sickness (SMS), caused by a canal-otolith conflict, is currently treated with intramuscular promethazine. However, the drug has an inconsistent efficacy against SMS. We hypothesize that pharmacological depression of the semicircular canals (SCC) might relieve SMS. The aim of the present study was to identify the effects of meclizine (25 mg), dimenhydrinate (40 mg) combined with cinnarizine (25 mg), and promethazine (25 mg) combined with d-amphetamine (10 mg) on the SCCs and the otoliths. METHODS: This double-blind, placebo-controlled study was performed on 20 healthy men. Function of the SCC was evaluated by means of an electronystagmography, whereas utricular function was assessed by a unilateral centrifugation test. A cervical vestibular evoked myogenic potentials test evaluated saccular function. RESULTS: Meclizine (0.54 +/- 0.05 vs. 0.38 +/- 0.06) and dimenhydrinate with cinnarizine (0.54 +/- 0.05 vs. 0.45 +/- 0.05) decreased the vestibulo-ocular reflex gain. Promethazine with d-amphetamine decreased the latency of the saccadic eye response (right eye: 185 +/- 3.8 ms vs. 165 +/- 4.5 ms; left eye: 181 +/- 4.9 ms vs. 165 +/- 4.8 ms) and also increased the phase of ocular counterrolling measured during unilateral centrifugation (0.32 +/- 0.35 degrees vs. 1.5 +/- 0.45 degrees). DISCUSSION: It is hypothesized that meclizine and dimenhydrinate with cinnarizine affect the medial vestibular nucleus. Promethazine is a vestibular suppressor, but study results show that d-amphetamine counterbalances this depression and abolishes the effect of fatigue on the saccadic reaction time The hypothesis that a SCC-suppression alleviates SMS should be further evaluated.

Baclofen affects the semicircular canals but not the otoliths in humans.

CONCLUSION: This study showed that GABAB agonist baclofen (10 mg) affects the semicircular canals (SCCs), both centrally and peripherally, but does not influence the otolithic function. OBJECTIVES: The aim of the study was to identify the effects of baclofen on the complete vestibular system, i.e. semicircular canals, saccules and utricles. METHODS: The study had a double-blind, placebo-controlled, repeated measures design and was conducted on healthy male volunteers. With electronystagmography (ENG), the SCC function was evaluated, whereas utricular function was determined by means of unilateral centrifugation (UC). Cervical vestibular evoked myogenic potentials (cVEMPs) tested saccular integrity. RESULTS: Baclofen caused a significant increase of the vestibulo-ocular reflex (VOR) phase and a significant decrease of the total caloric response (TCR), both measured during ENG. The drug also decreased the maximal contribution of the SCCs to ocular counter-rolling (OCR) evaluated during UC. No effects on saccules and utricules were observed.

Pharmaceutical countermeasures have opposite effects on the utricles and semicircular canals in man.

INTRODUCTION: Sensory conflicts in the vestibular system lead to motion sickness of which space motion sickness (SMS) is a special case. SMS affects up to 70% of the astronauts during the first 3 days in space. The search for effective countermeasures has led to several nonpharmacological and pharmacological approaches. The current study focuses on the effects of lorazepam (1 mg), meclizine (25 mg), promethazine (25 mg), and scopolamine (0.4 mg) on the vestibular system, with special focus on the canal and otolith functions separately. METHODS: The study had a placebo-controlled, single blind, repeated measures design. Sixteen healthy volunteers were subjected to a total of 7 test sessions, the first and last being without intake of medication. Semicircular canal function was evaluated by means of electronystagmography and otolith function with unilateral centrifugation. The horizontal semicircular canal function was characterized by the vestibulo-ocular reflex (VOR) gain measured during earth vertical axis rotation as well as the total caloric response. The function of the utricles was represented by the utricular sensitivity, reflecting the ocular counter roll relative to the virtual induced head tilt. RESULTS: Promethazine significantly decreased the semicircular canal and utricular parameters. Both scopolamine and lorazepam caused only a decrease in the utricular sensitivity, whereas meclizine only decreased the semicircular canal-induced VOR gain. DISCUSSION: The results show that the drugs affected different areas of the vestibular system and that the effects can thus be attributed to the specific pharmacological properties of each drug. Meclizine, as an antihistaminergic and weak anticholinergic drug, only affected the VOR gain, suggesting a central action on the medial vestibular nucleus. The same site of action is suggested for the anticholinergic scopolamine since acetylcholine receptors are present and utricular fibers terminate here. The global vestibular suppression caused by promethazine is probably a consequence of its anticholinergic, antihistaminergic, and antidopaminergic properties. Based on the fact that lorazepam increased the affinity of gamma-aminobutyric acid (GABA) for the GABA(A)-receptor and its effects on the utriculi, the site of action seems to be the lateral vestibular nucleus. CONCLUSION: Meclizine, scopolamine, and lorazepam selectively suppress specific parts of the vestibular system. Selective suppression of different parts of the vestibular system may be more beneficial for alleviating (space) motion sickness than general suppressive agents. Additionally, this knowledge may help the clinician in his therapeutic management of patients with either semicircular canal or otolith dysfunction.