Carlos R. Gordon

Transdermal scopolamine for prevention of motion sickness : clinical pharmacokinetics and therapeutic applications.

A transdermal therapeutic system for scopolamine (TTS-S) was developed to counter the adverse effects and short duration of action that has restricted the usefulness of scopolamine when administered orally or parenterally. The plaster contains a reservoir of 1.5mg of scopolamine programmed to deliver 0.5mg over a 3-day period. A priming dose (140μg) is incorporated into the adhesive layer to saturate certain binding sites within the skin and to accelerate the achievement of steady-state blood levels. The remainder is released at a constant rate of approximately 5 μg/hour. The protective plasma concentration of scopolamine is estimated to be 50 pg/mL. TTS-S attains that concentration after 6 hours; a steady state of about 100 pg/mL is achieved 8–12 hours after application. Yet 20–30% of subjects failed to attain the estimated protective concentration, and plasma concentrations measured in subjects who failed to respond to TTS-S were lower than in responders. These findings may explain some of the treatment failures. Overall, the product appears to be the approximate functional equivalent of a 72-hour slow intravenous infusion. A combination of transdermal and oral scopolamine (0.3 or 0.6mg) was effective and well tolerated in producing desired plasma concentrations 1-hour post-treatment.TTS-S has proved to be significantly superior to placebo in reducing the incidence and severity of motion sickness by 60–80%. It was more effective than oral meclizine or cinnarizine, similar to oral scopolamine 0.6mg or promethazine plus ephedrine, and the same as or superior to dimenhydrinate. The addition of ephedrine or the use of two patches did not improve its efficacy, but rather increased the rate of adverse effects. TTS-S was most effective against motion sickness 8–12 hours after application. Despite previous evidence to the contrary, a recent bioavailability study demonstrated similar intraindividual absorption and sustained clinical efficacy with long-term use of the drug.The adverse effects produced by TTS-S, although less frequent, are qualitatively typical of those reported for the oral and parenteral formulations of this agent. Dry mouth occurs in about 50–60% of subjects, drowsiness in up to 20%, and allergic contact dermatitis in 10%. Transient impairment of ocular accommodation has also been observed, in some cases possibly the result of finger-to-eye contamination. Low-dose pyridostigmine was found effective in preventing cycloplegia but not mydriasis. Adverse CNS effects, including toxic psychosis (mainly in elderly and paediatric patients), have been reported only occasionally, as have difficulty in urinating, headache, rashes and erythema. Adverse effects were not correlated with plasma scopolamine concentrations. TTS-S produced only about half the incidence of drowsiness caused by oral dimenhydrinate or cinnarizine, and a level of adverse effects similar to that found with oral meclizine. Performance is not affected by short-term use. Prolonged or repeated application may cause some impairment of memory storage for new information. However, sea studies revealed significantly less reports of a decrement in performance or drowsiness due to prevention of sea sickness.The recommended dosage is a single TTS-S patch applied to the postauricular area at least 6–8 hours before the anti-motion sickness effect is required. For faster protection, the patch may be applied 1 hour before the journey in combination with oral scopolamine (0.3 or 0.6mg). After 72 hours, the patch should be removed and a new one applied behind the opposite ear. Its place in therapy is mainly on long journeys (6–12 hours or longer), to avoid repeated oral doses, or when oral therapy is ineffective or intolerable.

Mal de Debarquement and Posture: Reduced Reliance on Vestibular and Visual Cues

Objective The neural mismatch theory assumes that the intersensory conflicts leading to motion sickness are resolved by changes in the relative weighting of the various senses that contribute to orientation. If this sensory rearrangement persists after disembarkment, it might result in mal de debarquement (MD): ataxia and a rocking sensation sometimes felt after landing. The objective of the present study was to examine possible changes in sensory organization in naval crew members with differing susceptibility to MD with computerized dynamic posturography (CDP).

The effects of dimenhydrinate, cinnarizine and transdermal scopolamine on performance

We assessed the influence of dimenhydrinate, cinnarizine and transdermal scopolamine on the ability to perform simulated naval crew tasks. The effect of single doses of dimenhydrinate, 100 mg, cinnarizine, 50 mg, and one transdermal scopolamine patch on psychomotor performance was evaluated using a double-blind, placebo-controlled, randomized, crossover design in three separate studies. A total of 60 young naval crew (20 for dimenhydrinate, 15 for cinnarizine and 25 for transdermal scopolamine) underwent a battery of computerized and paper and pencil performance tests, and filled out a questionnaire on side-effects and well-being self-assessment. Dimenhydrinate significantly impaired decision reaction time and auditory digit span. Most of the subjects who took dimenhydrinate also reported a subjective decrease in well-being and general performance abilities. Cinnarizine and transdermal scopolamine did not affect performance abilities. Cinnarizine was free of significant side-effects. Dry mouth was the only significant side-effect of transdermal scopolamine. These findings could be explained by the well-known sedative properties of dimenhydrinate and not by a specific effect on any particular cognitive or motor function. Our results suggest that dimenhydrinate, 100 mg, adversely affects psychomotor function, whereas single doses of cinnarizine, 50 mg, and transdermal scopolamine appear to be free of side-effects on performance and seem to be a preferable anti-seasickness drug for use by a naval crew.

Inner Ear Decompression Sickness in Sport Compressed-Air Diving

Objective We report our experience over the past 12 years with recreational diving‐related inner ear decompression sickness (IEDCS).

Diving-related inner ear injuries

Diving-related inner ear barotrauma (IEB) and inner ear decompression sickness (IEDS) most often result in permanent severe cochleovestibular deficits, unless immediate diagnosis is reached and the correct treatment is commenced early. Nine cases of sport-diving-induced inner ear injuries that were referred to the Israeli Naval Hyperbaric Institute between October 1987 and September 1989 are presented with regard to evaluation, treatment, and follow-up. The diagnosis was IEB in five divers and IEDS in four. Explorative tympanotomy was carried out with remarkable results in two patients with IEB, while the remaining three were relieved by bed rest alone. Three of the four IEDS patients were recompressed according to the extended US Navy Table 6 with good short-term results. The role of complete otoneurological evaluation in the decision-making process leading to the correct diagnosis and treatment is emphasized.

Performance of cervical motion in chronic whiplash patients and healthy subjects: the case of atypical patients.

Study Design. A comparative study of cervical motion performance in chronic whiplash (CW) patients and healthy subjects. Objectives. To examine the efficiency of total cervical range of motion (TCROM), which consists of the combined score of all six primary movements and their mean coefficient of variation (MCV), in differentiating CW patients from healthy subjects as well as typical from atypical patients. Additionally to explore in the patients possible relationships between their cervical motion profile and functional and personality traits. Summary of Background Data. Previous studies revealed that cervical motion was an efficient discriminator between healthy and CW patients. However, none of these studies provided either guidelines regarding cutoff scores or insight as to what should be considered typical compared with atypical patient with respect to cervical motion performance. Methods. Cervical motion was measured in 75 healthy subjects and 101 CW patients in each of the six primary movements. In addition, patients filled the functional neck disability index (NDI) and personality symptom check list (SCL-R-90) questionnaire. Results. Total CROM was significantly lower and the MCV was significantly higher in patients compared with healthy subjects. Age and gender affected TCROM significantly in both groups while MCV remained unaffected, respectively. Atypical patients were identified by having a TCROM < 58° and or MCV > 22%, both scores corresponding to 2 SDs below and above group means, respectively. These benchmarks resulted in classifying as atypical 6% of the CW group who also scored drastically higher in the NDI and SCL-R-90 questioners. Conclusions. Using MCV and TCROM adds new insight regarding what should be considered as atypical cervical motion profile in CW patients. Several aspects of this complex clinical entity are discussed.

Alterations in R-R variability associated with experimental motion sickness

Motion sickness is a complex integration of responses from multiple physiological systems. Whether the changes that occur during the time course of motion sickness are mediated by the sympathetic or parasympathetic systems is still controversial. The present study evaluates alterations in R-R variability during experimental motion sickness in motion sick and non-motion sick subjects. Ten motion sick subjects and 7 non-motion sick subjects participated in the study. Power spectrum analysis of R-R variation was conducted for all subjects 10 min before a brief vestibular disorientation test (BVDT), for 5-10 min of the test, and 10 min after the test. Subjects were also asked to report their symptoms during the test. The motion sick group showed a significant reduction in the power spectrum density of the R-R interval at the mid and high frequencies during the BVDT test period (BVDT), in comparison with the rest period (Rest). These changes probably indicate a decrease in parasympathetic activity during the time course of motion sickness. The non-motion sick group did not show significant differences at any of the frequencies during BVDT. Power spectrum analysis of the R-R interval provides an objective measure of the autonomic response to experimental motion sickness.

Vestibular Findings Associated with Chronic Noise Induced Hearing Impairment

Histological and functional derangements of the vestibular system have been reported in laboratory animals exposed to high levels of noise. However, clinical series describe contradictory results with regard to vestibular disturbances in industrial workers and military personnel suffering from noise induced hearing loss (NIHL). The purpose of the present study was to evaluate vestibular function in a group of subjects with documented NIHL, employing electronystagmography (ENG) and the smooth harmonic acceleration (SHA) test. Subjects were 22 men suffering from NIHL and 21 matched controls. Significantly lower vestibulo-ocular reflex gain (p = 0.05), and a tendency towards decreased caloric responses were found in the study group. No differences in the incidence of vertigo symptoms, spontaneous, positional and positioning nystagmus, directional preponderance and canal paresis in the ENG, or the SHA test phase and asymmetry parameters were observed between the groups. These results demonstrated a symmetrical centrally compensated decrease in the vestibular end organ response which is associated with the symmetrical hearing loss measured in the study group. Statistically significant correlations were found between the average hearing loss, the decrement in the average vestibulo-ocular reflex gain (p = 0.01), and ENG caloric lateralization (p = 0.02). These correlations might indicate a single mechanism for both cochlear and vestibular noise-induced injury. The results imply subclinical, well compensated malfunction of the vestibular system associated with NIHL.

Vestibulo-Ocular Reflex as a Parameter of Seasickness Susceptibility

The vestibulo-ocular reflex (VOR) is known to be modulated in response to changing vestibular and optokinetic stimuli. The purpose of this study was to investigate possible relationships between VOR and future susceptibility and habituation to seasickness. Thirty candidates for future maritime service were exposed to a series of yaw axis smooth harmonic accelerations before and after 6 months of regular sailing, and their VOR gain and phase responses were recorded. Seasickness severity was estimated after 1 and 6 months of service by a questionnaire. We conclude that VOR gain at 0.01 Hz may serve as a physiologic correlate helping to predict seasickness susceptibility, and that the increase in phase lead at 0.02 Hz may mark the habituation process to sea conditions.

Cinnarizine in the prophylaxis of seasickness: laboratory vestibular evaluation and sea study.

Cinnarizine was evaluated for the prevention of seasickness in a laboratory and sea study. The effects of 25 mg cinnarizine on the vestibulo‐ocular reflex were investigated in 13 subjects. Significant reduction of the gain in response to sinusoidal oscillations at 0.02, 0.08, and 0.16 Hz (p < 0.05) and increased phase lead at 0.16 Hz (p < 0.01) were observed. The effect of 25 and 50 mg cinnarizine on seasickness severity was examined in 95 subjects during a voyage in rough seas. Seasickness symptoms were improved in 69% of the subjects by 50 mg cinnarizine versus 35% and 31% in the groups receiving 25 mg cinnarizine and placebo (p < 0.05 and p < 0.01, respectively). The percentage of vomiting protection provided by 50 mg cinnarizine was 63% (p < 0.05). We conclude that 50 mg cinnarizine is an effective drug for the prevention of seasickness. The reduction in vestibular sensitivity observed even after administration of 25 mg cinnarizine may explain the potency of cinnarizine in the prevention of seasickness.