Randall Lee Kohl

New Pharmacologic Approaches to the Prevention of Space/Motion Sickness

Fundamental approaches in selection of new agents for evaluation in prevention of space/motion sickness (SMS) are reviewed. The discussion centers on drugs under investigation at the Johnson Space Center. Methodology that employs the rotating chair for measuring SMS symptomatology and susceptibility is described. The most obvious approach to the development of new agents relies on selection of agents from drug classes that possess pharmacologic properties of established anti‐motion sickness agents. A second approach selects drugs that are used to prevent emesis caused by means other than exposure to motion. The third approach relies on basic research that characterizes individual differences in susceptibility. The hypothesis is: detection of individual differences leads to identification of specific drugs, which target physiologic systems that show individual differences. These physiologic systems are targets for therapy and may play a role in the etiology of SMS. Two drugs that reduce susceptibility to SMS include dexamethasone and d(CH2)5Tyr(Me)AVP, a vasopressin (AVP)V1 antagonist. The latter peptide has demonstrated complete blockade of emesis and other significant symptoms in squirrel monkeys. These studies were predicated on observations that subjects who were more resistant to SMS had higher plasma AVP after severe nausea than subjects with lower resistances. Investigations are underway to test a 0.5‐mg intravenous dose in humans. Kappa opioid agonists inhibit AVP release and offer new therapeutic possibilities and advantages over AVP peptides. This review details the experimental data collected on AVP and adrenocorticotropic. The literature supports interrelated roles for AVP and opioid peptides in SMS. Experimental testing of kappa agonists is warranted because specific opioid agonists act at neuroanatomical sites causing nausea and vomiting. It is argued opioid receptors in the chemoreceptor trigger zone and vomiting center stimulate and inhibit the emetic response, respectively. The evidence suggests kappa and/or mu receptors at VC are involved in inhibition of emesis, whereas delta opioid receptors at CTZ are involved in stimulation of emesis.

Etiologic significance of arginine vasopressin in motion sickness.

There is abundant evidence implicating the role of arginine vasopressin in motion sickness. The effects of AVP analogs on motion sickness were investigated in squirrel monkeys. Two specific V1 antagonists (SK&F 100273 and SK&F 103561) and three mixed V1/V2 antagonists (SK&F 101926, SK&F 105494, and SK&F 104146‐D) were tested on six highly susceptible monkeys. Intravenous injections of 200 ug of a V1 antagonist abolished emesis in all six monkeys, and few prodromal symptoms remained (latency to emesis > 120 minutes, P < .001). Mixed V1/V2 antagonists failed to abolish emesis in all monkeys. However, there was a slight increase in the latency to the first bout of emesis/retching with the mixed antagonists when compared with the baseline. The dose‐response relationship and rate of onset of action of the V1 antagonists (SK&F 100273) were explored. Latency to the first bout of emesis/retching increased to about twice that of the baseline when half of the effective antiemetic dose was used. The efficacy demonstrated by the specific V1 antagonists indicates that V1 receptors may modulate emesis.

Investigation of Anti‐Motion Sickness Drugs in the Squirrel Monkey

Early attempts to develop an animal model for anti‐motion sickness drugs, using dogs and cats, were unsuccessful. Dogs did not show a beneficial effect of scopolamine (probably the best single anti‐motion sickness drug for humans thus far) and the findings in cats were not definitive. The authors have developed an animal model using the squirrel monkey (Saimiri sciureus) of the Bolivian phenotype. Unrestrained monkeys in a small lucite cage were tested in an apparatus that induces motion sickness by combining vertical oscillation and horizontal rotation in a visually unrestricted laboratory environment. Signs of motion sickness were scored using a rating scale. Ten susceptible monkeys (weighing 800–1000 g) were given a total of five tests each, to establish the baseline susceptibility level. Based on the anticholinergic activity of scopolamine, the sensitivity of squirrel monkey to scopolamine was investigated, and the appropriate dose of scopolamine for this species was determined. Then various anti‐motion sickness preparations were administered in subsequent tests: 100 ug scopolamine per monkey; 140 ug dexedrine; 50 ug scopolamine plus 70 ug dexedrine; 100 ug scopolamine plus 140 ug dexedrine; 3 mg promethazine; 3 mg promethazine plus 3 mg ephedrine. All these preparations were significantly effective in preventing motion sickness in the monkeys. Ephedrine, by itself, which is marginally effective in humans, was ineffective in the monkeys at the doses tried (0.3–6. 0 mg). The squirrel monkey appears to be a good animal model for antimotion sickness drugs. Peripherally acting antihistamines such as astemizole and terfenadine were found to be ineffective, whereas flunarizine, and an arginine vasopressin V1 antagonist, showed significant activity in preventing motion sickness.

Elevation of γ-Aminobutyric Acid in Cultured Rat C6 Glioma Cells Following Methionine Supplementation

Methionine is recognized as the most toxic amino acid in various mammalian species investigated (Harper et al., 1970). Serum, liver, and brain levels of glycine and serine are antagonized by excessive methionine intake (Klavins, 1965; Daniel and Waisman, 1969). Both the behavioral and metabolic toxicities of methionine are ameliorated by coadministration of glycine or serine (Benevenga and Harper, 1967; 1970; Girard-Globa et al., 1972; Beaton, 1975). These effects and the metabolic interrelations of methionine are of special interest in the investigation of the neurochemistry of schizophrenia and several other brain disorders. Schizophrenics have been reported to be deficient in two enzymes of one-carbon metabolism: serine hydroxymethyltransferase (L-serine-tetrahydrofolate 5,10-hydroxymethyltransferase, EC 2.1.2.1), and methionine adenosyltransferase (ATP: L-methionine Sadenosyltransferase, EC 2.5.1.6.) (Carl et al., 1978). It appears possible that the unique behavioral reaction of schizophrenics to methionine loads may be related to the diminished levels of these enzymes in their blood cells (Cohen et al., 1974). In relation to our interest in the above problem and basic neurometabolic questions pertaining to it, we have studied changes in amino acid concentrations in cultured rat C6 glioma cells following incubation in media supplemented with methionine, glycine, and serine. We found that intracellular levels of glycine and serine were unaltered by incubation for 6 days in either 0.4 or 1.2 mwmethionine. Changes in most of the remaining amino acids paralleled more closely those changes previously reported for brain than for liver or serum. y-Aminobutyric acid (GABA) was a distinct exception, in that its intracellular concentration doubled whenever excess methionine was present in the medium. Neither glycine nor serine was effective either in elevating intracellular GABA or in diminishing the effect of methionine on levels of GABA.

Facilitation of Adaptation and Acute Tolerance to Stressful Sensory Input by Doxepin and Scopolamine Plus Amphetamine

This work characterizes a new methodologic and pharmacologic approach to control terrestrial and space motion sickness (SMS). The experimental design allowed separate evaluation of drug action on susceptibility and adaptability, and used repeated measures to approximate the chronic stressful motion of microgravity. Daily exposure to cross‐coupled angular acceleration for 5 consecutive days demonstrated that the efficacy of doxepin and scopolamine plus amphetamine in the prevention of autonomic system dysfunction was not only apparent on the first test day (P < .01), but was also evident in the substantially enhanced resistance developed over the 5‐day test period (P < .01) as compared with placebo. This indicates that daily use of these medications does not diminish therapeutic efficacy (tolerance). The efficacy of doxepin was anticipated because it possesses pharmacologic properties similar to those of established anti‐motion sickness drugs. Comparable efficacy after doxepin loading for 4 hours, 3 days, or 21 days suggests a mechanism distinct from its antidepressant effects, possibly related to its potent antihistaminergic actions. Use of doxepin has operational significance to the National Aeronautics and Space Administration, in comparison with current preparations of scopolamine plus amphetamine, because of doxepins minimal impact on cognitive performance, and most importantly, its favorable pharmacokinetic profile, particularly its long half‐life.