Dose escalation pharmacokinetics of intranasal scopolamine gel formulation.

Astronauts experience Space Motion Sickness requiring treatment with an anti-motion sickness medication, scopolamine during space missions. Bioavailability after oral administration of scopolamine is low and variable, and absorption form transdermal patch is slow and prolonged. Intranasal administration achieves faster absorption and higher bioavailability of drugs that are subject to extrahepatic, first pass metabolism after oral dosing. We examined pharmacokinetics of 0.1, 0.2, and 0.4 mg doses of the Investigational New Drug formulation of intranasal scopolamine gel (INSCOP) in 12 healthy subjects using a randomized, double-blind cross-over study design. Subjects received one squirt of 0.1 g of gel containing either 0.1 mg or 0.2 mg/0.1 mL scopolamine or placebo in each nostril. Serial blood samples and total urine voids were collected after dosing and drug concentrations were determined using a modified LC-MS-MS method. Results indicate dose-linear pharmacokinetics of scopolamine with linear increases in Cmax and AUC within the dose range tested. Plasma drug concentrations were significantly lower in females than in males after administration of 0.4 dose. All three doses were well tolerated with no unexpected or serious adverse side effects reported. These results suggest that intranasal scopolamine gel formulation (INSCOP) offers a fast, reliable, and safe alternative for the treatment of motion sickness.

Evaluation of physical and chemical changes in pharmaceuticals flown on space missions.

Efficacy and safety of medications used for the treatment of astronauts in space may be compromised by altered stability in space. We compared physical and chemical changes with time in 35 formulations contained in identical pharmaceutical kits stowed on the International Space Station (ISS) and on Earth. Active pharmaceutical content (API) was determined by ultra- and high-performance liquid chromatography after returning to Earth. After stowage for 28 months in space, six medications aboard the ISS and two of matching ground controls exhibited changes in physical variables; nine medications from the ISS and 17 from the ground met the United States Pharmacopeia (USP) acceptance criteria for API content after 28 months of storage. A higher percentage of medications from each flight kit had lower API content than the respective ground controls. The number of medications failing API requirement increased as a function of time in space, independent of expiration date. The rate of degradation was faster in space than on the ground for many of the medications, and most solid dosage forms met USP standard for dissolution after storage in space. Cumulative radiation dose was higher and increased with time in space, whereas temperature and humidity remained similar to those on the ground. Exposure to the chronic low dose of ionizing radiation aboard the spacecraft as well as repackaging of solid dosage forms in flight-specific dispensers may adversely affect stability of pharmaceuticals. Characterization of degradation profiles of unstable formulations and identification of chemical attributes of stability in space analog environments on Earth will facilitate development of space-hardy medications.

Joint modeling of performance and subjective reporting to assess sensitivity to drug-induced sleepiness.

In an NASA ground study, two forms of cognitive tests were evaluated in terms of their sensitivity to sleepiness induced by the drug promethazine (PMZ). Performance for the two test modes (Y(1) and Y(2)), PMZ concentration, and a self-reported sleepiness using the Karolinska Sleepiness Scale (KSS) were monitored for 12 h post dose. A problem arises when using KSS to establish an association between true sleepiness and performance because KSS scores are discrete and also because they tend to concentrate on certain values. Therefore, we define a latent sleepiness measure X as an unobserved continuous random variable describing a subject's actual state of sleepiness. Under the assumption that drug concentration affects X, which then affects Y(1), Y(2), and KSS, we use Bayesian methods to estimate joint equations that permit unbiased comparison of the performance measures' sensitivity to X. The equations incorporate subject random effects and include a negativity constraint on subject-specific slopes of performance with respect to sleepiness.

The efficacy of low-dose intranasal scopolamine for motion sickness.

INTRODUCTION: Scopolamine is an effective motion sickness prophylactic, but oral and transdermal formulations are slowly absorbed. To enhance absorption and potentially efficacy, an intranasal formulation of scopolamine (INSCOP) was tested. METHOD: There were 16 motion sickness susceptible subjects with an average age of 23.5 +/- 3.0 yr and an average score of 11.3 +/- 4.7 on the Modified Motion Sickness Susceptibility Questionnaire-Short Form who volunteered to participate in the study. Each subject was given 0.4 mg of INSCOP and a placebo in a randomized, double-blind crossover design and, at 40 min post-dose, experienced Coriolis cross-coupling in a staircase progression until moderate nausea. Efficacy data and cognitive, physiological, and alertness assessments were collected during baseline control and throughout experimental testing. RESULTS: Intranasal scopolamine significantly increased the mean number of head movements tolerated [INSCOP 275.9 +/- 120.5, Placebo 230.7 +/- 76.4; t (15) = 2.21]. Estimation of medication absorption via plasma concentration indicated the drug was absorbed relatively rapidly to measurable levels by 15 min post-administration. Diastolic blood pressures and heart rate were significantly lower after administration of INSCOP compared to placebo. No significant cognitive or medication side effects were reported. Subjects reported no significant decrease in alertness as indicated by the Karolinska Sleepiness Scale. CONCLUSIONS: Results of the current study strongly suggest that intranasal scopolamine is efficacious for the treatment of motion sickness in susceptible individuals with no significant cognitive or sedative effects. Intranasal delivery offers a promising alternative for use in dynamic operational environments without cognitive detriment or increased side effects.

Relative bioavailability of scopolamine dosage forms and interaction with dextroamphetamine.

The NASA Reduced Gravity Office (RGO) uses scopolamine (SCOP) alone and in combination with dextoamphetamine (DEX) to treat motion sickness symptoms during DC-9 parabolic flights. The medications are sometimes dispensed as custom dosage forms in gelatin capsules for convenience. Reports of treatment failure during flights by the flight surgeons suggest that these formulations may be less efficacious for the treatment of motion sickness due to unreliable and inadequate bioavailability. We estimated bioavailability of four different oral formulations used by the NASA RGO physicians for the treatment of motion sickness.

Characterization of selective estrogen receptor modulator (SERM) activity in two triarylethylene oxybutyric acids.

Previously we identified 4-[1-(4-hydroxyphenyl)-2-phenylbuten-1-yl]phenoxy-n-butyric acid (4HBA) and its des-hydroxy analog (BA) as potential selective estrogen receptor modulators (SERMs) in the ovariectomized (OVX) rat. The aim of the present study was to characterize comprehensively the effects of 4HBA and BA in both the OVX rat and in estrogen-responsive cells. Thus, 4HBA was found to be an estrogen antagonist with partial agonist efficacy in estrogen-responsive reporter gene and estrogen-dependent proliferation assays (MVLN cells and MCF-7 human breast cancer cells, respectively). In the OVX rat, 4HBA and BA were equally effective and comparable to other known SERMs regarding (a) serum cholesterol reduction and suppression of serum markers of excessive bone metabolism, and (b) partial agonist efficacy in reproductive tissue relative to steroidal estrogens. Like steroidal estrogens, both compounds increased serum triglyceride levels, with BA being more effective in this regard. The maximal effects of 4HBA on all of these parameters except cholesterol lowering were seen at oral doses of 0.4 micromol/kg/day; maximal cholesterol lowering required doses of 10 micromol/kg/day. In OVX rat liver 9S fraction, BA was found to be efficiently converted to a single hydroxylated metabolite, 4HBA. These results suggest that the effects of BA in the OVX rat might, in part, be a consequence of biotransformation to 4HBA, and that those of 4HBA and BA in the OVX rat and in estrogen-responsive cells are qualitatively similar to those of SERMs such as tamoxifen and raloxifene.