Microcapsule-gel formulation of promethazine HCl for controlled nasal delivery: a motion sickness medication.

The current method of choice for astronauts to treat space motion sickness is an intra-muscular injection of promethazine hydrochloride (PMZ HCl) which is invasive and causes considerable local irritation and discomfort at the site of injection. Intra-nasal delivery is considered a feasible alternative route for administration of medications to treat space motion sickness. The purpose of this research is to develop a PMZ HCl formulation that can be administered intra-nasally without irritation (i.e. leukocyte infiltration) in the nasal epithelium when dosed at PMZ HCl concentrations greater than the cytotoxic limit. The biocompatibility of PMZ HCl was tested in vitro and was shown to be cytotoxic at concentrations greater than 10(-5) molar regardless of pH. A controlled-release microencapsulated dosage formulation was developed using spinning disk atomization and release rates for the PMZ HCl microcapsules were determined in phosphate buffered saline. An animal study was conducted to determine the irritation response of rat nasal mucosa when dosed with encapsulated and non-encapsulated PMZ HCl.

Quantitation of promethazine and metabolites in urine samples using on-line solid-phase extraction and column-switching.

A chromatographic method for the quantitation of promethazine (PMZ) and its three metabolites in urine employing on-line solid-phase extraction and column-switching has been developed. The column-switching system described here uses an extraction column for the purification of PMZ and its metabolites from a urine matrix. The extraneous matrix interference was removed by flushing the extraction column with a gradient elution. The analytes of interest were then eluted onto an analytical column for further chromatographic separation using a mobile phase of greater solvent strength. This method is specific and sensitive with a range of 3.75-1400 ng/ml for PMZ and 2.5-1400 ng/ml for the metabolites promethazine sulfoxide, monodesmethyl promethazine sulfoxide and monodesmethyl promethazine. The lower limits of quantitation (LLOQ) were 3.75 ng/ml with less than 6.2% C.V. for PMZ and 2.50 ng/ml with less than 11.5% C.V. for metabolites based on a signal-to-noise ratio of 10:1 or greater. The accuracy and precision were within +/- 11.8% in bias and not greater than 5.5% C.V. in intra- and inter-assay precision for PMZ and metabolites. Method robustness was investigated using a Plackett-Burman experimental design. The applicability of the analytical method for pharmacokinetic studies in humans is illustrated.

Invited review: gender issues related to spaceflight: a NASA perspective.

This minireview provides an overview of known and potential gender differences in physiological responses to spaceflight. The paper covers cardiovascular and exercise physiology, barophysiology and decompression sickness, renal stone risk, immunology, neurovestibular and sensorimotor function, nutrition, pharmacotherapeutics, and reproduction. Potential health and functional impacts associated with the various physiological changes during spaceflight are discussed, and areas needing additional research are highlighted. Historically, studies of physiological responses to microgravity have not been aimed at examining gender-specific differences in the astronaut population. Insufficient data exist in most of the discipline areas at this time to draw valid conclusions about gender-specific differences in astronauts, in part due to the small ratio of women to men. The only astronaut health issue for which a large enough data set exists to allow valid conclusions to be drawn about gender differences is orthostatic intolerance following shuttle missions, in which women have a significantly higher incidence of presyncope during stand tests than do men. The most common observation across disciplines is that individual differences in physiological responses within genders are usually as large as, or larger than, differences between genders. Individual characteristics usually outweigh gender differences per se.

A liquid chromatographic method for the simultaneous determination of promethazine and three of its metabolites in plasma using electrochemical and UV detectors.

A new assay method has been developed for the quantitation of promethazine (PMZ) with a sensitivity and reproducibility as good as any previously reported method. This method is also capable of quantitatively determining three metabolites of PMZ (monodemethylated, sulphoxidated, and monodemethylated sulphoxidated PMZ), which has not been previously described. The method uses high-performance liquid chromatography with amperometric and UV detection simultaneously and requires only one extraction step from serum with chloroform. The method uses trifluoperazine as the internal standard. The limit of detection level for PMZ is 1.0 ng/ml when a 0.2-mL specimen of plasma is assayed. A validation study is also conducted for evaluating the recovery, precision, linearity of response, sensitivity, and selectivity of the method.

Effects of pH and dose on nasal absorption of scopolamine hydrobromide in human subjects.

PURPOSE: The present study was conducted to evaluate the effects of formulation pH and dose on nasal absorption of scopolamine hydrobromide, the single most effective drug available for the prevention of nausea and vomiting induced by motion sickness. METHODS: Human subjects received scopolamine nasally at a dose of 0.2 mg/0.05 mL or 0.4 mg/0.10 mL, blood samples were collected at different time points, and plasma scopolamine concentrations were determined by LC-MS/MS. RESULTS: Following administration of a 0.2 mg dose, the average Cmax values were found to be 262+/-118, 419+/-161, and 488+/-331 pg/ mL for pH 4.0, 7.0, and 9.0 formulations, respectively. At the 0.4 mg dose the average Cmax values were found to be 503+/-199, 933+/-449, and 1,308+/-473 pg/mL for pH 4.0, 7.0, and 9.0 formulations, respectively. At a 0.2 mg dose, the AUC values were found to be 23,208+/-6,824, 29,145+/-9,225, and 25,721+/-5,294 pg x min/mL for formulation pH 4.0, 7.0, and 9.0, respectively. At a 0.4 mg dose, the average AUC value was found to be high for pH 9.0 formulation (70,740+/-29,381 pg x min/mL) as compared to those of pH 4.0 (59,573+/-13,700 pg x min/mL) and pH 7.0 (55,298+/-17,305 pg x min/mL) formulations. Both the Cmax and AUC values were almost doubled with doubling the dose. On the other hand, the average Tmax, values decreased linearly with a decrease in formulation pH at both doses. For example, at a 0.4 mg dose, the average Tmax values were 26.7+/-5.8, 15.0+/-10.0, and 8.8+/-2.5 minutes at formulation pH 4.0, 7.0, and 9.0, respectively. CONCLUSIONS: Nasal absorption of scopolamine hydrobromide in human subjects increased substantially with increases in formulation pH and dose.

Pharmaceutical use by U.S. astronauts on space shuttle missions.

We evaluated in-flight use of medications from astronaut debriefings after 79 U.S. Space Shuttle missions. From the 219 records obtained (each representing one person-flight), 94% included some medication being taken during flight; of that number, 47% were for space motion sickness, 45% for sleep disturbances, and smaller percentages for headache, backache, and sinus congestion. Drugs were taken most often orally, followed in decreasing order of frequency by intranasal, intramuscular, and rectal routes. Drugs for space motion sickness were taken mostly during the first 2 d of flight, drugs for pain during the first 4 d, and drugs for sleeplessness and sinus congestion were taken consistently for 9 flight days. About 85% of all doses had no reported side effects, and most of the side effects that were reported happened during the first mission day. About 80% of the drug-dose events were perceived effective by the recipients; most of the reports of ineffectiveness occurred during the first mission day. Promethazine, the only drug given by three different routes (orally, intramuscularly, and rectally), was most effective and had minimal side effects when taken intramuscularly. This information, although useful, should be expanded to include objective measures of effectiveness so that therapeutic efficacy can be assessed during flight.

Pharmacotherapeutics in space.

NASA: The goal of pharmacology research the Johnson Space Center has been to identify safe and effective diagnostic and pharmacological intervention products, procedures, and strategies in support of successful space medical operations. The specific objectives of research are to identify physiologic, pharmacokinetic, and pharmacodynamic changes in space; to develop simple, reliable, non-invasive, safe and effective acute and sustained-release dosage forms and regimens for pharmacological interventions in space; and to create and maintain a comprehensive space PK-PD and therapeutics database. Highlights of the pharmacology research reviewed include development and validation of methods for pharmacologic research, in-flight pharmacokinetics, and alternative drug delivery methods.^ieng

Bioavailability of intranasal promethazine dosage forms in dogs.

Intramuscular promethazine (PMZ) is used aboard the US Space Shuttle to ameliorate symptoms of space motion sickness. Bioavailability after an oral dose of PMZ during space flight is thought to be impaired because of gastrointestinal disturbances associated with weightlessness and space motion sickness. In an attempt to find an alternative dosage form for use in space, we evaluated two intranasal (i.n.) dosage forms of PMZ in dogs for absorption and bioavailability relative to that of an equivalent intramuscular dose. Promethazine (5 mg kg-1) was administered as two intranasal dosage forms and as an intramuscular (i.m.) dose to three dogs in a randomised cross-over design. Serial blood samples were taken and analysed for PMZ concentrations and the absorption and bioavailability of PMZ were calculated for the three dosage forms. PMZ absorption from the carboxymethyl cellulose microsphere i.n. dosage form was more rapid and complete than from the myverol cubic gel formulation or from an i.m. injection. Bioavailability of the microsphere formulation was also greater than that of the gel formulation (AUC 3009 vs 1727 ng h ml-1). The bioavailability of the two i.n. dosage forms (relative to that of the i.m. injection) were 94% (microsphere) and 54% (gel). The i.n. microsphere formulation of PMZ offers great promise as an effective non-invasive alternative for treating space motion sickness due to its rapid absorption and bioavailability equivalent to the i.m. dose.

Drug marker absorption in relation to pellet size, gastric motility and viscous meals in humans.

PURPOSE: The objective of this study was to evaluate drug marker absorption in relation to the gastric emptying (GE) of 0.7 mm and 3.6 mm enteric coated pellets as a function of viscosity and the underlying gastric motility. METHODS: Twelve subjects were evaluated in a 3-way crossover study. 0.7 mm caffeine and 3.6 mm acetaminophen enteric coated pellets were concurrently administered with a viscous caloric meal at the levels of 4000, 6000 and 8000 cP. Gastric motility was simultaneously measured with antral manometry and compared to time events in the plasma profiles of the drug markers. RESULTS: Caffeine, from the 0.7 mm pellets, was observed significantly earlier in the plasma than acetaminophen, from the 3.6 mm pellets, at all levels of viscosity. Motility related size differentiated GE was consistently observed at all viscosity levels, however, less variability was observed with the 4000 cP meal. Specifically, the onset of absorption from the of 3.6 mm pellets correlated with the onset of Phase II fasted state contractions (r = 0.929, p < 0.01). CONCLUSIONS: The timeframe of drug marker absorption and the onset of motility events were not altered within the range of viscosities evaluated. Rather, the differences in drug marker profiles from the non-digestible solids were most likely the result of the interaction between viscosity and motility influencing antral flow dynamics. The administration of the two sizes of pellets and a viscous caloric meal with subsequent monitoring of drug marker profiles is useful as a reference to assess the influence of motility patterns on the absorption profile of orally administered agents.

A method for preserving saliva samples at ambient temperatures.

To facilitate biochemical and biopharmaceutical studies when cold storage is unavailable, we assessed the stability of saliva samples containing preservatives stored at room temperature over a 1-year period. Two preservative mixtures were evaluated: sodium benzoate and citric acid (P1), and ethyl and propyl paraben (P2). Saliva samples were spiked with acetaminophen (APAP) or antipyrine (AP) and stored in preservative-coated vials and examined for concentrations of APAP, AP, melatonin, and cortisol at regular intervals as a function of preservative type and storage duration. Samples were stored at room temperature or at -20 degrees C (positive control) and analyzed periodically for APAP and AP by high-performance liquid chromatography and for melatonin and cortisol by radioimmunoassay. The effectiveness of the preservatives was determined by calculating the value of samples stored at room temperature in terms of percent of control (-20 degrees C) values. P1 effectively maintained the stability of APAP (100%) and AP (100%) for 360 days at room temperature; concentrations in samples at room temperature on day 360 were comparable to those on day 01. P1 also effectively maintained melatonin (100%) and cortisol (95%) concentrations for 180 days at room temperature. P2 preserved AP and cortisol in saliva for 60 days, but APAP for only 14 days.

Bioavailability of intranasal scopolamine in normal subjects.

The bioavailability of scopolamine in three dosage forms was compared in 12 healthy nonsmoking male volunteers. Subjects received 0.4-mg doses of scopolamine bromide in intravenous (i.v.), intranasal (i.n.), or oral (p.o.) dosage forms on three occasions, with at least 2 weeks separating the doses. Scopolamine concentrations in plasma were determined with a combined reverse-phase liquid chromatographic-radioreceptor binding assay. Saliva volume and flow rate and percent suppression of control flow rate were determined from each sample. Absorption after i.n. and po scopolamine administration was rapid; plasma concentrations [1680 (i.n.) and 164 pg/mL (p.o.)] peaked within 1 h of dosing [0.37 (i.n.) and 0.78 h (p.o.)], respectively. i.n. and i.v. scopolamine suppressed salivary flow rate to similar extents (95% and 99.7%), respectively. Times to reach maximum effect were 1.05 and 0.27 h after i.n. and i.v. dosage, respectively. Absolute intranasal bioavailability, calculated from the area under the drug concentration vs time curve, was found to be significantly greater than that of p.o. scopolamine (83% vs 3.7%, p < 0.05). The i.n. route may provide a noninvasive, reliable, fast, and effective route for administering scopolamine.

Melatonin and cortisol assessment of circadian shifts in astronauts before flight.

Melatonin and cortisol were measured in saliva and urine samples to assess the effectiveness of a 7-day protocol combining bright-light exposure with sleep shifting in eliciting a 12-hr phase-shift delay in eight U.S. Space Shuttle astronauts before launch. Baseline acrophases for 15 control subjects with normal sleep-wake cycles were as follows: cortisol (saliva) at 0700 (0730 in urine); melatonin (saliva) at 0130 (6-hydroxymelatonin sulfate at 0230 in urine). Acrophases of the astronaut group fell within 2.5 hr of these values before the treatment protocols were begun. During the bright-light and sleep-shifting treatments, both absolute melatonin production and melatonin rhythmicity were diminished during the first 3 treatment days; total daily cortisol levels remained constant throughout the treatment. By the fourth to sixth day of the 7-day protocol, seven of the eight crew members showed phase delays in all four measures that fell within 2 hr of the expected 11- to 12-hr shift. Although cortisol and melatonin rhythms each corresponded with the phase shift, the rhythms in these two hormones did not correspond with each other during the transition.

Factors affecting drug bioavailability in space.

Microgravity-induced changes in the bioavailability of drugs may influence the efficacy or toxicity of drugs. The bioavailability of orally administered drugs may be altered by changes in dissolution rate, intestinal microflora, intraluminal enzymes, epithelial enzymes, rate of passage across the gastrointestinal epithelium, gastric emptying rate, intestinal transit time, hepatic first pass metabolism, and gastrointestinal and hepatic blood flow. Limited data from antiorthostatic bed rest and inflight studies provide preliminary evidence that the bioavailability of orally administered drugs in space may be decreased or subject to more interindividual variation than expected from ground-based studies.

Application of physiologically based pharmacokinetic models for assessing drug disposition in space.

Exposure to weightlessness induces physiologic changes that may lead to pharmacokinetic and pharmacodynamic alterations of drugs administered to crew members in flight. Preliminary data from flight and ground-based studies indicate that pharmacologically significant changes occur in the kinetics of medications given in weightlessness and in simulated microgravity (head-down bed rest). Conducting flight studies on all available medications to identify the changes in their pharmacokinetic behavior in weightlessness is not feasible. An alternative approach for obtaining such information is to use computer simulations employing physiologically based pharmacokinetic (PBPK) models. Information thus obtained would be helpful in predicting the therapeutic effectiveness of medications in space, and also in developing plans for flight studies. This paper presents a brief review of relevant physiologic factors and pharmacokinetic implications of space flight, and includes a preliminary PBPK model for estimating plasma concentration-time profiles of acetaminophen under different experimental conditions.

Nutrition and human physiological adaptations to space flight.

Space flight provides a model for the study of healthy individuals undergoing unique stresses. This review focuses on how physiological adaptations to weightlessness may affect nutrient and food requirements in space. These adaptations include reductions in body water and plasma volume, which affect the renal and cardiovascular systems and thereby fluid and electrolyte requirements. Changes in muscle mass and function may affect requirements for energy, protein and amino acids. Changes in bone mass lead to increased urinary calcium concentrations, which may increase the risk of forming renal stones. Space motion sickness may influence putative changes in gastro-intestinal-hepatic function; neurosensory alterations may affect smell and taste. Some or all of these effects may be ameliorated through the use of specially designed dietary countermeasures.

Pharmacokinetic consequences of spaceflight.

Spaceflight induces a wide range of physiological and biochemical changes, including disruption of gastrointestinal (GI) function, fluid and electrolyte balance, circulatory dynamics, and organ blood flow, as well as hormonal and metabolic perturbations. Any of these changes can influence the pharmacokinetics and pharmacodynamics of in-flight medication. That spaceflight may alter bioavailability was proposed when drugs prescribed to alleviate space motion sickness (SMS) had little therapeutic effect. Characterization of the pharmacokinetic and/or pharmacodynamic behavior of operationally critical medications is crucial for their effective use in flight; as a first step, we sought to determine whether drugs administered in space actually reach the site of action at concentrations sufficient to elicit the therapeutic response.

Pharmacokinetics and oral bioavailability of scopolamine in normal subjects.

The pharmacokinetics and bioavailability of scopolamine were evaluated in six healthy male subjects receiving 0.4 mg of the drug by either oral or intravenous administration. Plasma and urine samples were analyzed using a radioreceptor binding assay. After iv administration, scopolamine concentrations in the plasma declined in a biexponential fashion, with a rapid distribution phase and a comparatively slow elimination phase. Mean and SE values for volume of distribution, systemic clearance, and renal clearance were 1.4 +/- 0.3 liters/kg, 65.3 +/- 5.2 liters/hr, and 4.2 +/- 1.4 liters/hr, respectively. Mean peak plasma concentrations were 2909.8 +/- 240.9 pg/ml following iv administration and 528.6 +/- 109.4 pg/ml following oral administration. Elimination half-life of the drug was 4.5 +/- 1.7 hr. Bioavailability of the oral dose was variable among subjects, ranging between 10.7 and 48.2%. The variability in absorption and poor bioavailability of oral scopolamine indicate that this route of administration may not be reliable and effective.

Effect of antiorthostatic bed rest on hepatic blood flow in man.

Physiological changes that occur during exposure to weightlessness may induce alterations in blood flow to the liver. Estimation of hepatic blood flow (HBF) using ground-based weightlessness simulation models may provide insight into functional changes of the liver in crewmembers during flight. In the present study HBF, indirectly estimated by indocyanine green (ICG) clearance, is compared in 10 subjects during the normal ambulatory condition and antiorthostatic (-6 degrees) bed rest. Plasma clearance of ICG was determined following intravenous administration of a 0.5-mg.kg-1 dose of ICG to each subject on two separate occasions, once after being seated for 1 h and once after 24 h of head-down bed rest. After 24 h of head-down bed rest, hepatic blood flow did not change significantly from the respective control value.

Toxicokinetics of 1,2-dibromo-3-chloropropane (DBCP) in the rat.

The objective of this study was to determine the kinetics of absorption, distribution, and elimination of DBCP after intravenous (iv) administration in plasma, and after oral administration in water or corn oil, to conscious, fed, male Fischer 344 rats. Rats were prepared with an external jugular vein cannula and were dosed with 0.1, 1, or 10 mg/kg DBCP into the penile sinus or orally as a solution in water or in corn oil (1 mg/kg only). Blood was sampled at various times up to 12 hr, concentrations of DBCP were determined by gas chromatography, and data were evaluated by classical pharmacokinetic techniques. After oral administration in water, absorption of DBCP was rapid, and the distribution and elimination phase was biexponential. There did not appear to be any saturation of DBCP absorption, distribution, or elimination at the high oral or iv dose. After oral administration of DBCP in a corn oil vehicle, absorption was prolonged, suggesting retention of DBCP in the stomach; this could contribute to the toxic effects of DBCP on the forestomach when chronically administered in corn oil. The areas under the blood concentration/time curve were similar regardless of vehicle, suggesting that systemic toxicity might be independent of the vehicle.

Toxicokinetics and bioavailability of oral and intravenous 1,1-dichloroethylene.

Although aliphatic halocarbons have been identified as contaminants of drinking water supplies, little definitive information is available on their gastrointestinal (G.I) absorption and toxicokinetics. Therefore, a study of a representative halocarbon, 1,1-dichloroethylene (1,1-DCE), was undertaken to contrast the kinetics of the chemical following iv injection with that following oral administration. Four dosage-levels of 1,1-DCE (10, 25, 50, and 100 mg/kg BW) in 50% aqueous polyethylene glycol 400 were given iv and po to fasted and nonfasted male Sprague-Dawley rats. Serial blood samples were taken from the tail artery of the lightly etherized animals for up to 490 min after dosing. 1,1-DCE concentrations in the whole blood were determined by gas chromatographic head-space analysis. Evaluation of the iv data revealed that disappearance of 1,1-DCE from the systemic circulation followed a triexponential pattern. Light ether anesthesia did not appear to alter the pharmacokinetics of iv-injected 1,1-DCE. There was no difference between nonfasted and fasted iv rats in biological half-life (t1/2) or in any other pharmacokinetic parameter. Total body clearance, t1/2, apparent volume of distribution and volume of distribution in the central compartment did show increases with increasing dose in these animals. Oral dosing experiments revealed that 1,1-DCE was absorbed very rapidly and completely from the G.I. tract. Peak blood levels were reached 2 to 8 min following oral administration of 1,1-DCE as an aqueous suspension. The t1/2 of 1,1-DCE in orally dosed rats was somewhat longer than in their iv counterparts. The t1/2 values for nonfasted, orally dosed rats were longer than for their fasted counterparts, suggesting delayed absorption due to the presence of food in the G.I. tract. Bioavailability of 1,1-DCE, as determined by comparing areas under blood concentration versus time curves (AUCs), was equivalent in animals given the same dose of 1,1-DCE iv and po. AUCs increased with increasing dose in iv and po groups, but the increases were not proportional to dose.