The ALTEA/ALTEINO projects: studying functional effects of microgravity and cosmic radiation.

The ALTEA project investigates the risks of functional brain damage induced by particle radiation in space. A modular facility (the ALTEA facility) is being implemented and will be operated in the International Space Station (ISS) to record electrophysiological and behavioral descriptors of brain function and to monitor their time dynamics and correlation with particles and space environment. The focus of the program will be on abnormal visual perceptions (often reported as "light flashes" by astronauts) and the impact on retinal and brain visual structures of particle in microgravity conditions. The facility will be made available to the international scientific community for human neurophysiological, electrophysiological and psychophysics experiments, studies on particle fluxes, and dosimetry. A precursor of ALTEA (the 'Alteino' project) helps set the experimental baseline for the ALTEA experiments, while providing novel information on the radiation environment onboard the ISS and on the brain electrophysiology of the astronauts during orbital flights. Alteino was flown to the ISS on the Soyuz TM34 as part of mission Marco Polo. Controlled ground experiments using mice and accelerator beams complete the experimental strategy of ALTEA. We present here the status of progress of the ALTEA project and preliminary results of the Alteino study on brain dynamics, particle fluxes and abnormal visual perceptions.

Study of the radiation environment on MIR space station with SILEYE-2 experiment.

In this work we present preliminary results of nuclear composition measurements on board space station MIR obtained with SILEYE-2 particle telescope. SILEYE-2 was placed on MIR in 1997 and has been working since then. It consists of an array of 6 active silicon strip detectors which allow nuclear and energetic identification of cosmic rays in the energy range between approximately 30 and 200 MeV/n. The device is attached to an helmet and connected to an eye mask which shields the cosmonaut eyes from light and allow studies of the Light Flashes (LF) phenomenon. In addition to the study of the causes of LF, the device is used to perform real time long term radiation environment monitoring inside the MIR, performing measurements in solar quiet and active days.

ALTEA: anomalous long term effects in astronauts. A probe on the influence of cosmic radiation and microgravity on the central nervous system during long flights.

The ALTEA project participates to the quest for increasing the safety of manned space flights. It addresses the problems related to possible functional damage to neural cells and circuits due to particle radiation in space environment. Specifically it aims at studying the functionality of the astronauts' Central Nervous Systems (CNS) during long space flights and relating it to the peculiar environments in space, with a particular focus on the particle flux impinging in the head. The project is a large international and multidisciplinary collaboration. Competences in particle physics, neurophysiology, psychophysiology, electronics, space environment, data analyses will work together to construct the fully integrated vision electrophysiology and particle analyser system which is the core device of the project: an helmet-shaped multi-sensor device that will measure concurrently the dynamics of the functional status of the visual system and passage of each particle through the brain within a pre-determined energy window. ALTEA is scheduled to fly in the International Space Station in late 2002. One part of the multi-sensor device, one of the advanced silicon telescopes, will be launched in the ISS in early 2002 and serve as test for the final device and as discriminating dosimeter for the particle fluences within the ISS.

Eye light flashes on the Mir space station.

The phenomenon of light flashes (LF) in eyes for people in space has been investigated onboard Mir. Data on particles hitting the eye have been collected with the SilEye detectors, and correlated with human observations. It is found that a nucleus in the radiation environment of Mir has roughly a 1% probability to cause an LF, whereas the proton probability is almost three orders of magnitude less. As a function of LET, the LF probability increases above 10 keV/micrometer, reaching about 5% at around 50 keV/micrometer.

The ALTEA facility on the International Space Station.

The ALTEA project studies the problems related to possible functional damage to the Central Nervous System (CNS) due to particle radiation in space environment. The project is a large international and multi-disciplinary collaboration. The ALTEA instrumentation is an helmet-shaped multi-sensor device that will measure concurrently the dynamics of the functional status of the visual system and the passage of each particle through the brain within a pre-determined energy window. ALTEA is scheduled to fly in the International Space Station in February 2003. One part of the multi-sensor device, one of the advanced silicon telescopes, will be launched in the ISS in early 2002 and serve as test for the final device and as discriminating dosimeter for the particle fluences within the ISS.

Study of cosmic rays and light flashes on board Space Station MIR: the SilEye experiment.

The SilEye experiment aims to study the cause and processes related to the anomalous Light Flashes (LF) perceived by astronauts in orbit and their relation with Cosmic Rays. These observations will be also useful in the study of the long duration manned space flight environment. Two PC-driven silicon detector telescopes have been built and placed aboard Space Station MIR. SilEye-1 was launched in 1995 and provided particles track and LF information; the data gathered indicate a linear dependence of FLF(Hz) ( 4 2) 10(3) 5.3 1.7 10(4) Fpart(Hz) if South Atlantic Anomaly fluxes are not included. Even though higher statistic is required, this is an indication that heavy ion interactions with the eye are the main LF cause. To improve quality and quantity of measurements, a second apparatus, SilEye-2, was placed on MIR in 1997, and started work from August 1998. This instrument provides energetic information, which allows nuclear identification in selected energy ranges; we present preliminary measurements of the radiation field inside MIR performed with SilEye-2 detector in June 1998.

Synthesis and benzodiazepine binding activity of a series of novel [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones.

Investigation of tricyclic heterocycles related to the 2-arylpyrazolo[4,3-c]quinolin-3(5H)-ones, structures with high affinity for the benzodiazepine (BZ) receptor, led to the synthesis of 2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one, a compound with 4 nM binding affinity to the BZ receptor. Analogues were prepared to assess the importance of the 2-substituent and ring substitution in modifying activity. Several novel synthetic routes were designed to prepare the target compounds, including a two-step synthesis beginning with an anthranilonitrile and a hydrazide. Of the 34 compounds screened in this series, three compounds were found to be potent BZ antagonists in rat models. The leading compound, 9-chloro-2-(2-fluorophenyl) [1,2,4]triazolo[1,5- c]quinazolin-5(6H)-one (CGS 16228), showed activity comparable to that of CGS 8216 from the pyrazolo[4,3-c]quinoline series.

The relationship between pKa and skin irritation for a series of basic penetrants in man.

For a series of bases, which penetrate through human skin in vitro at similar rates (0.056-0.49 microM/cm2/hr), penetrant pKa is shown to correlate with erythema, edema, and color meter readings. As estimates of irritation, erythema, edema, and redness measurements are highly linearly correlated. For the selected series, irritation becomes significant for bases with a pKa greater than 8. The irritation potential of acids with pKa less than or equal to 4 has been previously reported; pKa appears highly predictive of acute skin irritation for acids and bases in man.

Ethanol and water sorption into stratum corneum and model systems.

Sorption of ethanol and water into stratum corneum, delipidized stratum corneum, and triolein as a simple model lipid was investigated. Optima in ethanol sorption and flux are related to dehydration of keratins. There was no optimum for solubility in triolein; a linear cosolvency is observed with ethanol:triolein mixtures. A model is proposed which qualitatively predicts the key features of ethanol-enhanced skin permeation on the basis of these solubility phenomena and a constant diffusion coefficient.

Ethanol: water mutually enhanced transdermal therapeutic system II: skin permeation of ethanol and nitroglycerin.

An optimal concentration range of aqueous ethanol produces 5-10-fold increases in nitroglycerin flux across skin and ethanol skin permeation that are far greater than reported previously. For aqueous ethanol solutions saturated with nitroglycerin with an ethanol volume fraction less than or equal to 0.7, the flux of nitroglycerin across skin is linear with the ethanol flux and is traced to a linear solubility relationship and a constant diffusion coefficient.

Ethanol:water mutually enhanced transdermal therapeutic system. I: Nitroglycerin solution properties and membrane transport.

The solution properties of aqueous ethanol donor solutions were characterized for the particular case of an increased flux nitroglycerin transdermal system. Permeation through porous and nonporous polymer membranes was investigated and modelled. While the permeation of ethanol through the porous membranes is adequately described by theory, clogging of pores occurs in the presence of lactose. Permeation through ethylene vinyl acetate membranes reflects interactions of the solute and solvent with the polymer.

The relationship of pKa and acute skin irritation in man.

The relationship between pKa and skin irritation in man is studied for a homologous series of benzoic acid derivatives, which permeate through human skin at comparable rates (15-88 micrograms/cm2/hr). Skin irritation and pKa are correlated for pKa less than or equal to 4. Laser Doppler velocimetric assessment of skin blood flow, color meter readings, erythema, edema, and the primary irritation index are all linearly correlated and related to pKa; erythema at 24 hr appears to be the most sensitive parameter to variation in pKa when pKa less than or equal to 4.

Angiotensin converting enzyme inhibitors: 1,5-benzothiazepine derivatives.

The synthesis of chiral 1,5-benzothiazepines 2a-c, 14a-c, 15c, and 16a prepared from cysteine is described. In vitro inhibition of angiotensin converting enzyme (ACE) is reported for each compound. Compound 2c was the most potent in vitro having an IC50 of 2.95 nM. The ester of 2c, i.e. 14c, was found to inhibit the AI pressor response by 75% at a dose of 0.05 mg/kg iv and by 39% at 1.0 mg/kg po. Additionally, 14c lowered blood pressure in the spontaneous hypertensive rat (SHR) by 35 mmHg, at a dose of 10 mg/kg po.