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Session 1B-Dolman-HyperSpectral Data Compression and Clouds Screening using High-Performance Embedded Computing SoC for the Earth Surface Mineral Dust Source Instrument EMIT

With the availability of high-power (milliwatts) single-mode tunable laser sources that operate at room temperature across the infrared (IR) region, tunable laser spectrometers have seen an explosion of growth in applications that include commercial, Earth and planetary science, and medical and industrial sensing. While the laser sources themselves have shown steady improvement, the detection architecture of using a single-element detector at one end of a multipass cell has remained unchanged over the last few decades. We present here an innovative new approach using a detector array coupled to an IR-transmissive mirror to image all or part of the multipass spot pattern of the far mirror and record spectra for each pixel. This novel approach offers improved sensitivity, increased dynamic range, laser power normalization, contaminant subtraction, resilience to misalignment, and reduces the instrument power requirement by avoiding the need for “fringe-wash” heaters. With many tens of pixels representing each spot during the laser spectral scan, intensity and optical fringe amplitude and phase information are recorded. This allows selection and manipulation (e.g., co-addition, subtraction) of the pixel output spectra to minimize optical interference fringes thereby increasing sensitivity. We demonstrate a factor of ∼ 20 sensitivity improvement over traditional single-element detection. Dynamic range increase of a factor of ∼ 100 is also demonstrated through spot selection representing different pathlengths. Additionally, subtracting the spectrum of the first spot from that of the higher pass normalizes the laser power and removes the contribution of contaminant gas and fringes in the fore-optics region. These initial results show that this imaging method is particularly advantageous for multi-channel laser spectrometers, and, once the image field is analyzed, pixel selection can be used to minimize data rate and volume collection requirements. This technique could be beneficial to enhanced-cavity detection schemes.

We report new measurements of atmospheric methane by the Curiosity rover’s Tunable Laser Spectrometer that is part of the Sample Analysis at Mars suite (TLS-SAM), finding nondetections during two daytime measurements of average value 0.05 ± 0.22 ppbv (95% confidence interval CI). These are in marked contrast with nighttime background levels of 0.52 ± 0.10 (95% CI) from four measurements taken during the same season of northern summer. This large day-night difference suggests that methane accumulates while contained near the surface at night, but drops below TLS-SAM detection limits during the day, consistent with the daytime nondetection by instruments on board the ExoMars Trace Gas Orbiter. With no evidence for methane production by the rover itself, we propose that the source is one of planetary micro-seepage. Dynamical modeling indicates that such methane release is contained within the collapsed planetary boundary layer (PBL) at night due to a combination of nocturnal inversion and convergent downslope flow winds that confine the methane inside the crater close to the point where it is released. The methane abundance is then diluted during the day through increased vertical mixing associated with a higher altitude PBL and divergent upslope flow that advects methane out of the crater region. We also report detection of a large spike of methane in June 2019 with a mean in situ value over a two-hour ingest of 20.5 ± 4 ppbv (95% CI). If near-surface production is occurring widely across Mars, it must be accompanied by a fast methane destruction or sequestration mechanism, or both.

This paper discusses the building of a fully digital, Adaptive Tunable LAser Spectrometer (ATLAS) electronics/software platform for Earth and Planetary applications. Adaptive in this context refers to the real time analysis of the recorded spectra and using that information to continuously and autonomously optimize spectrometer performance if necessary/desirable. We discuss the results of rapid prototyping and how those results fed into design specifications for a new platform built with Zynq System-On-Chip (SoC) technologies from Xilinx. Existing TLS designs are limited to the extent that they employ analog implementations of filter, modulation/demodulation and phase sensitive detection circuitries. For our platform these functions are realized in the digital realm, allowing precise, reversible changes during instrument testing, integration and even after launch, all without the risk generally involved in physically removing hardware from a flight payload.

Of water and methane on Mars The Curiosity rover has been collecting data for the past 2 years, since its delivery to Mars (see the Perspective by Zahnle). Many studies now suggest that many millions of years ago, Mars was warmer and wetter than it is today. But those conditions required an atmosphere that seems to have vanished. Using the Curiosity rover, Mahaffy et al. measured the ratio of deuterium to hydrogen in clays that were formed 3.0 to 3.7 billion years ago. Hydrogen escapes more readily than deuterium, so this ratio offers a snapshot measure of the ancient atmosphere that can help constrain when and how it disappeared. Most methane on Earth has a biological origin, so planetary scientists have keenly pursued its detection in the martian atmosphere as well. Now, Webster et al. have precisely confirmed the presence of methane in the martian atmosphere with the instruments aboard the Curiosity rover at Gale crater. Science , this issue p. 412 , p. 415 ; see also p. 370

The effects of dextropropoxyphene on the steady-state kinetics of oxcarbazepine and its metabolites were investigated in eight patients with epilepsy or trigeminal neuralgia. One patient dropped out of the study, presumably due to side-effects of dextropropoxyphene. Dextropropoxyphene did not affect the plasma levels of the principal active metabolite, 10, 11-dihydro-10-hydroxy-carbamazepme. Since dextropropoxyphene is known to increase the plasma levels of carbamazepine, leading to toxicity, the findings of this study suggest that oxcarbazepine is a useful alternative to carbamazepine when concomitant dextropropoxyphene therapy is required.

A final market image (FMI) tablet formulation of oxcarbazepine was compared with the marketed formulation (current market formulation (CMF)) and with the clinical trial formulation (CTF) tablet used during clinical efficacy and safety studies. The goal of the study was to compare the bioavailability after single doses and at steady state of the FMI versus CMF and CTF as well. Additionally, the effect of food was evaluated on the final market formulation. The study was an open-label, single-center, 4-way crossover trial. Each treatment period consisted of a single dose of 600 mg OXC on Day 1. From Day 4 up to including Day 7, 600 mg b.i.d. were administered. A final dose of 600 mg was administered in the morning on Day 8. Blood samples were taken on Day 1 before and on Day 7 (predose) and on Day 8 (morning dose). Plasma concentrations of MHD (the main metabolite of OXC) were determined by using a validated HPLC assay. FMI as test formulation was compared with the CMF and CTF as reference formulations. FMI under fed conditions was also compared with FMI under fasting conditions. These comparisons were made using data following single-dose administration and steady state conditions. Plasma AUC for single dose or AUC(0-12h) for steady state, and plasma Cmax, log-transformed (natural base), were used for the assessment of bioequivalence. The 90% confidence interval (CI) approach was used for testing bioequivalence. Bioequivalence was accepted if the CI was contained within the region (0.8, 1.25). At steady state under fed conditions, tested formulation (FMI) was bioequivalent to CTF and with the reference marketed formulation (CMF) with regard to AUC and Cmax. After single dose under fed conditions, FMI and CTF were bioequivalent with regard to AUC and Cmax, and FMI and CMF were equivalent with regard to AUC but not Cmax. Food had no effect on the bioavailability of the FMI. These results clearly support the switch from the current market formulation (CMF) to the final market image tablet in the countries where Trileptal is or was already registered.

A 39-year-old woman presented in the first month of pregnancy with reflex sympathetic dystrophy involving both lower legs. Symptoms became so severe that she could not walk unassisted, and the pain worsened after delivery. Radiographs showed patchy reduction in apparent density in the tarsal bones and around the ankles and knees. Uptake was increased in these areas on technetium methylene diphosphonate bone scan. Bone density (dual-energy X-ray absorptiometry) was reduced in the spine, hip, and radius. Biochemical tests were normal except for an increase in urinary excretion of the N-telopeptide cross-linking region of type I collagen (NTx). Because the patient wanted to continue breast-feeding, intravenous pamidronate was administered at monthly intervals. Breast milk was collected for 48 h after the infusion. The pain began to decrease soon after drug administration was initiated, and it was virtually gone by 6 months. NTx excretion fell by 78% and bone density increased by as much as 18.9% over the 6-month treatment interval. The baby was healthy and grew normally. Milk expressed after the first treatment was assayed for pamidronate content by high-performance liquid chromatography with fluorescence detection. None was detected (limit of quantitation, 0.4 micromol/liter). This case shows that pamidronate may be considered for treatment of lactating women.

In situ measurements of hydrochloric acid (HCI) concentrations in the lower stratosphere from 1991 to 1996 reveal that its abundance relative to that of total inorganic chlorine (CIy) has evolved upwards from HCI/CIy=40% in late 1991 to 70% in 1996.

Objective: The pharmacokinetics of orally and intravenously administered valsartan were determined in two studies. In a first pilot study, three i.v. doses of valsartan were given in an ascending manner (5, 10 and 20 mg) to evaluate tolerability and basic pharmacokinetics of the i.v. formulation. In a second study, the absolute bioavailability of 80 mg valsartan from a capsule and a buffered solution was compared with a 20 mg i.v. dose. Methods: The concentrations of valsartan in plasma and urine were measured using HPLC. The disposition of valsartan after an i.v. dose was characterized by biphasic decay kinetics, with a distribution phase (half-life 1.0 h), followed by a longer elimination phase (half-life 9.5 h). The volume of distribution at steady state was 16.9 l, and the total body clearance 2.2 l · h−1. 29% of the i.v. dose was recovered unchanged in the urine. Results: Plasma levels peaked 2 h after oral administration of the 80 mg capsule. Thereafter, plasma levels declined biexponentially with a terminal t1/2 of 7.0 h. Cmax was reached 1 h after administration of the solution, and t1/2 was 7.5 h. On average 7.3% (capsule) and 12.6% (solution) of the dose was excreted in the urine as the unchanged drug. The fraction of dose absorbed and systemically available after oral administration was 0.23 for the capsule and 0.39 for the solution, based on AUC. Absorption appeared to follow two first-order processes. The first phase was rapid, with a half-life of 0.5 h and 0.9 h for solution and capsule, respectively. The slower absorption phase was characterized by a half-life of 6.5 h for the solution and 3.5 h for the capsule. Most of the drug was absorbed during the period 0.4 h to 3 h post-dosing, and 90% of the fraction absorbed from the capsule was absorbed within 5 h.

The aim of the study was to determine whether the concentration of CGP 53437 measured in the sera of normal volunteers following oral administration of a single dose, had retained its anti-HIV activity; and whether such results could be of predictive value for future clinical antiviral efficacy studies. CGP 53437 is an inhibitor of HIV-1 protease that suppresses HIV-1 replication in human lymphocytes in vitro at 100 nM. The in vitro anti-HIV activity of human sera obtained from CGP 53437-treated individuals was compared with that of sera spiked with known concentrations of CGP 53437 (in the presence or absence of α-1 acid glycoprotein). It was found that the concentration of the compound measured in the sera from treated individuals provided the expected in vitro anti-HIV activity. These results not only validate our analytical method for detection of CGP 53437, but also support the notion that interaction of CGP 53437 with plasma proteins does not significantly affect its antiviral activity (shift of the ED90 by a factor of three). In conclusion, ex vivo anti-HIV activity determinations of sera containing an HIV protease inhibitor, in conjunction with the pharmacokinetic evaluation during Phase I clinical studies, can provide valuable information regarding the suitability of such inhibitors for further clinical studies.

We introduce the dynamic nonlinear optical skin effect in which a pulse incident on a saturable absorbing interface is self-reflected from a moving absorption front. The motion of the front causes the self-reflected wave to be redshifted by the Doppler effect, which in turn serves as an experimentally observable signature for the front propagation.

Numerical integration of Maxwell's equations for propagation of a femtosecond pulse in a medium with linear Lorentz response and a Kerr nonlinearity shows shock formation on the underlying carrier wave prior to the envelope shock. The carrier shock is characterized by the appearance of a strong third harmonic pulse, whereas the envelope shock appears later as spectral broadening and modulation of the fundamental and higher harmonic spectral features.

An architecture and process for the rapid prototyping and subsequent development of an adaptive tunable laser absorption spectrometer (TLS) are described. Our digital hardware/firmware/software platform is both reconfigurable at design time as well as autonomously adaptive in real-time for both post-integration and post-launch situations. The design expands the range of viable target environments and enhances tunable laser spectrometer performance in extreme and even unpredictable environments. Through rapid prototyping with a commercial RTOS/FPGA platform, we have implemented a fully operational tunable laser spectrometer (using a highly sensitive second harmonic technique). With this prototype, we have demonstrated autonomous real-time adaptivity in the lab with simulated extreme environments.

An architecture and process for the rapid prototyping and subsequent development of an adaptive tunable laser absorption spectrometer (TLS) are described.12 Adaptive in this context refers to the real-time autonomous response of software and electronics to the harsh and hard-to-predict conditions that can be encountered in space flight missions. This approach takes advantage of both software tools as well as highly integrated RTOS/FPGA hardware modules now commercially available. The current state of space-qualified tunable laser spectrometers is described, along with motivations for adaptability.

An enantioselective liquid chromatographic assay for the simultaneous determination of the S-(+) and R-(-) enantiomers of the monohydroxylated metabolite of oxcarbazepine in human plasma is described. The metabolite is the active principle. The method is based on the extraction of plasma with diethyl ether-dichloromethane (2:1, v/v), separation of the organic phase, evaporation of the solvent and dissolution of the residue in the mobile phase. The two enantiomers were resolved on a Chiralcel OD (250 mm x 4.6 mm I.D.) high-performance liquid chromatographic column. The separation was achieved by isocratic elution with n-hexane-2-propanol (77:23, v/v). The flow-rate of the mobile phase was 1.0 ml/min and the two enantiomers were detected by ultraviolet absorbance at 210 nm. The analytical method is suitable for the quantitative and simultaneous determination of the two enantiomers in plasma at concentrations down to 0.4 mumol/l after administration of oxcarbazepine.

To determine if iron chelation therapy has activity against human malaria, we administered desferrioxamine B in amounts of 100 mg/kg per day by continuous 72-hour subcutaneous infusions to 28 volunteers with asymptomatic Plasmodium falciparum infection in a randomized, double- blind, placebo-controlled crossover trial. Peripheral blood concentrations of P falciparum ring forms were determined at 12-hour intervals in all subjects and serum concentrations of desferrioxamine B + ferrioxamine (the iron complex of desferrioxamine B) were measured in 26 subjects. Geometric mean concentrations of asexual intraerythrocytic parasites decreased with both chelator and placebo treatment, but the decrement with desferrioxamine B was significantly greater than that with placebo (P less than .006) during both the initial and crossover periods. Compared with placebo, desferrioxamine B treatment was associated with an almost 10-fold enhancement of the rate of parasite clearance during both phases of the trial (P less than .007). Mean +/- SEM steady state concentrations of desferrioxamine B + ferrioxamine were 6.90 +/- 0.60 mumol/L at 36 hours and 7.72 +/- 0.68 mumol/L at 72 hours; in vitro, the ID50 has been reported to be approximately 4 to 20 mumol/L. No drug toxicity was detected. Parasitemia recurred in 19 of 24 participants followed-up over 1 to 6 months. We conclude that desferrioxamine B enhances the clearance of P falciparum parasitemia and that iron chelation may provide a new strategy to be developed for the treatment of malaria.

To determine if iron chelation therapy has activity against human malaria, we administered desferrioxamine B in amounts of 100 mg/kg per day by continuous 72-hour subcutaneous infusions to 28 volunteers with asymptomatic Plasmodium falciparum infection in a randomized, double- blind, placebo-controlled crossover trial. Peripheral blood concentrations of P falciparum ring forms were determined at 12-hour intervals in all subjects and serum concentrations of desferrioxamine B + ferrioxamine (the iron complex of desferrioxamine B) were measured in 26 subjects. Geometric mean concentrations of asexual intraerythrocytic parasites decreased with both chelator and placebo treatment, but the decrement with desferrioxamine B was significantly greater than that with placebo (P less than .006) during both the initial and crossover periods. Compared with placebo, desferrioxamine B treatment was associated with an almost 10-fold enhancement of the rate of parasite clearance during both phases of the trial (P less than .007). Mean +/- SEM steady state concentrations of desferrioxamine B + ferrioxamine were 6.90 +/- 0.60 mumol/L at 36 hours and 7.72 +/- 0.68 mumol/L at 72 hours; in vitro, the ID50 has been reported to be approximately 4 to 20 mumol/L. No drug toxicity was detected. Parasitemia recurred in 19 of 24 participants followed-up over 1 to 6 months. We conclude that desferrioxamine B enhances the clearance of P falciparum parasitemia and that iron chelation may provide a new strategy to be developed for the treatment of malaria.

An improved method for the determination of 1-hydroxy-3-aminopropylidene-1,1-bisphosphonate (pamidronate) in human urine and plasma is described. The procedure is based on a co-precipitation of the bisphosphonates (pamidronate and 6-amino-1-hydroxypentilidene-bisphosphonate, used as internal standard) with calcium phosphate. After centrifugation the precipitate is redissolved in hydrochloric acid, followed by a second precipitation. Then the bisphosphonates are dissolved in ethylenediaminetetraacetic acid, derivatized with fluorescamine, and separated by high-performance liquid chromatography. Using fluorescence detection, the limit of quantitation for pamidronate was 0.8 mumol/l in plasma and 0.7 mumol/l in urine.

Oxcarbazepine (trileptal) oral suspension has been reformulated and a study was performed to compare the bioavailability after single doses and at steady state of the current and former oral suspension versus the marketed film-coated tablets and to compare the bioavailability of the current and former oral suspension. The results support the switch from the former oral suspension to the current oral suspension and also from both oral suspensions to the film-coated tablet and vice versa. The study was an open-label, single-center, 3-way crossover trial. Each treatment period consisted of a single dose of 600 mg oxcarbazepine on Day 1, 600 mg oxcarbazepine b.i.d. repeated administration from Day 4 up to including Day 7, and a final dose of 600 mg oxcarbazepine administered on the morning of Day 8. Blood samples were taken on Day 1, Day 7 and Day 8 (pre-dose). Plasma concentrations of the main metabolite of oxcarbazepine (MHD) were determined using a validated HPLC assay. The 2 oral suspensions were compared with the film-coated tablet as reference formulation under fasted conditions. Also the current oral suspension was compared with the former oral suspension. These comparisons were made using data following single dose administration and under steady state conditions. Plasma AUC for single dose and AUC(0-12h) at steady state and plasma Cmax, log-transformed (natural base) were used for the assessment of bioequivalence. The 90% confidence interval (CI) approach was used for testing bioequivalence. Bioequivalence was accepted if CI was contained within the region (0.8, 1.25). At steady state, both the former and the current oral suspensions showed bioequivalence with the film-coated tablet with respect to AUC and Cmax. The current oral suspension was also bioequivalent when compared to the former oral suspension with respect to AUC and Cmax. After single dose, the former oral suspension was bioequivalent when compared to the film-coated tablet with respect to both AUC and Cmax. However, the current oral suspension was bioequivalent to both the film-coated tablet and the former oral suspension with respect to AUC but not to Cmax.

[1] Four nitrous oxide (N2O) instruments were part of the NASA ER-2 aircraft payload during the 2000 SAGE-III Ozone Loss and Validation Experiment (SOLVE). Coincident data from the three in situ instruments and a whole air sampler are compared. Agreement between these instruments was typically good; however, there are several types of important differences between the data sets. These differences prompted a collaborative effort to combine data from the three in situ instruments, using an objective method, to produce a self-consistent, high-resolution, unified N2O data set for each SOLVE flight. The construction method developed by the four N2O instrument teams is described in detail. An important step in this method is the evaluation and reduction of bias in each of the in situ data sets before they are combined. The quality of unified N2O data is examined through its agreement with high-accuracy and high-precision N2O data from whole air samples collected from the ER-2 during SOLVE flights. Typical agreement between these two data sets is 2.9 ppb (1.5%), better than the typical agreement between any pair of N2O instruments.

During Arctic winters with a cold, stable stratospheric circulation, reactions on the surface of polar stratospheric clouds (PSCs) lead to elevated abundances of chlorine monoxide (ClO) that, in the presence of sunlight, destroy ozone. Here we show that PSCs were more widespread during the 1999/2000 Arctic winter than for any other Arctic winter in the past two decades. We have used three fundamentally different approaches to derive the degree of chemical ozone loss from ozonesonde, balloon, aircraft, and satellite instruments. We show that the ozone losses derived from these different instruments and approaches agree very well, resulting in a high level of confidence in the results. Chemical processes led to a 70% reduction of ozone for a region similar to1 km thick of the lower stratosphere, the largest degree of local loss ever reported for the Arctic. The Match analysis of ozonesonde data shows that the accumulated chemical loss of ozone inside the Arctic vortex totaled 117 +/- 14 Dobson units (DU) by the end of winter. This loss, combined with dynamical redistribution of air parcels, resulted in a 88 +/- 13 DU reduction in total column ozone compared to the amount that would have been present in the absence of any chemical loss. The chemical loss of ozone throughout the winter was nearly balanced by dynamical resupply of ozone to the vortex, resulting in a relatively constant value of total ozone of 340 +/- 50 DU between early January and late March. This observation of nearly constant total ozone in the Arctic vortex is in contrast to the increase of total column ozone between January and March that is observed during most years.

Objective: This was a randomised, open, three-way crossover study in 12 healthy male volunteers to determine the effect of a single oral dose of cimetidine on the pharmacokinetics of a single oral dose of the angiotensin II receptor antagonist valsartan – and vice versa. The volunteers received either valsartan alone (160 mg), or cimetidine alone (800 mg), or valsartan 1 h after cimetidine. The study was designed primarily to detect a possible influence of cimetidine on the rate and extent of absorption of valsartan. Methods: Plasma concentrations of valsartan and cimetidine, measured by means of high-performance liquid chromatography, were used to calculate pharmacokinetic parameters. The rate of absorption of valsartan and the fraction of the dose absorbed and systemically available after oral administration were calculated using data from an i.v. study with valsartan in healthy young volunteers. Results: The pharmacokinetics of cimetidine – area under curve (AUC0–48 h), maximum concentration (Cmax), time to reach Cmax (tmax) and apparent terminal plasma half-life (t1/2) – was not changed by co-administration of valsartan. For valsartan, the AUC0–48 h increased by 7% and the Cmax by 51% (ratio of geometric means) with co-administration of cimetidine. The higher value for Cmax was attributed to the initial increase in the rate of absorption of valsartan: ka was increased 2.7-fold and another indicator for the rate of absorption, Cmax/tmax, 2.2-fold. This effect was ascribed to inhibition of acid secretion by cimetidine, which leads to a higher gastric pH, thereby increasing the solubility of valsartan; the t1/2 of valsartan was not changed. After valsartan alone, 19% of the dose was absorbed, 23% with co-administration of cimetidine. It was estimated that only 2.2% of the possible change in AUC might be missed by giving a single high dose of cimetidine instead of multiple doses, with the aim to optimally inhibit formation of the inactive metabolite of valsartan. Cimetidine-related changes in the rate of elimination of valsartan were not anticipated, since the clearance from plasma occurs mainly by biliary excretion of unchanged valsartan; metabolism and renal excretion are only minor contributors. Therefore, even in the clinically relevant situation with multiple doses of valsartan and cimetidine, notable changes in the pharmacokinetics of valsartan, except for an increase in Cmax, are not to be expected. This increase in Cmax appears to be of no clinical significance. Valsartan alone and in combination with cimetidine was well tolerated by healthy subjects.

Pharmacokinetics, pharmacodynamic effects and tolerability of 200 mg valsartan, once-daily for 8 days, were investigated in 16 healthy, normotensive volunteers on a normal sodium diet.This was a double-blind, placebo-controlled, randomized crossover study. Drug concentrations in plasma and urine, angiotensin II (Ang II) concentrations in plasma, systolic (SBP) and diastolic (DBP) blood pressure, heart rate (HR) in the supine position and 3 min after passive head-up tilting, as well as safety parameters (ECG, clinical chemistry and hematology, renal water and electrolyte excretion) were measured over 24 h after the first dose (day 1) and at steady state on day 8.Absorption and distribution of valsartan were rapid (Cmax, 2 h; t1/2 lambda 11 h), followed by a slower terminal elimination phase (t1/2 lambda 2, 6 h) on days 1 and 8, with little accumulation in plasma (increase of 20% on day 8). Less than 10% of the dose was excreted unchanged in urine. The increase in plasma Ang II (Cmax, 6 h) was significantly enhanced at steady state. Supine SBP and DBP significantly decreased on day 8 only, by an average of -3.6 and -2.4 mmHg, respectively, versus placebo, without a concomitant increase in HR. Upon passive tilting, the increase in DBP, normally reinforced by sympathetic renin release, was slightly but significantly blunted on day 1 (-2.0 mmHg) and day 8 (-4.0 mmHg) of treatment with valsartan versus placebo. The orthostatic reflex increase in HR was slightly enhanced compared with placebo by an average of 2.8 beats min-1 on day 1 and by 2.9 beats.min-1 on day 8. Valsartan was well tolerated and had no influence on ECG, clinical laboratory parameters, and water, electrolyte and uric acid excretion.Pharmacokinetics of valsartan are unchanged after multiple once-daily dosing, with little (expected) accumulation in plasma. Effects of 200 mg valsartan on blood pressure in healthy subjects on a normal sodium intake are small and become more prominent after repeated dosing. Indirect evidence of AT1 blockade by valsartan is demonstrated by an increase of plasma Ang II and by a blunted DBP response to passive tilting. The decrease in blood pressure at steady state enhances the increase in plasma Ang II. Valsartan is well tolerated and is devoid of effects on water, electrolyte and uric acid excretion at 200 mg per day in healthy normotensive volunteers.

Pharmacokinetic and pharmacodynamic interactions between single oral doses of valsartan (160 mg) and furosemide (40 mg) were investigated in an open, randomized, three-period crossover study in twelve healthy male subjects.A washout period of one week was observed between treatments. Pharmacokinetic measurements included plasma concentrations of valsartan and furosemide, and urinary excretion of the latter. Plasma renin activity (PRA), plasma angiotensin II, blood pressure, heart rate, as well as urinary water and electrolyte excretion were determined as pharmacodynamic variables. Efficiency of furosemide for sodium and water excretion was calculated as the ratio of the measured pharmacodynamic effect and the urinary excretion of furosemide.Simultaneous administration of valsartan and furosemide did not modify the pharmacokinetics of valsartan. In contrast, Cmax, AUC, and urinary excretion of furosemide were significantly reduced following simultaneous treatment with valsartan. Inter- and intra-individual variability of the pharmacokinetic variables was high for both furosemide and valsartan. PRA and angiotensin II increased, and blood pressure decreased after all treatments. These effects were most pronounced after the combined treatment. The decrease in blood pressure was additive, at most, while the increase in PRA and angiotensin II appeared to exceed simple addition. No relevant effects on heart rate were observed. The diuretic effect of furosemide, as assessed by urinary water and electrolyte excretion, was unchanged after co-administration of valsartan, despite the lower bioavailability of furosemide after the combined treatment.

CGP 61755 is a novel hydroxyethylene derivative produced by a high yield 10 step chemical synthesis. It is highly specific for HIV-1 protease with an IC50 of 1 nM. The ED90 in MT-2, PBLs and macrophages is infected with laboratory strains of HIV-1 or clinical isolates is 30-100 nM. In chronically infected macrophages the ED90 is 1000 nM (1000 nM for saquinavir and 10 microM for indinavir). When the antiviral activity of CGP 61755 on HIV-1 infected lymphocytes was examined using serum free medium an ED99 of 60 nM was determined, while in the presence of 10% human serum the same activity was achieved with 120 nM. When examined in combination with RT inhibitors or protease inhibitors, either in a co-culture of CEM-SS and chronically infected H9IIIB cells or in a free virus lymphocyte infection, cooperativity of the antiviral activities was observed. Dog pharmacokinetic studies comparing p.o. and i.v. data indicate that CGP 61755 has a bioavailability between 50 and 80%. Following oral administration the area under the concentration curve (AUC) values increased in a dose proportional manner. The plasma levels of the drug at 6 hours after oral administration were above the ED90. Based on these properties we believe that CGP 61755 has an attractive profile that justifies further preclinical evaluation of the drug.

Electrical resistivity ρ and thermopower S of the Laves phase compound of NdCo2 has been investigated at temperatures from 2 K to 300 K. ρ has been measured under pressures up to 8 GPa and S has been measured under pressures up to 3 GPa. The magnetic transition temperature TC obtained by ρ measurement decreases with increasing pressure. The temperature Tmim where the thermopower S takes minimum at high temperature region increases linearly with increasing pressure. The high-temperature minimum of S is associated with a sharp peak in density of states related mainly to the Co 3d-electron density. Since the width of an itinerant electronic band depends on the extent of the corresponding overlapping of 3d orbitals, the pressure variation of Tmin can be attributed to the broadening of the peak width of 3d electron density of states.

To evaluate dose proportionality and absolute bioavailability of a new enteric-coated pellet formulation of pamidronate disodium (AREDIA), nine females (aged 52–66 years) were given three different single peroral doses of pamidronate disodium (75, 150, and 300 mg) and an i.v. infusion of 15 mg over 30 minutes at constant infusion rate. Repeated peroral doses (75 and 150 mg) were administered to 12 females (aged 51–70 years) for 10 consecutive days. Urinary excretion of pamidronate after peroral and i.v. administration was used for estimation of pamidronate absorption. Renal excretion of pamidronate ranged from 0.01% to 0.35% of dose, with mean values of 0.11, 0.16, and 0.18% for 75, 150, and 300 mg, respectively. After i.v. infusion, the renal excretion of pamidronate was 26–53% of the dose, lower than for other bisphosphonates. The absolute bioavailability was 0.31% (range 0.08–0.7%) after 75 mg, 0.43% (0.01–1.20%) after the 150-mg dose, and 0.48% (0.07–1.06%) following 300 mg of pamidronate disodium. Urinary excretion after the 10th intake showed a significant increase (difference 0.07% (range -0.003-0.29%),P < 0.02) when compared with the first dose. In conclusion, intestinal uptake of pamidronate was low with high intraindividual variation, like other bisphosphonates.

Background: Pamidronate is a secondgeneration bisphosphonate used in the treatment of tumor-induced hypercalcemia and in the management of bone metastases from breast cancer, myeloma, or prostate cancer. The pharmacokinetics of pamidronate is unknown in cancer patients. Purpose: To determine the influence of the rate of administration and of bone metabolism, we studied the pharmacokinetics of pamidronate at three different infusion rates in 37 patients with bone metastases. Methods: Three groups of 11-14 patients were given 60 mg pamidronate as an intravenous infusion over a period of 1, 4, or 24 hours. Urine samples were collected in the three groups of patients. Plasma samples were obtained only in the 1-hour infusion group. The assay of pamidronate in plasma and urine was performed by high-performance liquid chromatography with fluorescence detection after the derivatization of pamidronate with fluorescamine. Results: The body retention (BR) at 0-24 hours of pamidronate represented 60%-70% of the administered dose and was not significantly modified by the infusion rate. In particular, the BR at 0-24 hours was not reduced at the fastest infusion rate. Among patients, a threefold variability in BR at 0-24 hours occurred, which was related directly to the number of bone metastases and, to some extent, to creatinine clearance. At 60 mg/hour, the plasma kinetics followed a multiexponential course characterized by a short distribution phase. The mean (±SD) half-life of the distribution phase was 0.8 hour (±0.3), the mean (±SD) of the area under the curve for drug concentration in plasma × time at 0-24 hours was 22.0 × 8.8 μmol/L × hours, and the mean (±SD) of the maximum plasma concentration was 9.7 μmol/L (±3.2). Pharmacokinetic variables remained unchanged after repeated infusions applied to four patients. Clinically, the three infusion rates were equally well tolerated without significant toxicity. Conclusions: The 1-hour infusion rate could be proposed as kinetically appropriate for the administration of pamidronate to patients with metastatic bone diseases. [J Natl Cancer Inst 84: 788-792, 1992]

To determine if iron chelation therapy has activity against human malaria, we administered desferrioxamine B in amounts of 100 mg/kg per day by continuous 72-hour subcutaneous infusions to 28 volunteers with asymptomatic Plasmodium falciparum infection in a randomized, double-blind, placebo-controlled crossover trial. Peripheral blood concentrations of P falciparum ring forms were determined at 12-hour intervals in all subjects and serum concentrations of desferrioxamine B + ferrioxamine (the iron complex of desferrioxamine B) were measured in 26 subjects. Geometric mean concentrations of asexual intraerythrocytic parasites decreased with both chelator and placebo treatment, but the decrement with desferrioxamine B was significantly greater than that with placebo (P less than .006) during both the initial and crossover periods. Compared with placebo, desferrioxamine B treatment was associated with an almost 10-fold enhancement of the rate of parasite clearance during both phases of the trial (P less than .007). Mean +/- SEM steady state concentrations of desferrioxamine B + ferrioxamine were 6.90 +/- 0.60 mumol/L at 36 hours and 7.72 +/- 0.68 mumol/L at 72 hours; in vitro, the ID50 has been reported to be approximately 4 to 20 mumol/L. No drug toxicity was detected. Parasitemia recurred in 19 of 24 participants followed-up over 1 to 6 months. We conclude that desferrioxamine B enhances the clearance of P falciparum parasitemia and that iron chelation may provide a new strategy to be developed for the treatment of malaria.

The effects of dextropropoxyphene on the steady-state kinetics of oxcarbazepine and its metabolites were investigated in eight patients with epilepsy or trigeminal neuralgia. One patient dropped out of the study, presumably due to side-effects of dextropropoxyphene. Dextropropoxyphene did not affect the plasma levels of the principal active metabolite, 10,11-dihydro-10-hydroxy-carbamazepine. Since dextropropoxyphene is known to increase the plasma levels of carbamazepine, leading to toxicity, the findings of this study suggest that oxcarbazepine is a useful alternative to carbamazepine when concomitant dextropropoxyphene therapy is required.

A dynamic method for the damage evaluation of large bridges was developed by BVFA and Technical University Graz. The method is a combination of dynamic insitu-tests and dynamic calculations. The basic idea is to detect damages of bridges via changes of the dynamic parameters. The steps of application are dynamic insitu-testing, mathematical modelling, fitting of the mathematical model to the test results and sensitivity investigations. The development of the method is presented by discussing the history of application. Further references for detailed information and some examples from past projects are given. The latest investigations were started in Oct. 1988 on five bridges on Brenner motor-ways. The tests were finished in April 1989, analysis of measurements is still in process. More detailed results will be given in forthcoming papers.

We have designed and built a miniature near-IR tunable diode laser (TDL) spectrometer for measuring in situ the water vapor mixing ratio either in the Martian atmosphere or thermally evolved from Martian soil or ice samples. The laser hygrometer uses a thermoelectrically cooled single-mode distributed-feedback TDL at 1.87 microm to scan over a selected vibration-rotation line of both H2O and CO2 near 5327.3 cm(-1). A working prototype that weighs only 230 g has been built and used to generate spectra whose analysis demonstrates precision sensitivities as fine as 1 part in 10(6) by volume in 1 s or 0.1 part in 10(6) in 10 s at Martian pressures and temperatures. Absolute uncertainties of approximately 5% are calculated.

The Airborne Laser Infrared Absorption Spectrometer II (ALIAS-II) is a lightweight, high-resolution (0.0003-cm(-1)), scanning, mid-infrared absorption spectrometer based on cooled (80 K) lead-salt tunable diode laser sources. It is designed to make in situ measurements in the lower and middle stratosphere on either a balloon platform or high-altitude remotely piloted aircraft. Chemical species that can be measured precisely include long-lived tracers N(2)O and CH(4), the shorter-lived tracer CO, and chemically active species HCl and NO(2). Advances in electronic instrumentation developed for ALIAS-I, with the experience of more than 250 flights on board NASA's ER-2 aircraft, have been implemented in ALIAS-II. The two-channel spectrometer features an open cradle, multipass absorption cell to ensure minimal contamination from inlet and surfaces. Time resolution of the instrument isor=3 s, allowing rapid in situ measurements with excellent spatial resolution. ALIAS-II has completed successful balloon flights from New Mexico, Alaska, and Brazil providing CH(4) and N(2)O vertical profiles in the tropics, mid-latitudes, and high northern latitudes up to altitudes of 32 km.

2,3-Dihydro-2-azasqualene, its N-oxide and its N,N-diethyl analogue, as well as 2,3-dihydro-2,3-iminosqualene are potent inhibitors of the squalene to hopanoid (diplotene and diplopterol) cyclases in cell-free systems from Acetobacter pasteurianus ssp pasteurianus, Methylobacterium organophilum and Zymomonas mobilis. The inhibitory concentration giving 50% inhibition at a 120 μM squalene concentration was determined in each cases. The growth of hopanoid producing prokaryotes (with the exception of Acetobacter pasteurianus ssp pasteurianus and Pseudomonas syringae probably capable of degrading the drugs) was inhibited by these squalene analogues at concentrations in the μM range, whereas the growth of hopanoid non-producers was not affected at the highest tested concentration (200 μM). Thus hopanoids which have been shown to possess similar properties to those of sterols in membrane reinforcement are probably essential for the cells producing them. Furthermore, all tested hopanoid producers are very sensitive to trimethyloctadecyl ammonium bromide which does not inhibit the squalene to hopane cyclases at a 50 μM concentration, and do not grow after 24 h in its presence at a 1 μM minimal inhibitory concentration. Growth of hopanoid non-producers was however not affected by this ammonium salt (highest tested concentration: 200 μM). The mode of action of this cationic detergent is still unknown, but might be related to specific desorganization of hopanoid containing membranes.

Among the triterpenoids of the bacterium Zymomonas mobilis a novel hopanoid, 32-oxobacteriohopane-33,34,35-triol beta-linked via its primary hydroxy group to glucosamine, has been isolated as a minor compound.

Two groups of 75 incarcerated felons, one described as softcore and the other as hardcore differed from an equal-sized control group and from each other on 514 true-false items depicting attitudes and opinions. Two pools of test items were identified that will serve as test statements along with neutral filler items in a follow-up study to identify soft- and hardcore felons.

Summary.-This investigation concerned a comparison of the opinions and attitudes of male felons incarcerated for homicidal or assaultive behavior and matched with subjects of a normal, control group. The 5 0 incarcerated and 50 control subjects were closely matched on age, sex, race, and education. A specially designed questionnaire of 330 items was administered one-to-one or in groups of rwo to five subjects. The felons were screened for current psychotic disturbance, heavy medication, and mental retardation. They were classified as either homicidal or assaultive by review of their official records and the judgment of two three-member panels of judges. The data were subjected ro one-way analysis of variance and an item analysis using the Lawshe and Baker technique for testing the significance of differences becween percentages. There have been some efforts, although not large scale ones to use psychological evaluations and psychometric scales to assess the traits of convicted felons. This effort is increasing; yet need for research continues. Notable has been the work of Megargee and Bohn (1979) in classifying criminal offenders. Studies have concerned differentiating between violent and nonviolent felons (Justice & Birkman, 1972; Wilds, 1973; Perdue & Lester, 1974; Justice, Justice, & Kraft, 1974; Lester, et dl., 1975; Hays, Roberts, & Solway, 1981; Wolfgang & Ferracuti, 1982 ) . METHOD An inmate group of aggressive felons was divided into two groups. Homicidal felons were 50 incarcerated men serving time for first-degree murder in a maximum security prison. These inmates were first identified by examination of their institutional records and then qualified by two panels of judges, one of three psychologists and the other of three experienced correctional officers who knew the felons. The assaultive felons were 50 men convicted for assaultive crimes other than murder. Examples would be assault, malicious cutting and wounding, or malicious shooting and wounding. These subjects were also classified on the basis of their official records. The normal control group of 50 male factory/industrial workers was comprised mostly of hourly employees and some college students with no previous record of a conviction for adult felony.

A dynamic method for the damage evaluation of large bridges is developed by BFVA and Technical University Graz. The method is a combination of dynamic in-situ tests and dynamic calculations and is also useful for the general improvement of mathematical modelling for static and dynamic calculations. Experiences with prestressed bridges were obtained. In general damages decrease the stiffness and increase damping. The structures are very large and the influences of cracks on dynamic parameters are very small. The basic concept of the method is to elaborate a dynamic model in the virgin state of the structure. Damages of the structure will lead to a certain pattern of deviations of dynamic parameters from the virgin state and can be used for localisation and quantification of damages in a global manner.