Mars atmosphere. The imprint of atmospheric evolution in the D/H of Hesperian clay minerals on Mars.

The deuterium-to-hydrogen (D/H) ratio in strongly bound water or hydroxyl groups in ancient martian clays retains the imprint of the water of formation of these minerals. Curiosity's Sample Analysis at Mars (SAM) experiment measured thermally evolved water and hydrogen gas released between 550° and 950°C from samples of Hesperian-era Gale crater smectite to determine this isotope ratio. The D/H value is 3.0 (±0.2) times the ratio in standard mean ocean water. The D/H ratio in this ~3-billion-year-old mudstone, which is half that of the present martian atmosphere but substantially higher than that expected in very early Mars, indicates an extended history of hydrogen escape and desiccation of the planet.

Volatile and organic compositions of sedimentary rocks in Yellowknife Bay, Gale crater, Mars.

H2O, CO2, SO2, O2, H2, H2S, HCl, chlorinated hydrocarbons, NO, and other trace gases were evolved during pyrolysis of two mudstone samples acquired by the Curiosity rover at Yellowknife Bay within Gale crater, Mars. H2O/OH-bearing phases included 2:1 phyllosilicate(s), bassanite, akaganeite, and amorphous materials. Thermal decomposition of carbonates and combustion of organic materials are candidate sources for the CO2. Concurrent evolution of O2 and chlorinated hydrocarbons suggests the presence of oxychlorine phase(s). Sulfides are likely sources for sulfur-bearing species. Higher abundances of chlorinated hydrocarbons in the mudstone compared with Rocknest windblown materials previously analyzed by Curiosity suggest that indigenous martian or meteoritic organic carbon sources may be preserved in the mudstone; however, the carbon source for the chlorinated hydrocarbons is not definitively of martian origin.

Volatile, isotope, and organic analysis of martian fines with the Mars Curiosity rover.

Samples from the Rocknest aeolian deposit were heated to ~835°C under helium flow and evolved gases analyzed by Curiosity's Sample Analysis at Mars instrument suite. H2O, SO2, CO2, and O2 were the major gases released. Water abundance (1.5 to 3 weight percent) and release temperature suggest that H2O is bound within an amorphous component of the sample. Decomposition of fine-grained Fe or Mg carbonate is the likely source of much of the evolved CO2. Evolved O2 is coincident with the release of Cl, suggesting that oxygen is produced from thermal decomposition of an oxychloride compound. Elevated δD values are consistent with recent atmospheric exchange. Carbon isotopes indicate multiple carbon sources in the fines. Several simple organic compounds were detected, but they are not definitively martian in origin.

Pharmacokinetics of the monohydroxy derivative of oxcarbazepine and its enantiomers after a single intravenous dose given as racemate compared with a single oral dose of oxcarbazepine.

Oxcarbazepine (OXC) is an antiepileptic drug. In humans, OXC is metabolized via reduction and conjugation. Monohydroxy derivative of OXC (MHD) is the major pharmacologically active component after OXC ingestion. This study was performed to characterize the disposition of the two enantiomers of MHD after oral and intravenous administration and to estimate the bioavailability of MHD after a single oral dose administration of OXC compared to a single intravenous administration of MHD. The study was performed in two parts. In a first pilot study, three intravenous doses were given in an ascending manner (150, 200, and 250 mg of MHD; one subject per dose level) to assess the safety, tolerability, and basic pharmacokinetics. Part two was an open, single-center, randomized, two-way crossover, single-dose trial in 12 healthy adult subjects (n = 6 males and n = 6 females) given OXC orally (one film-coated 300-mg tablet of OXC) and MHD intravenously (250 mg infused over 30 min). Concentrations of OXC and its metabolites were measured by means of high-performance liquid chromatography methods. OXC given as a tablet is completely absorbed in man under fasting conditions. When MHD is given intravenously, (S)-MHD predominates as free compound in plasma. When OXC is administered orally, the ratio of the area-under-the-curve values of (S)-MHD over (R)-MHD equals 3.8, indicating an enantioselective reduction of the prochiral carbonyl group of OXC.

Assessment of the bioequivalence of two oxcarbazepine oral suspensions versus a film-coated tablet in healthy subjects.

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.

Oxcarbazepine final market image tablet formulation bioequivalence study after single administration and at steady state in healthy subjects.

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.

Quantum-cascade laser measurements of stratospheric methane and nitrous oxide.

A tunable quantum-cascade (QC) laser has been flown on NASA's ER-2 high-altitude aircraft to produce the first atmospheric gas measurements with this newly invented device, an important milestone in the QC laser's future planetary, industrial, and commercial applications. Using a cryogenically cooled QC laser during a series of 20 aircraft flights beginning in September 1999 and extending through March 2000, we took measurements of methane (CH(4)) and nitrous oxide (N(2)O) gas up to ~20 km in the stratosphere over North America, Scandinavia, and Russia. The QC laser operating near an 8-mum wavelength was produced by the groups of Capasso and Cho of Bell Laboratories, Lucent Technologies, where QC lasers were invented in 1994. Compared with its companion lead salt diode lasers that were also flown on these flights, the single-mode QC laser cooled to 82 K and produced higher output power (10 mW), narrower laser linewidth (17 MHz), increased measurement precision (a factor of 3), and better spectral stability (~0.1 cm(-1) K). The sensitivity of the QC laser channel was estimated to correspond to a minimum-detectable mixing ratio for methane of approximately 2 parts per billion by volume.

Oxcarbazepine placebo-controlled, dose-ranging trial in refractory partial epilepsy.

PURPOSE: The goal of the study was to evaluate the safety and efficacy of a broad oxcarbazepine (OXC) dosage range (600, 1200, and 2400 mg/d) as adjunctive therapy for uncontrolled partial seizures and to determine the relationship between trough plasma 10-monohydroxy derivative concentrations and OXC safety and efficacy. METHODS: This multinational, multicenter, randomized, 28-week, double-blind, placebo-controlled, four-arm, parallel-group trial enrolled 694 patients aged 15-65 years with uncontrolled partial seizures with or without secondarily generalized seizures. The primary efficacy variable was percentage change in seizure frequency per 28 days relative to baseline. RESULTS: The median reduction in seizure frequency was 26%, 40%, 50%, or 8% for patients receiving 600, 1200, or 2400 mg/d OXC or placebo, respectively (all p < or = 0.0001). Of patients in the 600, 1200, or 2400 mg/d OXC groups, 27%, 42%, and 50% respectively, had more than 50% reduction in seizure frequency compared with 13% for placebo (all p < 0.001). Higher plasma 10-monohydroxy derivative concentrations were associated with larger decreases in seizure frequency (p = 0.0001). During the double-blind treatment phase, 84%, 90%, 98%, and 76% of patients receiving 600, 1200, or 2400 mg/d OXC or placebo, respectively, reported one or more adverse events. The most common adverse events were related to the nervous and digestive systems. CONCLUSIONS: OXC is safe and effective as adjunctive therapy in patients with uncontrolled partial seizures. OXC 600 mg/d was the minimum effective dosage; effectiveness of OXC increased with dose. The rapid and fixed titration to high doses was associated with an increased risk of adverse events, which could potentially be reduced by adjusting concomitant antiepileptic medication and by using a slower, flexible OXC titration schedule.

Intravenous pamidronate for treatment of reflex sympathetic dystrophy during breast feeding.

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.

Airborne laser infrared absorption spectrometer (ALIAS-II) for in situ atmospheric measurements of N2O, CH4, CO, HCl, and NO2 from balloon or remotely piloted aircraft platforms.

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 is

An interaction study with cimetidine and the new angiotensin II antagonist valsartan.

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 of valsartan in patients with liver disease.

OBJECTIVES: Valsartan (CGP 48933), an orally active angiotensin II antagonist, is eliminated mainly by hepatic clearance. To characterize the compound(s) excreted in the bile, biliary excretion of valsartan was investigated by collection of bile after an intravenous dose of valsartan. In addition, to determine the exposure to valsartan when liver function is impaired, a pharmacokinetic study (open, single dose) was performed in patients with mild and moderate impairment of liver function. PATIENTS: Biliary excretion of valsartan (after intravenous administration of 20 mg valsartan) was assessed in a patient who underwent a hepaticojejunostomy with subsequent bile drainage. Exposure to valsartan in patients with mild (n = 6) or moderate (n = 6) impaired liver function (Child's-Pugh classification) and matching (sex, age, and weight) healthy volunteers (n = 12) was studied after oral administration of a single dose of 160 mg valsartan. RESULTS: After intravenous administration, valsartan was eliminated mainly as unchanged drug in the bile. Mean exposure (measured as area under the plasma valsartan concentration-time curve) to valsartan was increased about twofold in both the mild and the moderate groups compared with matched (age, sex, and weight) healthy volunteers. CONCLUSION: These data are consistent with the pharmacokinetics of valsartan in that biliary excretion is the main route of elimination.

Quantitative determination of CGP 61755, a protease inhibitor, in plasma and urine by high-performance liquid chromatography and fluorescence detection.

A liquid chromatographic assay for the determination of CGP 61755 (I) in plasma and urine is described. A similar method for CGP 53437, another HIV-1 protease inhibitor, has been developed and reported previously. After a deproteinization step, a liquid-liquid extraction is performed. Compound I and the internal standard CGP 55749 (II) are hydrolyzed and the primary amine group derivatized using fluorescamine. Chromatography is achieved by isocratic elution with a mobile phase of 30 mM borax buffer (pH 9)-acetonitrile (58:42, v/v). The derivatives of the compounds I and II fluoresce at 480 nm, on excitation at 395 nm and the retention times under these conditions were approximately 6 and 8 min, respectively. The limit of quantitation (LOQ) which is the lowest concentration of the analyte that can be measured with a coefficient of variation and a deviation from theory of less than 20%, was 15 ng/ml plasma and 20 ng/ml urine. The analyte is stable for at least four months in human plasma and sixteen months in dog plasma samples. Different human plasma sources and three different species (rat, rabbit and dog) were tested and no interference between analyte and plasma constituents was observed.

Absolute bioavailability and pharmacokinetics of valsartan, an angiotensin II receptor antagonist, in man.

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.

Pharmacokinetics, disposition and biotransformation of [14C]-radiolabelled valsartan in healthy male volunteers after a single oral dose.

1. The disposition of valsartan, a potent angiotensin II receptor antagonist, was investigated in six healthy male volunteers. They each received a single oral dose of 80 mg of a 14C-labelled preparation as a neutral buffered solution. 2. Peak concentrations of radioactivity and valsartan in plasma measured 1 h after dosing showed rapid onset of absorption. The results of this study combined with other available data indicate that at least 51% of the dose was absorbed. 3. Valsartan was the predominant radioactive compound in plasma. Elimination of valsartan and radioactivity was fast and multiexponential. beta-Half-lives of 6 +/- 1 h were observed. In a terminal elimination phase, low radioactivity levels decreased with a half-life of 81 +/- 33 h. A minor, pharmacologically inactive metabolite (valeryl-4-hydroxy-valsartan; M1) was detected in the plasma at time points later than 2 h after dosing, representing approximately 11% of the AUC(24 h) of plasma radioactivity. 4. The bulk of the dose was excreted within 4 days. The total excretion within 7 days amounted to 99 +/- 1% of dose. Faecal excretion was predominant (86 +/- 5% of dose). Valsartan was largely excreted unchanged (81 +/- 5% of the dose in the excreta). The predominant clearance mechanism appeared to be direct elimination via bile. 5. An inactive metabolite, M1, was formed by oxidative biotransformation and accounted for 9 +/- 3% of the dose in the excreta.

Pharmacokinetics and pharmacodynamic effects of the angiotensin II antagonist valsartan at steady state in healthy, normotensive subjects.

OBJECTIVE: 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. METHODS: 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. RESULTS: Absorption and distribution of valsartan were rapid (Cmax, 2 h; t1/2 lambda 1 < 1 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. CONCLUSIONS: 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 interaction of single oral doses of valsartan and furosemide.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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.

Profile of CGP 61755: a novel and potent HIV-1 protease inhibitor that shows enhanced anti-HIV activity when combined with other antiretroviral agents in vitro.

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.

Comparison of plasma and saliva concentrations of the active monohydroxy metabolite of oxcarbazepine in patients at steady state.

A study was performed in ten patients, stabilized with oxcarbazepine monotherapy (450-750 mg bid) for two weeks minimum, to investigate the possibility of using saliva to monitor the oxcarbazepine therapy. Thirteen paired blood and saliva samples were taken over 24 h. The saliva samples were obtained after stimulation. The analysis performed on the data suggests a dose dependence for the relationship between plasma and saliva concentrations of the main active metabolite, 10, 11-dihydro-10-hydroxycarbamazepine (MHD), and the importance of the type of stimulation for the saliva's production. Therefore it would be preferable to use plasma concentrations to monitor oxcarbazepine therapy, if necessary.

Replacing carbamazepine slow-release tablets with carbamazepine suppositories: a pharmacokinetic and clinical study in children with epilepsy.

A suppository for rectal administration of carbamazepine has been developed for situations in which it is unsuitable to use the oral route of administration. In an open, controlled, within-patient study, the pharmacokinetics, clinical efficacy, and tolerability of carbamazepine slow-release tablets were compared with those of carbamazepine suppositories in children with epilepsy. The pharmacokinetic part of the study comprised 22 children, and an additional nine children were included in the clinical part of the study. Treatment with slow-release tablets was replaced for 7 days with carbamazepine suppositories in bioequivalent dosage. Clinical factors such as the rate of seizures and the local tolerability were studied, and an overall assessment of efficacy was made. In the pharmacokinetic part, 24-hour plasma concentration curves for carbamazepine and carbamazepine-10,11-epoxide were recorded. The plasma concentration profiles (minimum, maximum, and mean concentrations, fluctuation index, and area under the curve) for carbamazepine and the other metabolites did not show any significant differences between oral and rectal administration when the suppository dose was increased by 25% compared to the tablets. No increase in seizure frequency was detected, and the overall assessment was very good to good in 25 of the 29 epileptic children. Increased flatulence during treatment with suppositories was noted in two children, one had anal irritation, and one had nausea/vomiting. Treatment with carbamazepine slow-release tablets in children with epilepsy can be replaced by carbamazepine suppositories in 25% higher dosage, with good clinical effect and appropriate pharmacokinetic values, when it is unsuitable to use the common oral route of administration.