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We have used the Sydney University Stellar Interferometer (SUSI) to measure the angular diameter of beta Hydri. This star is a nearby G2 subgiant whose mean density was recently measured with high precision using asteroseismology. We determine the radius and effective temperature of the star to be 1.814+/-0.017 R_sun (0.9%) and 5872+/-44 K (0.7%) respectively. By combining this value with the mean density, as estimated from asteroseismology, we make a direct estimate of the stellar mass. We find a value of 1.07+/-0.03 M_sun (2.8%), which agrees with published estimates based on fitting in the H-R diagram, but has much higher precision. These results place valuable constraints on theoretical models of beta Hyi and its oscillation frequencies., 3 figures, 3 tables, to appear in MNRAS Letters

ABSTRA C T The Sydney University Stellar Interferometer (SUSI) is a new long-baseline optical interferometer located in northern New South Wales, Australia. SUSI has been developed to tackle a range of problems in stellar astrophysics, and its design is based on a successful prototype instrument. In its initial configuration, observations are made with a single baseline selected from an array of fixed north‐south baselines covering the range from 5 to 640 m. Small apertures, wavefront-tilt correction and rapid signal sampling are employed to overcome the effects of atmospheric turbulence, and optical path equality is maintained by a dynamic optical delay line. The planned astrophysical programmes, the resulting design criteria, the instrument and its current status are described.

We have used the Sydney University Stellar Interferometer (SUSI) to measure the angular diameter of the F9 V star beta Virginis. After correcting for limb darkening and combining with the revised Hipparcos parallax, we derive a radius of 1.703 +/- 0.022 R_sun (1.3%). We have also calculated the bolometric flux from published measurements which, combined with the angular diameter, implies an effective temperature of 6059 +/- 49 K (0.8%). We also derived the luminosity of beta Vir to be L = 3.51 +/- 0.08 L_sun (2.1%). Solar-like oscillations were measured in this star by Carrier et al. (2005) and using their value for the large frequency separation yields the mean stellar density with an uncertainty of about 2%. Our constraints on the fundamental parameters of beta Vir will be important to test theoretical models of this star and its oscillations., accepted for publication in MNRAS. Updated references

The Sydney University Stellar Interferometer (SUSI) has now been operating with a significanly more sensitive beam combiner system (the Red Table) for several years. A number of novel results from the realms of single, binary and pulsating star astrophysics are presented. Simultaneous dual beam-combiner operation with the Red Table and an upgraded Blue Table has been demonstrated, enabling a high spectral dispersion oberving mode for stellar studies. Plans for a major upgrade are briefly described. One component of this will be remote operation of the array for routine observational data taking, with first steps on this path reported here with the inception of the Sydney Remote Operations Center. The backbone of future plans with SUSI center around the installation of the southern of the twin PAVO instruments. PAVO is also discussed in more detail in Ireland et al, this proceedings.

Observations of the southern Cepheids lCar and β Dor to yield the mean angular diameters and angular pulsation amplitudes have been made with the Sydney University Stellar Interferometer (SUSI)at a wavelength of 700 nm. The results of a preliminary analysis are compared with those obtained with the VLTI at 2.2 μm and excellent agreement between the results from the two instruments is found for lCar but there are significant differences for βDor.

New angular diameter determinations for the bright southern F8 supergiant Delta CMa enable the bolometric emergent flux and effective temperature of the star to be determined with improved accuracy. The spectral flux distribution and bolometric flux have been determined from published photometry and spectrophotometry and combined with the angular diameter to derive the bolometric emergent flux F = (6.50 plus/minus 0.24) x 10^7 W/m^2 and the effective temperature Teff = 5818 plus/minus 53 K. The new value for the effective temperature is compared with previous interferometric and infrared flux method determinations. The accuracy of the effective temperature is now limited by the uncertainty in the bolometric flux rather than by the uncertainty in the angular diameter., 8 pages, 4 figures

A new beam-combination and detection system has been installed in the Sydney University Stellar Interferometer working at the red end of the visual spectrum (wavelength range 500-950 nm) to complement the existing blue-sensitive system (wavelength range 430-520 nm) and to provide an increase in sensitivity. Dichroic beam-splitters have been introduced to allow simultaneous observations with both spectral system, albeit with some restriction on the spectral range of the longer wavelength system (wavelength range 550-760 nm). The blue system has been upgraded to allow remote selection of wavelength and spectral bandpass, and to enable simultaneous operation with the red system with the latter providing fringe-envelope tracking. The new system and upgrades are described and examples of commissioning tests presented. As an illustration of the improvement in performance the measurement of the angular diameter of the southern F supergiant delta CMa is described and compared with previous determinations., Comment: 13 pages, 14 figures

The Sydney University Stellar Interferometer is a long baseline optical interferometer located in northern New South Wales, Australia. It has a North-South array of eleven fixed input siderostat stations giving a range of baselines from 5 to 640 m. Currently ten baselines from 5 to 160 m are fully operational and beam-combination and detection systems for the spectral ranges 430-520nm and 550-950nm are available. Dichroic beam-splitters have been introduced to allow simultaneous observations with both spectral systems. The original blue beam-combination system has been upgraded to improve sensitivity and to allow rapid wavelength switching. A software scheduler has been developed to automate much of the observational procedure including the acquisition of a star, fringe search and acquisition, recording of fringe scans, and the taking of photometric scans. A data pipeline for processing the observational data has been further developed to include seeing corrections and this has improved the calibration of the observational data. Preliminary results of scientific observations with both blue and red systems, including observations of single stars, binary stars and Cepheid variables are described.

The SUSI control system is a distributed real-time system currently consisting of 17 processors. A custom real-time operating system and network protocols ensure synchronous operation of servo loops across multiple processors.

We have examined a small group of tantalum pentoxide (Ta2O5) wafers with grazing incidence x-ray reflectivity (GIXR) and powder diffraction. GIXR gives accurate measurements of layer thickness, layer interface widths, and densities for single and multilayer samples. Powder diffraction allows detection of crystallinity, identification of specific phases or verification of amorphous structure. The combination of these two methods permits fairly detailed characterization of polycrystalline thin films. The densities obtained by GIXR vary over a considerable range from 5.08 g/cm3 to 9.10 g/cm3. The theoretical densities for the hexagonal form and the orthorhombic form of Ta2O5 are 8.316 g/cm3 and 8.2 g/cm3 respectively. The large variation in density suggests that other oxides may have formed or that other polymorphs of Ta2O5 with lower densities may be present in some samples. The powder diffraction results indicate crystallinity in at least some of the samples. While this work has demonstrated good structura...

The goal of these studies was to examine the relationship between the rate of phencyclidine (PCP) administration and PCP tissue distribution. The time course of PCP distribution in serum, brain, and testis after rapid (i.v.) and slow (s.c.) administration was studied. Brain and serum PCP concentrations after an i.v. bolus dose (1 mg/kg at 900 microg/min) were highest at 30 s and decreased biphasically, with serum concentrations decreasing 30 times faster than brain concentrations during the early phase. Consequently, the brain-to-serum PCP concentration ratio increased from 8:1 at 30 s to 14:1 at 20 min before equilibrating at a ratio of 3:1 that remained constant from 1 to 8 h. In contrast, the testis-to-serum ratio increased slowly from 1:1 to 12:1 over 4 h, and then remained constant. In a separate group of animals, an s.c. infusion of PCP (18 mg/kg/day or 3.6 microg/min) produced a brain-to-serum ratio (6:1) that remained constant throughout the 96-h infusion. Testis-to-serum ratios increased from 4:1 at 1 h to 12:1 at 8 h and then remained constant for 96 h. Steady-state infusion of a pharmacologically inactive dose (2.5 mg/kg/day) produced a brain-to-serum ratio (3:1) that was significantly lower than the ratio (6:1) after infusion of the three pharmacologically active doses (10-25 mg/kg/day). The temporary high brain PCP concentrations and the dynamic disequilibrium between brain and serum concentrations after rapid i.v. administration could provide a better understanding of the preference of the human drug abuser for rapid rates (e.g., i.v. or smoking) of drug administration.

These studies examined the hypothesis that a single large dose of monoclonal anti-phencyclidine (PCP) antibody could provide long-term reductions in brain PCP concentrations despite continuous PCP administration. PCP (18 mg/kg/day, s.c.) was infused to steady-state (24 h) and then a mole-equivalent dose of a short-acting anti-PCP antigen-binding fragment (Fab) or a long-acting anti-PCP IgG was administered i.v. The PCP infusion continued for up to 27 days, even though the binding capacity of the single dose of antibody used should have been saturated within the first day. At selected time points after antibody administration, brain, testis, and serum PCP concentrations were measured. Serum PCP concentrations rapidly increased approximately 100- and 300-fold after Fab or IgG administration, respectively. Based on the antibody-bound PCP concentrations in serum, the functional elimination half-life (t(1/2lambdaZ)) values for PCP-Fab and PCP-IgG complexes were 9.4 h and 15.4 days, respectively. Fab and IgG administration produced a complete removal of PCP from the brain within 15 min. Although brain PCP concentrations were significantly decreased for only 4 h in Fab-treated animals, IgG administration resulted in significant decreases in brain PCP concentrations lasting for at least 27 days. In contrast, testis PCP concentrations were not substantially affected by antibody administration, suggesting that redistribution of PCP from the testis is too slow to benefit from a limited dose of antibody. These results indicate that anti-PCP IgG can preferentially protect the brain for approximately 4 weeks after IgG administration, even when the antibody binding capacity should have been saturated with continuously administered PCP.

These studies characterized the concentration-time profile of (+)-methamphetamine [(+)-METH] and its metabolite (+)-amphetamine [(+)-AMP] in the brain and five other tissues after (+)-METH administration. Male Sprague-Dawley rats received a pharmacologically active (+)-METH i.v. bolus dose (1.0 mg/kg) or a nonpharmacologically active s.c. infusion (20 h at 1.2 mg/kg/day). Tissues (n = 3 per time point) were collected for more than four elimination half-lives in the i.v. group, or at a single steady-state time point (20 h) in the s.c. group. Based on data from the area under the concentration-time curves after i.v. dosing, the rank order of (+)-METH tissue accumulation was kidneyspleenbrainliverheartserum with terminal elimination half-life values ranging from 53 to 66 min. (+)-METH concentrations were highest at the first measured time point (2 min) in all tissues except the spleen, which peaked at 10 min. The brain-to-serum concentration ratio rose from 7:1 at 2 min to a peak of 13:1 at 20 min before equilibrating to a constant value of 8:1 at 2 h. Following s.c. (+)-METH dosing, the (+)-METH brain-to-serum concentration ratio was the same as the equilibrated ratio following i.v. dosing. (+)-AMP concentrations peaked at 20 min in all tissues before decaying with terminal elimination half-life values ranging from 68 to 75 min. Analysis of the area under the concentration-time curve molar amounts of (+)-AMP and (+)-METH showed that (+)-AMP accounted for approximately one-third of the drug tissue exposure over time. Thus, these data indicate the importance of both (+)-METH and (+)-AMP in pharmacological effects following i.v. (+)-METH administration.

The purpose of these studies was to better understand the behavioral effects and pharmacokinetics of an i.v. bolus dose of (+)-methamphetamine [(+)-METH] in a rat model of (+)-METH abuse. We characterized the behavioral effects after increasing (+)-METH doses (0.1, 0.3, and 1.0 mg/kg) and the pharmacokinetics of (+)-METH (and its metabolite (+)-amphetamine [(+)-AMP)]) at the lowest and highest of these doses in adult male Sprague-Dawley rats. The doses and route of administration were selected to mimic aspects of human use on a dose/body weight basis. Although the 0.1 mg/kg dose did not cause statistically significant increases in locomotor activity compared with saline controls, the higher doses (0.3 and 1.0 mg/kg) caused statistically significant increases in locomotor activity (p.05), which lasted for up to 3 h at the highest dose. After the 1.0 mg/kg dose, the volume of distribution at steady state was 9.0 liters/kg, the total clearance was 126 ml/min/kg, and the average distribution and elimination half-lives were 9.2 and 63.0 min, respectively. Because the pharmacokinetic values after the 0.1 mg/kg dose were not different from those after the 1.0 mg/kg dose, the pharmacokinetics of (+)-METH were considered to be independent of the dose over this 10-fold range. (+)-AMP serum concentrations after the 1.0 mg/kg dose peaked from 10 to 30 min, and exhibited a T(1/2lambdaz) of 98.5 min. The statistically longer T(1/2lambdaz) of (+)-AMP (p.05) suggested that the (+)-AMP terminal elimination rate and not the (+)-AMP metabolic formation rate is the rate-limiting step in (+)-AMP elimination following i.v. (+)-METH dosing.

Studies were conducted to determine the differences in phencyclidine (PCP) in vitro metabolism and pharmacokinetics in female and male Sprague-Dawley (SD) rats. Formation rates of five major PCP metabolites in liver microsomes were significantly higher (p.05) in males compared with females in three different rat strains (SD, Fischer 344, and Dark Agouti). In addition, the formation rate for an irreversibly bound PCP metabolite in males was the second highest of the six metabolites measured in these studies. However, the liver microsomes from the females produced essentially no metabolite binding in any strain. To determine the in vivo consequences of these in vitro metabolism results, we determined PCP's pharmacokinetic profile in female SD rats after a pharmacologically active i.v. dose of PCP (1 mg/kg) and then compared these data with the pharmacokinetic profile in male SD rats. The value for PCP systemic (and nonrenal) clearance was more than 45% lower (p.05) in female rats. In addition, the terminal elimination T(1/2) was significantly longer (p.05) in the female rats (5.5 versus 3.4 h, respectively). Because the initial serum concentration, volume of distribution at steady state, and renal clearance were not significantly different between the sexes, the longer half-life was attributed directly to a decreased ability of females to metabolize the drug. Consequently, these pharmacokinetic data suggest pharmacological differences in PCP effects between female and male rats are due primarily to a decreased ability of female rats to metabolize the drug.

Our purpose was to determine mechanisms and methods for significantly increasing the renal coelimination of phencyclidine (PCP) and an anti-PCP monoclonal antibody binding fragment (anti-PCP Fab). To accomplish this goal, we performed a series of experiments to examine the dose-dependence of Fab elimination, mechanisms for enhancing PCP and Fab urinary coelimination and the antigenicity of repeated Fab administration. The results showed that urinary elimination of PCP and anti-PCP Fab was linear over a 30-fold range of doses. Anti-PCP Fab serum pharmacokinetics were best described using bi- or tri-exponential curves with a terminal elimination half-life of approximately 8 hr. Nevertheless, under all experimental conditions the early, nonterminal phase(s) were responsible for the majority (60%) of intact Fab elimination, with only 40% of the Fab eliminated during the terminal phase. These data suggest that the early rapid decline in Fab serum concentrations was primarily due to passive filtration and excretion of intact Fab, and not due to extravascular distribution as previously described. In comparison of methods for enhancing renal coelimination of Fab and PCP, systemic alkalinization produced a significant increase in Fab urinary elimination, with 69% of the Fab dose and 41% of the PCP dose recovered intact in the urine. Finally, in studies of the antigenicity of Fab, repeated administration of Fab produced no significant immune response or renal impairment. Overall, these experiments suggest that careful attention to the physiological status of the kidney during early time periods is essential for maximum coelimination of Fab and bound chemicals.

The development of treatment strategies for drug intoxication has been hindered in part by the lack of clinically useful antagonists. Consequently, the major goal of these studies was to determine whether a monoclonal antibody Fab fragment (of IgG) could be used as an effective drug class-selective antagonist and to understand better the dose-response relationships for reversing CNS drug toxicity. Changes in drug-induced locomotor effects in a rat model were used to assess the ability of the antiphencyclidine (anti-PCP) Fab to reverse the behavioral effects of PCP and other potent arylcyclohexylamines. In experiments to determine the pharmacodynamics of Fabinduced antagonism of behavioral effects, the Fab completely reversed all PCP-induced locomotor effects in a Fab dose-dependent manner with a minimal effective dose of 0.18 mole-equivalents of Fab and an ED50 value of about one-third mole-equivalent. The anti-PCP Fab also completely reversed the locomotor effects induced by two other structurally related potent analogs of PCP: 1-[1-(2-thienyl)cyclohexyl]piperidine and N-ethyl-1-phenylcyclohexylamine. In addition, pharmacological and immunological selectivity was further tested by treatment of the behavioral effects induced by the structurally unrelated locomotor stimulant (+)methamphetamine. The antibody did not effectively reverse the effects of methamphetamine-induced locomotor activity. These results indicate that antibody-based medications can be developed to treat toxicity caused by classes of drugs as well as by individual drugs.

These studies examined in vitro metabolism of phencyclidine (PCP) in a series of human liver microsomes (N = 10). Each sample was characterized for cytochrome P450 (CYP) content and for CYP1A, CYP2A, CYP2C, CYP2D, CYP2E, CYP3A, CYP4A, and lauric acid 11-hydroxylation metabolic activities. At least five PCP metabolites (c-PPC, t-PPC, PCHP, an unknown metabolite, and an irreversibly bound metabolite) were formed by the various human liver microsomes. Nevertheless, there was a large degree of inter-individual variation in the metabolite formation. For example, the irreversibly bound metabolite was formed in detectable amounts in only four of the ten samples. c-PPC, t-PPC and the irreversibly bound PCP metabolite formation rates significantly correlated with CYP3A activity. The CYP3A inhibitor troleandomycin was used to inhibit the formation of PCP metabolites. Troleandomycin inhibition was dose dependent with the highest dose producing complete inhibition of the formation of c-PPC, t-PPC, PCHP, and the irreversibly bound metabolite. In addition, PCP inhibited CYP3A-mediated testosterone 6 beta-hydroxylation by 50%. Furthermore, the relative intensity of CYP3A immunoreactive proteins significantly correlated with testosterone 6 beta-hydroxylation and with PCP metabolite formation (except for the unknown metabolite). PCHP formation also correlated with CYP1A activity, while the formation of the unknown PCP metabolite correlated with CYP2A activity. These studies suggest that several CYP isoforms contribute to PCP metabolism and that CYP3A plays a major role in PCP biotransformation in human liver microsomes.

These studies determined the effects of continuous phencyclidine (PCP) administration on cytochrome P450 2C11 (CYP2C11) function, protein expression and mRNA levels. Male Sprague-Dawley rats received s.c. PCP infusions (18 mg/kg/day) for 1, 3, 10 or 20 days (n = 4 per group). Control animals received saline infusions for 3 or 20 days. Livers were collected 24 hr postinfusion, a time when PCP was completely cleared from the animals. In microsomes from the 1- and 3-day PCP infusions, there was a significant decrease (P.05) in CYP2C11 protein expression (61 and 46% of control values, respectively) and in CYP2C11-mediated metabolism of PCP to a reactive metabolite (36 and 41% of control values). Both protein expression and PCP metabolite formation had returned to normal by 10 days of continuous PCP infusion. CYP2C11 function (as measured by 2alpha-OH testosterone formation) was decreased in the 1-, 3- and 10-day infused rats to 46, 28 and 45% of control values (P.05). CYP2C11 function, expression and reactive PCP metabolite formation returned to normal after 20 days of PCP infusion. In contrast, CYP2C11 mRNA levels were decreased (P.05) in liver tissue in PCP-treated rats from 1 to 20 days (43, 31, 37 and 47%, respectively). These data suggest that continuous PCP infusions initially decrease CYP2C11 function and protein expression by a pretranslational mechanism, but continued exposure to PCP leads to metabolic adaptation without the recovery of mRNA levels. Thus, chronic exposure to PCP can produce time-dependent regulation of CYP2C11-mediated metabolism of endogenous and exogenous compounds.

Phencyclidine (PCP) inactivates the 7-ethoxy-4-trifluoromethylcoumarin O-deethylase activity of P4502B1 in a reconstituted system containing NADPH-cytochrome P450 (P450) reductase (reductase) and L-alpha-phosphatidylcholine, dilauroyl in a time-, concentration-, and NADPH-dependent manner. Catalytic activity of the enzyme could not be restored upon reconstitution with fresh reductase, indicating that the effect was on the P450 and not on the reductase. Although the kinetics suggested that PCP would be classified as a classical mechanism-based inactivator, protection against inactivation of P450 by PCP by the presence of an exogenous nucleophile, such as glutathione (GSH), indicated otherwise. There was no loss of spectrally detectable P450 associated with inactivation either in the presence or absence of GSH. When radiolabeled PCP was used to inactivate the enzyme and the reaction mixture analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, radioactivity was found to be associated with P450, reductase, and catalase that had been added to protect against oxidative damage. When GSH was included in the reaction mixtures, analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated a marked decrease in the binding to all three proteins. Correspondingly, analysis of the components of the inactivated sample by reversed-phase HPLC demonstrated that radioactivity was associated with P450, reductase, and catalase, and that there was a marked decrease in the labeling of all three proteins in the presence of GSH. The stoichiometry of binding of radiolabeled PCP to the proteins in the incubation mixture in the absence of GSH was 4:1. In the presence of GSH, no significant amount of radioactivity was incorporated into the proteins. An anti-PCP metabolite antibody was used to detect PCP metabolite adducts bound to the inactivated enzyme by Western blot analysis. The antibody recognized adducts bound to P450, reductase, and catalase. In the presence of GSH, there was a decrease in immunoreactivity, although binding of PCP to all three proteins was still detected. Because the added nucleophile protects against inactivation and protein labeling by PCP, these data suggest that the reactive intermediate may escape from the active site and attack other sites on the P450, as well as other proteins in the milieu.

Antiphencyclidine monoclonal antibody binding fragments (anti-PCP Fab) were studied in rats as a possible treatment for phencyclidine (PCP) overdose. Each male Sprague-Dawley rat (n = 4 per group) received an i.v. dose of 1 mg/kg of PCP followed 5 min later (as toxicity maximized) by one of three treatments in a random cross-over design. The treatments were 1 ml of saline, a nonspecific polyclonal human Fab, or a high affinity (Kd = 1.8 nM) anti-PCP monoclonal Fab. The doses of the nonspecific and anti-PCP Fab were 0.3, 1.0 and 3.0 times the mole equivalent (mol-eq) dose of PCP. Changes in locomotor activity and ataxia were the best indicators of PCP-induced behaviors among several time-dependent behavioral changes that were evaluated. PCP administration followed by saline treatment resulted in increases in locomotor activity and ataxia that declined to base line after 35 to 40 min. Anti-PCP Fab at 1.0 and 3.0 times the mol-eq dose of PCP significantly (P.05) and rapidly reversed PCP-induced behaviors to base-line values. Although the 0.3 mol-eq dose of Fab appeared to slightly decrease the behavioral toxicity, the effects were not statistically different from controls in most cases. No significant effects on PCP-induced behaviors were observed after any dose of the nonspecific Fab. In addition, pharmacological and immunological specificity were tested further by treatment of MK-801 {(+)-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine-}-induced behavioral effects. MK-801 is a PCP-like, noncompetitive N-methyl-D-aspartate receptor antagonist which is structurally unrelated to PCP. The anti-PCP Fab treatment had no effect on MK-801-induced locomotor activity. These data clearly show that anti-PCP Fab is a specific PCP antagonist that can rapidly reverse PCP-induced behavioral toxicity in the rat.

These studies determined how high-affinity monoclonal antiphencyclidine (PCP) antigen binding fragments of immunoglobulin G (Fab) affects PCP tissue concentrations and serum protein binding in male rats. Animals received an i.v. bolus dose of 1.0 mg/kg of PCP, followed at 2 hr when distribution was complete (but about 70% of the dose remained) by either saline (for controls) or an equimolar dose of anti-PCP Fab. This dose of PCP was chosen because it produces behavioral effects and ataxia for about 40 min. The rats were sacrificed over the next 16 hr (n = 3 per time point) and blood, brain, fat, heart, kidney, liver, lung, muscle and testis were collected. After anti-PCP Fab treatment, serum PCP concentrations increased significantly (P.05) for the duration of the experiment. This resulted in a decrease in the PCP volume of distribution and systemic clearance to 11 and 12% of controls, respectively. Because these parameters decreased to a similar degree, the terminal elimination half-life was unaltered after Fab treatment. The percentage of unbound PCP in serum averaged 47 +/- 15% (mean +/- S.D.) in controls and 3 +/- 2% in Fab-treated animals for the duration of sampling. The area under the tissue concentration vs. time curves after anti-PCP Fab administration were decreased substantially in the brain (23% of controls), fat (24%), heart (52%), lung (74%) and testis (12%), but increased in the liver (137%). Because of anti-PCP Fab renal elimination, kidney PCP concentrations were significantly increased at all time points after Fab treatment (P.05), which resulted in an 18-fold increase in the PCP area under the curve. These studies show anti-PCP Fab can rapidly remove PCP from the brain and maintain it in a highly bound form for a significant time.

These studies were conducted to determine the effect of hormones on sex-related differences in phencyclidine (PCP) metabolite irreversible binding and to determine the cytochrome P450 isoform(s) involved in this process. Sprague-Dawley male rats were castrated or administered estradiol and Sprague-Dawley female rats were ovarectomized or ovarectomized and given testosterone. Liver microsomal metabolism studies demonstrated that PCP metabolite binding to proteins was significantly altered by testosterone and estrogen administration. Castration of male rats decreased metabolite binding to 57% of sham-operated male levels, and administration of testosterone to ovarectomized female rats increased metabolite binding to 41 % of normal male levels. No metabolite adducts could be detected in microsomes from male rats administered estradiol or from sham-operated females given vehicle. These hormone-induced changes in metabolite binding closely matched the hormone-induced changes in CYP2C11 function and expression in these same microsomes. PCP metabolite irreversible binding to microsomal proteins was highly correlated with CYP2C11 function (as assessed by the formation of 2alpha-OH-testosterone, r = 0.91) and with CYP2C11 expression (as assessed by Western blot analysis, r = 0.95). In addition, an anti-CYP2C11 monoclonal antibody almost completely inhibited PCP metabolite binding (down to 7% of control male values) in an antibody concentration-dependent manner. These data strongly implicate CYP2C11 as an isoform involved in PCP metabolism and the formation and/or binding of a reactive PCP metabolite to microsomal proteins.

Four peptides (pep23-33, pep26-38, pep283-297, and pep409-419) corresponding to unique sequences in rat cytochrome P450 (CYP) 2D1 and/or human CYP2D6 were selected for production of antipeptide antibodies. Rat liver microsomal protein was recognized by anti-serum to all four peptides in ELISAs; however, antisera against pep23-33 and pep26-36 proved not usable for any other applications. Western blots of microsomal protein from a cell line specifically expressing human CYP2D6 revealed that antisera to pep283-297 and pep409-419 recognized a single protein band of the same molecular size as CYP2D6. Antisera to pep283-297 and pep409-419 recognized a rat microsomal protein presumed to be CYP2D1, because it comigrated with human CYP2D6 and had an apparent molecular size of 52 kDa. An unknown protein of approximately 85 kDa was also recognized by pep409-419. Recognition of microsomal protein(s) by antisera to pep283-297 and pep409-419 was blocked by pep283-297 or a bovine serum albumin-pep409-419 conjugate, respectively. Antiserum to pep283-297 was used to analyze sex and strain differences in liver microsomes prepared from Sprague-Dawley, Fischer 344, and Dark Agouti male and female rats. Sprague-Dawley and Fischer 344 rats expressed similar amounts of CYP2D1, but expression in Dark Agouti rats was significantly lower. The antiserum did not detect a sexual dimorphism in any of the strains. A significant correlation between antipeptide283-297 immunoreactivity and Vmax for dextromethorphan O-demethylation existed in female rat strains; however, this relationship did not exist in male rat strains.(ABSTRACT TRUNCATED AT 250 WORDS)

The Sydney University Stellar Interferometer (SUSI) is a long baseline optical amplitude interferometer. In its initial configuration it is a two aperture, single ro instrument with wavefront-tilt corrections and dynamic optical path length compensation. It has been designed to measure the angular dimensions of stars of essentially all spectral types as well as the angular separations of binary stars. SUSI is located alongside the Australia Telescope at the Paul Wild Observatory, near Narrabri in northern New South Wales, Australia. It has a North-South array of input stations giving baselines covering the range from 5 m to 640 m. The baselines are being progressively commissioned, starting with the shorter ones, in parallel with an observing program aimed at fine-tuning the performance of the instrument. Progress and results from the commissioning program and the current status of the instrument are described.© (1994) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

The purpose of these studies was to explore the use of phencyclidine (PCP)-specific high affinity antibodies as a possible treatment for phencyclidine toxicity. High affinity (Kd = 1.8 nM) anti-PCP monoclonal Fab fragments were purified from papain digested anti-PCP immunoglobulin produced in mouse ascites. Control animals (n = 5) received an i.v. bolus dose of 1 mg/kg of PCP, along with a tracer dose of 250 microCi of [3H]PCP. Fab-treated rats (n = 5) also received this PCP dose, but at 2 hr after dosing (when PCP distribution was complete) they received an equimolar dose of anti-PCP Fab (50 mg). Within 5 min after the anti-PCP Fab administration, serum [3H]PCP concentrations increased approximately 60- to 100-fold. Fab treatment caused the [3H]PCP volume of distribution at steady state to decrease from 12.6 +/- 3.0 liters/kg (mean +/- S.D.) in control animals to 0.6 +/- 0.2 liters/kg in the Fab-treated animals (about 5% of control values). Systemic clearance changed from 66.3 +/- 16.9 to 6.8 +/- 2.8 ml/min/kg (about 10% of control values). Because both volume of distribution and systemic clearance decreased to a similar degree, the terminal elimination half-life did not change significantly (3.9 hr in controls vs. 4.9 hr in treated animals, harmonic means). Renal clearance decreased from 1.8 +/- 0.6 to 0.62 +/- 0.17 ml/min/kg after Fab treatment. The anti-PCP Fab caused the percentage of PCP recovered in urine to increase from 2.5 +/- 0.5 to 10.3 +/- 4.7%.(ABSTRACT TRUNCATED AT 250 WORDS)

The SUSI control system is a distributed real-time system currently consisting of 17 processors. A custom real-time operating system and network protocols ensure synchronous operation of servo loops across multiple processors.

Treatment of drug toxicity is problematic for compounds like phencyclidine (PCP) which have no known antagonists. With the advent of technology for production of large amounts of monoclonal antibody, it is now possible to explore the use of these antibodies as high affinity in vivo antagonists for treatment of PCP overdose. In the current study, the pharmacokinetics of an anti-PCP monoclonal antibody Fab (antigen binding fragment of immunoglobulin G) were determined in adult male Sprague-Dawley rats (n = 5). Each animal was cannulated and dosed with approximately 0.12 g/kg of unlabeled anti-PCP Fab fragments (Kd for PCP = 1.8 +/- 0.27 nM) along with a tracer dose of anti-PCP [3H]Fab. Blood was drawn at predetermined intervals and serum was analyzed for total radioactivity by liquid scintillation spectrometry. Serum and urine were analyzed for intact anti-PCP [3H]Fab after fractionation on a high-performance liquid chromatography molecular weight sizing column followed by quantitation by liquid scintillation spectrometry. The pharmacokinetic parameters for the [3H]Fab in rat serum were a terminal elimination T1/2 of 7.5 hr (harmonic mean), a volume of the central compartment of 0.17 +/- 0.026 liters/kg and a steady-state volume of distribution of 0.55 +/- 0.15 liters/kg (mean +/- S.D.). Systemic and renal clearances were 2.7 +/- 0.9 and 0.47 +/- 0.24 ml/min/kg, respectively. The total amount of the radioactive dose ([3H] Fab plus radioactive catabolic products) appearing in the urine was 51 +/- 11%, whereas urinary excretion of intact [3H]Fab accounted for 21 +/- 15% of the total dose. All animals tolerated the Fab infusion without adverse effect.(ABSTRACT TRUNCATED AT 250 WORDS)

We determined whether chronic dosing with phencyclidine (PCP) could affect the in vitro function of liver microsomal enzymes in male Sprague-Dawley rats. PCP chronic dosing of rats (n = 3 per group) for 3 days with 2.5, 10 and 18 mg/kg/day caused a dose-dependent decrease (23, 36 and 53%, respectively) in the ability of the microsomal enzymes to bind covalently PCP metabolites. The 10- and 18-mg/kg/day dosing groups were significantly different from the 3-day saline-infused control group (P.05). The results from time-dependent dosing studies indicated PCP covalent binding was significantly reduced (P.05) in rats (n = 3 per group) infused with 18 mg/kg/day of PCP for 1, 2, 3, 4 and 10 days. Subsequently, it returned to near control values in rats infused for 20 days. In parallel with the time-dependent decreases in covalent binding, the concentrations of at least three phase I PCP mono- and dihydroxylated metabolites were also significantly reduced (P.05) at the earlier time periods of dosing (3 and 10 days), but the rate of their formation returned to near normal values by 20 days of dosing. Total cytochrome P450 content did not differ from the control groups at any of the doses or time points. As dose- and time-dependent decreases in covalent binding suggested a specific metabolic pathway or isoenzyme was affected, we studied the affect on specific isoenzyme pathways. For these studies a series of cytochrome P450 inhibitors were used.(ABSTRACT TRUNCATED AT 250 WORDS)

The dependence-producing properties of 10 days of chronic i.v. infusions of phencyclidine (PCP) and the relationship between PCP serum concentrations and behavioral effects were studied in Sprague-Dawley rats. For dependence studies, rats were trained to respond for food under a fixed-ratio 30 schedule during half-hour response periods every 6 hr. After training, implantation of jugular catheters, and restabilization of behavior, the rats were infused with PCP.HCl at 3.2, 5.6, 10.0 or 17.8 mg/kg/day (n = 5 or 6 per dose). The two higher doses initially decreased response rates, but tolerance developed within 4 to 5 days. When PCP infusions were terminated, dose-dependent decreases in session response rate occurred in the three highest dose groups (P less than .05). Mild, overt signs of abstinence were observed only in the highest dose group. Response rates returned to base line within 2 to 3 days after stopping PCP infusions. PCP serum concentrations in rats infused with 10 mg of PCP.HCl/kg/day for 10 days were stable from hour 24 to day 10 (mean steady-state concentration (+/- S.D.) = 97 (+/- 20) ng of PCP/ml; n = 4). The average terminal elimination half-life after stopping infusions on day 10 was 4.6 hr. Comparison of the average response rates with the average serum concentrations showed that during the first 24 hr of infusions, the rate of responding for food decreased as PCP concentrations increased; however, once the animals became tolerant to PCP there was no relationship. In contrast, during the first 24 hr after stopping infusions, response rates decreased as serum concentrations decreased.

Gonadal steroids have been implicated in the modulation of GH secretory patterns in the rat. We have studied the effects of testosterone (T) or estradiol (E2) on the steady state clearance (Clss) and plasma half-life (t1/2) of GH in male and female rats (n = 4-6/group). A femoral and a jugular cannula were surgically implanted into adult Sprague-Dawley rats. At the time of cannulation some rats were orchidectomized, and a Silastic capsule containing E2, T, or nothing was implanted sc. After recovery from surgery, either purified rat GH or a crude extract of rat pituitary was infused iv to attain steady state plasma GH concentrations. Blood samples were taken every 30 min for 4 h during the infusion, and nine samples were taken at 2.5-min intervals immediately after stopping the infusion. The mean Clss for GH in female rats were significantly (P less than or equal to 0.001) less than that in males, whereas the t1/2 did not differ between the two groups. Neither the Clss nor the t1/2 was affected by castration in males or females. The Clss of GH in E2-treated castrated males was significantly less (P less than 0.001) than that for intact males, but the t1/2 did not differ between the two groups. The Clss for GH was greater in T-treated ovariectomized rats than in intact females, but the t1/2 did not differ with T treatment. These results suggest that 1) the Clss for GH is lower in female rats than in males; 2) 4 weeks of gonadectomy has no effect on the Clss in males or females; 3) under experimental conditions, E2 decreases and T increases the Clss for GH; and 4) the t1/2 for GH is not different in males or females. The steroid-induced changes in Clss in the absence of detectable effects on t1/2 suggest that factors affecting the volume of distribution at steady state (i.e. plasma GH-binding proteins or GH heterogeneity) are involved in the effects of gonadal steroids on GH clearance in the rat.

Digoxin protein binding and pharmacokinetics were studied in 4-, 14-, and 25-month-old male Fischer-344 rats to determine if there were age-dependent changes in digoxin disposition. Serum protein binding did not differ among age groups. The average percentage unbound digoxin for all animals was 61.3 +/- 5.3% (means +/- SD, n = 15). For pharmacokinetic studies, [3H]digoxin and 1 mg/kg unlabeled digoxin were administered as an intravenous bolus dose to animals from each age group. The [3H]digoxin terminal elimination half-life was 2.0, 2.3, and 2.5 hr, respectively. The steady-state volume of distribution in the three age groups was 1.51, 1.49, and 1.27 liters/kg, respectively. Total body clearance for the three age groups was 14.2, 12.1, and 7.5 ml/min/kg, respectively. Analysis of variance of these data followed by Duncan's multiple range test indicated a significant decrease in clearance in the aged rats (25-month-old, p less than 0.05). This age-dependent decrease in clearance suggested that digoxin pharmacokinetics could be a significant factor in age-related alterations in digoxin cardiotoxicity in the rat, as it is in humans, and that the Fischer-344 rat could be a useful model for studies of digoxin pharmacokinetic changes with age.

Phencyclidine (PCP) disposition kinetics has been examined in dogs as a function of dose and after i.v. and p.o. administration. Intravenous doses ranged from a tracer quantity of [3H]PCP to 5 mg/kg of unlabeled PCP. The elimination half-life of intact PCP was relatively short with harmonic mean values of 2.7, 5.4 and 3.9 hr for the tracer, 1- and 5-mg/kg doses, respectively. In contrast, measurement of total radioactivity gave a much longer half-life (35-52 hr) suggesting slower metabolite elimination. The drug has a large apparent volume of distribution (weighted mean of 20 liters/kg) and a systemic clearance (which is primarily metabolic) that approaches estimates of liver blood flow in the dog. Renal clearance of intact PCP represents a small fraction of total clearance. Percentage of the [3H]PCP dose recovered as total radioactivity was 49% in urine and 12% in feces. Several metabolites of PCP were determined in urine and they account for about 30% of the dose with the aminopentanoic acid derivative being present in the greatest amount. One of the hydroxylated metabolites is present in cis- and trans-forms, with the latter predominating. Three animals received an i.v. dose of [3H] PCP and a p.o. dose of unlabeled PCP at the same time to determine absolute bioavailability. Approximately 25% of the dose is absorbed intact. The p.o. (intrinsic) clearance of PCP is about four times greater than systemic clearance suggesting a blood flow-dependence in clearance and substantial first-pass hepatic metabolism.

Using adult male Sprague-Dawley rats, we examined the blood protein binding and pharmacokinetics of the potent phencyclidine (PCP) receptor ligand 1-[1-(2-thienyl)cyclohexyl]piperidine (TCP). The average percentage of unbound [3H]TCP in rat serum was 42 +/- 6% and the [3H]TCP blood to plasma ratio was 0.98 +/- 0.03 (mean +/- SD, n = 5 in both studies). For the pharmacokinetic studies, [3H]TCP and 1 mg/kg unlabeled TCP were administered as an iv bolus dose. The average [3H]TCP elimination half-life was 2.1 hr. In contrast, total radioactivity in the plasma had a much longer half-life, suggesting much slower metabolite elimination. The average distribution volumes were 27 +/- 17, 15.6 +/- 6.2, and 5.6 +/- 3.0 liters/kg for V beta, Vss, and Vc, respectively. Total body and renal clearance values were 132 +/- 45 and 1.1 +/- 0.4 ml/min/kg, respectively. When TCP pharmacokinetic parameters were compared to PCP pharmacokinetic data in rats from a previous study, a strikingly similar pharmacokinetic profile was found. These data indicated that TCP and PCP are equivalent, from a pharmacokinetic point of view, and that the higher pharmacological potency of TCP over PCP is probably due to receptor-mediated differences.

A radioimmunoassay for delta-9-THC in plasma, whole blood, or hemolyzed blood specimens has been presented. Samples and standards were diluted with methanol and centrifuged. An aliquot of the supernatant fluid was incubated with RIA buffer, 125I-labeled delta-8-THC and rabbit anti-THC serum. Solid phase goat anti-rabbit immunoglobulins were added to separate bound from free THC. After centrifugation the supernatant fluid was aspirated and the radioactivity of the precipitate was counted in a gamma counter. The concentration of THC was calculated from a standard curve using the logit-log transformation of the average counts of duplicate tubes. The assay had several advantages. Methanol dilution gave better results than direct analysis. The 125I-labeled THC had high specific activity and could be counted in a gamma counter. The immunological separation of antibody-bound THC from free THC was better than separation techniques using ammonium sulfate and activated charcoal. THC was determined in 0.1 ml of sample with a sensitivity of 1.5 ng/ml in plasma and 3.0 ng/ml in hemolyzed blood.

This accurate, sensitive radioimmunoassay for determining phencyclidine concentrations in serum specimens involves the use of anti-phencyclidine sera, 0.1 mL of serum specimen, an iodinated tracer, and a solid-phase separation. Phencyclidine metabolites do not show significant cross reactivity, but several phencyclidine analogs do cross react. Within-run coefficients of variation for human and dog serum ranged from 2.5 to 13% for concentrations from 2.0 to 500 micrograms/L. Day-to-day coefficients of variation for human and dog serum ranged from 4.3 to 16.7% for concentrations ranging from 2.0 to 90.0 micrograms/L. The sensitivity of the radioimmunoassay is less than 0.5 micrograms/L. Thirty serum specimens from two dogs given 1 mg of phencyclidine per kilogram body weight were analyzed by radioimmunoassay and a gas-chromatographic method. Nonparametric statistical comparison and linear regression showed that results from the two procedures correlate well (r2 = 0.952). Concentration-time data from the two dogs are presented to illustrate the utility of the radioimmunoassay for examining phencyclidine disposition.

Interspecies pharmacokinetic parameters (y) for phencyclidine [1-(1-phenylcyclohexyl)piperidine] were correlated with body weight (B) using linear regression and the allometric equation of the form y = aBx (which also may be written as the linear regression equation, log y = x log B + log a). The data were obtained from previously reported pharmacokinetic studies in mammals (i.e., humans, monkey, dog, rat and mouse) and new pharmacokinetic data for the pigeon. The animal body weights ranged from 32.5 to 77,000 g and included 6 animal species from 2 vertebrate classes. The pharmacokinetic parameters correlated with body weight were T1/2 (T1/2 = 126B0.32, r2 = 0.799), volume of distribution (V beta = 10B0.96, r2 = 0.966) and systemic clearance (CLs = 50B0.64, r2 = 0.891). In addition, clearance values were multiplied by the maximum lifespan potential (MLP) of each animal and correlated with body weight [CLs X MLP = (3.3 X 10(5))B1.0, r2 = 0.991]. This helped normalize for species differences in systemic clearance, which correlated with species longevity. These allometric equations should provide the information for scaling phencyclidine pharmacokinetic data among diverse species.

In this sensitive and specific radioimmunoassay for delta-9-tetrahydrocannabinol, an iodinated tracer with high specific activity and a solid-phase separation are used. Within-run coefficients of variation for 5.0 and 30.0 microgram/L concentrations were 7.8 and 4.2% for plasma and 14 and 10.6% for hemolyzed blood specimens, respectively. Day-to-day coefficients of variations ranged from 7.3 to 13.6% (for 7.6 to 33.0 microgram/L concentrations) for plasma and 13.4 to 18.1% (3.0 to 52.1 microgram/L) for hemolyzed blood specimens. Data for time after start of smoking of a standard THC-containing cigarette vs the concentration of delta-9-tetrahydrocannabinol in the plasma were similar to those obtained by others. Positive plasma specimens from the smoking study were analyzed by gas chromatography-mass spectrometry and by our radioimmunoassay. Nonparametric statistical comparison and linear regression (r2 = 0.972) showed that results by the two methods of analysis correlate well. The sensitivity of the assay was at least 0.3 microgram/L for plasma, 1.1 microgram/L for hemolyzed blood.

High affinity antibodies (K0 = 3 X 10(9) M-1) against the widely abused drug phencyclidine (PCP) were produced in goats and then purified and extensively characterized for use in in vivo pharmacokinetic studies. An iv dose of 3H-PCP was administered to three dogs, followed 2 hr later by an equimolar dose of PCP-specific antigen-binding fragments (Fab). Within 10 min after Fab administration, the concentration of PCP in the serum had increased 17-56-fold in the three dogs. The Fab administration also produced a 10-fold decrease in volume of distribution and in systemic and renal clearances. The concentration of PCP metabolites decreased for a period of time after Fab administration. Equilibrium dialysis studies showed that the percentage of unbound PCP changed from about 50% before Fab administration to less than 1% unbound after Fab. In addition, the blood/plasma ratio of PCP changed from a near-equal distribution between red blood cells and plasma before Fab to virtually all of the drug being confined to the plasma fraction after Fab administration. Although Fab produced a dramatic redistribution and extensive protein binding of PCP, the route of elimination of PCP was not altered. These data suggest that high affinity anti-PCP Fab could reverse the toxicity of PCP.