Estimating the rate constants in a two-compartment stochastic model

A procedure is described for estimating the rate constants of a two-compartment stochastic model for which the covariance structure over time of the observations is known. The proposed estimation procedure, by incorporating the known (as a function of the parameters to be estimated) covariance structure of the observations, produces regular best asymptotically normal (RBAN) estimators for the parameters. In addition, the construction of approximate confidence intervals and regions for the parameters is made possible by identification of the asymptotic covariance matrix of the estimators. The explicit form of the inverse of the covariance matrix, which is required in the estimation procedure, is presented. The procedure is illustrated by application to real as well as simulated data, and a comparison is made to the widely used nonlinear least squares procedure, which does not account for correlations over time.     

A model to assess the effectiveness of topical antipruritics

A model has been developed to determine the effectiveness of topical antipruritics. It utilizes controlled, experimentally induced itch and has demonstrated the effectiveness of the direct action on cutaneous receptor sites of a topical anesthetic, benzocaine, in a topical antipruritic formulation, and has been used to differentiate between two effective topical antipruritics. Three studies are presented: The first study examined the reliability of the experimentally induced itch. Several indices of reliability were computed from the data of this first study. Cronbach's alpha was 0.92. Winer's theta also was 0.92. Simple test-retest reliability, computed at intervals of 29 min, 1 day, and 6-7 days, resulted in Pearson correlations of 0.84, 0.73, and 0.60, respectively. In the second study, the model differentiated statistically between the itch relief resulting from the topical application of a formulation with 6% benzocaine and the same formulation without benzocaine. The third study examined 2 known topical antipruritics: one containing 6% benzocaine and the other 1% hydrocortisone. Both topical antipruritics were found to relieve itch; however, the benzocaine antipruritic produced statistically significantly greater itch relief in more subjects than the hydrocortisone antipruritic at both 1 and 30 min after application. These results demonstrate that OTC antipruritics can be differentiated for effectiveness.     

Effect of ethanol on human placental transport and metabolism of adenosine

It has been suggested that adenosine is involved in the acute effects of ethanol in a number of tissues. The present study was undertaken to evaluate the role of adenosine on the vascular responses of perfused isolated human placental cotyledons after the acute administration of ethanol. The possibility that ethanol may effect the uptake and metabolism adenosine was also investigated. Uptake of adenosine was studied using the single-circulation paired-tracer dilution technique. Both adenosine and ethanol caused a dose-related increase in perfusion pressure of placental lobules. Pharmacologically relevant concentrations of ethanol (10-65 mM) significantly inhibited the uptake of [3H]adenosine between 25 and 50 per cent. Thin-layer chromatographic analysis of the perfusate after the administration of ethanol showed in a 17.9 +/- 0.6 per cent reduction of [3H]adenosine metabolism. These findings support the working hypothesis that placental adenosine, at least partially, mediates the placental disturbance elicited by the administration of acute ethanol, which may contribute to the pathogenesis of fetal alcohol syndrome.     

Use of concurrent verbalization to assess the dissociation of conscious controls.

The degree of dissociation of conscious controls that occurred when, according to the neodissociation theory (Hilgard, 1977, 1979), conditions were optimal for such an event was assessed. A task that required subjects to locate specified sentences in a textbook was conducted under these optimal conditions, as well as under conditions that were expected to mitigate against the occurrence of dissociation. The sentence-search task necessitated rehearsal for its successful completion. The correspondence between task rehearsal and task performance did not differ between optimal and mitigating conditions, thus suggesting a failure to dissociate. Nevertheless, search behavior was self-rated as substantially more involuntary under the optimal than under the mitigating conditions. The implications of these findings for the neodissociation and social role theories of hypnosis were discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Angiographic methods to assess human coronary angiogenesis

It is unclear how agents designed to promote angiogenesis in the human heart affect the arteriographic appearance of the collateral circulation. Possible changes in collateral vessels include new collateral vessels arising from epicardial arteries, new branches emanating from existing collateral vessels, wider or longer collateral vessels, and higher dye transit rates that result in improved recipient vessel filling. Given the multiple mechanisms by which these new agents may improve myocardial perfusion, a rigorous, systematic, and comprehensive analysis of coronary arteriograms is required to discern the true mechanism of benefit. The method of analysis must account for potential changes in collateral blood flow, number, branching pattern, and length as well as changes in recipient vessel filling. The ability to detect differences between intricate networks of vessels in an angiographic study is dependent on maintaining consistency in cinefilming as well as the core laboratory methods between time points. In this report, we describe the methodology our angiographic core laboratory has found to be most effective to evaluate these very complex angiograms and attempt to capture all the possible modalities of angiogenesis.     

Use of capillary electrophoresis methods to characterize the pharmacokinetics of antisense drugs

As antisense drugs become mature for clinical trials, analytical techniques to analyze antisense DNA in biological media for characterization of their pharmacokinetics will be in demand. Due to the superior resolving power of capillary gel electrophoresis (CGE), CGE will likely be a preferred method in quantifying intact oligonucleotides as well as the putative metabolic products. Nonetheless, biological mediums can influence the stability of the gel column, making a CGE assay time-consuming. In one approach, high-performance liquid chromatography (HPLC) was used to quantify the total amount of antisense compounds to increase the sample throughput and CGE was used to determine the relative percentage of the intact and metabolic species on specific samples. Alternatively, extensive sample pretreatment procedures were performed and the samples were quantified and characterized directly by CGE alone with the use of an internal standard. Both methods have been used to characterize the pharmacokinetics of antisense compounds. This review focuses on the instrumental and technical aspects of analyzing antisense DNA in biological mediums using CGE either as a single or a combined method towards better understanding of the pharmacokinetics of antisense DNA. Moreover, the newer analytical technologies of capillary electrophoresis (CE), which hold great potential to be used for pharmacokinetic applications, such as the replenishable sieving matrix combined with an innovative coupling approach and microchip CE, will also be explored.     

Critical analysis of "flip-flop" phenomenon in two-compartment pharmacokinetic model

Computer simulations were used to examine the effect of first-order absorption on the disposition of one- and two-compartment model drugs. Two-compartment systems that attain a clinically acceptable beta-phase after rapid intravenous injection were perturbed by introduction of drug via first-order absorption. The validity of perceiving such a system as a potential "flip-flop" model was tested by comparing the negative slopes of log-linear plasma-time profiles to known values for ka and beta for various values of ka, k12, k21, and k10. Although most log-linear plots showed excellent correlation coefficients (r2 greater than 0.996), their negative slopes (S) did not represent either ka or beta under various combinations. A similar consideration of the one-compartment model enabled a comparison to be made between the two systems. Maximum negative errors were observed for both one- and two-compartment drugs as ka leads to k2 or beta, respectively. The value for S provided a good estimate of the absorption rate constant, ka, when k2 greater than or equal 2ka (one compartment) or beta greater than or equal 2ka. The elimination rate constant (k2 or beta) could be obtained from S for all one-compartment and some two-compartment drugs when the value of ka was approximately twice that of k2 or beta. Large positive errors also were observed with certain two-compartment drugs where the ratio of the four rate constants apparently linearized a nonlinear plasma profile. Conditions wherein S may be expected to approach beta wherein S approaches ka are clearly defined.     

Use of polymerase chain reaction to assess efficacy of leprosy chemotherapy

The assessment of chemotherapy efficacy in leprosy is difficult, since the only reliable method for determining whether the causative organism, Mycobacterium leprae, is viable depends on its growth in mouse foot pads. In an attempt to replace this expensive, time-consuming test, methods based on the polymerase chain reaction (PCR) have been developed. These methods depend on detection of DNA, which is more susceptible to degradation on cell death than are other cell components, so should be a more accurate indicator of viability. We have used a specific PCR assay to detect M leprae DNA in skin biopsy samples from leprosy patients. By use of limiting dilution PCR (LD-PCR), the concentration of M leprae DNA in the original sample could be measured. The DNA concentration was more closely correlated with the morphological index (derived from a staining technique that distinguishes morphologically intact and damaged bacteria) than with the number of bacteria visible (bacterial index, BI, which counts both alive and dead bacteria). In a longitudinal study of multibacillary patients on multi-drug therapy, skin biopsy samples were collected before treatment and 3, 6, 12, and 24 months after the start of therapy. While the BI showed little or no change during treatment, the number of genomes detected by PCR fell sharply, in parallel with the MI. We propose that PCR can be used as a rapid measure of M leprae viability and that this approach can be used for monitoring individual leprosy patients and for assessment of existing and new regimens. The method may be applicable to other infectious diseases in which culture of the causative organism is slow or impossible.     

Use of the Personality Assessment Inventory to assess psychopathy in offender populations.

The authors investigated the validity of the Antisocial Features (ANT) scale of the Personality Assessment Inventory (PAI; L. C. Morey, 1991) with respect to assessments of psychopathy in 2 offender samples. Study 1 included 46 forensic psychiatric inpatients who were administered the Screening Version of the Hare Psychopathy Checklist (PCL:SV; S. D. Hart, D. N. Cox, and R. D. Hare, 1995). In Study 2, 55 sex offenders were administered the Hare Psychopathy Checklist—Revised (PCL—R; R. D. Hare, 1991). ANT scores correlated highly with the PCL:SV total score (r?=?.54) and moderately with the PCL—R total score (r?=?.40). ANT tapped primarily behavioral symptoms of psychopathy rather than interpersonal and affective symptoms. Also, ANT had low to moderate diagnostic efficiency regarding diagnoses of psychopathy, suggesting that it may be better used as a dimensional rather than categorical measure of this construct. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The pharmacokinetics and metabolism of 14C/13C-labeled ortho-phenylphenol formation following dermal application to human volunteers

1. The pharmacokinetics and metabolism of uniformly labeled 14C/13C-ortho-phenylphenol (OPP) were followed in six human male volunteers given a single 8 h dermal dose of 6 microg OPP/kg body weight formulated as a 0.4% (w/v) solution in isopropyl alcohol. The application site was covered with a non-occlusive dome allowing free movement of air, but preventing the loss of radioactivity due to physical contact. At 8 h post-exposure the non-occlusive dome was removed, the dose site was wiped with isopropyl alcohol containing swabs and the skin surface repeatedly stripped with tape. Blood specimens, urine, and feces were collected from each volunteer over a 5 day post-exposure period and were analyzed for radioactivity and metabolites (urine only). 2. Following dermal application, peak plasma levels of radioactivity were obtained within 4 h post-exposure and rapidly declined with virtually all of the absorbed dose rapidly excreted into the urine within 24 h post-exposure. A one-compartment pharmacokinetic model was used to describe the time-course of OPP absorption and clearance in male human volunteers. Approximately 43% of the dermally applied dose was absorbed through the skin with an average absorption half-life of 10 h. Once absorbed the renal clearance of OPP was rapid with an average half-life of 0.8 h. The rate limiting step for renal clearance was the relatively slower rate of dermal absorption; therefore the pharmacokinetics of OPP in humans was described by a 'flip-flop' single compartment model. Overall, the pharmacokinetics were similar between individuals, and the model parameters were in excellent agreement with the experimental data. 3. Approximately 73% of the total urinary radioactivity was accounted for as free OPP, OPP-sulfate and OPP-glucuronide conjugates. The sulfate conjugate was the major metabolite (approximately 69%). Therefore, total urinary OPP equivalents (acid-labile conjugates+free OPP) can be used to estimate the systemically absorbed dose of OPP. 4. The rapid excretion of OPP and metabolites into the urine following dermal exposure indicates that OPP is unlikely to accumulate in humans upon repeated exposure. Based on these data, blood and/or urinary OPP concentration (acid-labile conjugates) could be utilized to quantify the amount of OPP absorbed by humans under actual use conditions.     

Changes in hepatic enzyme activities related to ethanol metabolism in mice following chronic ethanol administration

Male mice of three strains, C57BL, DBA and C3H/He, were fed on commercial food with 10% (v/v) ethanol solution as drinking liquid ad libitum for eighty days, and the changes in the activities of enzymes in the metabolic pathway of ethanol in the liver were examined. C57BL and C3H/He mice showed a preference for drinking the 10% (v/v) ethanol solution, while DBA mice did not. The ethanol intake g/g of body weight of C3H/He mice showed the highest value among all three strains and that of C57BL mice tended to show higher value than that of DBA mice. The liver weights of C57BL and C3H/He mice increased significantly following chronic ethanol administration, but that of DBA did not. The cytosolic enzyme alcohol dehydrogenase (ADH) showed no changes in any of the strains following chronic ethanol administration. The microsomal ethanol-oxidizing system (MEOS) of C57BL mice exhibited approximately 2-fold higher activity compared to that of DBA and C3H/He mice but did not increase in any strain following chronic ethanol administration. However, the microsomal aniline hydroxylase activity in the liver increased significantly in C57BL and C3H/He mice following chronic administration of ethanol. The microsomal cytochrome P-450 content also tended to slightly increase in the same strains of mice. It seemed that cytochrome P-450IIE1 was induced in the liver microsomes of these strains. Total aldehyde dehydrogenase (ALDH) activities together with high-Km ALDH activity increased markedly in the microsomes of C57BL mice and tended to increase in C3H/He mice, while it did not change in DBA mice following chronic ethanol administration. In the mitochondria of C57BL, total ALDH activities increased slightly and high-Km ALDH activities tended to increase. These mitochondrial ALDH activities of C3H/He and DBA mice tended to increase following chronic ethanol administration. The cytosolic ALDH activity showed no changes in any strain of mice following chronic ethanol administration. It seemed that in the microsomes, the activities of enzymes related to oxidation of ethanol increased in C57BL and C3H/He mice, which tended to consume a large amount of ethanol, and did not in DBA mice which tended to consume a small amount of it. It seemed that the increases in activities of enzymes related to oxidation of acetaldehyde in the microsomes and in the mitochondria were responsible for the strain difference.     

Use of total of Escherichia coli counts to assess the hygienic characteristics of a beef carcass dressing process

Swab samples were obtained from 3 sites on the surfaces of beef carcasses passing through a high speed dressing process, with 24 samples from each site being obtained at each of 4 points in the process. The aerobic microflora recovered from each swab after incubation at 25 degrees C was enumerated and characterized, and numbers of coliforms and Escherichia coli were determined. The data on aerobic flora indicated that skinning results in similar contamination of all 3 sites, that further deposition of bacteria at the brisket site occurs after skinning, and that trimming and washing achieve modest decontamination of the neck and brisket site, and extensive decontamination of the rump site. Changes in flora compositions during processing were too limited to much affect the assessment based on the aerobic flora total counts alone. The E. coli data indicated that during skinning the rump site was more heavily contaminated with faecal organisms than the other sites, that contamination of the brisket site is little altered between skinning and carcass splitting, although there is an extensive redistribution of E. coli at the neck site and sporadic, limited decontamination of the rump site, and that trimming and washing do not decontaminate the neck or rump sites, but that the rump site is extensively decontaminated by trimming. There was good correlation between E. coli and coliform counts, but weak correlation between E. coli and aerobic, 25 degrees C, counts. The findings suggest that assessments of beef carcass dressing processes for Hazard Analysis: Critical Control Point (HACCP) purposes should be based on enumerations of E. coli, or perhaps coliforms, rather than of the aerobic flora, to avoid important misunderstandings of the hygienic effects of the various operations in a process.     

Use of a metacontrast and a paracontrast procedure to assess the visual information processing of hypothetically schizotypic college students.

Compared the metacontrast and paracontrast performance of 2 groups of hypothetically schizotypic college students with that of a psychiatric control group and normal control group. There were 12 undergraduate Ss in each group. Ss were defined by 2 sets of criteria: (1) the 2-7-8 Minnesota Multiphasic Personality Inventory (MMPI) profile and (2) the 8-9 MMPI profile. The quality of the short-term visual store (STVS) was evaluated through the use of a critical stimulus duration (CSD) procedure. Speed of information transfer from the STVS into short-term memory was assessed in the metacontrast condition. Schizotypics demonstrated impaired speed of information transfer in comparison with controls. However, as expected, no group differences in paracontrast effects were found. Ss in the 2-7-8 group (showing vulnerability to schizophrenia) evidenced a significant CSD deficit when compared with the other 3 groups. Results suggest that vulnerability to backward masking may be a trait marker of schizophrenia. (39 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Absorption, pharmacokinetics and metabolism of 14C-sumatriptan following intranasal administration to the rat

1. Studies have been carried out to investigate the absorption of sumatriptan after intranasal administration to rats. The pharmacokinetics, metabolism and excretion of 14C-sumatriptan were compared following intranasal and intravenous dosing to male and female albino rats using an aqueous buffered formulation at pH 5.5. 2. Following intravenous administration sumatriptan was eliminated from plasma with a half-life of about 1.1 h. After intranasal administration there was rapid absorption of part of the dose and two peak plasma concentrations were observed, initially at 0.5 and then at 1.5-2 h. The elimination half-life after the second peak was estimated as being about 4 h. 3. Radioactivity was largely excreted in urine (up to 89% of dose in 168 h) after both intravenous and intranasal administration, with a faster rate of excretion after intravenous dosage (73% males, 64% females within 6 h) than after intranasal dosage (37% males, 40% females within 6 h). 4. 14C-sumatriptan was the major component in urine and in extracts of faeces after both intravenous and intranasal administration. The major metabolite excreted in urine and faeces was GR49336, the indole acetic acid analogue. 5. The results of this in vivo rat study suggest that absorption of the dose via the nasal mucosa is incomplete after intranasal administration and that there is a secondary absorption phase probably reflecting oral absorption of part of the dose. The bioavailability is estimated as about 30%, for the period 0-6 h.