A parameter to quantify the degree of genetic mixing among individuals in hybrid populations.

Hybridization between genetically distinct taxa is a complex evolutionary process. One challenge to studying hybrid populations is quantifying the degree to which non-native genes have become evenly mixed among individuals in the population. In this paper, we present a variance-based parameter, md, that measures the degree to which non-native genes are evenly distributed among individuals in a population. The parameter has a minimum value of 0 for populations in which individuals from multiple taxa are present but have not interbred, and a maximum value of 1 for populations in which all individuals have the same amount of non-native ancestry. A recurrence equation showed that relatively few generations of random mating are required for md to approach 1 (indicating a well-mixed population), and that md is independent of initial amounts of non-native ancestry. The parameter is mathematically equivalent to FST and we show how existing formulae for FST can be used to estimate md when diagnostic loci are available. Computer simulations showed this estimator to have very little bias for realistic amounts of data.

Cognitive and psychological correlates of smoking abstinence, and predictors of successful cessation.

The neural circuitry implicated in addictive drug use, which appears to be down-regulated in early abstinence, corresponds closely with brain reward pathways. A literature review suggests that responses to incentive stimuli and the ability to inhibit reflexive responses, both of which have been associated with normal functioning in these pathways, might be weakened during acute abstinence from chronic drug use. In an ongoing study, 82 smokers, abstinent overnight before two separate testing occasions, have been assessed after administration of nicotine and placebo lozenges (order of sessions counterbalanced). Nicotine administration is associated with a significant reduction in anhedonia, a near-significant increase in response to financial incentive, enhanced ability to inhibit reflexive eye movements, and increased attentional bias to words with appetitive significance. Fifty-nine participants then initiated a quit attempt and 19 reported relapsing within 7 days. Comparing their performance in the two prequit lozenge assessment sessions, relapsers showed a stronger effect of nicotine on enhancing their ability to inhibit reflexive eye movements and a near-significant trend towards greater nicotine-induced increases in attentional bias toward appetitive words.

Risedronate pharmacokinetics and intra- and inter-subject variability upon single-dose intravenous and oral administration.

PURPOSE: To determine the pharmacokinetics and absolute bioavailability of risedronate after single-dose oral administration of 30 mg risedronate as a tablet and an aqueous solution, and 0.3 mg risedronate as an intravenous infusion. METHODS: This study was a randomized, three-treatment, four-period, partial replicate crossover study involving 33 healthy volunteers. Treatments were administered 7 weeks apart, and the third treatment was repeated during the fourth period. Serum and urine were collected over 72 hours and 672 hours, respectively. RESULTS: Following intravenous administration, renal clearance accounted for 87% of total clearance, with 65% of the dose excreted within 24 hours and 85% of the dose excreted within four weeks. The absolute bioavailability was approximately 0.62% after both oral formulations, and the relative bioavailability of the tablet compared with the oral solution was 104%. The rate and extent of absorption from the two formulations were bioequivalent based on the range proposed for highly variable drugs. Intrasubject variability following oral administration was 50-80%, and was primarily associated with absorption. CONCLUSION: The majority of the total clearance after intravenous administration of risedronate was renal clearance, indicating that only a small percentage of a systemic dose is potentially incorporated, or "cleared," into bone. The absolute bioavailability of orally administered risedronate is approximately 0.6%, and is independent of formulation. Variability in the pharmacokinetics following oral administration is primarily associated with intrasubject variability in absorption.

Recreational use of 3,4-methylenedioxymethamphetamine (MDMA) or 'ecstasy': evidence for cognitive impairment.

BACKGROUND: It has recently been shown that 3,4-methylenedioxymethamphetamine (MDMA) or 'ecstasy' causes long-lasting alterations to brain structure and function in animals, and there is mounting evidence that recreational users of the drug show impairments in some aspects of cognitive functioning including memory for verbal information. The present study investigates possible effects on other cognitive functions and explores the temporal course of development and resolution of these impairments by comparing novice, regular and abstaining users with a matched group of non-users. METHODS: Eighty participants categorized as non-users, novice users, regular users or currently abstinent users of MDMA were assessed on tests of verbal IQ, reversed digit span, immediate and delayed recall of a prose passage and of a complex geometric figure and verbal fluency. RESULTS: The four groups were well-matched for verbal IQ and on demographic variables. They differed in frequency of cannabis use over the last month, but this did not correlate with any cognitive test scores. All three groups of MDMA users showed significantly poorer verbal fluency and immediate and delayed prose recall than non-users. Days since last use and total lifetime consumption of MDMA made separate contributions to the variance in recall scores, accounting jointly for almost half of the variance in delayed recall. By contrast, the groups did not differ on either visual recall or reversed digit span. CONCLUSIONS: The observed deficits provide further evidence of impairments of verbal but not visual memory in MDMA users, and indicate that the deficits are not attributable either to differences in general reasoning ability or to impairment of working memory. The data further suggest that the observed impairments may be attributable to a combination of reversible acute effects of MDMA resolving over a period of 2-3 weeks and more long-term changes associated with extent of lifetime consumption.

The effect of aerobic training on rehabilitation outcomes after recent severe brain injury: a randomized controlled evaluation.

OBJECTIVE: To examine the impact of fitness training with recently brain-injured inpatients on exercise capacity and functional and psychologic outcome measures. DESIGN: A randomized controlled trial of exercise versus relaxation training for 3 months. Blind assessments were conducted before and after the end of a 12-week training program, as well as at follow-up assessment 12 weeks posttraining. SETTING: Four regional neurologic inpatient rehabilitation units. PATIENTS: Of 157 patients recruited 24 +/- 14 weeks after single-incident brain injury, 142 patients were assessed at week 12, and 128 patients at follow-up. INTERVENTIONS: Patients were randomized between cycle ergometer aerobic training and a relaxation training control condition, which was theoretically inert with respect to cardiovascular fitness. MAIN OUTCOME MEASURES: Validation of exercise training (peak work rate, peak heart rate, body mass index); mobility and physical function (modified Ashworth scale, Berg balance scale, Rivermead Mobility Index, 10-m walk velocity); disability and dependency (Barthel index, FIMtrade mark instrument, Nottingham Extended Activities of Daily Living); and psychologic function (fatigue questionnaire, Hospital Anxiety and Depression Scale). RESULTS: Significant improvements in exercise capacity (p <.05) in the exercise training group (n = 70) relative to the control group (n = 72) were not matched by greater improvements in functional independence, mobility, or psychologic function, at either 12 weeks or follow-up. CONCLUSIONS: The benefits of improved cardiovascular fitness did not appear to extend to measurable change in function or psychologic state.

Evaluation of ethnic minorities and gender effects in clinical trials: opportunities lost and rediscovered.

Recent recognition has been given to the notion of demonstrating a beneficial effect of randomly allocated interventions utilized in controlled clinical trials to women and ethnic minorities. However, despite National Institutes of Health (NIH) guidelines on the inclusion of ethnic minorities and women into these studies, clinical trial investigators continue to suffer from an inability to persuasively reach conclusions about the intervention effect in these subgroups. Although a major factor in this limitation has been the inability to recruit large numbers of these patients into controlled clinical trials, an additional dilemma has been the clinical trial community's well demonstrated inability to draw reliable conclusions from the relevant subgroup analyses. As currently designed in clinical trials, subgroup analyses with neither good prospective planning nor concern for the multiplicity of type I error that accompanies the testing of multiple hypotheses are appropriately relegated to exploratory analyses which merely raise questions, not answer them. This article demonstrates that taking advantage of: (a) prospective, subgroup specific endpoint selection; (b) prospective, subgroup specific endpoint event rates; (c) prospective, subgroup specific therapy efficacy, and (d) prospective, subgroup specific nonuniform type I error levels will fortify a subgroup analysis. Thus, the tools traditionally available to clinical trialists, when wielded with renewed vigor and innovation, in concert with energetic, focused recruitment efforts can lead to a confirmatory analysis with appropriate statistical rigor for the effect of the randomly allocated intervention in these important demographic subgroups.

Effect of renal function on risedronate pharmacokinetics after a single oral dose.

AIMS: To determine the relationship between risedronate pharmacokinetics and renal function. METHODS: Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15-126 ml min-1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). Risedronate serum concentration-time and urinary excretion rate-time profiles were analysed simultaneously using nonlinear regression. RESULTS: Renal clearance and volume of distribution were linearly related to creatinine clearance (r2=0.854, P<0.001; and r2=0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min-1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min-1 (P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population. CONCLUSIONS: Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min-1 ).

Comparative oral bioavailability of azimilide dihydrochloride in the fed and fasted states.

AIMS: This study investigated the relative oral bioavailability of azimilide dihydrochloride following administration in the fed (high-fat meal) and fasted states. METHODS: This was a single-dose, randomized, two-way crossover study in 30 healthy, Caucasian, male subjects. Following oral administration, blood samples were collected over 27 days and analysed for azimilide using h.p.l.c. with u.v. detection. Pharmacokinetic parameters were determined using 'noncompartmental' analysis and compared using an ANOVA and 90% or 95% confidence intervals. RESULTS: The extent of absorption was equivalent in the fed and fasted states (ratio = 96.2%; 90% CI=90.5% -102.4%). However, Cmax was decreased 19% following a high-fat meal (ratio=81.4%; 90% CI= 76.2% -87.0%). No difference in tmax or t(1/2),z was observed. CONCLUSIONS: Azimilide dihydrochloride may be orally administered to patients without regard to the prandial state.

Dose-proportional pharmacokinetics of risedronate on single-dose oral administration to healthy volunteers.

Risedronate is a pyridinyl bisphosphonate approved for the treatment of Paget's disease (US-FDA) and in development for the treatment and prevention of osteoporosis. This study examined risedronate pharmacokinetics and tolerability after oral administration using a randomized, double-blind, parallel-group design. Healthy male and female volunteers (n = 22-23 subjects per dose) received a single oral dose of 2.5, 5, or 30 mg risedronate. Serum and urine samples were collected for 72 and 672 hours, respectively, and risedronate concentrations were determined by ELISA. Safety was evaluated by monitoring adverse events, clinical laboratory measurements, vital signs, and electrocardiograms. Mean Cmax (0.41, 0.94, and 5.1 ng/mL for 2.5, 5, and 30 mg, respectively), AUC (1.8, 3.9, and 21 ng.h/mL for 2.5, 5, and 30 mg, respectively), and urinary excretion (22, 63, and 260 micrograms for 2.5, 5, and 30 mg, respectively) were dose proportional, and there were no significant differences in tmax or CLR among the three doses. All doses were well tolerated; no serious adverse events occurred, and all but one of the adverse events were mild or moderate in severity. There was no evidence of an acute phase reaction occurring after oral administration of risedronate.

Absence of pharmacokinetic interaction between orally co-administered naproxen sodium and diphenhydramine hydrochloride.

The potential for a pharmacokinetic interaction between naproxen and diphenhydramine was examined in a randomized three-way crossover design with a 1-week washout between dosing. Single oral doses of 220 mg of naproxen sodium and 50 mg of diphenhydramine hydrochloride were given separately and together to 30 healthy male and female subjects. Heparinized blood samples obtained for 48 h postdose were assayed for plasma naproxen and diphenhydramine concentrations using validated high-performance liquid chromatography (HPLC) and gas chromatography (GC) assay methods, respectively. The area under the plasma concentration-time curve (AUC), maximum plasma concentrations (C(max)), time of C(max) (T(max)) and terminal exponential half-life (t(1/2,z)), were analysed for significant treatment differences by analysis of variance (ANOVA). Based on absence of significant treatment effects on AUC and C(max), single-dose oral co-administration of 220 mg of naproxen sodium with 50 mg of diphenhydramine hydrochloride does not alter the pharmacokinetics of either naproxen or diphenhydramine. Significant treatment differences seen for naproxen T(max) (0.3 h, males only) and diphenhydramine t(1/2,z) (0.8 h, females only) were minor and are unlikely to have therapeutic consequences. Thus, efficacy and safety of concomitant naproxen and diphenhydramine should not be altered due to a pharmacokinetic interaction.

Azimilide pharmacokinetics following intravenous and oral administration of a solution and capsule formulation.

Azimilide dihydrochloride (NE-10064) is a novel class III anti-arrhythmic agent that blocks both the slowly and rapidly acting components of the delayed rectifier potassium current of human atrial and ventricular myocytes. In clinical studies, azimilide reduced the frequency of symptomatic episodes of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia. This study was conducted to characterize azimilide pharmacokinetics following single-dose administration of a 1 mg/kg intravenous infusion (18 min), 2 mg/kg oral solution, and a 150 mg orally administered capsule. This was a three-period, randomized, crossover study in 27 healthy, drug-free (including caffeine and alcohol), non-smoking male volunteers (mean [SD]; age, 25.9 [1.0] years; weight 74.3 [0.7] kg; 23 Caucasians and 4 Hispanics). Blood and urine samples were collected for 27 days and analyzed for azimilide using HPLC with UV detection. Subjects were monitored for adverse events and abnormalities in clinical laboratory tests, vital signs, and electrocardiography (including Holter monitoring). Mean (%CV) azimilide parameters were total clearance = 0.143 L/h/kg (38%), renal clearance = 0.014 L/h/kg (35%), steady-state volume of distribution = 13.2 L/kg (23%), and terminal exponential half-life = 78.8 h (44%). Similar parameter estimates were obtained following oral administration. Both the oral solution and capsule formulations were completely absorbed. In addition, the rate (Cmax) and extent of absorption (AUC) following oral administration of the capsule dosage form were bioequivalent to the oral solution with means for times of maximum blood concentration of 7.08 and 7.18 hours for the oral solution and capsule, respectively. Azimilide dihydrochloride was generally well tolerated in all subjects.

C8-Arylguanine and C8-aryladenine formation in calf thymus DNA from arenediazonium ions.

Arylhydrazides, arylhydrazines, and N-alkyl-N-arylnitrosamines are metabolized to arenediazonium ions which yield C8-arylpurine adducts in calf thymus and cellular DNA. The mechanism of adduct formation has not been fully elucidated. C8-Arylguanine adducts likely form from direct aryl radical (Ar*) addition to the C8 position of guanine. However, the amounts of C8-aryladenine adducts measured here are inconsistent with direct radical attack at the C8 position of adenine. An intermediate product, an aryltriazene, is likely formed which then decomposes to the C8-aryladenine adduct. We have demonstrated that N1-aryl-N3-purinyltriazene adducts are formed from a variety of para-substituted arenediazonium ions with adenine. Decomposition of the N1-aryl-N3-purinyltriazene, at high pH and elevated temperatures, has been shown to give C8-aryladenine derivatives, and a free radical mechanism for this process has been proposed. Here we show that this process can occur under physiological conditions and that the C8-aryladenine adduct can be quantitated by HPLC. ESR studies, in which DMPO was used as a spin trap, have been used to demonstrate the intermediacy of aryl radicals during the decomposition of the N1-aryl-N3-purinyltriazenes and to demonstrate that this process also occurs in calf thymus (ct) DNA treated with arenediazonium ions. These results suggest the involvement of an aryl radical in the formation of the observed DNA adducts. Finally, we have found that the treatment of ct DNA with arenediazonium ions produces a significant amount of depurination. Both the formation of C8-arylguanine and C8-aryladenine adducts and the generation of apurinic sites may contribute to the genotoxicity of arylhydrazides, arylhydrazines, N-alkyl-N-arylnitrosamines, and arenediazonium ions.

Significant differences in estradiol bioavailability from two similarly labelled estradiol matrix transdermal systems.

OBJECTIVE: To compare the bioavailabilities of estradiol delivered by two transdermal estradiol matrix systems; Alora and Evorel. STUDY DESIGN: A single-center, open-label, randomized, two-period cross-over study in 33 postmenopausal women. The subjects received two successive 84-h applications of either Alora or Evorel (each labelled to deliver 50 micrograms/day 17 beta-estradiol) in a randomized sequence. Serial serum samples, collected over the 84-h period following the application of the second patch, were analyzed for estradiol using a validated radioimmunoassay method. RESULTS: The fluctuation index produced by Evorel was significantly higher than that produced by Alora (Evorel, 135%; Alora, 76%; p < 0.0005). In addition, the estradiol baseline-corrected area under the curve for Evorel was significantly lower than that for Alora (Alora, 2871.8 pg h/ml; Evorel, 1870.6 pg h/ml; p < 0.0005). Both patches were found to be generally well tolerated. CONCLUSION: Alora delivered a higher, more consistent concentration of estradiol into the systemic circulation over the entire dosing interval than did Everol. Although the full clinical significance of these findings is currently unknown, this study demonstrates that there are significant differences in estradiol delivery from these two products, although they are labelled with the same nominal delivery rate.

Measuring progress and outcome in community rehabilitation after brain injury with a new assessment instrument--the BICRO-39 scales. Brain Injury Community Rehabilitation Outcome.

OBJECTIVE: Construction and validation of a new instrument, the Brain Injury Community Rehabilitation Outcome scales, to assess problems experienced by brain-injured patients living in the community. DESIGN: Seventy-six items describing aspects of personal and social functioning were generated. Two hundred thirty-five patients and/or their carers (separately) rated the items on 6-point scales, and patients retrospectively rated their functioning before injury. Seven scales were derived from factor analysis; one was included a priori. Thirty-nine items with high factor loadings were retained. Test-retest reliability, interrater reliability, and construct validity were examined in subsamples. SETTING: Patients were recruited from four centers: two community-based teams, a day-patient clinic, and an outpatient clinic. PATIENTS: Of the patients, 127 had traumatic brain injury, 72 had cerebrovascular accidents, 15 had multiple sclerosis, and 21 had acquired brain injury of other origins. Mean time since brain injury was 2.6 years; mean age was 43 years; 164 were men and 71 were women. RESULTS: All scales showed good test-retest reliability, and agreement between patient and carer ratings was moderate to high. They showed predicted moderate correlations with other relevant scales. Postinjury scores differed significantly from preinjury scores, and 6 of the 8 scales showed change over a period of recovery/rehabilitation. CONCLUSIONS: The scales appear reliable and easy to complete. They may have utility as quantitative measures of outcome for clinical and treatment evaluations.

Motivational deficits after brain injury: a neuropsychological approach using new assessment techniques.

Deficits of motivation are recognized as a significant clinical problem following brain injury, and a neuropsychological model is postulated linking such deficits with cognitive deficits of a frontal type. However, few, if any, quantitative assessment measures exist; most descriptions in the literature are qualitative, and this has limited the scope and robustness of research into the problem. The authors in the present research have developed new tools for assessing patients' level of motivation in therapy (percent participation index) and their behavioral responsiveness to experimental incentive (the card-arranging reward responsivity objective test). Relationships among poor motivation, reward responsiveness, frontal lobe function, and mood were explored in a sample of 54 patients with nonfocal vascular or traumatic brain injury; the results were consistent with the neuropsychological model. Preliminary reliability and validation data on the new measures are reported.

The differential optomotor response of the four-eyed fish Anableps anableps.

The perception of motion is important for the survival and reproduction of many animals, including fish. In the laboratory, support for this idea comes from the observation that many fish show a tendency to follow a series of stripes revolving around a circular aquarium. This response, known as the optomotor response (OMR), is recognized as an innate behavior in many species. The 'four-eyed' fishes of the genus Anableps are an unusual fish from Central and South America and actually have only two eyes. Each eye is divided into upper and lower halves internally and externally. This peculiar dual visual system allows Anableps to feed on creatures that swim or land near or on the water surface or to flee from flying predators attacking from above. It was hypothesized that Anableps should also possess the OMR. We used the OMR as a test to investigate potential differential visual processing in Anableps on normal and 'blinded' fish (the eyes are actually covered--not physically blinded). It was found that the OMR does exist in Anableps and that the strength of this response is dependent on the visual field being tested--a stronger OMR was seen as a result of visual stimulation from the aerial environment.

Assessment of doxylamine influence on mixed function oxidase activity upon multiple dose oral administration to normal volunteers.

The primary purpose of this study was to assess the influence of doxylamine and phenobarbital on antipyrine/metabolites pharmacokinetics and 6 beta-hydroxycortisol urinary excretion. This study was conducted in 48 healthy male human volunteers (16 per treatment group) using a parallel study design. Treatment groups consisted of 12.5 mg of doxylamine succinate, placebo, or 30 mg of phenobarbital administered orally every 6 h for 17 days. Results indicate that no statistically significant differences were observed between the doxylamine and placebo groups that are indicative of enzyme induction. For the phenobarbital group, a significant increase for antipyrine total (36 versus 45 mL/h/kg) and nonrenal (35 versus 44 mL/h/kg) clearances and 6 beta-hydroxycortisol excretion (338 versus 529 micrograms) and a significant decrease in the terminal exponential half-life (11 versus 9 h) of antipyrine were observed.

Motivational deficits after brain injury: effects of bromocriptine in 11 patients.

OBJECTIVE: To test the hypothesis that treatment with bromocriptine would ameliorate deficits in clinical motivation, responsiveness to reward, and frontal cognitive function after brain injury. METHOD: An open trial in six men and five women who had had either traumatic brain injury or subarachnoid haemorrhage between two months and five years previously. After repeated baseline assessments, bromocriptine was given in gradually increasing doses. Assessments were repeated at increasing doses, during maintenance, and after withdrawal. Novel structured instruments for quantifying motivation were developed; measures of anxiety and depression, and cognitive tests sensitive to motivation or frontal lobe involvement were also given. RESULTS: Bromocriptine treatment was followed by improved scores on all measures other than mood. Improvement was maintained after bromocriptine withdrawal in eight of the patients. CONCLUSION: Poor motivation in patients with brain injury may result from dysfunction in the mesolimbic/mesocortical dopaminergic circuitry, giving rise to associated deficiencies in reward responsiveness and frontal cognitive function.