PXR as a mediator of herb-drug interaction.

Medicinal herbs have been a part of human medicine for thousands of years. The herb-drug interaction is an extension of drug-drug interaction, in which the consumptions of herbs cause alterations in the metabolism of drugs the patients happen to take at the same time. The pregnane X receptor (PXR) has been established as one of the most important transcriptional factors that regulate the expression of phase I enzymes, phase II enzymes, and drug transporters in the xenobiotic responses. Since its initial discovery, PXR has been implicated in multiple herb-drug interactions that can lead to alterations of the drug's pharmacokinetic properties and cause fluctuating therapeutic efficacies, possibly leading to complications. Regions of the world that heavily incorporate herbalism into their primary health care and people turning to alternative medicines as a personal choice could be at risk for adverse reactions or unintended results from these interactions. This article is intended to highlight our understanding of the PXR-mediated herb-drug interactions.

Antimicrobial efficacy of an innovative emulsion of medium chain triglycerides against canine and feline periodontopathogens.

OBJECTIVES: To test the in vitro antimicrobial efficacy of a non-toxic emulsion of free fatty acids against clinically relevant canine and feline periodontopathogens METHODS: Antimicrobial kill kinetics were established utilising an alamarBlue(®) viability assay against 10 species of canine and feline periodontopathogens in the biofilm mode of growth at a concentration of 0·125% v/v medium chain triglyceride (ML:8) emulsion. The results were compared with 0·12% v/v chlorhexidine digluconate and a xylitol-containing dental formulation. Mammalian cellular cytotoxicity was also investigated for both the ML:8 emulsion and chlorhexidine digluconate (0·25 to 0·0625% v/v) using in vitro tissue culture techniques. RESULTS: No statistically significant difference was observed in the antimicrobial activity of the ML:8 emulsion and chlorhexidine digluconate; a high percentage kill rate (>70%) was achieved within 5 minutes of exposure and was maintained at subsequent time points. A statistically significant improvement in antibiofilm activity was observed with the ML:8 emulsion compared with the xylitol-containing formulation. The ML:8 emulsion possessed a significantly lower (P < 0·001) toxicity profile compared with the chlorhexidine digluconate in mammalian cellular cytotoxicity assays. CLINICAL SIGNIFICANCE: The ML:8 emulsion exhibited significant potential as a putative effective antimicrobial alternative to chlorhexidine- and xylitol- based products for the reduction of canine and feline periodontopathogens.

Dysregulation of neurosteroids in obsessive compulsive disorder.

Alterations in hormone concentrations, including adrenocorticotropin, corticotropin releasing hormone, and cortisol have been reported in patients with obsessive compulsive disorder (OCD). Dehydroepiandrosterone (DHEA) and its sulfated metabolite, DHEA-S, have not been assessed in patients with OCD. We report 24-h serum DHEA, DHEA-S, and cortisol concentrations in a young man with OCD and 15 healthy young men. Circadian patterns of DHEA and cortisol were markedly different in the subject with OCD than in the control subjects. DHEA and DHEA-S concentrations were substantially higher in the OCD subject than in the control subjects. In contrast, cortisol concentrations were similar in the OCD subject and the control subjects. Future clinical studies are needed to evaluate the significance of DHEA and DHEA-S in OCD.

Impaired oculomotor response inhibition in children of alcoholics: The role of attention deficit hyperactivity disorder.

OBJECTIVE: The aim of the project was to determine whether children at high risk for alcohol use disorder (AUD) are impaired at performing oculomotor response inhibition tasks sensitive to detecting prefrontal cortex dysfunction. METHODS: Three antisaccade tasks were administered to 67 10-12-year-old children having fathers with AUD and 12 children whose fathers had no psychiatric disorder. RESULTS: Children of AUD+ fathers performed similar to children of AUD- fathers on measures of response latency and gain to target. Peak velocity discriminated the two groups on only one task. Children of AUD+ fathers exhibited a higher rate of prosaccade errors on the most difficult antisaccade task. Within the AUD+ group of men, offspring who qualified for attention deficit hyperactivity disorder (ADHD; N = 13) exhibited more response suppression errors than children without ADHD on two of three tasks. No differences were observed between children without ADHD whose fathers either qualified for AUD+ or had no psychiatric disorder. CONCLUSION: Inhibiting a response to a prepotent stimulus in children of AUD+ fathers is circumscribed to ADHD youths. These findings suggest that frontal-striatal mechanisms may underlie the risk for AUD among ADHD children.

A novel spectrofluorometric microassay for Streptococcus mutans adherence to hydroxylapatite.

Adherence to the tooth surface by Streptococcus mutans is an important step in initiation of dental caries. Current in vitro methods used to study bacterial adherence are time-consuming and may involve the use of radiolabels. The aim of this study was to develop a more convenient, high-throughput, microtitre-plate assay of bacterial adherence to hydroxylapatite. S. mutans was labelled with the fluorescent indicator BCECF/AM and fluorescence measured using a spectrofluorometer. Fluorescence microscopy confirmed label uptake. Optimal labelling occurred at 120 min with 50 microM BCECF/AM in DMSO. Viability was similar in control untreated bacterial cells, bacteria treated with DMSO alone or with the label for up to 4 h. Preliminary adherence experiments were performed using four commercially available types of hydroxylapatite. Fluorescence from pre-labelled bacteria was measured for bound cells. The assay was then optimised with respect to time and bacterial concentration using Fluka crude hydroxylapatite. Time course studies demonstrated that adherence reached saturation by 30 min incubation when using 1x10(7) cfu/ml labelled bacteria to 1 mg hydroxylapatite, coated with PBS or saliva. The fluorescence-based adherence assay was highly reproducible in repeated analyses and was useful in demonstrating interference with adherence. In conclusion, this microtitre-plate assay offers a more convenient approach to examine streptococcal adherence and could be used to screen for potential anti-adhesive agents.

Dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and cortisol concentrations in intensive care unit patients.

STUDY OBJECTIVE: This purpose of this study was to determine whether severity of illness, as defined by the intensive care unit (ICU) admission APACHE II (updated Acute Physiology and Chronic Health Evaluation) score, is correlated with early morning cortisol, dehydroepiandrosterone (DHEA), and/or dehydroepiandrosterone-sulfate (DHEA-S) concentrations. DESIGN: Early morning concentrations of DHEA, DHEA-S, and cortisol were determined within 24 hrs of admission and compared with admission APACHE II scores. SETTING: Medical (MICU), neurologic (NICU), and surgical (SICU) intensive care units of the University of Pittsburgh Medical Center. PATIENTS: A total of 191 men and women ranging in age from 16 to 93 yrs. All had been admitted to an ICU. MEASUREMENTS AND MAIN RESULTS: Statistically significant correlations between APACHE II scores and cortisol were observed for women in the MICU and SICU (r = .68, p = .0001; r = .35 p = .017, respectively) and for men in the NICU (r = .55, p = .003) and the SICU (r = .29, p = .036). The correlations between APACHE II scores and DHEA concentration data were statistically significant for women in the MICU (r = .37, p = .047) and SICU (r = .43, p = .002), as was the correlation between APACHE II and DHEA-S concentrations among women in the SICU (r = .38, p = .008). Although not statistically significant, a similar relationship was observed in the smaller group of NICU women (r = .40, p = .099). Each correlation was essentially unchanged when adjusted for age. CONCLUSION: These data show a positive correlation between APACHE II and cortisol concentrations in all groups except the MICU men. Also evident is the positive correlation between APACHE II scores and DHEA and DHEA-S concentrations in women, but not in men.

Sex differences in the pharmacokinetics of dehydroepiandrosterone (DHEA) after single- and multiple-dose administration in healthy older adults.

The pharmacokinetics of exogenously administered DHEA have not been well characterized despite its increasing use in therapeutic and research investigations. The purpose of this study was to evaluate the pharmacokinetics of DHEA and its sulfated metabolite (DHEA-S) after single- and multiple-dose oral administration of DHEA 200 mg. Healthy older adult volunteers (7 women, 6 men) ages 65 to 79 years were studied on five visits separated by 1 week. Subjects received daily administration of placebo (days 1 to 7), DHEA 200 mg (days 8 to 22), and placebo (days 23 to 29). Blood samples were collected over 24 hours on days 1, 8, 15, 22, and 29 for DHEA and DHEA-S determinations by RIA. Pharmacokinetic parameter estimates were calculated by noncompartmental methods. Administration of DHEA 200 mg resulted in higher DHEA Cmax, AUC, and overall concentrations in women than in men (p < 0.03); DHEA-S parameter estimates were similar between men and women. Following a single dose of DHEA 200 mg, DHEA concentrations increased 5- to 6-fold in both men and women, and DHEA-S concentrations increased 5-fold in men and 21-fold in women relative to endogenous concentrations. The results of this study indicate that the pharmacokinetics of DHEA differ between older men and women.

Inhibition of caffeine metabolism by estrogen replacement therapy in postmenopausal women.

This study was conducted to investigate the effect of therapeutic estrogen on cytochrome P450 1A2-mediated metabolism in postmenopausal women using caffeine as a model substrate. Twelve healthy postmenopausal women underwent estrogen replacement therapy in the form of estradiol (Estrace). Estradiol was initiated at a dose of 0.5 mg a day and titrated to achieve a steady-state plasma concentration of 50 to 150 pg/ml. Caffeine metabolic ratios (CMR; paraxanthine/caffeine) were assessed both before and after 8 weeks of estrogen replacement. For the 12 subjects, there was a mean reduction in CMR of -29.2 +/- 25.0 (p = 0.0019). Consistent with previous results found in younger women, these results indicate that exogenous estrogen in older women may inhibit CYP1A2-mediated caffeine metabolism.

Do alprazolam-induced changes in saccadic eye movement and psychomotor function follow the same time course?

The purpose of this study was to determine whether short-term tolerance develops to GABA-agonist-induced changes in saccadic eye movements (SEMs), and whether the time course for GABA-agonist induced onset and offset of impairment is similar for SEMs and for psychomotor function. An additional goal was to determine whether there are differences in sensitivity between SEMs and psychomotor function. Six healthy volunteers participated in this balanced double-blind, three-way crossover, single-dose study of placebo and two different dosage forms of the GABA-agonist alprazolam: a rapidly absorbed oral 1.5-mg compressed tablet (CT) and a 3.0-mg sustained release (SR) tablet. Treatments were separated by a 7-day washout period. Peak concentrations did not differ between CT and SR treatments, although area under the concentration-time curve (AUC) of alprazolam was greater after administration of SR than after CT, because plateau concentrations were attained after SR. Both SEM and psychomotor tests showed time-dependent responses consistent with the development of tolerance. SEMs discriminated the differences in rate of drug input of the CT and SR formulations, with impairment evident at low concentrations during absorption. SEM impairment also persisted longer than did psychomotor impairment. Peak saccade velocity is a more sensitive indicator of pharmacologic effects mediated by the GABA-benzodiazepine receptor complex than are psychomotor responses. This is probably the result of the very high GABA dependency of SEMs, along with their limited sensitivity to motivation.

Coadministration of nefazodone and benzodiazepines: I. Pharmacodynamic assessment.

One hundred two healthy men were evaluated in one of three studies conducted to evaluate the coadministration of nefazodone, 200 mg twice daily, and three benzodiazepines: triazolam, 0.25 mg; alprazolam, 1 mg twice daily; or lorazepam, 2 mg twice daily. In the first study, psychomotor performance, memory, and sedation were assessed at 0, 0.5, 1.5, 2.5, and 9 hours after single doses of triazolam alone and again after 7 days of nefazodone. Data from 6 of 12 subjects in this study were evaluable because of a dosing error in the other 6 subjects. In the subsequent two parallel design studies, groups of 12 volunteers received 7 days of either placebo; nefazodone, 200 mg; alprazolam, 1 mg twice daily; or alprazolam plus nefazodone or, in the second study, either placebo; nefazodone; lorazepam, 2 mg twice daily; or lorazepam plus nefazodone; the studies were identical, double-dummy, double-blind designs. Psychomotor performance, memory, and sedation were assessed at 0, 1, 3, and 8 hours after the 8 a.m. dose on days 1, 3, 5, and 7 of the studies. In all studies, blood samples were also obtained at testing times so that effect/concentration comparisons could be made and so full pharmacokinetic analyses could be done for separate studies. Nefazodone had no effect on psychomotor performance, memory, or sedation relative to placebo in any study. The mean maximum observed effect (MaxOE) on psychomotor performance and sedation were increased when triazolam was given after 7 days of nefazodone (p < 0.05); also, triazolam concentration was 60% higher at this time. Alprazolam and lorazepam impaired performance on day 1 (mean MaxOE, 34 and 30%, respectively) relative to placebo and nefazodone. By day 7 of alprazolam or lorazepam, psychomotor impairment decreased, indicating the development of tolerance. Alprazolam plus nefazodone increased psychomotor impairment (MaxOE, approximately 50%) and sedation relative to alprazolam alone on days 3, 5, and 7 (p < 0.05). Higher alprazolam concentrations explained the increased impairment in the alprazolam plus nefazodone treatment group; however, it is also possible that there was a delay in the development of tolerance. There were no differences in psychomotor impairment, memory, sedation, or lorazepam concentration detected between the lorazepam alone and lorazepam plus nefazodone treatments. This is consistent with the absence of a pharmacokinetic interaction between nefazodone and lorazepam. These results indicate that if the coadministration of a benzodiazepine is required in patients receiving nefazodone therapy, clinically significant interactions would be less likely with those eliminated by conjugative metabolism such as lorazepam. In cases where a benzodiazepine eliminated by oxidative metabolism is required, a reduction in initial dosage and careful clinical evaluation for signs of psychomotor impairment may be appropriate.

Design and pharmacodynamic evaluation of novel dual release formulations of triazolam.

Triazolam is an effective hypnotic that can cause amnesia and psychomotor performance decrements, particularly after a 0.5 mg dose. Previous pharmacodynamic studies suggested a relationship between these effects and triazolam plasma concentration. A novel dual release bilayer tablet was designed to mimic the onset of action of a 0.25 mg dose and to maintain the duration of a 0.5 mg dose without the side effects associated with the 0.5 mg dose. The immediate release component of the bilayer tablet contained 0.25 mg triazolam while the sustained release component contained 0.15 mg triazolam. Two prototype formulations of the bilayer tablet, differing in rate of release in the sustained release component, were tested against a conventional 0.5 mg triazolam compressed tablet and placebo in a single-dose, double-blind, four-way crossover study in healthy male subjects. Triazolam plasma concentration time profile was obtained over 12 hours following single administration of each treatment. Effects of triazolam on central nervous system function were evaluated using psychomotor performance tests, immediate and delayed recall tests and rating of sedation. The triazolam plasma concentrations were not significantly different among the active drug treatments, although the dual release tablets did give the expected profiles. There were significant differences in triazolam effects on memory and psychomotor performance. The slowest releasing dual-release tablet showed significantly less psychomotor impairment and memory deficit than the conventional tablet. There was no difference in sedation among the active drug treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Coming of age in nursing. Rethinking the philosophies behind holism and nursing process.

No one is going to like everything that Kobert and Folan say in this article, but it offers a rich bouquet of ideas for discussion and debate. Are they right to assert that holism and nursing process are incompatible? That nursing process is associated with an immature level of professional development? That holism is the answer for nursing? That holism equates with feminism while nursing process represents a masculine reductionism?