Evaluation of a Standardized Tacrolimus Therapeutic Drug Monitoring Protocol in Stable Kidney Transplant Recipients.

Introduction: Transplant nurse coordinators have assisted in accurately adjusting tacrolimus doses under a collaborative practice agreement for kidney transplant recipients in the early post-operative period. This study evaluated the efficiency of a standardized tacrolimus therapeutic drug monitoring (TDM) protocol in stable outpatient recipients. Design: We conducted a single-center, retrospective study of adult patients who received a kidney transplant at least 3 years ago and were taking immediate-release tacrolimus. Before September 2019, transplant coordinators consulted transplant providers for management of all tacrolimus trough levels (Pre-Arm). Under the standardized protocol, coordinators directly responded to out-of-range tacrolimus trough levels (Post-Arm). The primary outcome was the time to intervention for out-of-range levels. Secondary outcomes included adverse events, time in therapeutic range, coefficient of variation (CV), and protocol compliance. Results: Of 1712 levels (from 174 patients), 259 levels (15.1%) were out-of-range. The overall time to intervention was 13.2 hours shorter (95% CI: -26.4 to -0.1 hours; P = 0.048) in the Post-Arm. There was no rejection, graft loss, or death during the study period. The time in therapeutic range was 89.3% (17.6%) vs 89% (19.4%; P = 0.816) and CV was 19.7% (15.8%) vs 18.4 (10.7%; P = 0.358) in the Pre-Arm and Post-Arm, respectively. Within the Post-Arm, the protocol required coordinators to independently intervene on 96 out-of-range levels (65.8%), which were accurately addressed 57.5% of the time. Conclusion: Implementation of a standardized TDM protocol improved efficiency without compromising major clinical outcomes or intrapatient variability (IPV) of tacrolimus levels for stable kidney recipients in the outpatient setting.

Evidence-based Practices Addressed in Community-based Children's Mental Health Clinical Supervision.

CONTEXT: Clinical supervision is the principal method of training for psychotherapeutic practice, however there is virtually no research on supervision practice in community settings. Of particular interest is the role supervision might play in facilitating implementation of evidence-based (EB) care in routine care settings. OBJECTIVE: This study examines the format and functions of clinical supervision sessions in routine care, as well as the extent to which supervision addresses psychotherapeutic practice elements common to EB care for children with disruptive behavior problems, who represent the majority of patients served in publicly-funded routine care settings. METHODS: Supervisors (n=7) and supervisees (n=12) from four publicly-funded community-based child mental health clinics reported on 130 supervision sessions. RESULTS: Supervision sessions were primarily individual in-person meetings lasting one hour. The most common functions included case conceptualization and therapy interventions. Coverage of practice elements common to EB treatments was brief. DISCUSSION: Despite the fact that most children presenting to public mental health services are referred for disruptive behavior problems, supervision sessions are infrequently focused on practice elements consistent with EB treatments for this population. Supervision is a promising avenue through which training in EB practices could be supported to improve the quality of care for children in community-based "usual care" clinics.

Methodological challenges of characterizing usual care psychotherapeutic practice.

There is minimal existing research providing detailed, reliable data characterizing usual community-based psychotherapy practice, and, thus, limited established methods for such research. This article identifies methodological challenges of usual care descriptive research, including, (a) general design considerations, (b) measurement, (c) data analytic, and (d) ethical challenges. Case examples drawn from studies reported in this special issue are used to illustrate the implications, strengths, and weaknesses of different methodological decisions. Central themes include achieving an acceptable balance of scientific rigor, feasibility, and generalizable practice relevance, as well as working collaboratively with practice partners to select and implement study methods.

An effective indoor mesocosm for studying populations of Anopheles gambiae in temperate climates.

To study the indoor behavior of Anopheles gambiae populations in a temperate climate, we have devised a walk-in mesocosm, built within a greenhouse. The structure provides conditions more natural than laboratory cages, including sufficient room for swarming and for flight between resting sites, sugar-bearing plants, a human host, and an oviposition site. These activities impose energy demands closer to those encountered in the field. The structure also has predators, fluctuating temperatures, natural daylight, and an evening crepuscular period. Most important, its resting sites comprise a bank of tubes that can be inspected or removed individually to obtain, at regular time intervals, random representative samples of an experimental population while all individuals are inactive. Samples from aging cohorts of mosquitoes, released at emergence, can yield information on behavioral sequences, mate competition, reproductive success, and survival under different nutritional regimes.

Modafinil influences the pharmacokinetics of intravenous cocaine in healthy cocaine-dependent volunteers.

OBJECTIVE: To determine if modafinil, a putative treatment for cocaine dependence, influences the pharmacokinetics of intravenous cocaine in otherwise healthy cocaine-dependent volunteers. METHODS: Cocaine 20 or 40 mg was administered intravenously on consecutive days over 1 minute at baseline and after modafinil administration at each of two dosages of 400 and 800 mg/day for 7 days. RESULTS: Twelve subjects completed the clinical protocol. Compared with baseline, the cocaine peak plasma concentration was decreased after both the 20 and 40 mg cocaine infusions, but the reduction was only statistically significant after the 40 mg cocaine infusion (p < 0.01 after modafinil 400 mg/day; p < 0.05 after modafinil 800 mg/day). The area under the cocaine plasma concentration-time curve from 0 to 180 minutes (AUC180) was significantly decreased by modafinil administration (p < 0.01 and p < 0.001 for modafinil 400 and 800 mg/day, respectively, for the cocaine 20mg dose; p < 0.001 for the cocaine 40 mg dose at both modafinil levels). There were no significant changes in total AUC, clearance or elimination half-life of cocaine. CONCLUSION: This study did not find evidence for a harmful pharmacokinetic interaction between modafinil and cocaine. In contrast, long-term administration of modafinil significantly decreased systemic exposure to cocaine during the first 180 minutes following intravenous cocaine administration.

Green tea (Camellia sinensis) extract does not alter cytochrome p450 3A4 or 2D6 activity in healthy volunteers.

Green tea extract is a widely used dietary supplement. The objective of this study was to assess the influence of a decaffeinated green tea (DGT; Camellia sinensis) extract on the activity of the drug-metabolizing enzymes cytochrome P-450 2D6 and 3A4. Probe drugs dextromethorphan (30 mg, CYP2D6 activity) and alprazolam (ALPZ; 2 mg, CYP3A4 activity) were administered orally to healthy volunteers (n = 11) at baseline, and again after treatment with four DGT capsules/day for 14 days. Each DGT capsule contained 211 +/- 25 mg of green tea catechins and <1 mg of caffeine. Dextromethorphan metabolic ratios (DMRs) and alprazolam pharmacokinetics were determined at baseline and after DGT treatment. There were no significant differences in ALPZ pharmacokinetics at baseline and after DGT treatment (all P values >/= 0.05; maximum concentration in plasma, 33 +/- 8 versus 34 +/- 13 ng/ml; time to reach maximum concentration in plasma, 1.4 +/- 1.2 versus 1.4 +/- 1.2 h; area under the plasma concentration versus time curve, 480 +/- 119 versus 510 +/- 107 h. ng. ml(-1); half-life of elimination, 12.3 +/- 1.7 versus 13.1 +/- 3.4 h). The DMR was 0.053 +/- 0.045 at baseline and 0.041 +/- 0.032 after DGT supplementation (P > 0.05). The plasma concentration of the green tea flavonoid, (-)-epigallocatechin gallate, reached 1.3 +/- 1.8 microM 2 h after DGT treatment. Our results indicate that DGT is unlikely to alter the disposition of medications primarily dependent on the CYP2D6 or CYP3A4 pathways of metabolism.

Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of Abcb1a gene knockout mice.

RATIONALE: Methadone maintenance treatment is complicated by the wide variability of efficacy among patients. The large interindividual variability of the plasma concentrations of methadone was previously thought to be responsible for the variable therapeutic efficacy. However, recent studies suggested that methadone may be a substrate of P-glycoprotein (P-gp). Therefore, the function of P-gp in blood-brain barrier (BBB) may affect the concentration of methadone at its site(s) of action in the central nervous system, thereby contributing to its therapeutic efficacy and/or adverse events. OBJECTIVE: To investigate the effect of P-gp on brain penetration of methadone (R)- and (S)-enantiomers and their major oxidative metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). METHODS: We compared the tissue distribution of methadone (R)- and (S)-enantiomers and EDDP in the Abcb1a-/- gene knockout mice and the Abcb1a+/+ wild-type mice 1 h following intraperitoneal administration of 15 microg Rac-methadone/g mouse. RESULTS: Plasma concentrations of (R)- and (S)-methadone were similar between the two animal groups. However, the brain concentrations of (R)- and (S)-methadone in the Abcb1a-/- mice were markedly higher (15- and 23-fold, respectively, P<0.0001) than those of the Abcb1a+/+ wild-type mice. No statistically significant difference was found for other organs between the mutants and controls. No organ difference was found for EDDP between the mutants and controls. CONCLUSIONS: (R)- and (S)-methadone are substrates of P-gp. The P-gp in BBB greatly limits the brain entry of (R)- and (S)-methadone to their central nervous system acting sites. The interindividual variation in expression of P-gp in BBB may represent a source of variation for the access and effects of methadone in the brain.

The brain entry of risperidone and 9-hydroxyrisperidone is greatly limited by P-glycoprotein.

P-glycoprotein (P-gp) in the brain capillary endothelial cell limits the entry of many drugs into the brain. Our previous in-vitro study using ATPase as a marker of P-gp activity suggested that risperidone might be effectively transported by P-gp. In the present study, we compared the concentrations of risperidone and its major pharmacologically active metabolite 9-hydroxyrisperidone (9-OH-risperidone), in plasma, brain and various other tissues between abcb1ab-/- knockout mice which are functionally devoid of P-gp in their blood-brain barrier vs. FVB wild-type mice. One hour after intraperitoneal injection of 4 microg/g risperidone, the brain concentrations and ratios of brain:plasma concentrations of risperidone (13.1-fold and 12-fold respectively, p<0.05) and 9-OH-risperidone (29.4-fold and 29-fold respectively, p<0.01) were significantly higher in the abcb1ab-/- mice than those in the FVB mice. These results indicate that P-gp in the blood-brain barrier significantly influences the brain concentrations of risperidone and 9-OH-risperidone by limiting their CNS access.

Multiple doses of saw palmetto (Serenoa repens) did not alter cytochrome P450 2D6 and 3A4 activity in normal volunteers.

Saw palmetto (Serenoa repens) is the most commonly used herbal preparation in the treatment of benign prostatic hyperplasia. The objective of this study was to determine whether a characterized saw palmetto product affects the activity of cytochrome P450 (CYP) 2D6 or 3A4 in healthy volunteers (6 men and 6 women). The probe substrates dextromethorphan (CYP2D6 activity) and alprazolam (CYP3A4 activity) were administered orally at baseline and again after exposure to saw palmetto (320-mg capsule once daily) for 14 days. Dextromethorphan metabolic ratios and alprazolam pharmacokinetics were determined at baseline and after saw palmetto treatment. The mean ratio of dextromethorphan to its metabolite was 0.038 +/- 0.044 at baseline and 0.048 +/- 0.080 after 14 days of saw palmetto administration (P =.704, not significant [NS]), indicating a lack of effect on CYP2D6 activity. The area under the plasma alprazolam concentration versus time curve was 476 +/- 178 h. ng. mL(-1) at baseline and 479 +/- 125 h. ng. mL(-1) after saw palmetto treatment (P =.923, NS), indicating a lack of effect on CYP3A4 activity. The elimination half-life of alprazolam was 11.4 +/- 3.1 hours at baseline and 11.6 +/- 2.7 hours after saw palmetto treatment (P =.770, NS), also indicating a lack of effect on CYP3A4 activity. Our results indicate that extracts of saw palmetto at generally recommended doses are unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or CYP3A4 pathways for elimination. These conclusions must be weighed in the context of the study's limited assessments and regarded as only the initial investigation into the drug interaction potential of saw palmetto.

Effect of St John's wort on drug metabolism by induction of cytochrome P450 3A4 enzyme.

CONTEXT: St John's wort is a popular herbal product used to treat depression but it has been implicated in drug interactions. OBJECTIVE: To assess the potential of St John's wort administration to alter the activity of the cytochrome P450 (CYP) enzymes extensively involved in drug metabolism. DESIGN, SETTING, AND PARTICIPANTS: Open-label crossover study with fixed treatment order conducted March 2002 to February 2003 in a US general clinical research center involving 12 healthy volunteers (6 men and 6 women) aged 22 to 38 years before and after 14 days of administration of St John's wort. INTERVENTION: Participants were given probe drugs (30 mg of dextromethorphan and 2 mg of alprazolam) to establish baseline CYP 3A4 and CYP 2D6 activity. After a minimum 7-day washout period, participants began taking one 300-mg tablet 3 times per day. After 14 days of St John's wort administration, participants were given the probe drugs along with 1 St John's wort tablet to establish postadministration CYP activity; the St John's wort dosing regimen was continued for 48 hours. MAIN OUTCOME MEASURES: Changes in plasma pharmacokinetics of alprazolam as a probe for CYP 3A4 activity and the ratio of dextromethorphan to its metabolite, dextrorphan, in urine as a probe for CYP 2D6 activity. RESULTS: A 2-fold decrease in the area under the curve for alprazolam plasma concentration vs time (P<.001) and a 2-fold increase in alprazolam clearance (P<.001) were observed following St John's wort administration. Alprazolam elimination half-life was shortened from a mean (SD) of 12.4 (3.9) hours to 6.0 (2.4) hours (P<.001). The mean (SD) urinary ratio of dextromethorphan to its metabolite was 0.006 (0.010) at baseline and 0.014 (0.025) after St John's wort administration (P =.26). CONCLUSIONS: A 14-day course of St John's wort administration significantly induced the activity of CYP 3A4 as measured by changes in alprazolam pharmacokinetics. This suggests that long-term administration of St John's wort may result in diminished clinical effectiveness or increased dosage requirements for all CYP 3A4 substrates, which represent at least 50% of all marketed medications.

Effects of garlic (Allium sativum L.) supplementation on cytochrome P450 2D6 and 3A4 activity in healthy volunteers.

Garlic (Allium sativum L.) is a commonly used food and herbal supplement. The objective of this study was to assess in healthy volunteers (N = 14) the influence of a garlic extract on the activity of cytochrome P450 (CYP) 2D6 and 3A4. Probe substrates dextromethorphan (CYP2D6) and alprazolam (CYP3A4) were administered orally at baseline and again after treatment with garlic extract (3 x 600 mg twice daily) for 14 days. Urinary dextromethorphan/dextrorphan ratios and alprazolam plasma concentrations were determined by HPLC at baseline and after garlic extract treatment. The ratio of dextromethorphan to its metabolite was 0.044 +/- 0.48 at baseline and 0.052 +/- 0.095 after garlic supplementation. There were no significant differences between the baseline and garlic phases (P > or =.05). For alprazolam, there were no significant differences in pharmacokinetic parameters at baseline and after garlic extract treatment (all P values > or =.05; maximum concentration in plasma, 27.3 +/- 2.6 ng/mL versus 27.3 +/- 4.8 ng/mL; time to reach maximum concentration in plasma, 1.9 +/- 1.4 h versus 2.4 +/- 1.8 h; area under the time-versus-concentration curve, 537 +/- 94 h. ng. mL(-1) versus 548 +/- 159 h. ng. mL(-1); half-life of elimination, 13.7 +/- 4.4 h versus 14.5 +/- 4.3 h). Our results indicate that garlic extracts are unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or CYP3A4 pathway of metabolism.

Siberian ginseng (Eleutheroccus senticosus) effects on CYP2D6 and CYP3A4 activity in normal volunteers.

Siberian ginseng ([SG]; Eleutherococcus senticosus) is a commonly used herbal preparation. The objective of this study was to assess in normal volunteers (n = 12) the influence of a standardized SG extract on the activity of cytochrome P450 CYP2D6 and 3A4. Probe substrates dextromethorphan (CYP2D6 activity) and alprazolam (CYP3A4 activity) were administered orally at baseline and again following treatment with SG (1 x 485 mg twice daily) for 14 days. Urinary concentrations of dextromethorphan and dextorphan were quantified, and dextromethorphan metabolic ratios (DMRs) were determined at baseline and after SG treatment. Likewise, plasma samples were collected (0-60 h) for alprazolam pharmacokinetics at baseline and after SG treatment to assess effects on CYP3A4 activity. Validated high performance liquid chromatography methods were used to quantify all compounds and relevant metabolites. There were no statistically significant differences between pre- and post-SG treatment DMRs indicating a lack of effect on CYP2D6 (P > 0.05). For alprazolam there also were no significant differences in the pharmacokinetic parameters determined by noncompartmental modeling (C(max), T(max), area under the curve, half-life of elimination) indicating that SG does not significantly induce or inhibit CYP3A4 (P > 0.05). Our results indicate that standardized extracts of SG at generally recommended doses for over-the-counter use are unlikely to alter the disposition of coadministered medications primarily dependent on the CYP2D6 or CYP3A4 pathways for elimination.

Personality characteristics of patients showing suboptimal cognitive effort.

This study examined the relationship between performance on the Portland Digit Recognition Test (PDRT) and the MMPI-2 in a group of veterans who were suspected of having motivation to exaggerate cognitive and/or psychiatric symptoms. Number correct on "easy" trials on the PDRT correlated inversely with MMPI-2 measures of psychopathology, whereas number correct on "hard" trials positively correlated with the same scales. Some individuals performed poorly across both types of PDRT trials and had significant MMPI-2 elevations, whereas others performed poorly only on "hard" PDRT trials and had less extreme MMPI-2 elevations. This study reinforces the need to assess the validity of both cognitive and psychiatric symptom complaints.