Negative-pressure wound therapy for III/IV pressure injuries: A meta-analysis.

This meta-analysis was conducted to identify the potential benefits and the efficacy of negative-pressure wound therapy (NPWT) for III/IV pressure injuries (PIs) compared with standard wound care (SWC). Sixteen RCTs with 629 patients were included in our analysis. The methodological quality was assessed by the Cochrane Collaboration Tool. The outcomes included complete ulcer healing rate, wound healing time, pain score, the frequency of dressing change, hospitalization cost, the condition of the exudate, and the wound improvement. The percentage of healing rate was 61.45% for the NPWT group and 36.90% for SWC (95% CI: 1.32-1.70). There were significant differences in wound healing time (WMD = -16.47 days, 95% [CI (-22.36, - 10.59) days, P ≤ .001]). The pain score and hospitalization cost in NPWT was lower compared with SWC group (WMD = -2.39, 95% CI [-3.47, -1.30], P ≤ .001); (SMD = -2.55, 95% CI [-4.07, -1.03], P < .01). The frequency of dressing change in both NPWT groups was greatly reduced (SMD = -3.61, 95% [CI (-4.57, - 2.66) times, P ≤ .001]). Our meta-analysis indicated that NPWT was associated with greater improvements in improving PIs and shorting healing time for III/IV PIs. However, this conclusion needs to be confirmed by high-quality multicenter RCTs.

Incidence of Pressure Injury in Individuals With Spinal Cord Injury: A Systematic Review and Meta-analysis.

PURPOSE: The purpose of this systematic review and quantitative analysis of pooled data was to assess the global incidence of pressure injury (PI), across time frames and countries, in individuals with spinal cord injury (SCI). DESIGN: Systematic review and meta-analysis. SEARCH STRATEGY: PubMed, Web of Science, and EMBASE databases were systematically searched for studies published from database inception to January 2019, with only English language studies that reported the incidence of PIs in individuals with SCI were included. Study quality was assessed by a 14-item standardized checklist. We calculated the incidence of PIs as the number of new PIs in individuals with SCI and the total number of individuals with SCI during the study period. Findings are presented as incidence rate with 95% confidence intervals (CIs). RESULTS: The search yielded 1652 studies; after studies were reviewed for inclusion criteria, 29 studies representing N = 82,722 patients were retained for data extraction. The global incidence of PIs was 0.23 (95% CI, 0.20-0.26). Data for regional distribution by country showed a pooled incidence of 0.43 (95% CI, 0.28-0.57) in individuals with SCI in South American countries, 0.36 (95% CI, 0.16-0.56) in African countries, 0.25 (95% CI, 0.14-0.37) in European countries, 0.23 (95% CI, 0.19-0.27) in North American countries, and 0.16 (95% CI, 0.06-0.25) in Asian countries. The incidence was 0.22 (95% CI, 0.19-0.26) in developing countries versus 0.27 (95% CI, 0.17-0.37) in developed countries. From 2000 to 2009, the incidence of PIs in individuals with SCI was 0.28 (95% CI, 0.09-0.47). The incidence rate of PIs before 2000 and after 2009 was 0.23. The hospital- and community-acquired PI incidence was 0.22 (95% CI, 0.19-0.26) and 0.26 (95% CI, 0.20-0.32), respectively. CONCLUSIONS: Study findings indicate that more than 1 in 5 individuals with SCI will develop a PI. Individuals with SCI are at high risk of developing PI, especially in community settings or low- and middle-income developing countries. The findings highlight the importance of further investigation of risk factors and prevention and management strategies for PIs in individuals with SCI.

The relationship between pressure injury complication and mortality risk of older patients in follow-up: A systematic review and meta-analysis.

Pressure injuries (PIs) have now become a common complication of the elderly patients. Some studies have observed that pressure injuries may increase mortality, but this area of evidence has not been evaluated and summarised. The aim of this study was to compare the mortality of patients with pressure injuries and those without pressure injuries. A meta-analysis of observational studies was performed. PubMed, Cochrane Library, Embase, and Web of Science were searched up to April 2019. Studies about mortality among the elderly patients with and without pressure injuries were included. Methodological quality was assessed by the Newcastle-Ottawa Scale (NOS). The fixed effect or random effect model was determined by the test of heterogeneity. The subgroup analysis was performed based on the pressure injuries stages, the region, and the type of study design. The meta-regression analysis was performed to investigate the relationship between the mortality and patients' enrolled year, average age, the incidence of pressure injuries, and gender ratio. The sensitivity analysis was used to explore the impact of an individual study by excluding one at a time. The hazard ratio (HR) and 95% confidence intervals (CIs) in terms of the comparison of two groups were extracted for meta-analysis. A survival curve between two groups by individual patient-level was drew. Eight studies with 5523 elderly patients were included in the analysis. Follow-up periods for the included studies ranged from about 0.5 to 3 years. The elderly patients who complicated with pressure injuries had a higher risk of death. The pooled HR was 1.78 (95% CI 1.46-2.16). A funnel plot showed no publication bias. Further subgroup analysis showed that HR values for the patient stage 3 to 4 pressure injuries (HR:2.41; 95% CI:1.08-5.37) were higher than stage 1-4 and 2-4 pressure injuries (HR: 1.66; 95% CI: 1.35-2.05; HR: 1.74; 95% CI: 1.16-2.60). The meta-regression analysis found that patients' enrolled year, average age, the incidence of pressure injuries, and gender ratio were not the sources of heterogeneity. Sensitivity analyses showed that the outcomes of the study did not change after removing the Onder's article. The survival curve at the individual patient-level also indicated that patients complicated with pressure injuries significantly increased the risk of death (HR: 1.958; 95% CI: 1.79-2.14) in elderly patients. Our meta-analysis indicated that patients complicated with pressure injuries are estimated to have a two times higher risk on mortality compared with patients without pressure injuries during the 3 years follow-up period. Particular attention should be given to the elderly patients who are at higher risk for mortality.

Altered expression of small heterodimer partner governs cytochrome P450 (CYP) 2D6 induction during pregnancy in CYP2D6-humanized mice.

Substrates of a major drug-metabolizing enzyme CYP2D6 display increased elimination during pregnancy, but the underlying mechanisms are unknown in part due to a lack of experimental models. Here, we introduce CYP2D6-humanized (Tg-CYP2D6) mice as an animal model where hepatic CYP2D6 expression is increased during pregnancy. In the mouse livers, expression of a known positive regulator of CYP2D6, hepatocyte nuclear factor 4α (HNF4α), did not change during pregnancy. However, HNF4α recruitment to CYP2D6 promoter increased at term pregnancy, accompanied by repressed expression of small heterodimer partner (SHP). In HepG2 cells, SHP repressed HNF4α transactivation of CYP2D6 promoter. In transgenic (Tg)-CYP2D6 mice, SHP knockdown led to a significant increase in CYP2D6 expression. Retinoic acid, an endogenous compound that induces SHP, exhibited decreased hepatic levels during pregnancy in Tg-CYP2D6 mice. Administration of all-trans-retinoic acid led to a significant decrease in the expression and activity of hepatic CYP2D6 in Tg-CYP2D6 mice. This study provides key insights into mechanisms underlying altered CYP2D6-mediated drug metabolism during pregnancy, laying a foundation for improved drug therapy in pregnant women.

Risk factor evaluation of cuff pressure of >30 cmH2O to stop air leakage during mechanical ventilation: A prospective observational study.

AIM: The commonly recommended endotracheal tube cuff pressure is 20-30 cmH2O. However, some patients require a cuff pressure of >30 cmH2O to prevent air leakage. The study aims to determine the risk factors that contribute to the endotracheal tube cuff pressure of >30 cmH2O to prevent air leakage. DESIGN: A multi-centre prospective observational study. METHODS: Eligible patients undergoing mechanical ventilation in the intensive care unit of three hospitals between March 2020 and July 2022 were included. The endotracheal tube cuff pressure to prevent air leakage was determined using the minimal occlusive volume technique. The patient demographics and clinical information were collected. RESULTS: A total of 284 patients were included. Among these patients, 55 (19.37%) patients required a cuff pressure of >30 cmH2O to prevent air leakage. The multivariate logistic regression results revealed that the surgical operation (odds ratio [OR]: 8.485, 95% confidence interval [CI]: 1.066-67.525, p = 0.043) was inversely associated with the endotracheal tube cuff pressure of >30 cmH2O, while the oral intubation route (OR: 0.127, 95% CI: 0.022-0.750, p = 0.023) and cuff inner diameter minus tracheal area (OR: 0.949, 95% CI: 0.933-0.966, p < 0.001) were negatively associated with the endotracheal tube cuff pressure of >30 cmH2O. Therefore, a significant number of patients require an endotracheal tube cuff pressure of ＞30 cmH2O to prevent air leakage. Several factors, including the surgical operation, intubation route, and difference between the cuff inner diameter and tracheal area at the T3 vertebra, should be considered when determining the appropriate cuff pressure during mechanical ventilation.

Pharmacokinetic interactions between monoamine oxidase A inhibitor harmaline and 5-methoxy-N,N-dimethyltryptamine, and the impact of CYP2D6 status.

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT or street name "5-MEO") is a newer designer drug belonging to a group of naturally occurring indolealkylamines. Our recent study has demonstrated that coadministration of monoamine oxidase A (MAO-A) inhibitor harmaline (5 mg/kg) increases systemic exposure to 5-MeO-DMT (2 mg/kg) and active metabolite bufotenine. This study is aimed at delineating harmaline and 5-MeO-DMT pharmacokinetic (PK) interactions at multiple dose levels, as well as the impact of CYP2D6 that affects harmaline PK and determines 5-MeO-DMT O-demethylation to produce bufotenine. Our data revealed that inhibition of MAO-A-mediated metabolic elimination by harmaline (2, 5, and 15 mg/kg) led to a sharp increase in systemic and cerebral exposure to 5-MeO-DMT (2 and 10 mg/kg) at all dose combinations. A more pronounced effect on 5-MeO-DMT PK was associated with greater exposure to harmaline in wild-type mice than CYP2D6-humanized (Tg-CYP2D6) mice. Harmaline (5 mg/kg) also increased blood and brain bufotenine concentrations that were generally higher in Tg-CYP2D6 mice. Surprisingly, greater harmaline dose (15 mg/kg) reduced bufotenine levels. The in vivo inhibitory effect of harmaline on CYP2D6-catalyzed bufotenine formation was confirmed by in vitro study using purified CYP2D6. Given these findings, a unified PK model including the inhibition of MAO-A- and CYP2D6-catalyzed 5-MeO-DMT metabolism by harmaline was developed to describe blood harmaline, 5-MeO-DMT, and bufotenine PK profiles in both wild-type and Tg-CYP2D6 mouse models. This PK model may be further employed to predict harmaline and 5-MeO-DMT PK interactions at various doses, define the impact of CYP2D6 status, and drive harmaline-5-MeO-DMT pharmacodynamics.

Sigma-1 receptor knockout disturbs gut microbiota, remodels serum metabolome, and exacerbates isoprenaline-induced heart failure.

Introduction: Heart failure (HF) is usually the end stage of the continuum of various cardiovascular diseases. However, the mechanism underlying the progression and development of HF remains poorly understood. The sigma-1 receptor (Sigmar1) is a non-opioid transmembrane receptor implicated in many diseases, including HF. However, the role of Sigmar1 in HF has not been fully elucidated. Methods: In this study, we used isoproterenol (ISO) to induce HF in wild-type (WT) and Sigmar1 knockout (Sigmar1-/-) mice. Multi-omic analysis, including microbiomics, metabolomics and transcriptomics, was employed to comprehensively evaluate the role of Sigmar1 in HF. Results: Compared with the WT-ISO group, Sigmar1-/- aggravated ISO-induced HF, including left ventricular systolic dysfunction and ventricular remodeling. Moreover, Sigmar1-/- exacerbated ISO-induced gut microbiota dysbiosis, which was demonstrated by the lower abundance of probiotics g_Akkermansia and g_norank_f_Muribaculaceae, and higher abundance of pathogenic g_norank_f_Oscillospiraceae and Allobaculum. Furthermore, differential metabolites among WT-Control, WT-ISO and Sigmar-/--ISO groups were mainly enriched in bile secretion, tryptophan metabolism and phenylalanine metabolism, which presented a close association with microbial dysbiosis. Corresponding with the exacerbation of the microbiome, the inflammation-related NOD-like receptor signaling pathway, NF-kappa B signaling pathway and TNF signaling pathway were activated in the heart tissues. Conclusion: Taken together, this study provides evidence that a Sigmar1 knockout disturbs the gut microbiota and remodels the serum metabolome, which may exacerbate HF by stimulating heart inflammation.

Nonlinear pharmacokinetics of 5-methoxy-N,N-dimethyltryptamine in mice.

5-Methoxy-N,N,-dimethyltryptamine (5-MeO-DMT), an abused serotonergic indolealkylamine drug, was placed into Schedule I controlled substance status in the United States as of January 19, 2011. In previous studies, we have shown the impact of monoamine oxidase A and cytochrome P450 2D6 enzymes on 5-MeO-DMT metabolism and pharmacokinetics. The aim of this study was to investigate 5-MeO-DMT pharmacokinetic properties after intravenous or intraperitoneal administration of three different doses (2, 10, and 20 mg/kg) to CYP2D6-humanized (Tg-CYP2D6) and wild-type control mice. Systemic exposure [area under the curve (AUC)] to 5-MeO-DMT was increased nonproportionally with the increase in dose. The existence of nonlinearity in serum 5-MeO-DMT pharmacokinetics was clearly manifested by dose-normalized AUC values, which were approximately 1.5- to 2.0-fold (intravenous) and 1.8- to 2.7-fold (intraperitoneal) higher in wild-type or Tg-CYP2D6 mice dosed with 10 and 20 mg/kg 5-MeO-DMT, respectively, than those in mice treated with 2 mg/kg 5-MeO-DMT. Furthermore, a two-compartment model including first-order absorption, nonlinear (Michaelis-Menten) elimination, and CYP2D6-dependent linear elimination from the central compartment was developed to characterize the intravenous and intraperitoneal pharmacokinetic data for 5-MeO-DMT in wild-type and Tg-CYP2D6 mice. In addition, 5-MeO-DMT was readily detected in mouse brain after drug treatment, and brain 5-MeO-DMT concentrations were also increased nonproportionally with the increase of dose. The results establish a nonlinear pharmacokinetic property for 5-MeO-DMT in mice, suggesting that the risk of 5-MeO-DMT intoxication may be increased nonproportionally at higher doses.

The Braden Scale for Predicting the Outcome and Prognosis of Pressure Injuries in Older Inpatients: A Multicenter, Retrospective Cohort Study.

INTRODUCTION: The Braden scale is used to assess the risk of patients with pressure injuries (PIs), but there are limitations to the prediction of PI healing. There is a lack of tools for evaluating PI healing and outcome in clinical practice. OBJECTIVE: The purpose of this study was to examine the ability of the Braden scale to predict the outcome and prognosis of PIs in older patients. MATERIALS AND METHODS: Outcome indicator was the wound healing rate of patients with PIs at discharge. The receiver operating characteristic (ROC) and Hosmer-Lemeshow goodness-of-fit test were used to evaluate the discrimination and calibration. RESULTS: Completed data were available for 309 patients, 181 of whom (58.6%) were male. The Braden scale had poor discrimination to predict the outcome and prognosis of PIs with an area under the curve (AUC) of 0.63 (95% CI, 0.56-0.70; P = .01). Subgroup analyses showed the Braden scale had low diagnostic value for patients aged over 90 years (AUCROC = 0.56; 95% CI, 0.17-0.96; P = .738), patients with respiratory diseases (AUCROC = 0.51; 95% CI, 0.37-0.65; P = .908), and digestive system diseases (AUCROC = 0.59; 95% CI, 0.42-0.75; P = .342). The level of calibration ability by Hosmer-Lemeshow goodness-of-fit test was acceptable, defined as P >.200 (χ2 = 6.59; P = .473). In patients aged more than 90 years (χ2 = 4.88; P = .431) and female patients (χ2 = 7.03; P = .425), the Braden scale was also fitting. It was not suitable for patients with respiratory diseases (χ2 = 11.35; P = .078). CONCLUSIONS: The Braden scale had low discrimination for predicting the outcome and prognosis of PIs in older inpatients. The development of a new tool is needed to predict healing in patients with preexisting PIs.

Zinc Therapy Is a Reasonable Choice for Patients With Pressure Injuries: A Systematic Review and Meta-Analysis.

The aim of this systematic review was to summarize the evidence on the efficacy of zinc supplementation in patients with pressure injuries (PIs). Electronic data bases (Embase, MEDLINE, and Web of Science) were searched from inception to 2019 for randomized controlled trials (RCTs) and non-RCTs addressing the efficacy of zinc supplementation compared with a control nutrition invention on PI outcomes. The primary study outcome was the healing rate of PIs during treatment; the secondary outcomes were the improvement of PI area and pressure ulcer scale for healing (PUSH) score. A total of 7 studies were included in this systematic review and meta-analysis. The intervention group significantly had improved healing vs that of the control group (relative risk, 1.44; 95% CI, 1.01-2.06; P = 0.043, I2 = 19.3%). There was no obvious asymmetry in the funnel plot and no strong evidence of publication bias. Sensitivity analysis showed that meta-analysis has good stability. Studies showed a greater mean reduction in PI area. All the studies we included had a significant improvement in the PUSH score of PIs. Our systematic review and meta-analysis from clinical research confirmed that zinc therapy can promote wound healing and suggest that medical staff should consider providing patients with zinc during PI treatment.

Pinoline may be used as a probe for CYP2D6 activity.

Pinoline, 6-methoxy-1,2,3,4-tetrahydro-beta-carboline, is a serotonin analog that selectively inhibits the activity of monoamine oxidase-A and shows antidepressant activity. Our previous study using a panel of recombinant cytochrome P450 (P450) enzymes suggests that pinoline O-demethylation may be selectively catalyzed by polymorphic CYP2D6. The current study, therefore, aimed to delineate the impact of CYP2D6 status on pinoline metabolism. Enzyme kinetic studies using recombinant CYP2D6 allelic isozymes revealed that CYP2D6.2 exhibited 5-fold lower enzyme efficiency (V(max)/K(m)) toward pinoline compared with CYP2D6.1, and CYP2D6.10 did not show any catalytic activity. Inhibition study showed that quinidine (1 microM) completely blocked pinoline O-demethylase activity in human liver microsomes, whereas other P450 isoform-selective inhibitors had no or minimal effects. Pinoline O-demethylase activities in 10 human liver microsomes showed significantly strong correlation with bufuralol 1'-hydroxylase activities (R(2)=0.93; p<0.0001) and CYP2D6 contents (R(2)=0.82; p=0.005), whereas no appreciable correlations with enzymatic activities of other P450 enzymes were found. Furthermore, we compared pinoline urinary metabolic ratio (pinoline/6-hydroxy-1,2,3,4-tetrahydro-beta-carboline) between CYP2D6-humanized and wild-type control mice after intraperitoneal injection of pinoline (30 mg/kg). Results indicated that the two genotyped mice were clearly distinguished by pinoline metabolic ratio (mean +/- S.D.), which was much higher in wild-type mice (0.29+/-0.19, n=4) than in CYP2D6-humanized transgenic mice (0.0070+/-0.0048, n=4). Our findings suggest that pinoline O-demethylation is governed by CYP2D6 status, and pinoline, at a proper concentration or dose, may be a good probe to evaluate CYP2D6 activity.

Modification of 5-methoxy-N,N-dimethyltryptamine-induced hyperactivity by monoamine oxidase A inhibitor harmaline in mice and the underlying serotonergic mechanisms.

BACKGROUND: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are indolealkylamine (IAA) drugs often abused together. Our recent studies have revealed the significant effects of co-administered harmaline, a monoamine oxidase inhibitor (MAOI), on 5-MeO-DMT pharmacokinetics and thermoregulation. This study was to delineate the impact of harmaline and 5-MeO-DMT on home-cage activity in mouse models, as well as the contribution of serotonin (5-HT) receptors. METHODS: Home-cage activities of individual animals were monitored automatically in the home cages following implantation of telemetry transmitters and administration of various doses of IAA drugs and 5-HT receptor antagonists. Area under the effect curve (AUEC) of mouse activity values were calculated by trapezoidal rule. RESULTS: High dose of harmaline (15mg/kg, ip) alone caused an early-phase (0-45min) hypoactivity in mice that was fully attenuated by 5-HT1A receptor antagonist WAY-100635, whereas a late-phase (45-180min) hyperactivity that was reduced by 5-HT2A receptor antagonist MDL-100907. 5-MeO-DMT (10 and 20mg/kg, ip) alone induced biphasic effects, an early-phase (0-45min) hypoactivity that was completely attenuated by WAY-100635, and a late-phase (45-180min) hyperactivity that was fully suppressed by MDL-100907. Interestingly, co-administration of MAOI harmaline (2-15mg/kg) with a subthreshold dose of 5-MeO-DMT (2mg/kg) induced excessive hyperactivities at late phase (45-180min) that could be abolished by either WAY-100635 or MDL-100907. CONCLUSIONS: Co-administration of MAOI with 5-MeO-DMT provokes excessive late-phase hyperactivity, which involves the activation of both 5-HT1A and 5-HT2A receptors.

Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice.

We have shown recently that concurrent harmaline, a monoamine oxidase-A inhibitor (MAOI), potentiates serotonin (5-HT) receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT)-induced hyperthermia. The objective of this study was to develop an integrated pharmacokinetic/pharmacodynamic (PK/PD) model to characterize and predict the thermoregulatory effects of such serotonergic drugs in mice. Physiological thermoregulation was described by a mechanism-based indirect-response model with adaptive feedback control. Harmaline-induced hypothermia and 5-MeO-DMT-elicited hyperthermia were attributable to the loss of heat through the activation of 5-HT1A receptor and thermogenesis via the stimulation of 5-HT2A receptor, respectively. Thus serotonergic 5-MeO-DMT-induced hyperthermia was readily distinguished from handling/injection stress-provoked hyperthermic effects. This PK/PD model was able to simultaneously describe all experimental data including the impact of drug-metabolizing enzyme status on 5-MeO-DMT and harmaline PK properties, and drug- and stress-induced simple hypo/hyperthermic and complex biphasic effects. Furthermore, the modeling results revealed a 4-fold decrease of apparent SC50 value (1.88-0.496 µmol/L) for 5-MeO-DMT when harmaline was co-administered, providing a quantitative assessment for the impact of concurrent MAOI harmaline on 5-MeO-DMT-induced hyperthermia. In addition, the hyperpyrexia caused by toxic dose combinations of harmaline and 5-MeO-DMT were linked to the increased systemic exposure to harmaline rather than 5-MeO-DMT, although the body temperature profiles were mispredicted by the model. The results indicate that current PK/PD model may be used as a new conceptual framework to define the impact of serotonergic agents and stress factors on thermoregulation.

Potentiation of 5-methoxy-N,N-dimethyltryptamine-induced hyperthermia by harmaline and the involvement of activation of 5-HT1A and 5-HT2A receptors.

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are serotonin (5-HT) analogs often abused together, which alters thermoregulation that may indicate the severity of serotonin toxicity. Our recent studies have revealed that co-administration of monoamine oxidase inhibitor harmaline leads to greater and prolonged exposure to 5-HT agonist 5-MeO-DMT that might be influenced by cytochrome P450 2D6 (CYP2D6) status. This study was to define the effects of harmaline and 5-MeO-DMT on thermoregulation in wild-type and CYP2D6-humanized (Tg-CYP2D6) mice, as well as the involvement of 5-HT receptors. Animal core body temperatures were monitored noninvasively in the home cages after implantation of telemetry transmitters and administration of drugs. Harmaline (5 and 15 mg/kg, i.p.) alone was shown to induce hypothermia that was significantly affected by CYP2D6 status. In contrast, higher doses of 5-MeO-DMT (10 and 20 mg/kg) alone caused hyperthermia. Co-administration of harmaline (2, 5 or 15 mg/kg) remarkably potentiated the hyperthermia elicited by 5-MeO-DMT (2 or 10 mg/kg), which might be influenced by CYP2D6 status at certain dose combination. Interestingly, harmaline-induced hypothermia was only attenuated by 5-HT1A receptor antagonist WAY-100635, whereas 5-MeO-DMT- and harmaline-5-MeO-DMT-induced hyperthermia could be suppressed by either WAY-100635 or 5-HT2A receptor antagonists (MDL-100907 and ketanserin). Moreover, stress-induced hyperthermia under home cage conditions was not affected by WAY-100635 but surprisingly attenuated by MDL-100907 and ketanserin. Our results indicate that co-administration of monoamine oxidase inhibitor largely potentiates 5-MeO-DMT-induced hyperthermia that involves the activation of both 5-HT1A and 5-HT2A receptors. These findings shall provide insights into development of anxiolytic drugs and new strategies to relieve the lethal hyperthermia in serotonin toxicity.

Humanized transgenic mouse models for drug metabolism and pharmacokinetic research.

Extrapolation of the metabolic, pharmacokinetic and toxicological data obtained from animals to humans is not always straightforward, given the remarkable species difference in drug metabolism that is due in large part to the differences in drug-metabolizing enzymes between animals and humans. Furthermore, genetic variations in drug-metabolizing enzymes may significantly alter pharmacokinetics, drug efficacy and safety. Thus, humanized transgenic mouse lines, in which the human drug-metabolizing enzymes are expressed in mouse tissues in the presence or absence of mouse orthologues, have been developed to address such challenges. These humanized transgenic mice are valuable animal models in understanding the significance of specific human drug-metabolizing enzymes in drug clearance and pharmacokinetics, as well as in predicting potential drug-drug interactions and chemical toxicity in humans. This review, therefore, aims to summarize the development and application of some humanized transgenic mouse models expressing human drug-metabolizing enzymes. The limitations of these genetically modified mouse models are also discussed.

Psychedelic 5-methoxy-N,N-dimethyltryptamine: metabolism, pharmacokinetics, drug interactions, and pharmacological actions.

5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) belongs to a group of naturally-occurring psychoactive indolealkylamine drugs. It acts as a nonselective serotonin (5-HT) agonist and causes many physiological and behavioral changes. 5-MeO-DMT is O-demethylated by polymorphic cytochrome P450 2D6 (CYP2D6) to an active metabolite, bufotenine, while it is mainly inactivated through the deamination pathway mediated by monoamine oxidase A (MAO-A). 5-MeO-DMT is often used with MAO-A inhibitors such as harmaline. Concurrent use of harmaline reduces 5-MeO-DMT deamination metabolism and leads to a prolonged and increased exposure to the parent drug 5-MeO-DMT, as well as the active metabolite bufotenine. Harmaline, 5-MeO-DMT and bufotenine act agonistically on serotonergic systems and may result in hyperserotonergic effects or serotonin toxicity. Interestingly, CYP2D6 also has important contribution to harmaline metabolism, and CYP2D6 genetic polymorphism may cause considerable variability in the metabolism, pharmacokinetics and dynamics of harmaline and its interaction with 5-MeO-DMT. Therefore, this review summarizes recent findings on biotransformation, pharmacokinetics, and pharmacological actions of 5-MeO-DMT. In addition, the pharmacokinetic and pharmacodynamic drug-drug interactions between harmaline and 5-MeO-DMT, potential involvement of CYP2D6 pharmacogenetics, and risks of 5-MeO-DMT intoxication are discussed.

Effects of monoamine oxidase inhibitor and cytochrome P450 2D6 status on 5-methoxy-N,N-dimethyltryptamine metabolism and pharmacokinetics.

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural psychoactive indolealkylamine drug that has been used for recreational purpose. Our previous study revealed that polymorphic cytochrome P450 2D6 (CYP2D6) catalyzed 5-MeO-DMT O-demethylation to produce active metabolite bufotenine, while 5-MeO-DMT is mainly inactivated through deamination pathway mediated by monoamine oxidase (MAO). This study, therefore, aimed to investigate the impact of CYP2D6 genotype/phenotype status and MAO inhibitor (MAOI) on 5-MeO-DMT metabolism and pharmacokinetics. Enzyme kinetic studies using recombinant CYP2D6 allelic isozymes showed that CYP2D6.2 and CYP2D6.10 exhibited 2.6- and 40-fold lower catalytic efficiency (V(max)/K(m)), respectively, in producing bufotenine from 5-MeO-DMT, compared with wild-type CYP2D6.1. When co-incubated with MAOI pargyline, 5-MeO-DMT O-demethylation in 10 human liver microsomes showed significantly strong correlation with bufuralol 1'-hydroxylase activities (R(2)=0.98; P<0.0001) and CYP2D6 contents (R(2)=0.77; P=0.0007), whereas no appreciable correlations with enzymatic activities of other P450 enzymes. Furthermore, concurrent MAOI harmaline sharply reduced 5-MeO-DMT depletion and increased bufotenine formation in human CYP2D6 extensive metabolizer hepatocytes. In vivo studies in wild-type and CYP2D6-humanized (Tg-CYP2D6) mouse models showed that Tg-CYP2D6 mice receiving the same dose of 5-MeO-DMT (20mg/kg, i.p.) had 60% higher systemic exposure to metabolite bufotenine. In addition, pretreatment of harmaline (5mg/kg, i.p.) led to 3.6- and 4.4-fold higher systemic exposure to 5-MeO-DMT (2mg/kg, i.p.), and 9.9- and 6.1-fold higher systemic exposure to bufotenine in Tg-CYP2D6 and wild-type mice, respectively. These findings indicate that MAOI largely affects 5-MeO-DMT metabolism and pharmacokinetics, as well as bufotenine formation that is mediated by CYP2D6.