Phosphatidylethanol in whole blood of rhesus monkeys correlates with ethanol consumption.

BACKGROUND: Phosphatidylethanol (PEth) homologs are ethanol metabolites used to identify and monitor alcohol drinking in humans. In this study, we measured levels of the 2 most abundant homologs, PEth 16:0/18:1 and PEth 16:0/18:2, in whole blood samples from rhesus macaque monkeys that drank ethanol daily ad libitum to assess the relationship between PEth levels and recent ethanol exposure in this animal model. METHODS: Blood samples were obtained from The Monkey Alcohol Tissue Research Resource. The monkeys were first induced to consume 4% (w/v) ethanol in water from a panel attached to their home cage. Then, monkeys were allowed to drink ethanol and water ad libitum 22 h daily for 12 months and the daily amount of ethanol each monkey consumed was measured. Whole, uncoagulated blood was collected from each animal at the end of the entire experimental procedure. PEth 16:0/18:1 and PEth 16:0/18:2 levels were analyzed by HPLC with tandem mass spectrometry, and the ethanol consumed during the preceding 14 days was measured. Combined PEth was the sum of the concentrations of both homologs. RESULTS: Our results show that (1) PEth accumulates in the blood of rhesus monkeys after ethanol consumption; (2) PEth homolog levels were correlated with the daily average ethanol intake during the 14-day period immediately preceding blood collection; (3) the application of established human PEth 16:0/18:1 cutoff concentrations indicative of light social or no ethanol consumption (<20 ng/ml), moderate ethanol consumption (≥ 20 and < 200 ng/ml) and heavy ethanol consumption (≥ 200 ng/ml) predicted significantly different ethanol intake in these animals. PEth homologs were not detected in ethanol-naïve controls. CONCLUSIONS: This study confirms that PEth is a sensitive biomarker for ethanol consumption in rhesus macaque monkeys. This nonhuman primate model may prove useful in evaluating sources of variability previously shown to exist between ethanol consumption and PEth homolog levels among humans.

Effects of acute and repeated treatment with methocinnamox, a mu opioid receptor antagonist, on fentanyl self-administration in rhesus monkeys.

Methocinnamox (MCAM), a mu opioid receptor antagonist with a long duration of action, attenuates heroin self-administration in rhesus monkeys, suggesting it could be an effective treatment for opioid use disorder (OUD). This study examined effects of acute and repeated MCAM administration on self-administration of the high-efficacy mu opioid receptor agonist fentanyl and characterized MCAM pharmacokinetics. Four rhesus monkeys self-administered i.v. infusions of fentanyl (0.00032 mg/kg/infusion) or cocaine (0.032 mg/kg/infusion). MCAM (0.1-0.32 mg/kg) or the opioid receptor antagonist naltrexone (0.001-0.032 mg/kg) was injected prior to test sessions to evaluate acute effects. On a separate occasion, 0.32 mg/kg MCAM was injected every 12 days for 5 total injections to evaluate the effectiveness of repeated treatment. Following acute injection, MCAM and naltrexone decreased fentanyl self-administration on the day of treatment, with attenuation lasting for up to 2 weeks after the larger MCAM dose and <1 day after naltrexone. Repeated MCAM administration decreased fentanyl self-administration for more than 2 months without altering cocaine self-administration. MCAM plasma concentrations peaked 15-45 min after injection, with a half-life ranging from 13.7 to 199.8 min, and decreased markedly 1 day after injection. MCAM selectively reduced opioid self-administration and remained effective with repeated administration. Moreover, MCAM was effective at times when plasma levels were very low, suggesting that pharmacodynamic (i.e., pseudoirreversible binding to mu opioid receptors) and not pharmacokinetic factors play a significant role in its long-lasting effects. Taken together with previous studies, these data indicate that MCAM could be a safe, effective, and long-acting treatment for OUD.

[Is there a risk of adverse health effects from the consumption of fortified foods in Mexico?] / ¿Hay riesgo de efectos adversos por el consumo de nutrimentos a partir de productos alimenticios adicionados en México?

INTRODUCTION: according to the nutriment addition scheme from the current Mexican legislation, there is no data about overdose or adverse effects caused by a nutriment, or any information showing the risk for the population in Mexico. This work is classified as descriptive and observational. AIM: to assess the risk of consuming fortified food products (FFP) in Mexico. METHODS: the study was done in three phases: a) selection of the FFP and acquisition of the information from the nutritional facts label; b) elaboration of six diets according to the socioeconomic status, both in rural and urban areas, based on the ENIGH and ENSANUT surveys; and c) comparison of these diets with regimes containing FFP, calculated for an adult-equivalent (2,828 kcal). RESULTS: the FFP represent 10% of all the products in the market, being milk, corn and wheat flour, and their byproducts the most abundant. The six diets containing FFP were deficient in calcium, ascorbic acid and vitamins D and E. However, vitamins from the B complex were over the recommendation values. In general, any added nutriment was over the tolerable upper intake levels (UL). CONCLUSIONS: we demonstrated that the nutriment concentrations in the FFP do not reach the UL values and are not a risk for the Mexican population; however, they improve the nutritional contribution of the FFP.

INTRODUCCIÓN: en México no existen datos de sobredosis o reacciones adversas causadas por algún nutrimento o dato alguno que indique riesgo a la población de acuerdo al esquema de adición de nutrimentos de la legislación mexicana vigente. Este trabajo se clasifica como descriptivo y observacional. OBJETIVO: valorar el riesgo por consumo de productos alimenticios adicionados (PAA) en México. MÉTODOS: se realizó en tres fases: a) selección de PAA y obtención de la información nutrimental de las etiquetas; b) elaboración de seis dietas de acuerdo al estrato socioeconómico, tanto en el ámbito rural como en el urbano con base a las encuestas ENIGH y ENSANUT; y c) comparación de estas dietas con dietas que incluyen PAA, calculadas para un adulto equivalente (2.828 kcal). RESULTADOS: los PAA representan el 10% del total de productos presentes en el mercado. Los más frecuentes son: leche, harinas de maíz y trigo y sus derivados. Las seis dietas con PAA presentaron deficiencias en calcio, ácido ascórbico, vitamina D y E. Sin embargo, las vitaminas del complejo B superaron la recomendación. En general, ningún nutrimento adicionado se encontró por arriba del nivel de ingestión tolerable superior (UL). CONCLUSIONES: se demostró que las concentraciones de los nutrimentos en los PAA no alcanzan los UL y no representan un riesgo para la población mexicana, sin embargo, mejoran su aporte nutrimental.

¿Hay riesgo de efectos adversos por el consumo de nutrimentos a partir de productos alimenticios adicionados en México? / Is there a risk of adverse health effects from the consumption of fortified foods in Mexico?

Introducción: en México no existen datos de sobredosis o reacciones adversas causadas por algún nutrimento o dato alguno que indique riesgo a la población de acuerdo al esquema de adición de nutrimentos de la legislación mexicana vigente. Este trabajo se clasifica como descriptivo y observacional. Objetivo: valorar el riesgo por consumo de productos alimenticios adicionados (PAA) en México. Métodos: se realizó en tres fases: a) selección de PAA y obtención de la información nutrimental de las etiquetas; b) elaboración de seis dietas de acuerdo al estrato socioeconómico, tanto en el ámbito rural como en el urbano con base a las encuestas ENIGH y ENSANUT; y c) comparación de estas dietas con dietas que incluyen PAA, calculadas para un adulto equivalente (2.828 kcal). Resultados: los PAA representan el 10% del total de productos presentes en el mercado. Los más frecuentes son: leche, harinas de maíz y trigo y sus derivados. Las seis dietas con PAA presentaron deficiencias en calcio, ácido ascórbico, vitamina D y E. Sin embargo, las vitaminas del complejo B superaron la recomendación. En general, ningún nutrimento adicionado se encontró por arriba del nivel de ingestión tolerable superior (UL). Conclusiones: se demostró que las concentraciones de los nutrimentos en los PAA no alcanzan los UL y no representan un riesgo para la población mexicana, sin embargo, mejoran su aporte nutrimental

Introduction: according to the nutriment addition scheme from the current Mexican legislation, there is no data about overdose or adverse effects caused by a nutriment, or any information showing the risk for the population in Mexico. This work is classified as descriptive and observational. Aim: to assess the risk of consuming fortified food products (FFP) in Mexico. Methods: the study was done in three phases: a) selection of the FFP and acquisition of the information from the nutritional facts label; b) elaboration of six diets according to the socioeconomic status, both in rural and urban areas, based on the ENIGH and ENSANUT surveys; and c) comparison of these diets with regimes containing FFP, calculated for an adult-equivalent (2,828 kcal). Results: the FFP represent 10% of all the products in the market, being milk, corn and wheat flour, and their byproducts the most abundant. The six diets containing FFP were deficient in calcium, ascorbic acid and vitamins D and E. However, vitamins from the B complex were over the recommendation values. In general, any added nutriment was over the tolerable upper intake levels (UL). Conclusions: we demonstrated that the nutriment concentrations in the FFP do not reach the UL values and are not a risk for the Mexican population; however, they improve the nutritional contribution of the FFP

Pharmacokinetics of Phosphatidylethanol 16:0/20:4 in Human Blood After Alcohol Intake.

BACKGROUND: The purpose of this study was to characterize the pharmacokinetics of the phosphatidylethanol (PEth) 16:0/20:4 homolog in uncoagulated human blood samples taken from 18 participants in a clinical laboratory setting after consumption of 2 standard doses of ethanol (EtOH). METHODS: Male and female participants received either 0.4 or 0.8 g/kg oral doses of EtOH during a 15-minute period. Blood samples were collected before and throughout 6 hours immediately after alcohol administration and then again at days 2, 4, 7, 11, and 14 of the follow-up period. PEth 16:0/20:4 levels were quantified by high-performance liquid chromatography with tandem mass spectrometry detection. RESULTS: (i) The increase in PEth 16:0/20:4 from baseline to maximum concentration was less than that of PEth 16:0/18:1 or PEth 16:0/18:2 homologs during the 6-hour period after EtOH administration; (ii) the mean half-life of PEth 16:0/20:4 was 2.1 ± 3 (SD) days, which was shorter than the mean half-life of either PEth 16:0/18:1 or PEth 16:0/18:2, 7.6 ± 3 (SD) or 6.8 ± 4 (SD) days, respectively. CONCLUSIONS: The pharmacokinetics of PEth 16:0/20:4 in whole blood samples is detectable after alcohol consumption and differs in amount synthesized and rate of elimination versus PEth 16:0/18:1 and 16:0/18:2. Measuring the concentrations of these 3 homologs has the potential to provide more information about the amount and time frame of alcohol consumption than any one alone.

Acute dietary tryptophan manipulation differentially alters social behavior, brain serotonin and plasma corticosterone in three inbred mouse strains.

Clinical evidence indicates brain serotonin (5-HT) stores and neurotransmission may be inadequate in subpopulations of individuals with autism, and this may contribute to characteristically impaired social behaviors. Findings that depletion of the 5-HT precursor tryptophan (TRP) worsens autism symptoms support this hypothesis. Yet dietetic studies show and parents report that many children with autism consume less TRP than peers. To measure the impact of dietary TRP content on social behavior, we administered either diets devoid of TRP, with standard TRP (0.2 g%), or with 1% added TRP (1.2 g%) overnight to three mouse strains. Of these, BTBRT(+)Itpr3(tf)/J and 129S1/SvImJ consistently exhibit low preference for social interaction relative to C57BL/6. We found that TRP depletion reduced C57BL/6 and 129S social interaction preference, while TRP enhancement improved BTBR sociability (p < 0.05; N = 8-10). Subsequent marble burying did not differ among diets or strains. After behavior tests, brain TRP levels and plasma corticosterone were higher in TRP enhanced C57BL/6 and BTBR, while 5-HT levels were reduced in all strains by TRP depletion (p < 0.05; N = 4-10). Relative hyperactivity of BTBR and hypoactivity of 129S, evident in self-grooming and chamber entries during sociability tests, were uninfluenced by dietary TRP. Our findings demonstrate mouse sociability and brain 5-HT turnover are reduced by acute TRP depletion, and can be enhanced by TRP supplementation. This outcome warrants further basic and clinical studies employing biomarker combinations such as TRP metabolism and 5-HT regulated hormones to characterize conditions wherein TRP supplementation may best ameliorate sociability deficits.

Purity of synthetic cannabinoids sold online for recreational use.

The recreational use of synthetic cannabinoids has recently increased. This increase is due, in part, to the recent availability of inexpensive compound sold legally online in bulk. In particular, JWH-018 (1-pentyl-3-(1-naphthoyl)indole) and JWH-073 (1-butyl-3-(1-naphthoyl)indole) have been found in herbal blends marketed as alternatives to cannabis. Although these particular compounds have recently been emergency scheduled in the United States, online suppliers have shifted sales to other, similar compounds that are not currently scheduled. However, the purity of the drugs obtained from online suppliers is not known. Relative purity of JWH-018 and JWH-073 from three different online suppliers was determined using high-performance liquid chromatography with ultraviolet detection and validated standards obtained from a traditional research chemical supplier. Our results show that JWH-018 and JWH-073 obtained from online vendors was of comparable purity to validated standards, even though the physical properties varied in color, texture, and odor. It is concluded that adverse events following consumption of synthetic cannabinoid preparations is unlikely to be due to impurities or residue from the manufacturing process, but rather to effects of the active drug or interactions with other psychoactive chemicals from herbs blended into products marketed as cannabis alternatives.

Quantification of rimonabant (SR 141716A) in monkey plasma using HPLC with UV detection.

Using an isocratic high-performance liquid chromatography (HPLC) system and UV detection, a simple and precise analytical procedure was developed to quantify levels of the CB(1) receptor antagonist rimonabant in the plasma of rhesus monkeys. Rimonabant was extracted from plasma samples into 5% isopropanol in hexane. After separation, the isopropanol-hexane fractions were dried to residue, redissolved in mobile phase, and then injected into the HPLC. The HPLC system included an acetonitrile-phosphate buffer (62:38, v/v) mobile phase (pH 6.7), flow rate of 1.5 mL/min, C(18) column (4.6 mm i.d. x 150 mm length, 5 microm), and UV detection at 280 nm. Retention times for rimonabant and doxepin (internal standard) were 9.9 and 2.4 min, respectively. The regression of the spiked calibrator curve was linear from 60 to 4000 ng/mL (r(2) = 0.996). The lower limit of quantification was 60 ng/mL, and recovery was 83.6%. Rimonabant was stable in stock solutions and monkey plasma across a range of temperatures and concentrations. To demonstrate utility, plasma rimonabant was measured in six rhesus monkeys at 60 and 240 min after intramuscular administration of 1 mg/kg rimonabant. Rimonabant levels ranged from 175 to 1290 ng/mL. The analytical assay described here provides a simple and accurate procedure for multiple within-subject measurements of the CB(1) antagonist rimonabant.

Expression of the Breast Cancer Metastasis Suppressor 1 (BRMS1) maintains in vitro chemosensitivity of breast cancer cells.

The Breast Cancer Metastasis Suppressor 1 (BRMS1) belongs to an expanding category of proteins called metastasis suppressors that demonstrate in vivo metastasis suppression while still allowing growth of the orthotopic tumor. Since BRMS1 decreases either the expression or function of multiple mediators implicated in resistance to chemotherapy (NF-kappaB, AKT, EGFR), we asked whether breast carcinoma cells expressing BRMS1 could be sensitized upon exposure to commonly used therapeutic agents that inhibit some of these same cellular mediators as BRMS1. In this report, we demonstrate that chemosensitivity of breast cancer cells is preserved in the presence of BRMS1. Further, BRMS1 does not change expression of AKT isoforms or PTEN, implicated in chemoresistance to common drug agents. Overall, our data with two different metastatic breast cancer cell lines indicates that BRMS1 expression status may not interfere with the response to commonly used chemotherapeutic agents in the management of solid tumors such as breast cancer. Since tumor protein expression analysis increasingly guides therapy decisions, our data may be of clinical benefit in disease management including profiling for BRMS1 expression before start of therapy.