Estimates of tobacco use by wastewater analysis of anabasine and anatabine

Wastewater analysis, the chemical analysis of municipal sewage, is fast becoming the technique of choice to monitor changes in community consumption of a range of compounds over time. Currently wastewater analyses which estimate tobacco consumption focus on the major alkaloid nicotine and its urinary metabolite, cotinine. As nicotine is also present in replacement therapies such as nicotine gum and patches, this analysis is not specific and hence does not truly reflect the harmful consumption of tobacco. Two alkaloids – anabasine and anatabine – which are specific to dried tobacco, were assessed as biomarkers for tobacco consumption in wastewater, together with nicotine and cotinine. Consequently, solid phase extraction (SPE) and liquid chromatography-mass spectrometry (LC-MS) methods for the detection of anabasine, anatabine, nicotine, and cotinine in municipal wastewater were validated. All compounds were detected in wastewater extracts and found to have satisfactory recovery, accuracy, precision, and stability in wastewater. Daily flow volume and catchment population of the wastewater facility were used to estimate normalized consumption figures of mg/day/1000 people for composite samples collected over one week, in an application of the method. Anabasine and anatabine were found to be suitable wastewater biomarkers of tobacco and can be used to assess tobacco consumption of communities via wastewater analysis. Application of this methodology can be used to collect temporal consumption data which could be used to determine the efficacy of tobacco reduction strategies. Copyrigh

Pharmacokinetics of fexofenadine following LPS administration to rats

The function and expression of drug transporters, including P-glycoprotein (P-gp) and organic-anion transporting polypeptides (Oatps), have been investigated but it is not well established how variables such as disease processes affect them. Fexofenadine is a substrate of these transporters and it was previously shown that its clearance is reduced in the rat isolated perfused liver following treatment with E.coli lipopolysaccharide (LPS). However, whether this translates to altered fexofenadine pharmacokinetics in vivo is yet to be established. E.coli LPS at 5?mg/kg or sterile saline (control) was injected intraperitoneally in rats. Oral or intravenous (IV) fexofenadine (10?mg/kg) was administered 24?h later and plasma and urine samples collected for pharmacokinetic analysis. LPS treatment did not significantly change the pharmacokinetics of IV fexofenadine, although there was a good correlation between weight loss and clearance suggesting reduced clearance in more severely affected animals. However, AUC0–8 of oral fexofenadine was a significantly higher in LPS-treated animals (13.9?±?9.76 min·µg/ml) compared to controls (5.53?±?1.12 min·µg/ml). In conclusion, LPS treatment increased the bioavailability of fexofenadine but did not affect other pharmacokinetic parameters. This is consistent with a reduction in hepatic Oatp and/or P-gp for a high extraction ratio drug such as fexofenadine.

Trends in stimulant use in Australia: a comparison of wastewater analysis and population surveys

Levels of community drug use are usually described by national surveys; data relied upon by decision makers in health and law enforcement. In recent years the analysis of wastewater for drugs and their metabolites has become prominent. Both methods convey unique drug use information. This paper demonstrates differences arising from the two approaches, using methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA) and cocaine data from the state of South Australia. The proportion of people using each drug, obtained from three prominent drug surveys, was compared with estimates of total community drug use derived by wastewater analysis. Temporal trends were compared for available years of the surveys and wastewater analysis from 2010 to 2013. Wastewater results showed methamphetamine to be the most prevalent stimulant in Adelaide, South Australia, with an average of 24.4. ±. 1.7 doses per day per 1000 inhabitants for 2013, while consumption of MDMA and cocaine were much lower at 0.52. ±. 0.12 and 0.42. ±. 0.06 doses per day per 1000 inhabitants, respectively. Survey data typically had MDMA as the most used stimulant on a proportion of the population basis. The difference in magnitude of drug use between MDMA and methamphetamine was also less apparent. Temporal trends of the proportion of the population using a drug by surveys did not generally reflect total use within the community which was observed by wastewater analysis. Survey data are excellent for describing users demographically. However, discrepancies between the proportion of the population who are users and the magnitude of drug use can lead to misrepresentation of the overall scale of use. The results from this study indicate methamphetamine was used to a much greater extent than suggested by the surveys. Together, wastewater analysis and survey data give a comprehensive view of the drug problem enabling more informed decisions on drug policy

Temporal trends in drug use in Adelaide, South Australia by wastewater analysis

Analysis of municipal wastewater for drug metabolites can reveal the scale of drug use within communities. An Australian city with a population of 1.2 million inhabitants was assessed for 4 stimulants: cocaine, methamphetamine, 3.4-methylenedioxymethamphetamine (MDMA) and amphetamine; 6 opioids: codeine, morphine, heroin, fentanyl, oxycodone and methadone; 11 new psychoactive substances (NPS); benzylpiperazine (BZP), trifluoromethylphenylpiperazine (TFMPP), methcathinone, methylone, mephedrone, methylenedioxypyrovalerone (MDPV), alpha pyrrolidinopentiophenone (alpha-PVP), paramethoxyamphetamine (PMA), 25C-NBOMe, 25B-NBOMe, 25I-NBOMe; and cannabis, for up to four years between December 2011 and December 2015. Temporal trends revealed increasing usage rates of methamphetamine, cocaine, oxycodone, and fentanyl, while decreasing rates of use were observed for MDMA, BZP and methylone. Use of other opioids and cannabis was generally stable across years, while use of new psychoactive substances fluctuated without an apparent direction. Opioids and cannabis were used at a consistent level through the course of the week, while use of stimulants and some NPS increased on the weekend. Seasonal differences in use were observed for MDMA and cannabis (p &< 0.05) where, on average, MDMA use was approximately 90% higher in December than in other months and cannabis use was approximately 45% lower in each February. Residual month-to-month variability measures on trend-free data showed NPS use had higher variability than the stimulants and opioids. Frequent wastewater sampling and analysis over prolonged periods has yielded valuable insights into long-term drug use trends, in some instances revealed important within-year trends, and demonstrated the differing patterns of use of drugs on weekends compared to weekdays

Effect of Garlic, Gingko and St. John&apos;s Wort Extracts on the Pharmacokinetics of Fexofenadine: A Mechanistic Study Running title: Effect of Herbal Extracts on Fexofenadine Pharmacokinetics

Number of References: 50 Number of words in the Abstract: 247 words Number of words in the Introduction: 749 words Number of words in the Discussion: 1500 words Non-standard abbreviations: AUC0-∞, total area under the curve; Ae0-60, cumulative amount excreted into bile from time 0 to 60 min; AUC0-60, the area under the concentration-time curve from 0 to 60 min; B/L, ratio of the concentrations of fexofenadine HCl in bile to liver at 60 min; CL, clearance; CLb,p, biliary clearance with respect to the concentration in perfusate; CLb,l, biliary clearance with respect to the concentration in liver; Cmax, maximum plasma concentration; F, bioavailability; IPRL, isolated perfused rat liver; L/P, ratio of the concentrations of fexofenadine HCl in liver to perfusate at 60 min; Oatp, organic anion transporting polypeptide; P-gp, P-glycoprotein; SJW, St. John&apos;s wort; Tmax, time to maximum plasma concentration; t1/2, half-life; Vss, volume of distribution at steady state Abstract The aim of this study was to determine the effects of garlic and ginkgo herbal extracts on the pharmacokinetics of the P-glycoprotein (P-gp)/Organic anion transporting polypeptides (Oatps) substrate fexofenadine. Male rats were dosed orally with garlic (120 mg/kg), ginkgo (17 mg/kg), St. John&apos;s wort (SJW; 1000 mg/kg; positive control) or milli Q water for 14 days. On day 15, rats were either administered fexofenadine (orally or intravenously), had their livers isolated and perfused with fexofenadine, or the small intestine divided into four segments (SI-SIV) and analysed for P-gp and Oatp1a5. In vivo, SJW increased the CL of intravenously administered fexofenadine by 28%. Garlic increased the AUC0-∞ and Cmax of orally administered fexofenadine by 47% and 85%, respectively. Ginkgo and SJW had no effect on the oral absorption of fexofenadine. In the perfused liver, garlic, ginkgo and SJW increased the biliary clearance of fexofenadine with respect to perfusate by 71%, 121% and 234%, respectively. SJW increased the biliary clearance relative to the liver concentration by 64%. The ratio of liver to perfusate concentrations significantly increased in all treated groups. The expression of Oatp1a5 in SI was increased by garlic (88%) and SJW (63%). There were no significant changes in the expression of P-gp. Induction of intestinal Oatp1a5 by garlic may explain the increased absorption of orally administered fexofenadine. Ginkgo had no effect on the expression of intestinal P-gp or Oatp1a5. A dual inductive effect by SJW on opposing intestinal epithelial transport by Oatp1a5 and P-gp remains a possibility. DMD #73528

Is there a role for routinely screening children with autism spectrum disorder for creatine deficiency syndrome?

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that presents in the first three years of life. Currently, diagnosis of ASD is based on its behavioural manifestations, as laboratory diagnostic tests do not exist. Creatine deficiency syndrome (CDS) is one form of inborn error of metabolism where affected individuals have similar clinical features to individuals with ASD. Abnormal urinary creatine (CR) and guanidinoacetate (GAA) levels have been reported as biomarkers of CDS. We hypothesized that screening for abnormal levels of urinary CR and GAA in children with ASD may assist in identifying a subgroup of ASD individuals who can be managed with dietary interventions. Morning urine samples were collected from children with and without autism and analyzed for CR and GAA levels. Results showed there was no statistically significant difference in urinary CR:creatinine and GAA:creatinine between the children with ASD and sibling or unrelated controls. In conclusion, routine screening for abnormal urinary CR and GAA could be considered in ASD diagnostic protocols; however, individuals positive for CDS are likely to be rare in an ASD cohort.

Is the tissue persistence of O6-methyl-2′-deoxyguanosine an indicator of tumour formation in the gastrointestinal tract?

Azoxymethane (AOM) is a methylating agent capable of inducing mutations in DNA by forming adducts with DNA bases. It has been used to understand the mechanisms involved in colon carcinogenesis. Of the adducts formed in response to AOM, O6-methyl-2′-deoxy-guanosine (O6-mdGua) is the most mutagenic. Based on studies in rodents of the abundance and persistence of DNA adducts in various tissues after treatment with alkylating agents, previous results suggest, as a generalization, that the longer O6-mdGua adducts remain unrepaired in the cells of a tissue, the greater the risk for tumorigenesis. To test this hypothesis, we have built on these studies, expanding the number of tissues in which O6-mdGua abundance and persistence were examined and correlating these data with tumour distribution and abundance in rats maintained for 26 weeks after the treatment with AOM. Our study revealed firstly the existence of groups of tissues that developed relatively large amounts (proximal and distal colon, proximal small intestine (SI), liver and kidney) and relatively low levels (stomach, distal SI, bladder, spleen, blood and lung) of O6-mdGua after AOM exposure. Secondly, while all tissues showed an increase in adduct levels at 6 h after mutagen treatment and most showed a significant drop in adduct levels between 6 h and 48 h (stomach, proximal and distal SI, liver, spleen, blood and lung), one group of tissues displayed O6-mdGua levels that did not decrease at 48 h (proximal and distal colon, kidney and bladder). Predictably, the colon displayed tumours 26 weeks after treatment. Interestingly, however, the proximal SI also displayed significant tumour formation at that time. Our findings demonstrate (1) a direct association between exposure to O6-mdGua and tumours of the distal colon and (2) a dissociation of the relationship between adduct clearance and tumorigenesis in the SI. This diversity of response in the gastrointestinal tract warrants further analysis.