Publications by authors named "Aaron M Shapiro"

11 Publications

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An outbreak of novel psychoactive substance benzodiazepines in the unregulated drug supply: Preliminary results from a community drug checking program using point-of-care and confirmatory methods.

Int J Drug Policy 2021 Feb 21:103169. Epub 2021 Feb 21.

Department of Medicine, University of British Columbia, Vancouver, BC, Canada; British Columbia Centre on Substance Use, 1045 Howe Street, Vancouver, BC, V6Z 2A9, Canada. Electronic address:

Background: From mid-2018, an increase in novel psychoactive substance (NPS) benzodiazepines was noted on surveillance of the unregulated drug market around Vancouver, British Columbia, Canada. The rise was concordant with an outbreak of atypical overdoses suspicious for benzodiazepine adulteration of unregulated opioids. This study sought to describe the number and type of NPS benzodiazepines in a sample drawn from a community drug checking program during this period, and to explore accuracy of point-of-care drug checking technologies when compared to confirmatory methods in this sample.

Methods: Point-of-care drug checking data using fentanyl and benzodiazepine test strips as well as Fourier transform infrared spectroscopy were gathered at harm reduction sites in the Vancouver area from October 2018 to January 2020. A convenience subsample underwent confirmatory testing with gas chromatography-mass spectrometry, liquid chromatography-mass spectrometry, or quantitative nuclear magnetic resonance spectroscopy.

Results: Of 159 samples with both point-of-care and confirmatory results, 24 (15.1%) contained at least one NPS benzodiazepine, including etizolam (n = 18), flubromazolam (n = 3), flualprazolam (4), and flubromazepam (n = 1). Of 114 confirmatory samples expected by participants on self-report to contain opioids, 18 (15.8%) contained some NPS benzodiazepine, with 16 (14.0%) containing both an NPS benzodiazepine and an opioid, always fentanyl. False positive and negative rates were 15.5% and 37.5% for test strips, and 3.9% and 91.7% for FTIR, respectively. Combined together, false positive and negative rates of point-of-care methods were 17.8% and 29.2%.

Conclusions: NPS benzodiazepine adulteration in an unregulated drug supply sample reveals new risks compounding ongoing harms associated with the synthetic opioid epidemic. Given substantial false positive and false negative rates noted in our sample for point-of-care detection methods, cautious use of combined point-of-care methods, routinely paired with confirmatory drug checking may aid in early detection and monitoring of unregulated drug markets and inform targeted harm reduction strategies and health policy approaches.
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http://dx.doi.org/10.1016/j.drugpo.2021.103169DOI Listing
February 2021

Drug checking identifies counterfeit alprazolam tablets.

Drug Alcohol Depend 2021 Jan 22;218:108300. Epub 2020 Oct 22.

British Columbia Centre on Substance Use, 400-1045 Howe Street, Vancouver, British Columbia, V6Z 2A9, Canada; Department of Medicine, University of British Columbia, 10th Floor-2775 Laurel Street, Vancouver, British Columbia, V5Z 1M9, Canada. Electronic address:

Background: Non-prescribed benzodiazepine use is increasing in North America, especially among youth. Owing to increasing demand, counterfeit benzodiazepine tablets are mass-produced in clandestine, unregulated environments and sold as legitimate pharmaceuticals. This study aimed to examine the contents of counterfeit alprazolam tablets available in the unregulated drug market in British Columbia, Canada.

Methods: Data were collected from an ongoing evaluation of a community drug checking service in British Columbia between October 2017 and March 2020. The service operates point-of-care in harm reduction sites using Fourier-transform infrared (FTIR) spectrometers coupled with fentanyl and benzodiazepine immunoassay strips. A subset of samples were sent for confirmatory analysis at partner laboratories and underwent one or more of gas chromatography/mass spectrometry, liquid chromatography/mass spectrometry, and quantitative nuclear magnetic resonance analysis.

Results: During the study period, 10,814 total samples were submitted for drug checking, 139 of which were expected to be Xanax (alprazolam) or generic tablets and met the criteria for inclusion. Using FTIR analysis, 33 (23.7 %) samples were identified to contain alprazolam. Only 122 samples were checked using benzodiazepine immunoassay strips and 88 (72.1 %) tested positive. Qualitative results from the 20 samples submitted for confirmatory analysis included various new psychoactive substances and only 2 contained only alprazolam.

Conclusions: Our findings provide evidence that Xanax tablets obtained from the unregulated drug market are likely to be counterfeit and may not contain alprazolam. Drug checking offers people who use drugs a valuable means to determine the contents of their substances; however, limitations of point-of-care technologies must be considered.
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http://dx.doi.org/10.1016/j.drugalcdep.2020.108300DOI Listing
January 2021

A Call for Medical Schools to Teach Opioid Use Disorder Treatment.

Authors:
Aaron M Shapiro

Acad Med 2019 12;94(12):1843

First-year resident in primary care social internal medicine, Montefiore Medical Center, Bronx, New York; ORCID: http://orcid.org/0000-0003-2308-0843.

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http://dx.doi.org/10.1097/ACM.0000000000002976DOI Listing
December 2019

Measurement of the Oxidative DNA Lesion 8-Oxoguanine (8-oxoG) by ELISA or by High-Performance Liquid Chromatography (HPLC) with Electrochemical Detection.

Methods Mol Biol 2019 ;1965:313-328

Department of Pharmaceutical Sciences and Centre for Pharmaceutical Oncology, University of Toronto, Toronto, ON, Canada.

Reactive oxygen species (ROS) can oxidize cellular macromolecules like DNA, causing DNA damage. The most common form of DNA damage is the 8-oxoguanine (8-oxoG) lesion, typically repaired by the base excision repair (BER) pathway, which is initiated by the enzyme oxoguanine glycosylase 1 (OGG1). ROS are produced endogenously and can be enhanced by environmental factors, such as xenobiotics, radiation, and microbial pathogens. As a commonly used biomarker of oxidative damage, 8-oxoG can be measured in two different ways described herein. Commercially available ELISA kits allow for easy detection of the 8-oxoG lesion, while more difficult HPLC assays with UV and electrochemical detection allow for a more definitive identification and quantification of 8-oxoG.
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http://dx.doi.org/10.1007/978-1-4939-9182-2_21DOI Listing
November 2019

Breast cancer 1 (BRCA1)-deficient embryos develop normally but are more susceptible to ethanol-initiated DNA damage and embryopathies.

Redox Biol 2016 Apr 18;7:30-38. Epub 2015 Nov 18.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

The breast cancer 1 (brca1) gene is associated with breast and ovarian cancers, and heterozygous (+/-) brca1 knockout progeny develop normally, suggesting a negligible developmental impact. However, our results show BRCA1 plays a broader biological role in protecting the embryo from oxidative stress. Sox2-promoted Cre-expressing hemizygous males were mated with floxed brca1 females, and gestational day 8 +/- brca1 conditional knockout embryos with a 28% reduction in protein expression were exposed in culture to the reactive oxygen species (ROS)-initiating drug ethanol (EtOH). Untreated +/- brca1-deficient embryos developed normally, but when exposed to EtOH exhibited increased levels of oxidatively damaged DNA, measured as 8-oxo-2'-deoxyguanosine, γH2AX, which is a marker of DNA double strand breaks that can result from 8-oxo-2'-deoxyguanosine, formation, and embryopathies at EtOH concentrations that did not affect their brca1-normal littermates. These results reveal that even modest BRCA1 deficiencies render the embryo more susceptible to drug-enhanced ROS formation, and corroborate a role for DNA oxidation in the mechanism of EtOH teratogenesis.
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http://dx.doi.org/10.1016/j.redox.2015.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683388PMC
April 2016

A role for glutathione, independent of oxidative stress, in the developmental toxicity of methanol.

Toxicol Appl Pharmacol 2013 Dec 2;273(3):508-15. Epub 2013 Oct 2.

Division of Biomolecular Sciences, Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.

Oxidative stress and reactive oxygen species (ROS) have been implicated in the teratogenicity of methanol (MeOH) in rodents, both in vivo and in embryo culture. We explored the ROS hypothesis further in vivo in pregnant C57BL/6J mice. Following maternal treatment with a teratogenic dose of MeOH, 4 g/kg via intraperitoneal (ip) injection on gestational day (GD) 12, there was no increase 6h later in embryonic ROS formation, measured by 2',7'-dichlorodihydrofluorescin diacetate (DCFH-DA) fluorescence, despite an increase observed with the positive control ethanol (EtOH), nor was there an increase in embryonic oxidatively damaged DNA, quantified as 8-oxo-2'-deoxyguanosine (8-oxodG) formation. MeOH teratogenicity (primarily ophthalmic anomalies, cleft palate) also was not altered by pre- and post-treatment with varying doses of the free radical spin trapping agent alpha-phenyl-N-tert-butylnitrone (PBN). In contrast, pretreatment with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione (GSH) synthesis, depleted maternal hepatic and embryonic GSH, and enhanced some new anomalies (micrognathia, agnathia, short snout, fused digits, cleft lip, low set ears), but not the most common teratogenic effects of MeOH (ophthalmic anomalies, cleft palate) in this strain. These results suggest that ROS did not contribute to the teratogenic effects of MeOH in this in vivo mouse model, in contrast to results in embryo culture from our laboratory, and that the protective effect of GSH in this model may arise from its role as a cofactor for formaldehyde dehydrogenase in the detoxification of formaldehyde.
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http://dx.doi.org/10.1016/j.taap.2013.09.020DOI Listing
December 2013

Embryonic catalase protects against ethanol-initiated DNA oxidation and teratogenesis in acatalasemic and transgenic human catalase-expressing mice.

Toxicol Sci 2013 Aug 2;134(2):400-11. Epub 2013 Jun 2.

Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

Reactive oxygen species (ROS) are implicated in fetal alcohol spectrum disorders (FASD) caused by alcohol (ethanol, EtOH). Although catalase detoxifies hydrogen peroxide, embryonic catalase activity is only about 5% of maternal levels. To determine the roles of ROS and embryonic catalase in FASD, pregnant mice with enhanced (expressing human catalase, hCat) or deficient (acatalasemic, aCat) catalase activity, or their respective wild-type (WT) controls, were treated ip on gestational day 9 with 4 or 6g/kg EtOH or its saline vehicle, and embryos and fetuses were, respectively, evaluated for oxidatively damaged DNA and structural anomalies. Untreated hCat and aCat dams had, respectively, more and less offspring than their WT controls. hCat progenies were protected from all EtOH fetal anomalies at the low dose (p < .01) and from reduced head diameter and resorptions at the high dose (p < .001). Conversely, aCat progenies were more sensitive to dose-dependent EtOH fetal anomalies (p < .001) and exhibited a 50% increase in maternal lethality (p < .05) at the high dose. Maternal pretreatment of aCat mice with polyethylene glycol-conjugated catalase (PEG-Cat) reduced EtOH fetal anomalies (p < .001). EtOH-initiated embryonic DNA oxidation was reduced in hCat and WT mice pretreated with PEG-Cat and enhanced in aCat mice. Plasma concentrations of EtOH in catalase-altered mice were similar to controls, precluding a pharmacokinetic basis for altered EtOH teratogenesis. Endogenous embryonic catalase, despite its low level, is an important embryoprotective enzyme for EtOH teratogenesis and a likely determinant of individual risk.
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http://dx.doi.org/10.1093/toxsci/kft122DOI Listing
August 2013

The free radical spin trapping agent phenylbutylnitrone reduces fetal brain DNA oxidation and postnatal cognitive deficits caused by in utero exposure to a non-structurally teratogenic dose of ethanol: a role for oxidative stress.

Free Radic Biol Med 2013 Jul 26;60:223-32. Epub 2013 Feb 26.

Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada M5S 1A8.

Reactive oxygen species (ROS), although implicated in morphological birth defects caused by ethanol (EtOH) during pregnancy, have not been directly linked to its behavioral deficits. To determine this, a pathogenic oxidative DNA lesion was measured in fetal brain, and a passive avoidance learning test was assessed postnatally in the progeny of CD-1 mice treated once on gestational day 17 with 4g/kg EtOH or its saline vehicle, with or without pretreatment with the free radical spin trapping agent α-phenyl-N-tert-butylnitrone (PBN; 40mg/kg). EtOH-exposed CD-1 progeny, unlike C57BL/6 progeny, had no morphological birth defects, but exhibited a learning deficit at 12 weeks of age (p<0.001), which continued to 16 weeks in males (p<0.01). Peak blood EtOH concentrations were 2.5-fold higher in C57BL/6 mice compared to CD-1 mice given the same dose. PBN pretreatment of CD-1 dams blocked both EtOH-initiated DNA oxidation in fetal brain (p<0.05) and postnatal learning deficits (p<0.01), providing the first direct evidence for ROS in the mechanism of EtOH-initiated neurodevelopmental deficits.
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http://dx.doi.org/10.1016/j.freeradbiomed.2013.02.015DOI Listing
July 2013

Protective role of endogenous catalase in baseline and phenytoin-enhanced neurodevelopmental and behavioral deficits initiated in utero and in aged mice.

Reprod Toxicol 2012 Jun 8;33(3):361-73. Epub 2012 Feb 8.

University of Toronto, Toronto, Ontario, Canada.

We used mutant catalase-deficient mice (acatalasemic, aCat) and transgenic mice expressing human catalase (hCat) to determine the neuroprotective role of catalase in utero and in aged animals treated with vehicle or the reactive oxygen species (ROS)-initiating drug phenytoin. Phenytoin-initiated postnatal death was enhanced in aCat mice and reduced in hCat mice. Catalase deficiency reduced postnatal surface righting, negative geotaxis and rotarod performances independent of drug treatment, and enhanced phenytoin-initiated negative geotaxis and rotarod deficits in aCat females. Untreated aged female but not male aCat mice exhibited reduced motor coordination. Conversely, hCat offspring showed treatment-independent increased surface righting, negative geotaxis, air righting and, in females, improved phenytoin-impaired rotarod performance. Gender dependencies were consistent with higher brain catalase activities in male than female neonatal and aged animals. Endogenous catalase plays an important gender-dependent neuroprotective role in utero and in aged mice, and reduces neurodevelopmental effects of phenytoin.
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http://dx.doi.org/10.1016/j.reprotox.2012.01.010DOI Listing
June 2012

Characterization of demethylation of methylmercury in cultured astrocytes.

Chemosphere 2008 Dec 23;74(1):112-8. Epub 2008 Oct 23.

Community Health Science Program, University of Northern British Columbia, Prince George, British Columbia, Canada.

Mercury (Hg) is a well-known neurotoxicant but its toxicity depends on the species present. A steady emergence of inorganic Hg in the brain following chronic and accidental exposure to methylmercury (MeHg) has suggested that MeHg can undergo demethylation. The objective of this study is to develop an in vitro model to study factors affecting Hg demethylation in the central nervous system. Astrocytes obtained from neonatal rat pups were cultured for 24h with 1 microM MeHg in the presence of two pro-oxidants, buthionine sulphoximine (BSO) and rotenone. The BSO treatment produced a 21% increase in reactive oxygen species (ROS) content compared to the control (control vs. BSO; 100+/-1.35 vs. 121+/-1.52 relative fluorescence units (RFU)mg(-1) protein, p<0.001) but did not affect total Hg accumulation (control vs. BSO=86.5+/-4.14 ng mg(-1) vs. 95.7+/-9.26 ng mg(-1)). Rotenone increased ROS levels 107% (control vs. rotenone; 100%+/-1.35 vs. 207%+/-6.78RFU mg(-1)protein, p<0.001) and significantly increased the accumulation of total Hg (control vs. rotenone=86.5+/-4.14 ng mg(-1) vs. 124+/-3.80 ng mg(-1), p<0.001). There was no detectable demethylation in the control or BSO treated group, however, the rotenone treatment significantly increased the demethylation (control vs. rotenone=-1.86+/-5.57% vs. 16.3+/-2.68%, p<0.05). For the first time, we have demonstrated in an in vitro primary astrocyte culture model that MeHg can be converted to inorganic Hg and demethylation increases with oxidative stress. Our results provide a useful model to study demethylation of Hg in astrocytes and to explore potential ways to protect against Hg toxicity.
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http://dx.doi.org/10.1016/j.chemosphere.2008.09.019DOI Listing
December 2008

Potential for interferon beta-induced serum antibodies in multiple sclerosis to inhibit endogenous interferon-regulated chemokine/cytokine responses within the central nervous system.

Arch Neurol 2006 Sep;63(9):1296-9

Neuroimmunology Unit and Multiple Sclerosis Clinic, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec.

Background: A proportion of patients with multiple sclerosis (MS) receiving systemic interferon beta therapy will develop serum neutralizing antibodies (NAbs) that can reduce the activity of the drug. Interferon-beta (IFN-beta) is produced by glial cells within the central nervous system. Although systemic interferon beta does not access the central nervous system, titers of serum NAbs may be sufficient that some will access the central nervous system.

Objective: To address whether serum samples that contain high titers of NAbs could inhibit glial cell production of chemokines and cytokines that are regulated by endogenous IFN-beta.

Design: We used an in vitro assay involving toll-like receptor 3 ligand (polyinosinic-polycytidylic acid) signaling to assess the effect of serum samples containing high titers of NAbs (1800-20 000 U) on production of the chemokine CXCL10 and the cytokine interleukin 6 by human astrocytes.

Results: Serum samples positive for NAbs significantly inhibited polyinosinic-polycytidylic acid-induced CXCL10 and IL-6 production by astrocytes.

Conclusion: High-titer NAbs to interferon beta may block endogenous IFN-beta function and alter the chemokine/cytokine microenvironment within the central nervous system, thereby modulating the profile and course of the local inflammatory response.
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http://dx.doi.org/10.1001/archneur.63.9.1296DOI Listing
September 2006