Ultrahigh-performance liquid chromatography-tandem mass spectrometry quantitation of o-cresol in hydrolyzed human urine to assess toluene exposure.

RATIONALE: Toluene is a volatile organic compound used in domestic and industrial applications. The main routes of workplace exposure to toluene are inhalation and dermal contact. As toluene exposure can cause severe nervous system damage, its quantification is crucial to prevent occupational illness. Toluene is metabolized mainly as hippuric acid, S-benzylmercapturic acid and epoxides. These are rapidly converted to o-/p-cresol, which is then excreted in the urine as conjugated glucuronides and sulfates. o-Cresol and its conjugates can be chemically hydrolyzed to form free o-cresol, which can then serve as a urinary biomarker of toluene exposure. Current analytical methods for quantifying o-cresol in hydrolyzed urine are, however, either weakened by interference, are not sensitive enough or require water-sensitive sample preparation. Development of a liquid chromatography-tandem mass spectrometry method for assessing exposure to toluene is thus required. METHOD: Urine samples were acidified and heated to form free o-cresol and then derivatized with dansyl chloride and diluted. Extracts were separated by reverse-phase chromatography on a BEH phenyl column and then analyzed using a triple quadrupole instrument in selected reaction monitoring mode. RESULTS: The dansyl chloride derivatization step was optimized to produce the derivative within a reaction time of 3 min. Hydrolysis efficiency in forming free o-cresol from conjugated metabolites was evaluated using o-cresol-ß-d-glucuronidespiked human urine: complete hydrolysis occurred in 45 min. Dynamic range was 0.4 to 40 µM, and the method was useful for toluene monitoring in non-occupational (0.1 µmol/mmol creatinine) as well as occupational (0.3 µmol/mmol creatinine) exposure. The calculated limit of detection and limit of quantitation of the method were 0.06 and 0.21 µM, respectively. Intraday and interday precisions were 3.2% and 4.4%, respectively. Method accuracy was established as 99% using ClinChek® urine controls. CONCLUSION: An ultrahigh-performance liquid chromatography-tandem mass spectrometry method for analysis of o-cresol was developed for biological monitoring of toluene exposure in human urine. This is the method of choice used by occupational health and safety practitioners in the province of Québec, Canada.

Opti'care protocol: a randomised control trial to evaluate the impact of a mobile antenatal care clinic in isolated rural areas on prenatal follow-up.

INTRODUCTION: Rural residence appears to be a factor of vulnerability among pregnant women with poor clinical antenatal care. Our principal objective is to assess the impact of an infrastructure for a mobile antenatal care clinic on the completion of antenatal care for women identified as geographically vulnerable in a perinatal network. METHODS AND ANALYSIS: Controlled cluster-randomised study in two parallel arms comparing an intervention group with an open-label control group. This study will concern the population of pregnant women who must live in one of the municipalities covered by the perinatal network and considered to be an area of geographic vulnerability. The cluster randomisation will take place according to the municipality of residence. The intervention will be the implementation of pregnancy monitoring by a mobile antenatal care clinic. The completion of antenatal care between the intervention and control groups will be a binary criterion: 1 will be attributed to each antenatal care that includes all visits and supplementary examinations. Sample size has been estimated to be 330 at least with an 80% participation rate.The univariate analyses will compare the follow-up rates (with Fisher's exact test), and all individual characteristics collected (Fisher's exact test, Student's t-test) between the two groups. The multivariate analysis will use a mixed linear model analysis and consider the cluster effect as random; the initial model will include known confounders from the literature, confounders identified in univariate analyses, and the clinically relevant prognostic factors. All of these factors will be taken into account in the model as a fixed effect. ETHICS AND DISSEMINATION: The Patient Protection Committee North-West II approved this study on 4 February 2021 (IRB 2020-A02247-32). The results will be the subject of scientific communications and publications. TRIAL REGISTRATION NUMBER: NCT04823104.

Opioid Prescribing Practices and Training Needs of Québec Family Physicians for Chronic Noncancer Pain.

AIM: To examine medical practices and training needs of Québec family physicians with respect to pain management and opioid prescription for chronic noncancer pain (CNCP). METHODOLOGY: An online survey was carried out in 2016. RESULTS: Of 636 respondents (43.0% men; 54.3% ≥ 50 years old), 15.2% and 70.9% felt very or somewhat confident that they could properly prescribe opioids for CNCP. Concerns related to abuse (72.5% strongly/somewhat agree), dependence (73.2%), and lack of support (75.4%) were the main barriers reported. Only 19.7% always/often screened their patients for risks of abuse and dependence using a screening tool. About two-thirds of participants (65.7%) had recently (last five years) taken part in continuing education programs on opioid use for CNCP and 73.4% on CNCP management. Patient evaluation and differential diagnoses of chronic pain syndromes were rated as a top priority for further training. CONCLUSIONS: This study provides insights into Québec family physicians' concerns, practices, and needs with respect to the management of CNCP. Physicians' difficulties around the application of strategies to mitigate the problem of opioid abuse and addiction are worrying. The need to better train physicians in the field of pain and addiction cannot be emphasized enough.

Correction and comparability of phthalate metabolite measurements of Canadian biomonitoring studies (2007-2012).

Phthalate metabolites are often measured in biomonitoring studies to evaluate a population's exposure to ubiquitous phthalates. During the course of national biomonitoring studies in Canada, we identified an issue with the accuracy of several commercial phthalate metabolite standards that are commonly used in such studies. The validity of the results from these studies was then questioned. Altogether, three (3) large studies were affected, involving a total of 9302 samples and 105000 individual phthalate metabolite measurements. Data from our previous investigation suggested that the inaccuracies in the commercially-available phthalate metabolite standards were compound- and lot-specific. Therefore, an approach was developed to derive correction factors for each lot of phthalate metabolite standard and was applied to the previously-acquired measurements with the goal of obtaining accurate and comparable data. A statistical analysis was performed to support the approach. It is expected that the corrected phthalate metabolite data from all three Canadian biomonitoring studies are comparable to one another. However, caution is still advised when comparing data obtained from biomonitoring studies for which the calibration standards have not been investigated for their accuracy. Suggestions are made based on quality assurance aspects to improve the validity of phthalate metabolite measurements.

Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses.

The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.

Multicenter study of environmental contamination with antineoplastic drugs in 33 Canadian hospitals.

PURPOSE: No occupational exposure limit exists for antineoplastic drugs. The main objective of this study was to describe environmental contamination with cyclophosphamide, ifosfamide and methotrexate in pharmacy and patient care areas of Canadian hospitals in 2012. The secondary objective was to compare the 2012 environmental monitoring results with the 2008-2010 results. METHODS: Six standardized sites in the pharmacy and six sites on patient care areas were sampled in each participating center. Samples were analyzed for the presence of cyclophosphamide, ifosfamide and methotrexate by UPLC-MS-MS. The limit of detection (LOD) was 1.8 pg/cm² for cyclophosphamide, 2.2 pg/cm² for ifosfamide and 8.0 pg/cm² for methotrexate. The comparison of surface contamination between the 2008-2010 and 2012 studies was made with the 75th percentile of cyclophosphamide concentration. RESULTS: A total of 33 hospitals participated in the study and 363 samples were collected. Overall, 40 % (147/363) of the samples were positive for cyclophosphamide, 18 % (68/363) were positive for ifosfamide and 5 % (17/363) were positive for methotrexate. In 2012, the 75th percentile value of cyclophosphamide surface concentration was of 9.4 pg/cm², which is four times lower than the 2008-2010 75th percentile of 40 pg/cm². In both studies, the 75th percentile for ifosfamide and methotrexate concentration was lower than the LOD. CONCLUSIONS: Surface contamination by cyclophosphamide, ifosfamide and methotrexate in Canadian hospitals is improving both in terms of the proportions of positive samples and in terms of the surface concentration of antineoplastic drugs. A local 75th percentile value should be use to assess local contamination and interpret local results.

Environmental contamination with methotrexate in Canadian community pharmacies.

OBJECTIVES: To evaluate environmental contamination with methotrexate, cyclophosphamide, and ifosfamide in Quebec, Canada, community pharmacies and to describe hazardous drug handling practices in these pharmacies. METHODS: Three standardized sites were sampled in each participating community pharmacy. Samples were analyzed for the presence of cyclophosphamide, ifosfamide, and methotrexate by high-performance liquid chromatography tandem mass spectrometry. The limits of detection were 0.10, 0.12, and 0.41 ng/mL for cyclophosphamide, ifosfamide, and methotrexate, respectively. Nine working practices were assessed. RESULTS: 20 community pharmacies participated in the study, and 60 samples were analyzed. No traces of cyclophosphamide or ifosfamide were detected. Traces of methotrexate were found in 12 of 20 pharmacies (60%). Of the 20 pharmacies, 8 (40%) had a storage space reserved for hazardous drugs and none had a preparation area reserved for handling methotrexate tablets. All of the participating community pharmacies had a tablet counter reserved for the handling of hazardous drugs, and all pharmacies cleaned their tablet counter reserved for handling hazardous drugs after use. None of the pharmacies cut or crushed methotrexate tablets. CONCLUSION: The growing number of hazardous drugs represents a challenge for community pharmacies. Community pharmacists must be made aware of their presence and the need to comply with personal protection measures to reduce staff occupational exposure to hazardous drugs.

Biomonitoring of phthalate metabolites in the Canadian population through the Canadian Health Measures Survey (2007-2009).

Human exposure to phthalates occurs through multiple sources and pathways. In the Canadian Health Measures Survey 2007-2009, 11 phthalate metabolites, namely, MMP, MEP, MnBP, MBzP, MCHP, MCPP, MEHP, MEOHP, MEHHP, MnOP, and MiNP were measured in urine samples of 6-49 year old survey respondents (n=3236). The phthalate metabolites biomonitoring data from this nationally-representative Canadian survey are presented here. The metabolites MEP, MnBP, MBzP, MCPP, MEHP, MEOHP and MEHHP were detected in >90% of Canadians while MMP, MCHP, MnOP and MiNP were detected in <20% of the Canadian population. Step-wise regression analyses were carried out to identify important predictors of volumetric concentrations (µg/L) of the metabolites in the general population. Individual multiple regression models with covariates age, sex, creatinine, fasting status, and the interaction terms age×creatinine, age×sex and fasting status×creatinine were constructed for MEP, MnBP, MBzP, MCPP, MEHP, MEOHP and MEHHP. The least square geometric mean (LSGM) estimates for volumetric concentration (µg/L) of the metabolites derived from respective regression models were used to assess the patterns in the metabolite concentrations among population sub-groups. The results indicate that children had significantly higher urinary concentrations of MnBP, MBzP, MEHP, MEHHP, MEOHP and MCPP than adolescents and adults. Moreover, MEP, MBzP, MnBP and MEOHP concentrations in females were significantly higher than in males. We observed that fasting status significantly affects the concentrations of MEHP, MEHHP, MEOHP, and MCPP metabolites analyzed in this study. Moreover, our results indicate that the sampling time could affect the DEHP metabolite concentrations in the general Canadian population.

Accuracy investigation of phthalate metabolite standards.

Phthalates are ubiquitous compounds whose metabolites are usually determined in urine for biomonitoring studies. Following suspect and unexplained results from our laboratory in an external quality-assessment scheme, we investigated the accuracy of all phthalate metabolite standards in our possession by comparing them with those of several suppliers. Our findings suggest that commercial phthalate metabolite certified solutions are not always accurate and that lot-to-lot discrepancies significantly affect the accuracy of the results obtained with several of these standards. These observations indicate that the reliability of the results obtained from different lots of standards is not equal, which reduces the possibility of intra-laboratory and inter-laboratory comparisons of results. However, agreements of accuracy have been observed for a majority of neat standards obtained from different suppliers, which indicates that a solution to this issue is available. Data accuracy of phthalate metabolites should be of concern for laboratories performing phthalate metabolite analysis because of the standards used. The results of our investigation are presented from the perspective that laboratories performing phthalate metabolite analysis can obtain accurate and comparable results in the future. Our findings will contribute to improving the quality of future phthalate metabolite analyses and will affect the interpretation of past results.

Restoring methicillin-resistant Staphylococcus aureus susceptibility to ß-lactam antibiotics.

Despite the need for new antibiotics to treat drug-resistant bacteria, current clinical combinations are largely restricted to ß-lactam antibiotics paired with ß-lactamase inhibitors. We have adapted a Staphylococcus aureus antisense knockdown strategy to genetically identify the cell division Z ring components-FtsA, FtsZ, and FtsW-as ß-lactam susceptibility determinants of methicillin-resistant S. aureus (MRSA). We demonstrate that the FtsZ-specific inhibitor PC190723 acts synergistically with ß-lactam antibiotics in vitro and in vivo and that this combination is efficacious in a murine model of MRSA infection. Fluorescence microscopy localization studies reveal that synergy between these agents is likely to be elicited by the concomitant delocalization of their cognate drug targets (FtsZ and PBP2) in MRSA treated with PC190723. A 2.0 Å crystal structure of S. aureus FtsZ in complex with PC190723 identifies the compound binding site, which corresponds to the predominant location of mutations conferring resistance to PC190723 (PC190723(R)). Although structural studies suggested that these drug resistance mutations may be difficult to combat through chemical modification of PC190723, combining PC190723 with the ß-lactam antibiotic imipenem markedly reduced the spontaneous frequency of PC190723(R) mutants. Multiple MRSA PC190723(R) FtsZ mutants also displayed attenuated virulence and restored susceptibility to ß-lactam antibiotics in vitro and in a mouse model of imipenem efficacy. Collectively, these data support a target-based approach to rationally develop synergistic combination agents that mitigate drug resistance and effectively treat MRSA infections.

Environmental contamination with hazardous drugs in quebec hospitals.

BACKGROUND: Since publication of the US National Institute for Occupational Safety and Health alert on hazardous drugs in 2004, many health care organizations have reviewed their procedures for handling hazardous drugs. Occupational exposure may occur when handling, compounding, or administering a drug considered to be hazardous, at any stage from storage to waste management. OBJECTIVES: To describe environmental contamination with cyclophosphamide, ifosfamide, and methotrexate in pharmacy and patient care areas of Quebec hospitals. METHODS: Sixty-eight hospitals were invited to participate. At each hospital, 12 prespecified measurement sites (6 each within pharmacy and patient care areas) were sampled once (midweek, end of day). The samples were analyzed by ultra-performance liquid chromatography tandem mass spectrometry to determine the presence of the 3 drugs. The limits of detection (LODs) were 0.0015 ng/cm(2) for cyclophosphamide, 0.0012 ng/cm(2) for ifosfamide, and 0.0060 ng/cm(2) for methotrexate. RESULTS: Twenty-five (37%) of the hospitals agreed to participate. Samples from sites other than the 12 prespecified sites were excluded. Overall, 259 valid samples were collected between April 2008 and January 2010 (147 samples from pharmacy areas in 25 hospitals and 112 samples from patient care areas in 24 hospitals). No hospital was using a closed-system drug transfer device at the time of the study. The median (minimum, maximum) number of sites per hospital with at least 1 positive sample for at least 1 of the 3 hazardous drugs was 6 (1, 12). A total of 135 (52%) samples were positive for cyclophosphamide, 53 (20%) for ifosfamide, and 7 (3%) for methotrexate. The median (minimum, maximum) concentration in positive samples was 0.0035 ng/cm(2) (below LOD, 28 ng/cm(2)) for cyclophosphamide, below LOD (below LOD, 8.6 ng/cm(2)) for ifosfamide, and below LOD (below LOD, 0.58 ng/cm(2)) for methotrexate. CONCLUSIONS: The levels of environmental contamination with 3 hazardous drugs in this multicentre study were similar to or below those in most published studies. Periodic measurement of surface contamination is necessary to ensure that current practices limit occupational exposure to hazardous drugs.

Pilot study comparing the efficacy of two cleaning techniques in reducing environmental contamination with cyclophosphamide.

OBJECTIVE: Compare the efficacy of the cleaning technique usually employed in our healthcare facility to eliminate environmental contamination with cyclophosphamide with that of the Surface Safe commercial kit. METHODS: This is a three-step evaluative and comparative study involving: (i) the voluntary contamination of the surface of a hood with a pre-established quantity of cyclophosphamide (20,000,000 ng), (ii) the cleaning of the work surface of the hood using a cleaning technique usually employed in our healthcare facility or that of the product Surface Safe, and (iii) the quantification of cyclophosphamide detected on the work surface. The usual cleaning technique involves the use of a mixture of 0.05% chlorhexidine and 70% ethyl alcohol to clean surfaces, whereas the product Surface Safe involves a combined two-step sodium hypochlorite and sodium thiosulfate wash. RESULTS: The median concentrations of cyclophosphamide detected after the use of the usual technique and the product Surface Safe came to 165 ng cm(-2) (40-570) and 65 ng cm(-2) (57-110), respectively. The results obtained showed an average 99.5% efficacy in reducing the quantity of cyclophosphamide (ng) detected on the work surface for each of the two techniques that were evaluated. CONCLUSION: The study demonstrates that reducing the residual concentration of cyclophosphamide on work surfaces to levels lower than 1 ng cm(-2) remains difficult despite the use of cleaning techniques with a high percentage of efficacy. It stressed the importance of combining two successive cleaning techniques to maximally restrict the residual concentration of hazardous drugs and suggests the use of a combination of sodium hypochlorite and sodium thiosulfate to best reduce environmental contamination levels.

Determinants of plasma concentrations of perfluorooctanesulfonate and brominated organic compounds in Nunavik Inuit adults (Canada).

Perfluorooctanesulfonate (PFOS) and brominated organic compounds (BOCs) have been found in biota and humans worldwide with levels of BOCs being the highest in North America. PFOS and BOC exposure of remote populations that consume species of a marine food web for their subsistence has seldom been investigated. In 2004, we determined the concentrations of these contaminants in 883 Nunavik Inuit adults from the Canadian Arctic and investigated the demographic and dietary factors associated with them. Demographic and dietary information were collected by questionnaires. Multiple linear regressions were conducted to investigate predictors of exposure to those contaminants. Polychlorinated biphenyl (PCB) congener 153 concentrations are presented for comparative purposes. PFOS and PCB 153 were detected in all samples, with plasma concentrations several times higher than BOCs. The consumption of fish and marine mammals appears to be an important contributor to PFOS exposure among Nunavik Inuit. While PBDE 153 also appears as a persistent PBDE congener, exposure to PBDE 47 seems to be more recent in this population. Adoption of a westernized lifestyle seems to be related to an increased exposure to PBDE 47, but specific sources remain to be elucidated. In conclusion, we found that the remote geographical location and traditional lifestyle of the Nunavik Inuit population do not protect them against exposure to emerging POPs, particularly PFOS.

Evaluation of surface contamination in a hospital hematology--oncology pharmacy.

OBJECTIVE: To describe environmental contamination with hazardous drugs in a hospital pharmacy setting before and after reorganizing a hematology- oncology satellite pharmacy. METHODS: This is a descriptive study of surface contamination with cyclophosphamide, ifosfamide, and methotrexate in two hematology-oncology satellite pharmacies. In order to measure surface contamination with hazardous drugs, samples from four distinct measurement sites within the pharmacy were taken in each of the two phases (pre-and postphases) using a sampling procedure and an analytical method modified from Larson et al. RESULTS: A total of 133 samples from four measurement sites were taken and analyzed over the course of the study (specifically 60 prephase samples and 73 postphase samples). The study showed a significant increase in the number of positive samples (from 66.7% to 90.4%, p<0.001) from the pre- to the postphase. The increase, however, is only significant in terms of the location where completed preparations were placed after they had come out from under the hood (from 0/15 to 21/28, p<0.001) and the work surface (from 8/15 to 15/15, p=0.006) and only in terms of ifosfamide. Furthermore, for the other sites studied, the number of positive samples remained unchanged between the pre- and postphase. A statistically significant difference between the pre- and postphase was observed in terms of ifosfamide for three of the four measurement sites studied and methotrexate for one of the four sites. Average concentrations were higher in the post phase in three of the four cases. CONCLUSION: This study describes environmental contamination with hazardous drugs in a hospital pharmacy setting before and after reorganizing a hematology-oncology satellite pharmacy. The study showed that a refitting of the hemato-oncology pharmacy is not a sufficient strategy to reduce the environmental contamination by ifosfamide because a significant increase in the number of positive samples from the pre- to the postphase have been observed. Many factors can contribute to influence the contamination of hazardous drugs such as the workflow and the training of the personal. Continuous environmental surveillance of hazardous drugs is required to document traces and help reduce risks.

Cyclophosphamide contamination observed on the external surfaces of drug vials and the efficacy of cleaning on vial contamination.

OBJECTIVE: Evaluate contamination on the external surfaces of cyclophosphamide vials available on the Canadian market during storage in pharmacy departments and the efficacy of decontaminating the external surfaces of vials using various cleaning techniques. METHODS: The study consisted of three phases: the quantification of cyclophosphamide on the external surfaces of 10 vials of Procytox and 10 vials of Cytoxan available on the Canadian market with or without prewashing (Phases I and II) and the quantification of cyclophosphamide on the surfaces of 30 deliberately contaminated empty sterile vials cleaned using three different washing techniques (Phase III). The quantification of cyclophosphamide was conducted using ultra performance liquid chromatography with tandem mass spectrometry. RESULTS: In Phase I, we observed that 9 of 10 vials of Procytox and 4 of 10 vials of Cytoxan had traces of cyclophosphamide. The average concentration of cyclophosphamide measured on the vials was higher for Procytox than it was for Cytoxan. In Phase II, we observed that simply by washing vials with water we could effectively eliminate the presence of contamination on 6 of 10 Procytox vials and on 10 of 10 Cytoxan vials. Phase III demonstrated the efficacy of using a cloth soaked in soapy water to clean the contaminated vials. CONCLUSION: This pilot study demonstrates the presence of contamination on the external surfaces of cyclophosphamide vials from two manufacturers on the Canadian market. It suggests that cleaning vials from manufacturers and wholesalers may help to reduce the risk of occupational exposure. There is a need for a pilot study to establish guidelines on decontamination agents and cleaning process to eliminate the presence of contamination on vial surfaces.

An interlaboratory study of perfluorinated alkyl compound levels in human plasma.

We conducted an interlaboratory study which differed from the typical study of this type because of its emphasis on comparing intralaboratory variability in results. We sent specimens to six laboratories experienced in the analysis of perfluorinated alkyl compounds in blood matrices and that use stringent procedures to control and assure accuracy and precision. Each received an identical set of 60 plasma specimens that were analyzed in six completely independent batches. Split specimens were included so that within- and between-batch coefficients of variation could be calculated. All laboratories used liquid chromatography-tandem mass spectrometry (LC-MS/MS). The concentrations of perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexanesulfonate (PFHxS) measured in the specimens in general showed a high level of agreement, although in some cases the agreement was only moderate. The average within- and between-batch coefficient of variation for PFOS was 9.1% and 9.3%; for PFOA was 14.5% and 14.5%; and for PFHxS was 14.5% and 17.0%. The recent availability of labeled internal standards, among other advances, has facilitated improvement in the accuracy and precision of the assays. Considering the degree of between-subject variation in levels among people in background-exposed populations, the results indicate that biomarker-based epidemiologic studies of associations with health could have reasonable precision.

Visuospatial working memory in school-aged children exposed in utero to cocaine.

OBJECTIVE: Among the neurocognitive impairments reported as associated with prenatal cocaine exposure, slower response time, and less efficient learning in school-aged children are common to findings from several laboratories. This study presents performance data on a spatial working memory task in 75 prenatally cocaine exposed (CE) and 55 nondrug-exposed (NDE) 8- to 10-year-old children. METHODS: Children were administered a novel neuropsychological measure of immediate- and short-term memory for visuospatial information, the Groton Maze Learning Test (GMLT), a computer-based hidden maze learning test that consists of a "timed chase test" (a simple measure of visuomotor speed), eight learning trials followed by a delayed recall trial after an 8-minute delay and a reverse learning trial. Performance is expressed as correct moves per second and number of errors per trial. RESULTS: Across all trials, the cocaine-exposed group showed significantly slower correct moves per second and made significantly more errors. There were no significant main effects for amounts of alcohol, tobacco, or marijuana exposure. After an 8-minute delay and compared to the eighth trial, cocaine-exposed children showed less consolidation in learning compared to nonexposed children. When asked to complete the maze in reverse, cocaine-exposed children showed a greater decrement in performance (decreased correct moves per second and increased errors) compared to the eighth learning trial. CONCLUSIONS: Children exposed in utero to cocaine exhibit a possible impairment in procedural learning and diminished efficiency in creating and accessing an internal spatial map to master the hidden maze.