Impact of Pre-exposure History and Host Genetics on Antibody Avidity Following Norovirus Vaccination.

Background: Development of high avidity, broadly neutralizing antibodies (Abs) is a priority after vaccination against rapidly evolving, widely disseminated viruses like human norovirus. After vaccination with a multivalent GI.1 and GII.4c norovirus virus-like particle (VLP) vaccine candidate adjuvanted with alum and monophosphoryl lipid A (MPL), blockade Ab titers peaked early, with no increase in titer following a second vaccine dose. Methods: Blockade Ab relative avidity was evaluated by measuring the slope of blockade Ab neutralization curves. Results: Blockade Ab avidity to the GI.1 vaccine component peaked at day 35 (7 days after dose 2). Avidities to heterotypic genogroup I VLPs were not sustained at day 35 after vaccination or GI.1 infection, as measured from archived sera. Only secretor-positive participants maintained high avidity blockade Ab to GI.1 at day 180. Avidity to the GII.4c vaccine component peaked at day 7, remained elevated through day 180, and was not secretor dependent. Avidity to an immunologically novel GII.4 strain VLP correlated with preexisting Ab titer to an ancestral strain Epitope A. Conclusions: Host genetics and pre-exposure history shape norovirus vaccine Ab responses, including blockade Ab avidity. Avidity of potentially neutralizing Ab may be an important metric for evaluating vaccine responses to highly penetrant viruses with cross-reactive serotypes.

Sponsors' and investigative staffs' perceptions of the current investigational new drug safety reporting process in oncology trials.

BACKGROUND/AIMS: The Food and Drug Administration's final rule on investigational new drug application safety reporting, effective from 28 March 2011, clarified the reporting requirements for serious and unexpected suspected adverse reactions occurring in clinical trials. The Clinical Trials Transformation Initiative released recommendations in 2013 to assist implementation of the final rule; however, anecdotal reports and data from a Food and Drug Administration audit indicated that a majority of reports being submitted were still uninformative and did not result in actionable changes. Clinical Trials Transformation Initiative investigated remaining barriers and potential solutions to full implementation of the final rule by polling and interviewing investigators, clinical research staff, and sponsors. METHODS: In an opinion-gathering effort, two discrete online surveys designed to assess challenges and motivations related to management of expedited (7- to 15-day) investigational new drug safety reporting processes in oncology trials were developed and distributed to two populations: investigators/clinical research staff and sponsors. Data were collected for approximately 1 year. Twenty-hour-long interviews were also conducted with Clinical Trials Transformation Initiative-nominated interview participants who were considered as having extensive knowledge of and experience with the topic. Interviewees included 13 principal investigators/study managers/research team members and 7 directors/vice presidents of pharmacovigilance operations from 5 large global pharmaceutical companies. RESULTS: The investigative site's responses indicate that too many individual reports are still being submitted, which are time-consuming to process and provide little value for patient safety assessments or for informing actionable changes. Fewer but higher quality reports would be more useful, and the investigator and staff would benefit from sponsors'"filtering" of reports and increased sponsor communication. Sponsors replied that their greatest challenges include (1) lack of global harmonization in reporting rules, (2) determining causality, and (3) fear of regulatory repercussions. Interaction with the Food and Drug Administration has helped improve sponsors' adherence to the final rule, and sponsors would benefit from increased communication with the Food and Drug Administration and educational materials. CONCLUSION: The goal of the final rule is to minimize uninformative safety reports so that important safety signals can be captured and communicated early enough in a clinical program to make changes that help ensure patient safety. Investigative staff and sponsors acknowledge that the rule has not been fully implemented although they agree with the intention. Clinical Trials Transformation Initiative will use the results from the surveys and interviews to develop new recommendations and educational materials that will be available to sponsors to increase compliance with the final rule and facilitate discussion between sponsors, investigators, and Food and Drug Administration representatives.

Prevention of Medical Device-Related Pressure Injuries Associated With Respiratory Equipment Use in a Critical Care Unit: A Quality Improvement Project.

Medical devices have been identified as an extrinsic risk factor for development of pressure injuries, with as many as 30% to 70% of medical device-related pressure injuries resulting from respiratory equipment. This article describes a quality improvement project undertaken to reduce the occurrence of respiratory device-related pressure injuries in a critically care unit. Multiple actions were implemented to achieve this goal. Respiratory therapists were trained to document occurrences on a daily basis, and apparent cause analyses were conducted on each occurrence. An interdisciplinary team conducted biweekly rounds on patients with respiratory devices and consulted other professionals as indicated. Nurses and respiratory therapists attended an evidence-based, collaborative, educational offering and completed a measure of team functioning before the program and at the end of the study period. The occurrence rates of respiratory device-related pressure injuries were reduced over the project period, and these changes were sustained over the subsequent 12 months.

Norovirus vaccine against experimental human GII.4 virus illness: a challenge study in healthy adults.

BACKGROUND: Vaccines against norovirus, the leading cause of acute gastroenteritis, should protect against medically significant illness and reduce transmission. METHODS: In this randomized, double-blind, placebo-controlled trial, 18- to 50-year-olds received 2 injections of placebo or norovirus GI.1/GII.4 bivalent vaccine-like particle (VLP) vaccine with 3-O-desacyl-4'-monophosphoryl lipid A (MPL) and alum. Participants were challenged as inpatients with GII.4 virus (4400 reverse transcription polymerase chain reaction [RT-PCR] units), and monitored for illness and infection. RESULTS: Per protocol, 27 of 50 (54.0%) vaccinees and 30 of 48 (62.5%) controls were infected. Using predefined illness and infection definitions, vaccination did not meet the primary endpoint, but self-reported cases of severe (0% vaccinees vs. 8.3% controls; P = .054), moderate or greater (6.0% vs. 18.8%; P = .068), and mild or greater severity of vomiting and/or diarrhea (20.0% vs. 37.5%; P = .074) were less frequent. Vaccination also reduced the modified Vesikari score from 7.3 to 4.5 (P = .002). Difficulties encountered were low norovirus disease rate, and inability to define illness by quantitative RT-PCR or further antibody rise in vaccinees due to high vaccine-induced titers. By day 10, 11 of 49 (22.4%) vaccinees were shedding virus compared with 17 of 47 (36.2%) placebo recipients (P = .179). CONCLUSIONS: Bivalent norovirus VLP vaccine reduced norovirus-related vomiting and/or diarrhea; field efficacy studies are planned. Clinical Trials Registration. NCT01609257.

Broad blockade antibody responses in human volunteers after immunization with a multivalent norovirus VLP candidate vaccine: immunological analyses from a phase I clinical trial.

BACKGROUND: Human noroviruses (NoVs) are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab) binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus-like particle (VLP) candidate vaccine in human volunteers. METHODS AND FINDINGS: Sera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4) were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated. CONCLUSIONS: Vaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and support the potential feasibility of an efficacious multivalent NoV VLP vaccine for future use in human populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT01168401.

A novel intramuscular bivalent norovirus virus-like particle vaccine candidate--reactogenicity, safety, and immunogenicity in a phase 1 trial in healthy adults.

BACKGROUND: Noroviruses are the most important viral causes of gastroenteritis-related morbidity and mortality. A randomized, double-blind, placebo-controlled study evaluated an adjuvanted bivalent intramuscular norovirus virus-like particle (VLP) vaccine. METHODS: Forty-eight adults aged 18-49 years received either 2 doses containing genotype GI.1 VLP and a consensus GII.4 VLP or 2 doses of placebo. Doses (5 µg, 15 µg, 50 µg, or 150 µg of each VLP) were administered 4 weeks apart in the first stage. Subsequently, 54 adults, aged 18-49 (n=16), 50-64 (n=19), and 65-85 (n=19) years, received 2 doses of vaccine containing 50 µg of each VLP. Total and class-specific antibody responses, as well as histoblood group antigen (HBGA) blocking antibody responses, were measured before and after each dose. RESULTS: Local reactions were mainly injection site pain/tenderness, with no reported fever or vaccine-related serious adverse events. One dose of vaccine containing 50 µg of each VLP increased GI.1 geometric mean titers (GMTs) by 118-fold, 83-fold, and 24-fold and increased GII.4 GMTs by 49-fold, 25-fold, and 9-fold in subjects aged 18-49, 50-64, and 65-83 years, respectively. Serum antibody responses peaked at day 7 after the first dose, with no evidence of boosting following a second dose. Most subjects achieved HBGA-blocking antibody titers of ≥200. CONCLUSIONS: The vaccine was well tolerated and immunogenic. Rapid immune response to a single dose may be particularly useful in military personnel and travelers and in the control of outbreaks. Clinical Trials Registration. NCT01168401.

3,4-Methylenedioxymethamphetamine (MDMA) and metabolites disposition in blood and plasma following controlled oral administration.

3,4-Methylenedioxymethamphetamine (MDMA) is an illicit phenethylamine ingested for entactogenic and euphoric effects. Although blood is more commonly submitted for forensic analysis, previous human MDMA pharmacokinetics research focused on plasma data; no direct blood-plasma comparisons were drawn. Blood and plasma specimens from 50 healthy adult volunteers (33 males, 17 females, 36 African-American) who ingested recreational 1.0 and 1.6 mg/kg MDMA doses were quantified for MDMA and metabolites 4-hydroxy-3-methoxymethamphetamine (HMMA), 3,4-methylenedioxyamphetamine (MDA), and 4-hydroxy-3-methoxyamphetamine (HMA) by two-dimensional gas chromatography-mass spectrometry. Specimens were collected up to 3 h post-dose and evaluated for maximum concentration (C max), first detection time (t first), time of C max (t max), and 3-h area under the curve (AUC0-3 h); as well as blood metabolite ratios and blood/plasma ratios. Median blood MDMA and MDA C max were significantly greater (p < 0.0005) than in plasma, but HMMA was significantly less (p < 0.0005). HMA was detected in few blood specimens, at low concentrations. Nonlinear pharmacokinetics were not observed for MDMA or MDA in this absorptive phase, but HMMA C max and AUC0-3 h were similar for both doses despite the 1.6-fold dose difference. Blood MDA/MDMA and MDA/HMMA significantly increased (p < 0.0001) over the 3-h time course, and HMMA/MDMA significantly decreased (p < 0.0001). Blood MDMA C max was significantly greater in females (p = 0.010) after the low dose only. Low-dose HMMA AUC0-3 h was significantly decreased in females' blood and plasma (p = 0.027) and in African-Americans' plasma (p = 0.035). These data provide valuable insight into MDMA blood-plasma relationships for forensic interpretation and evidence of sex- and race-based differential metabolism and risk profiles. Figure Median (interquartile range) blood/plasma 3,4-methylenedioxymethamphetamine (MDMA) (a), 4-hydroxy-3-methoxymethamphetamine (HMMA) (b), and 3,4-methylenedioxyamphetamine (MDA) (c) ratios for 3 h after controlled MDMA administration. Changes over time were significant after the 1.6 mg/kg dose for HMMA and MDA (p = 0.013 and p = 0.021), but not for MDMA. No changes over time were significant after the 1.0 mg/kg dose. Note: y-axes do not begin at 0. *p < 0.05 (low vs. high).

Cannabis withdrawal in chronic, frequent cannabis smokers during sustained abstinence within a closed residential environment.

OBJECTIVES: Chronic, frequent cannabis smokers may experience residual and offset effects, withdrawal, and craving when abstaining from the drug. We characterized the prevalence, duration, and intensity of these effects in chronic frequent cannabis smokers during abstinence on a closed research unit. METHODS: Non-treatment-seeking participants (N = 29 on admission, 66% and 34% remaining after 2 and 4 weeks) provided subjective effects data. A battery of five instruments was computer-administered daily to measure psychological, sensory, and physical symptoms associated with cannabinoid intoxication and withdrawal. Plasma and oral fluid specimens were concurrently collected and analyzed for cannabinoids. Outcome variables were evaluated as change from admission (Day 0) with regression models. RESULTS: Most abstinence effects, including irritability and anxiety were greatest on Days 0-3 and decreased thereafter. Cannabis craving significantly decreased over time, whereas decreased appetite began to normalize on Day 4. Strange dreams and difficulty getting to sleep increased over time, suggesting intrinsic sleep problems in chronic cannabis smokers. Symptoms likely induced by residual drug effects were at maximum intensity on admission and positively correlated with plasma and oral fluid cannabinoid concentrations on admission but not afterward; these symptoms showed overall prevalence higher than cannabis withdrawal symptoms. CONCLUSIONS: The combined influence of residual/offset drug effects, withdrawal, and craving was observed in chronic cannabis smokers during monitored abstinence. Abstinence symptoms were generally more intense in the initial phase, implying importance of early intervention in cannabis quit attempts. Sleep disturbance persisting for an extended period suggests that hypnotic medications could be beneficial in treating cannabis dependence.

A Retrospective Analysis of Needle Thoracostomies at a Tertiary Level 2 Trauma Center.

BACKGROUND: A tension pneumothorax is a condition that results in elevated pressure within the pleural space. The effective management of tension pneumothorax relies on needle decompression, commonly performed at the second intercostal space (ICS) midclavicular line (MCL). However, some literature suggests that catheters placed in the second intercostal space midclavicular line are prone to higher failure rates compared to the fifth intercostal space midaxillary line (MAL) (42.5% versus 16.7%, respectively). In this study, we aim to identify and scrutinize the prevalence of prehospital needle decompression from one tertiary care center over eight years and examine their trends, efficacies, or pitfalls. It is hypothesized that preclinical providers are performing needle decompression prematurely and unnecessarily. METHODS: A set of 90 patient records obtained using the trauma registry at Saint Francis Hospital, Tulsa, Oklahoma, were retrospectively reviewed to evaluate the management and outcomes of tension pneumothorax, as well as the indications documented for needle decompression. Patient charts were reviewed via Epic Hyperspace (Epic, Madison, WI). The Oklahoma Emergency Medical Service Information System (OKEMSIS) also provided information contributing to the sample population. RESULTS: The most documented indications for needle decompressions included diminished or absent breath sounds (52.70%), hypoxia (15.54%), hypotension, and hemodynamic instability (6.76%). Emergency medical services (EMS) reported improvements in 51 (56.67%) patients after needle thoracostomy. Improvements in vital signs after needle decompression were sporadic. The most common complication was catheter dislodging, which occurred most in the second intercostal space midclavicular line. Only nine patients had an oxygen saturation (SpO2) below 92% and a systolic blood pressure (SBP) below 100 mm Hg prior to receiving needle decompression. CONCLUSION: Current practices for tension pneumothorax show little improvement in vital signs before and after needle decompression. Vital signs prior to needle decompression often do not indicate tension pneumothorax physiology. Preclinical providers may be inappropriately performing needle decompressions, an invasive procedure with complications.

Impact of prolonged cannabinoid excretion in chronic daily cannabis smokers' blood on per se drugged driving laws.

BACKGROUND: Cannabis is the illicit drug most frequently reported with impaired driving and motor vehicle accidents. Some "per se" laws make it illegal to drive with any amount of drug in the body, while others establish blood, saliva, or urine concentrations above which it is illegal to drive. The persistence of Δ(9)-tetrahydrocannabinol (THC) in chronic daily cannabis smokers' blood is unknown. METHODS: Thirty male chronic daily cannabis smokers resided on a secure research unit for up to 33 days, with daily blood collection. Samples were processed in an ice bath during sample preparation to minimize cannabinoid adsorption onto precipitant material. We quantified THC by 2-dimensional GC-MS. RESULTS: Of the 30 participants, 27 were THC-positive on admission, with a median (range) concentration of 1.4 µg/L (0.3-6.3). THC decreased gradually; only 1 of 11 participants was negative at 26 days, 2 of 5 remained THC-positive (0.3 µg/L) for 30 days, and 5.0% of participants had THC ≥ 1.0 µg/L for 12 days. Median 11-hydroxy-THC concentrations were 1.1 µg/L on admission, with no results ≥ 1.0 µg/L 24 h later. 11-Nor-9-carboxy-THC (THCCOOH) detection rates were 96.7% on admission, decreasing slowly to 95.7% and 85.7% on days 8 and 22, respectively; 4 of 5 participants remained THCCOOH positive (0.6-2.7 µg/L) after 30 days, and 1 remained positive on discharge at 33 days. CONCLUSIONS: Cannabinoids can be detected in blood of chronic daily cannabis smokers during a month of sustained abstinence. This is consistent with the time course of persisting neurocognitive impairment reported in recent studies.

Oral fluid and plasma 3,4-methylenedioxymethamphetamine (MDMA) and metabolite correlation after controlled oral MDMA administration.

Oral fluid (OF) offers a noninvasive sample collection for drug testing. However, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) in OF has not been adequately characterized in comparison to plasma. We administered oral low-dose (1.0 mg/kg) and high-dose (1.6 mg/kg) MDMA to 26 participants and collected simultaneous OF and plasma specimens for up to 143 h after dosing. We compared OF/plasma (OF/P) ratios, time of initial detection (t first), maximal concentrations (C max), time of peak concentrations (t max), time of last detection (t last), clearance, and 3,4-methylenedioxyamphetamine (MDA)-to-MDMA ratios over time. For OF MDMA and MDA, C max was higher, t last was later, and clearance was slower compared to plasma. For OF MDA only, t first was later compared to plasma. Median (range) OF/P ratios were 5.6 (0.1-52.3) for MDMA and 3.7 (0.7-24.3) for MDA. OF and plasma concentrations were weakly but significantly correlated (MDMA: R(2) = 0.438, MDA: R(2) = 0.197, p < 0.0001). Median OF/P ratios were significantly higher following high dose administration: MDMA low = 5.2 (0.1-40.4), high = 6.0 (0.4-52.3, p < 0.05); MDA low = 3.3 (0.7-17.1), high = 4.1 (0.9-24.3, p < 0.001). There was a large inter-subject variation in OF/P ratios. The MDA/MDMA ratios in plasma were higher than those in OF (p < 0.001), and the MDA/MDMA ratios significantly increased over time in OF and plasma. The MDMA and MDA concentrations were higher in OF than in plasma. OF and plasma concentrations were correlated, but large inter-subject variability precludes the estimation of plasma concentrations from OF.

Around-the-clock oral THC effects on sleep in male chronic daily cannabis smokers.

BACKGROUND AND OBJECTIVES: Δ9-tetrahydrocannabinol (THC) promotes sleep in animals; clinical use of THC is associated with somnolence. Human laboratory studies of oral THC have not shown consistent effects on sleep. We prospectively evaluated self-reported sleep parameters during controlled oral THC administration to research volunteers. METHODS: Thirteen male chronic daily cannabis smokers (mean ± SD age 24.6± 3.7 years, self-reported smoking frequency of 5.5 ± 5.9 (range 1-24) joint-equivalents daily at study entry) were administered oral THC doses (20 mg) around-the-clock for 7 days (40-120 mg daily) starting the afternoon after admission. The St. Mary's Hospital Sleep Questionnaire was completed every morning. Plasma THC and 11-OH-THC (active metabolite) concentrations were measured in venous blood samples collected every evening. Changes in sleep characteristics over time and associations between sleep characteristics and plasma cannabinoid concentrations were evaluated with repeated measures mixed linear regression. RESULTS: Higher evening THC and 11-OH-THC concentrations were significantly associated with shorter sleep latency, less difficulty falling asleep, and more daytime sleep the following day. In contrast, the duration of calculated and self-reported nighttime sleep decreased slightly (3.54 and 5.34 minutes per night, respectively) but significantly during the study. CONCLUSIONS: These findings suggest that tolerance to the somnolent effects of THC may have occurred, but results should be considered preliminary due to design limitations. SCIENTIFIC SIGNIFICANCE: Somnolence from oral THC may dissipate with chronic, high-dose use. This has implications for patients who may take chronic oral THC for medicinal purposes, including cannabis dependence treatment. (Am J Addict 2013;22:510-514).

Fremantle protocol: Multicenter clinical outcomes for a pragmatic protocol for intravesical bacillus Calmette-Guerin.

OBJECTIVES: To examine the utility and efficacy of a multifaceted protocol for the administration of intravesical bacillus Calmette-Guerin (BCG) for non-muscle-invasive bladder cancer (NMIBC). SUBJECTS AND METHODS: A multicenter retrospective review was conducted among 83 patients undergoing Fremantle protocol intravesical BCG for NMIBC within 4 major hospitals in Western Australia between January 2016 and December 2018. The Fremantle protocol consists of weekly BCG instillations for 6 weeks during the induction phase, followed by monthly BCG instillations for 10 months during the maintenance phase with integrated clearance-to-proceed algorithms for urine MSU checks, flexible cystoscopies performed at 3 monthly intervals during maintenance BCG, and repeat GA cystoscopies with four quadrant bladder biopsies routinely obtained following the completion of induction and maintenance treatment. RESULTS: For patients undergoing Fremantle protocol BCG, 98.8% (82/83) and 75.9% (63/83) of patients completed their induction and maintenance courses of BCG, respectively. Induction BCG was delivered over a median duration of 35 days (range 34-84 days), and maintenance BCG was delivered over a median duration of 266 days (range 1-682 days). The tumor recurrence rate was 10.8% (9/83) at the time of post-induction biopsies, 2.4% (2/83) during maintenance treatment, 0% (0/60) at the time of post-maintenance biopsies, and 8.8% (5/57) after a median further follow-up of 16 months (range 0-51 months). CONCLUSION: The Fremantle protocol appears to be a safe and effective BCG regimen with several advantages over other BCG protocols, including high completion rates, low recurrence rates, and being highly pragmatic.

Methadone and metabolites in hair of methadone-assisted pregnant women and their infants.

INTRODUCTION: Methadone is the recommended pharmacotherapy for opioid-dependent pregnant women. The primary aims of this study were to determine whether a dose-concentration relationship exists between cumulative maternal methadone dose, methadone and metabolite concentrations in maternal hair during pregnancy and whether maternal hair methadone and metabolite concentrations predict neonatal outcomes. MATERIALS AND METHODS: Hair specimens were collected monthly from opioid-dependent mothers enrolled in methadone treatment and 4 of their infants. Hair specimens were segmented (3 cm), washed (maternal hair only), and analyzed for methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), and 2-ethyl-5-methyl-3,3-diphenylpyrroline by liquid chromatography tandem mass spectrometry. RESULTS: There was large intersubject variability and no dose-concentration relationship for cumulative methadone dose and methadone, EDDP, 2-ethyl-5-methyl-3,3-diphenylpyrroline, or total concentrations in hair. For individual women, a positive trend was noted for cumulative methadone dose and methadone and EDDP concentrations in hair. There was a positive linear trend for cumulative methadone dose and EDDP/methadone ratio in maternal hair, perhaps reflecting methadone's induction of its own metabolism. Maternal methadone concentrations were higher than those in infant hair, and infant EDDP hair concentrations were higher than those in maternal hair. Maternal methadone dose, and methadone and EDDP hair concentrations were not correlated with peak infant neonatal abstinence syndrome (NAS) scores, days to peak NAS, duration of NAS, time to NAS onset, birth length, head circumference, or amount of neonatal morphine pharmacotherapy. Maternal cumulative third trimester methadone dose was positively correlated with infant birth weight. CONCLUSIONS: Methadone and EDDP in pregnant women's hair are markers of methadone exposure and do not predict total methadone dose, nor neonatal outcomes from in utero methadone exposure.

CB1 - cannabinoid receptor antagonist effects on cortisol in cannabis-dependent men.

BACKGROUND: The endocannabinoid system modulates the hypothalamic-pituitary-adrenal (HPA) axis, but the effect of cannabinoid type 1 (CB1) receptor antagonism following chronic CB1 receptor stimulation in humans is unknown. OBJECTIVES: To evaluate effects of the CB1 receptor antagonist rimonabant on the HPA axis in cannabis-dependent individuals. METHODS: Fourteen daily cannabis smokers received increasingly frequent 20 mg oral Δ9-tetrahydrocannabinol (THC) doses (60-120 mg/day) over 8 days to standardize cannabis tolerance. Concurrent with the last THC dose, double-blind placebo or rimonabant (20 or 40 mg) was administered. Cannabinoid, rimonabant, and cortisol plasma concentrations were measured 1.5 hours prior to rimonabant administration and 2.0, 5.5, and 12.5 hours post-dose. RESULTS: Ten participants completed before premature study termination due to rimonabant's withdrawal from development. Five participants received 20 mg, three received 40 mg, and two placebo. There was a significant positive association between rimonabant concentration and change in cortisol concentration from baseline (r = .53, p < .01). There also was a borderline significant association between rimonabant dose and cortisol concentrations when the dose-by-time interaction was included. Four of eight participants receiving rimonabant (none of two receiving placebo) had greater cortisol concentrations 2 hours after dosing (at 11:30) than at 08:00, while normal diurnal variation should have peak concentrations at 08:00. CONCLUSION: Rimonabant 20 or 40 mg did not significantly increase plasma cortisol concentrations, consistent with an absence of antagonist-elicited cannabis withdrawal. SCIENTIFIC SIGNIFICANCE: Rimonabant doses >40 mg might elicit cortisol changes, confirming a role for CB1 receptors in modulating the HPA axis in humans.

Ureteral embolisation for the management of persistent uretero-ileal anastomotic leak.

Ureteral embolisation has been described in the use of complete occlusion of the ureter to manage urinary leaks, haematuria, and fistulas. This is usually a management option of last resort in patients who have many co-morbidities, poor surgical candidates, or previous pelvic surgery. We report the use of vascular coils and glue to manage a uretero-ileal anastomotic leak following radical cystoprostatectomy.

Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration.

BACKGROUND: Sativex(®), a cannabis extract oromucosal spray containing Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), is currently in phase III trials as an adjunct to opioids for cancer pain treatment, and recently received United Kingdom approval for treatment of spasticity. There are indications that CBD modulates THC's effects, but it is unclear if this is due to a pharmacokinetic and/or pharmacodynamic interaction. METHODS: Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study. Participants received 5 and 15 mg synthetic oral THC, low-dose (5.4 mg THC and 5.0 mg CBD) and high-dose (16.2 mg THC and 15.0 mg CBD) Sativex, and placebo over 5 sessions. CBD, THC, 11-hydroxy-THC, and 11-nor- 9-carboxy-THC were quantified in plasma by 2-dimensional GC-MS. Lower limits of quantification were ≤0.25 µg/L. RESULTS: Nine cannabis smokers completed all 5 dosing sessions. Significant differences (P < 0.05) in maximum plasma concentrations (C(max)) and areas under the curve from 0-10.5 h postdose (AUC(0→10.5)) for all analytes were found between low and high doses of synthetic THC and Sativex. There were no statistically significant differences in C(max), time to maximum concentration or in the AUC(0→10.5) between similar oral THC and Sativex doses. Relative bioavailability was calculated to determine the relative rate and extent of THC absorption; 5 and 15 mg oral THC bioavailability was 92.6% (13.1%) and 98.8% (11.0%) of low- and high-dose Sativex, respectively. CONCLUSION: These data suggest that CBD modulation of THC's effects is not due to a pharmacokinetic interaction at these therapeutic doses.

Oral fluid cannabinoids in chronic, daily Cannabis smokers during sustained, monitored abstinence.

BACKGROUND: Oral fluid (OF) is an accepted alternative biological matrix for drug treatment, workplace, and DUID (driving under the influence of drugs) investigations, but establishing the cannabinoid OF detection window and concentration cutoff criteria are important. METHODS: Cannabinoid concentrations were quantified in OF from chronic, daily cannabis smokers during monitored abstinence. Δ(9)-tetrahydrocannabinol (THC)(3), cannabidiol (CBD), cannabinol (CBN), and 11-nor-9-carboxy-THC (THCCOOH) were determined in daily OF samples collected with the Quantisal™ device. GC-MS limits of quantification (LOQ) were 0.5 µg/L for THC and CBD, 1 µg/L for CBN, and 7.5 ng/L for THCCOOH. RESULTS: After providing written informed consent for this institutional review board-approved study, 28 participants resided from 4 to 33 days on the secure research unit and provided 577 OF specimens. At the LOQ, THC was generally quantifiable for 48 h, whereas CBD and CBN were detected only at admission. Median THCCOOH detection time was 13 days (CI 6.4-19.6 days). Mean THC detection rates decreased from 89.3% at admission to 17.9% after 48 h, whereas THCCOOH gradually decreased from 89.3% to 64.3% within 4 days. Criteria of THC ≥2 µg/L and THCCOOH ≥20 ng/L reduced detection to <48 h in chronic cannabis smokers. An OF THCCOOH/THC ratio ≤4 ng/µg or presence of CBD or CBN may indicate more recent smoking. CONCLUSIONS: THC, THCCOOH, CBD, and CBN quantification in confirmatory OF cannabinoid testing is recommended. Inclusion of multiple cannabinoid cutoffs accounted for residual cannabinoid excretion in OF from chronic, daily cannabis smokers and could reduce the potential for positive test results from passive cannabis smoke exposure and lead to greatly improved test interpretation.

Urinary excretion kinetics of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) and its phase I and phase II metabolites in humans following controlled MDMA administration.

BACKGROUND: 3,4-Methylendioxymethamphetamine (MDMA) is excreted inhuman urine as unchanged drug and phase I and II metabolites. Previous urinary excretion studies after controlled oral MDMA administration have been performed only after conjugate cleavage. Therefore, we investigated intact MDMA glucuronide and sulfate metabolite excretion. METHODS: We used LC-high-resolution MS and GC-MS to reanalyze blind urine samples from 10 participants receiving 1.0 or 1.6 mg/kg MDMA orally. We determined median C(max),t(max), first and last detection times, and total urinary recovery; calculated ratios of sulfates and glucuronides; and performed in vitro-in vivo correlations. RESULTS: Phase II metabolites of 3,4-dihydroxymethamphetamine (DHMA),4-hydroxy-3-methoxymethamphetamine (HMMA),3,4-dihydroxyamphetamine (DHA), and 4-hydroxy-3-methoxyamphetamine were identified, although only DHMA sulfates, HMMA sulfate, and HMMA glucuronide had substantial abundance. Good correlation was observed for HMMA measured after acid hydrolysis and the sum of unconjugated HMMA, HMMA glucuronide, and HMMA sulfate (R(2) = 0.87). More than 90% of total DHMA and HMMA were excreted as conjugates. The analyte with the longest detection time was HMMA sulfate. Median HMMA sulfate/glucuronide and DHMA 3-sulfate/4-sulfate ratios for the first 24 h were 2.0 and 5.3, respectively, in accordance with previous in vitro calculations from human liver microsomes and cytosol experiments. CONCLUSIONS: Human MDMA urinary metabolites are primarily sulfates and glucuronides,with sulfates present in higher concentrations than glucuronides. This new knowledge may lead to improvements in urine MDMA and metabolite analysis in clinical and forensic toxicology, particularly for the performance of direct urine analysis.

Oral fluid and plasma cannabinoid ratios after around-the-clock controlled oral Δ(9)-tetrahydrocannabinol administration.

BACKGROUND: Oral fluid (OF) testing is increasingly important for drug treatment, workplace, and drugged-driving programs. There is interest in predicting plasma or whole-blood concentrations from OF concentrations; however, the relationship between these matrices is incompletely characterized because of few controlled drug-administration studies. METHODS: Ten male daily cannabis smokers received around-the-clock escalating 20-mg oral Δ(9)-tetrahydrocannabinol (THC, dronabinol) doses (40-120 mg/day) for 8 days. Plasma and OF samples were simultaneously collected before, during, and after dosing. OF THC, 11-hydroxy-THC and 11-nor-9-carboxy-THC (THCCOOH) were quantified by GC-MS at 0.5-µg/L, 0.5-µg/L, and 7.5-ng/L limits of quantification (LOQs), respectively. In plasma, the LOQs were 0.25 µg/L for THC and THCCOOH, and 0.5 µg/L for 11-hydroxy-THC. RESULTS: Despite multiple oral THC administrations each day and increasing plasma THC concentrations, OF THC concentrations generally decreased over time, reflecting primarily previously self-administered smoked cannabis. The logarithms of the THC concentrations in oral fluid and plasma were not significantly correlated (r = -0.10; P = 0.065). The OF and plasma THCCOOH concentrations, albeit with 1000-fold higher concentrations in plasma, increased throughout dosing. The logarithms of OF and plasma THCCOOH concentrations were significantly correlated (r = 0.63; P < 0.001), although there was high interindividual variation. A high OF/plasma THC ratio and a high OF THC/THCCOOH ratio indicated recent cannabis smoking. CONCLUSIONS: OF monitoring does not reliably detect oral dronabinol intake. The time courses of THC and THCCOOH concentrations in plasma and OF were different after repeated oral THC doses, and high interindividual variation was observed. For these reasons, OF cannabinoid concentrations cannot predict concurrent plasma concentrations.