Impaired Driving Associated with the Synthetic Cannabinoid 5f-Adb.

Synthetic marijuana compounds are more potent than Δ9-tetrahydrocannabinol (∆9-THC) and are known to produce a wide variety of clinical symptoms including cardiac toxicity, seizures, and death. Erratic driving by a 45 y/o male was witnessed in the fall of 2017 and roadside evaluation of the driver by the responding law enforcement officer concluded that the driver was intoxicated. Comprehensive analysis of the cigarettes by gas chromatography-mass spectrometry detected the synthetic cannabinoid 5-fluoro-ADB (5F-ADB or 5F-MDMB-PINACA). Validated forensic liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods were used to detect the 5-fluoro ADB metabolite 7 (26.37 ng/mL) in the driver's blood sample. No other drugs were detected. This case report is one of the first to conclusively show that designer synthetic cannabinoids, commonly referred to as "K2" and "Spice", can significantly impair driving at relatively low concentrations.

The impact of strength level on adaptations to combined weightlifting, plyometric, and ballistic training.

The purpose of this investigation was to determine whether the magnitude of adaptation to integrated ballistic training is influenced by initial strength level. Such information is needed to inform resistance training guidelines for both higher- and lower-level athlete populations. To this end, two groups of distinctly different strength levels (stronger: one-repetition-maximum (1RM) squat = 2.01 ± 0.15 kg·BM-1 ; weaker: 1.20 ± 0.20 kg·BM-1 ) completed 10 weeks of resistance training incorporating weightlifting derivatives, plyometric actions, and ballistic exercises. Testing occurred at pre-, mid-, and post-training. Measures included variables derived from the incremental-load jump squat and the 1RM squat, alongside muscle activity (electromyography), and jump mechanics (force-time comparisons throughout the entire movement). The primary outcome variable was peak velocity derived from the unloaded jump squat. It was revealed that the stronger group displayed a greater (P = .05) change in peak velocity at mid-test (baseline: 2.65 ± 0.10 m/s, mid-test: 2.80 ± 0.17 m/s) but not post-test (2.85 ± 0.18 m/s) when compared to the weaker participants (baseline 2.43 ± 0.09, mid-test. 2.47 ± 0.11, post-test: 2.61 ± 0.10 m/s). Different changes occurred between groups in the force-velocity relationship (P = .001-.04) and jump mechanics (P ≤ .05), while only the stronger group displayed increases in muscle activation (P = .05). In conclusion, the magnitude of improvement in peak velocity was significantly influenced by pre-existing strength level in the early stage of training. Changes in the mechanisms underpinning performance were less distinct.

Caffeine decreases intermittent hypoxia in preterm infants nearing term-equivalent age.

OBJECTIVE: To determine whether intermittent hypoxia (IH) persisting after 36 weeks postmenstrual age (PMA) can be attenuated using caffeine doses sufficient to maintain caffeine concentrations >20 µg ml-1. STUDY DESIGN: Twenty-seven infants born <32 weeks were started on caffeine citrate at 10 mg kg-1 day-1 when clinical caffeine was discontinued. At 36 weeks PMA, the dose was increased to 14 or 20 mg kg-1 day-1 divided twice a day (BID) to compensate for progressively increasing caffeine metabolism. Caffeine concentrations were measured weekly. The extent of IH derived from continuous pulse oximetry was compared to data from 53 control infants. RESULT: The mean (s.d.) gestational age of enrolled infants was 27.9±2 weeks. Median caffeine levels were >20 µg ml-1 on study caffeine doses. IH was significantly attenuated through 38 weeks PMA compared with the control group. CONCLUSION: Caffeine doses of 14 to 20 mg kg-1 day-1 were sufficient to maintain caffeine concentrations >20 µg ml-1 and reduce IH in preterm infants at 36 to 38 weeks PMA.

Mitochondrial pharmacology: its future is now.

Mitochondrial medicine is an evolving discipline whose importance derives from the central function of mitochondria in adenosine triphosphate (ATP) production, generation of reactive oxygen species, and cell death by necrosis or apoptosis. Consequently, mitochondrial dysfunction plays an important role in the progression of aging and the pathophysiology of many common diseases and off-target drug effects. This provides an impetus for the development of mitochondrial pharmacology, and some promising therapeutic targets for mitochondrial protective therapy have been identified.

Metabolomics: integration of a new "omics" with clinical pharmacology.

The term "pharmacometabolomics" was coined in 2006 to reflect the potential of the predrug metabolomic signature to predict the postdrug response. Metabolomics can be used to examine the contribution of nongenomic factors, such as the environment, diet, or the gut microbiome, to the overall drug response. As such, the complexity of human biology afforded by metabolomics can complement genomic approaches, ultimately moving the discipline of clinical pharmacology closer to full implementation of personalized medicine.

Protein tyrosine phosphatase 1B modulates GSK3ß/Nrf2 and IGFIR signaling pathways in acetaminophen-induced hepatotoxicity.

Acute hepatic failure secondary to acetaminophen (APAP) poisoning is associated with high mortality. Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of tyrosine kinase growth factor signaling. In the liver, this pathway confers protection against injury. However, the involvement of PTP1B in the intracellular networks activated by APAP is unknown. We have assessed PTP1B expression in APAP-induced liver failure in humans and its role in the molecular mechanisms that regulate the balance between cell death and survival in human and mouse hepatocytes, as well as in a mouse model of APAP-induced hepatotoxicity. PTP1B expression was increased in human liver tissue removed during liver transplant from patients for APAP overdose. PTP1B was upregulated by APAP in primary human and mouse hepatocytes together with the activation of c-jun (NH2) terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK), resulting in cell death. Conversely, Akt phosphorylation and the antiapoptotic Bcl2 family members BclxL and Mcl1 were decreased. PTP1B deficiency in mouse protects hepatocytes against APAP-induced cell death, preventing glutathione depletion, reactive oxygen species (ROS) generation and activation of JNK and p38 MAPK. APAP-treated PTP1B(-/-) hepatocytes showed enhanced antioxidant defense through the glycogen synthase kinase 3 (GSK3)ß/Src kinase family (SKF) axis, delaying tyrosine phosphorylation of the transcription factor nuclear factor-erythroid 2-related factor (Nrf2) and its nuclear exclusion, ubiquitination and degradation. Insulin-like growth factor-I receptor-mediated signaling decreased in APAP-treated wild-type hepatocytes, but was maintained in PTP1B(-/-) cells or in wild-type hepatocytes with reduced PTP1B levels by RNA interference. Likewise, both signaling cascades were modulated in mice, resulting in less severe APAP hepatotoxicity in PTP1B(-/-) mice. Our results demonstrated that PTP1B is a central player of the mechanisms triggered by APAP in hepatotoxicity, suggesting a novel therapeutic target against APAP-induced liver failure.

Gastrohepatology: tools, targets, and trajectories.

Gastrointestinal (GI) and hepatic conditions are a leading source of health-care utilization today. A significant segment of the over-the-counter and prescription drug market comprises drugs used to alleviate symptoms localized to the alimentary tract. The discovery of new mechanisms of disease pathogenesis will inform the future development of targeted therapeutics for conditions managed by gastroenterologists and hepatologists. Newly approved drugs and evolving mechanistic targets offer a promising trajectory to both clinicians and patients with GI and liver disorders.

Accuracy of primary systematic template guided transperineal biopsy of the prostate for locating prostate cancer: a comparison with radical prostatectomy specimens.

PURPOSE: We determined whether systematic template guided transperineal biopsies can accurately locate and sensitively detect prostate cancer. In addition, we reported discrepancies between diagnostic and pathological Gleason scores, and investigated whether prostate size had an effect on the cancer detection rate. MATERIALS AND METHODS: This retrospective diagnostic accuracy study compares the results of primary transperineal biopsies with the radical prostatectomy pathology of 414 consecutive patients treated at a single institution between November 2002 and August 2010. RESULTS: The average sensitivity and specificity for the detection of cancer in all prostates across all biopsy zones was 48% (95% CI 42.6-53.4) and 84.1% (95% CI 80-88.2), respectively. There was a statistically significant decrease in the sensitivity of transperineal biopsy in larger prostates (t11=4.687, p=0.001). The overall Kappa value was 0.255 (95% CI 0.212-0.298). Grading concordance between biopsy and pathology specimens was achieved in 65.7% of patients. Upgrading of Gleason scores occurred in 25.6% of patients and downgrading occurred in 8.8%. CONCLUSIONS: Our current transperineal biopsy method has only demonstrated fair agreement with the histopathology findings of the corresponding radical prostatectomy specimens. This finding is most likely due to the small, multifocal nature of prostate cancer in the patient series. The cancer detection rate was lower in larger prostates. Thus, clinicians may consider increasing the number of cores in larger prostates as a strategy to improve cancer detection.

Severe toxicity following synthetic cannabinoid ingestion.

OBJECTIVE: To report a case of seizures and supraventricular tachycardia (SVT) following confirmed synthetic cannabinoid ingestion. BACKGROUND: Despite widespread use of legal synthetic cannabinoids, reports of serious toxicity following confirmed use of synthetic cannabinoids are rare. We report severe toxicity including seizures following intentional ingestion of the synthetic cannabinoid JWH-018 and detail confirmation by laboratory analysis. CASE REPORT: A healthy 48 year old man had a generalized seizure within thirty minutes of ingesting an ethanol mixture containing a white powder he purchased from the Internet in an attempt to get high. Seizures recurred and abated with lorazepam. Initial vital signs were: pulse, 106/min; BP, 140/88 mmHg; respirations, 22/min; temperature, 37.7 °C. A noncontrast computed tomography of the brain and EEG were negative, and serum chemistry values were normal. The blood ethanol concentration was 3.8 mg/dL and the CPK 2,649 U/L. Urine drug screening by EMIT was negative for common drugs of abuse, including tetrahydrocannabinol. On hospital day 1, he developed medically refractory SVT. The patient had no further complications and was discharged in his normal state of health 10 days after admission. The original powder was confirmed by gas chromatography mass spectrometry to be JWH-018, and a primary JWH-018 metabolite was detected in the patient's urine (200 nM) using liquid chromatography tandem mass spectrometry. DISCUSSION: Synthetic cannabinoids are legal in many parts of the world and easily obtained over the Internet. Data on human toxicity are limited and real-time confirmatory testing is unavailable to clinicians. The potential for toxicity exists for users mistakenly associating the dose and side effect profiles of synthetic cannabinoids to those of marijuana. CONCLUSION: Ingestion of JWH-018 can produce seizures and tachyarrhythmias. Clinicians, lawmakers, and the general public need to be aware of the potential for toxicity associated with synthetic cannabinoid use.

Characterization of delayed liquid gastric emptying in children by the (13)C-acetate breath test.

The (13)C-acetate breath test represents a potential alternative to conventional scintigraphy to measure liquid gastric emptying (GE). The purpose of this study was to compare the (13)C-acetate breath test to gastric scintigraphy in children with functional dyspepsia. Simultaneous assessment of GE was performed in 28 children (9-17 years of age) using a liquid test meal that was double labeled with (13)C-acetate and (99 m)Technetium. (13)CO(2) versus time profiles were fit using traditional pharmacokinetic analyses. For each subject, GE half-life [Formula: see text] determined by scintigraphy was plotted against parameters determined from the (13)C-acetate breath test. Linear regression was used to explore the associations between the tests. Complete (13)CO(2) versus time profiles were available for 25 subjects. There was no association between the scintigraphy GE T½ and the(13)CO(2) half-exhalation time. However, significant associations were observed between the gastric half-emptying time as determined by scintigraphy and two of the breath test parameters: the enrichment of (13)CO(2) present in breath samples at 60 min (DOB(60)) (r = -0.52, p = 0.01) and the area under the curve from 0 to 60 min (AUC(0-60 min)) (r = -0.54; p < 0.01). The (13)C-acetate breath test has the potential to serve as a rapid, technically simple and inexpensive means to assess liquid GE in children with functional dyspepsia and possibly serve as a pharmacodynamic surrogate in studies of prokinetic drugs in children.

Acetaminophen-associated hepatic injury: evaluation of acetaminophen protein adducts in children and adolescents with acetaminophen overdose.

Acetaminophen protein adducts (APAP adducts) were quantified in 157 adolescents and children presenting at eight pediatric hospitals with the chief complaint of APAP overdose. Two of the patients required liver transplantation, whereas all the others recovered spontaneously. Peak APAP adducts correlated with peak hepatic transaminase values, time-to-treatment with N-acetylcysteine (NAC), and risk determination per the Rumack-Matthews nomogram. A population pharmacokinetic analysis (NONMEM) was performed with post hoc empiric Bayesian estimates determined for the elimination rate constants (k(e)), elimination half-lives (t(1/2)), and maximum concentration of adducts (C(max)) of the subjects. The mean (+/-SD)k(e) and half-life were 0.486 +/- 0.084 days(-1) and 1.47+/- 0.30 days, respectively, and the C(max) was 1.2 (+/-2.92) nmol/ml serum. The model-derived, predicted adduct value at 48 h (Adduct 48) correlated with adductC(max), adduct T(max), Rumack-Matthews risk determination, peak aspartate aminotransferase (AST), and peak alanine aminotransferase (ALT). The pharmacokinetics and clinical correlates of APAP adducts in pediatric and adolescent patients with APAP overdose support the need for a further examination of the role of APAP adducts as clinically relevant and specific biomarkers of APAP toxicity.

Ontogeny of dextromethorphan O- and N-demethylation in the first year of life.

The exponential increase in the number of drugs used to treat infant and childhood illnesses necessitates an understanding of the ontogeny of drug biotransformation for the development of safe and effective therapies. Healthy infants received an oral dose (0.3 mg/kg) of dextromethorphan (DM) at 0.5, 1, 2, 4, 6, and 12 months of age. DM and its major metabolites were measured in urine. CYP2D6 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. Genotyping data indicated a strong correlation between CYP2D6 genotype and DM O-demethylation (beta=-0.638; 95% CI: -0.745, -0.532; P<0.001). CYP2D6 activity was detectable and concordant with genotype by 2 weeks of age, showed no relationship with gestational age, and did not change with post natal age up to 1 year. In contrast, DM N-demethylation developed significantly more slowly over the first year of life. Genotype and the temporal acquisition of drug biotransformation are critical determinants of a drug response in infants.

Elevation of serum interleukin 8 levels in acetaminophen overdose in children and adolescents.

BACKGROUND: Elevations of inflammatory cytokines have been reported in animal models of acetaminophen (INN, paracetamol) toxicity. In addition, interleukin 8, a chemokine, has been found to be elevated in toxin-associated hepatic disease (ie, acute alcoholic hepatitis). The purpose of this study was to measure serum cytokine levels in children and adolescents with acetaminophen overdose and to evaluate relationships between cytokine elevation and hepatotoxicity. METHODS: Serum levels of tumor necrosis factor alpha, interleukin 1beta, interleukin 6, interleukin 8, and interleukin 10 were measured by ELISA in children and adolescents (n = 35) with acetaminophen overdose. Peak cytokine levels were examined relative to biochemical evidence of hepatocellular injury, nomogram risk assessment, and prothrombin time. RESULTS: Five patients had aspartate aminotransferase or alanine aminotransferase levels >1000 IU/L, and 4 patients had aspartate aminotransferase or alanine aminotransferase levels > or =100 IU/L and < or =1000 IU/L. No elevations of tumor necrosis factor alpha or interleukin 1beta were detected. Peak interleukin 8, but not interleukin 6 or interleukin 10, correlated with hepatotoxicity (Mann-Whitney exact test, P <.001). The peak interleukin 8 level was greater in patients at high risk by the nomogram combined with those presenting at >15 hours, as compared with other patients (Mann-Whitney U test, P <.01). The interleukin 8 level peaked before aspartate aminotransferase or alanine aminotransferase in 5 of the 9 patients with hepatotoxicity. In addition, interleukin 8 concentrations of >20 pg/mL were associated with peak prothrombin time values (Mann-Whitney exact test, P <.015). CONCLUSIONS: Interleukin 8 elevation in patients with acetaminophen hepatotoxicity corresponds with other common clinical measures that are predictive of hepatocellular injury. Further study is warranted to evaluate possible mechanistic relationships between inflammatory cytokines and acetaminophen hepatotoxicity in children and adults.

Measurement of acetaminophen-protein adducts in children and adolescents with acetaminophen overdoses. .

Acetaminophen-protein adducts are biomarkers of acetaminophen toxicity present in the centrilobular region of the liver of laboratory animals following the administration of toxic doses of acetaminophen. These biomarkers are highly specific for acetaminophen-induced hepatic injury and correlate with hepatic transaminase elevation. The objective of this prospective, multicenter study was to evaluate the clinical application of the measurement of acetaminophen-protein adducts in pediatric acetaminophen overdose patients. Serum samples were obtained from 51 children and adolescents with acetaminophen overdose at the time of routine blood sampling for clinical monitoring. Six subjects developed "severe" hepatotoxicity (transaminase elevation > 1,000 IU/L), and 6 subjects had transaminase elevation of 100 to 1,000 IU/L. Acetaminophen-protein adducts were detected in the serum of only 1 study subject, a patient with marked transaminase elevation (> 6,000 IU/L) and high risk for the development of hepatotoxicity according to the Rumack nomogram. While this study provides further support for the occurrence of covalent binding of acetaminophen to hepatic protein in humans following acetaminophen overdose, the detection of acetaminophen-protein adducts in serum with the current methodology requires significant biochemical evidence of hepatocellular injury.

Evaluation of occult acetaminophen hepatotoxicity in hospitalized children receiving acetaminophen. Pediatric Pharmacology Research Unit Network.

The safety of repeated doses of acetaminophen in ill children with the potential of reduced glutathione stores has been questioned. This study measured hepatic transaminases in children and adolescents (n=100) who received > or = 6 therapeutic doses of acetaminophen over a 48-hour period of hospitalization. Acetaminophen-protein adducts were measured in a cohort of subjects with hepatic transaminase elevation (n=8) and in those (n=10) receiving concurrent drug therapy with agents that induce the cytochrome P450 enzymes involved in acetaminophen metabolism. Acetaminophen-protein adducts were not detected in this cohort of 18 subjects. Based on this pilot study, the routine use of acetaminophen at therapeutic doses in ill, hospitalized children and adolescents appears safe.

The Myc/Max/Mad network and the transcriptional control of cell behavior.

The Myc/Max/Mad network comprises a group of transcription factors whose distinct interactions result in gene-specific transcriptional activation or repression. A great deal of research indicates that the functions of the network play roles in cell proliferation, differentiation, and death. In this review we focus on the Myc and Mad protein families and attempt to relate their biological functions to their transcriptional activities and gene targets. Both Myc and Mad, as well as the more recently described Mnt and Mga proteins, form heterodimers with Max, permitting binding to specific DNA sequences. These DNA-bound heterodimers recruit coactivator or corepressor complexes that generate alterations in chromatin structure, which in turn modulate transcription. Initial identification of target genes suggests that the network regulates genes involved in the cell cycle, growth, life span, and morphology. Because Myc and Mad proteins are expressed in response to diverse signaling pathways, the network can be viewed as a functional module which acts to convert environmental signals into specific gene-regulatory programs.

Single dose pharmacokinetics of pleconaril in neonates. Pediatric Pharmacology Research Unit Network.

BACKGROUND: Pleconaril is an orally active, broad spectrum antipicornaviral agent with activity against nonpolio enteroviruses. Pleconaril phamacokinetics was evaluated in 16 neonates (16.4 +/- 8.7 days postnatal age) with suspected enteroviral infection. METHODS: Pleconaril (5 or 7.5 mg/kg) was administered orally to study subjects and plasma pleconaril concentrations quantified from serial blood samples obtained during 24 h after a single oral dose by gas chromatography with electrochemical detection. Pharmacokinetic parameter estimates were determined by noncompartmental methods and compared between doses and with similar data obtained from a previous study of pleconaril disposition in children (n = 18, 2 to 12 years). RESULTS: Pleconaril was well-tolerated in all neonates without discernible adverse events. Comparison between the 5.0- and 7.5-mg/kg doses revealed no significant differences in peak plasma concentration (Cmax 686.7 vs. 617.1 ng/ml), elimination half-life (t 1/2; 4.6 vs. 6.6 h), area under the plasma concentration vs. time curve (AUC; 5162.6 vs. 5523.9 ng/ml/h), apparent steady state volume of distribution (V(dss)/F; 9.3 vs. 17.1 liters/ kg) and apparent oral clearance (Cl/F; 1.3 vs. 1.7 liters/h/kg). In addition, no correlation was observed between postconceptional age and AUC, V(dss)/F, t 1/2 or Cl/F for pleconaril. Comparison of pleconaril pharmacokinetics between neonates and children suggested a significant difference in V(dss)/F (9.3 vs. 4.7 liters/kg), dose-normalized Cmax, (686.7 vs. 1272.5 ng(ml) and AUC (5125.6 vs. 8131.2 ng/ml/h). In contrast, the mean elimination t 1/2 between neonates and children was not appreciably different. CONCLUSIONS: The apparent age-dependent differences in the pharmacokinetics of pleconaril may in part be related to increased bioavailability of the drug in older children and adults than in neonates. Our data appear to support the use of a 5.0-mg/kg dose given every 8 to 12 h in future studies of pleconaril in neonatal patients with enteroviral infection.

Acute mental status changes and hyperchloremic metabolic acidosis with long-term topiramate therapy.

Mental status changes and metabolic acidosis may occur with topiramate therapy. These adverse events were reported during dosage titration and with high dosages of the drug. A 20-year-old man receiving topiramate, valproic acid, and phenytoin experienced acute-onset mental status changes with hyperchloremic metabolic acidosis. He had been receiving a modest dose of topiramate for 9 months. He was weaned off topiramate over 5 days, and his mental status returned to baseline within 48 hours of discontinuing the agent. This case illustrates the need for close evaluation of patients who experience acute-onset mental status changes during topiramate therapy.

Single dose pharmacokinetics of linezolid in infants and children.

BACKGROUND: Linezolid is an oxazolidinone antibiotic with excellent in vitro activity against a number of Gram-positive organisms including antibiotic-resistant isolates. The safety and pharmacokinetics of intravenously administered linezolid were evaluated in children and adolescents to examine the potential for developmental dependence on its disposition characteristics. METHODS: Fifty-eight children (3 months to 16 years old) participated in this study; 44 received a single 1.5-mg/kg dose and 14 received a single 10-mg/kg dose of linezolid administered by intravenous infusion. Repeated blood samples (n = 10 in children > or = 12 months; n = 8 in children 3 to 12 months) were obtained during 24 h after drug administration, and linezolid was quantitated from plasma by high performance liquid chromatography with mass spectrometry detection. Plasma concentration vs. time data were evaluated with a model independent approach. RESULTS: Linezolid was well-tolerated by all subjects. The disposition of linezolid appears to be age-dependent. A significant although weak correlation between age and total body clearance was observed. The mean (+/- SD) values for elimination half-life, total clearance and apparent volume of distribution were 3.0 +/- 1.1 h, 0.34 +/- 0.15 liter/h/kg and 0.73 +/- 0.18 liter/kg, respectively. Estimates of total body clearance and volume of distribution were significantly greater in children than historical values of adult data. As such maximum achievable linezolid plasma concentrations were slightly lower in children, and concentrations 12 h after a single 10-mg/kg dose were below the MIC90 for selected pathogens with in vitro susceptibility to the drug. CONCLUSION: Based on these data a linezolid dose of 10 mg/kg given two to three times daily would appear appropriate for use in pediatric therapeutic clinical trials of this agent.