Janine R. Hutson

Colchicine poisoning: the dark side of an ancient drug

Introduction. Colchicine is used mainly for the treatment and prevention of gout and for familial Mediterranean fever (FMF). It has a narrow therapeutic index, with no clear-cut distinction between nontoxic, toxic, and lethal doses, causing substantial confusion among clinicians. Although colchicine poisoning is sometimes intentional, unintentional toxicity is common and often associated with a poor outcome. Methods. We performed a systematic review by searching OVID MEDLINE between 1966 and January 2010. The search strategy included “colchicine” and “poisoning” or “overdose” or “toxicity” or “intoxication.” Toxicokinetics. Colchicine is readily absorbed after oral administration, but undergoes extensive first-pass metabolism. It is widely distributed and binds to intracellular elements. Colchicine is primarily metabolized by the liver, undergoes significant enterohepatic re-circulation, and is also excreted by the kidneys. Therapeutic and toxic doses. The usual adult oral doses for FMF is 1.2–2.4 mg/day; in acute gout 1.2 mg/day and for gout prophylaxis 0.5–0.6 mg/day three to four times a week. High fatality rate was reported after acute ingestions exceeding 0.5 mg/kg. The lowest reported lethal doses of oral colchicine are 7–26 mg. Drug interactions. CYP 3A4 and P-glycoprotein inhibitors, such as clarithromycin, erythromycin, ketoconazole, ciclosporin, and natural grapefruit juice can increase colchicine concentrations. Co-administration with statins may increase the risk of myopathy. Mechanisms of toxicity. Colchicines toxicity is an extension of its mechanism of action – binding to tubulin and disrupting the microtubular network. As a result, affected cells experience impaired protein assembly, decreased endocytosis and exocytosis, altered cell morphology, decreased cellular motility, arrest of mitosis, and interrupted cardiac myocyte conduction and contractility. The culmination of these mechanisms leads to multi-organ dysfunction and failure. Reproductive toxicology and lactation. Colchicine was not shown to adversely affect reproductive potential in males or females. It crosses the placenta but there is no evidence of fetal toxicity. Colchicine is excreted into breast milk and considered compatible with lactation. Clinical features. Colchicine poisoning presents in three sequential and usually overlapping phases: 1) 10–24 h after ingestion – gastrointestinal phase mimicking gastroenteritis may be absent after intravenous administration; 2) 24 h to 7 days after ingestion – multi-organ dysfunction. Death results from rapidly progressive multi-organ failure and sepsis. Delayed presentation, pre-existing renal or liver impairment are associated with poor prognosis. 3) Recovery typically occurs within a few weeks of ingestion, and is generally a complete recovery barring complications of the acute illness. Diagnosis. History of ingestion of tablets, parenteral administration, or consumption of colchicine-containing plants suggest the diagnosis. Colchicine poisoning should be suspected in patients with access to the drug and the typical toxidrome (gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia). Management. Timely gastrointestinal decontamination should be considered with activated charcoal, and very large, recent (<60 min) ingestions may warrant gastric lavage. Supportive treatments including administration of granulocyte colony-stimulating factor are the mainstay of treatment. Although a specific experimental treatment (Fab fragment antibodies) for colchicine poisoning has been used, it is not commercially available. Conclusion. Although colchicine poisoning is relatively uncommon, it is imperative to recognize its features as it is associated with a high mortality rate when missed.

The human placental perfusion model: a systematic review and development of a model to predict in vivo transfer of therapeutic drugs.

Dual perfusion of a single placental lobule is the only experimental model to study human placental transfer of substances in organized placental tissue. To date, there has not been any attempt at a systematic evaluation of this model. The aim of this study was to systematically evaluate the perfusion model in predicting placental drug transfer and to develop a pharmacokinetic model to account for nonplacental pharmacokinetic parameters in the perfusion results. In general, the fetal‐to‐maternal drug concentration ratios matched well between placental perfusion experiments and in vivo samples taken at the time of delivery of the infant. After modeling for differences in maternal and fetal/neonatal protein binding and blood pH, the perfusion results were able to accurately predict in vivo transfer at steady state (R2 = 0.85, P < 0.0001). Placental perfusion experiments can be used to predict placental drug transfer when adjusting for extra parameters and can be useful for assessing drug therapy risks and benefits in pregnancy.

Novel Methods for the Detection of Drug and Alcohol Exposure During Pregnancy: Implications for Maternal and Child Health

Despite extensive evidence of fetal and neonatal risk, a large number of pregnant women are involved in excessive alcohol and drug abuse, such as with cocaine, methamphetamine, opioids, and cannabinoids.

Breast cancer resistance protein (BCRP)-mediated glyburide transport: effect of the C421A/Q141K BCRP single-nucleotide polymorphism.

The antidiabetic agent glyburide (glibenclamide) is frequently used for the treatment of type II diabetes and is increasingly being used for the treatment of gestational diabetes. Evidence suggests that breast cancer resistance protein/ATP-binding cassette, subfamily G, member 2 (ABCG2) expressed in the placenta protects the fetus against the accumulation of glyburide. A number of studies have investigated the significance of several single-nucleotide polymorphisms (SNPs) in the ABCG2 gene. Associations between the Q141K (C421A) SNP and ABCG2 protein expression, membrane surface translocation, efflux activity, or ATPase activity have been shown. Therefore, alterations in glyburide transport across the placenta, resulting in increased fetal glyburide exposure, may be seen in individuals carrying the C421A allele. The purpose of this study is to investigate whether the Q141K SNP causes alterations in ABCG2-mediated glyburide transport. Glyburide accumulation assays were carried out with stably transfected human embryonic kidney (HEK)-293 cells expressing wild-type ABCG2 (Arg482) and polymorphic ABCG2 (Q141K). Glyburide kinetic parameters were determined for comparison of wild-type and SNP ABCG2 activity by simultaneously fitting data for ABCG2-expressing cells (saturable transport) and empty vector-expressing cells (nonsaturable transport) by nonlinear regression analysis. The apparent Kt and Vmax values for the transfected HEK-293 cells expressing the polymorphic variant (Q141K) of ABCG2 were significantly higher than those values determined for the wild-type ABCG2-expressing cells (p < 0.05). Our results indicate that the Q141K variant of ABCG2 may have the potential to alter the placental pharmacokinetics of glyburide used in pregnancy.

Risk of suicide following deliberate self-poisoning

IMPORTANCE Suicide is the tenth leading cause of death in the United States, and its rate has risen by 16% in the past decade. Deliberate self-poisoning is the leading method of attempted suicide. Unlike more violent methods, which are almost universally fatal, survival following self-poisoning is common, providing an opportunity for secondary prevention. However, the long-term risk of suicide following a first episode of self-poisoning is unknown. OBJECTIVE To determine the risk of suicide and mortality from other causes following a first self-poisoning episode. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study using multiple linked health care databases. We identified all individuals with a first self-poisoning episode in Ontario, Canada, from April 1, 2002, through December 31, 2010, and followed up all surviving participants until December 31, 2011, or death, whichever occurred first. For each individual with a deliberate self-poisoning episode, we randomly selected 1 control from the same population with no such history, matched for age (within 3 months), sex, and calendar year. MAIN OUTCOMES AND MEASURES The primary analysis examined the risk of suicide following discharge after self-poisoning. The secondary analyses explored factors associated with suicide and examined the risk of death caused by accidents or any other cause. RESULTS We identified 65 784 patients (18 482 [28.1%] younger than 20 years) who were discharged after a first self-poisoning episode. During a median follow-up of 5.3 years (interquartile range, 3.1-7.6 years), 4176 died, including 976 (23.4%) by suicide. The risk of suicide following self-poisoning was markedly increased relative to controls (hazard ratio, 41.96; 95% CI, 27.75-63.44), corresponding to a suicide rate of 278 vs 7 per 100 000 person-years, respectively. The median time from hospital discharge to completed suicide was 585 days (interquartile range, 147-1301 days). Older age, male sex, multiple intervening self-poisoning episodes, higher socioeconomic status, depression, and recent psychiatric care were strongly associated with suicide. Patients with a self-poisoning episode were also more likely to die because of accidents (hazard ratio, 10.45; 95% CI, 8.10-13.47) and all causes combined (hazard ratio, 5.55; 95% CI, 5.12-6.02). CONCLUSIONS AND RELEVANCE A first self-poisoning episode is a strong predictor of subsequent suicide and premature death. Most suicides occur long after the index poisoning, emphasizing the importance of longitudinal, sustained secondary prevention initiatives.

Methadone: a review of drug-drug and pathophysiological interactions

Numerous established and potential drug interactions with methadone are clinically important in people treated with methadone either for addiction or for chronic pain. Methadone users often have comorbidities and are prescribed drugs that may interact with methadone. Methadone is extensively metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP 1A2, 2D6, 2D8, 2C9/2C8, 2C19, and 2B6. Eighty-six percent of methadone is protein bound, predominately to α1 -acid glycoprotein (AGP). Polymorphisms in or interactions with CYPs that metabolize methadone, changes in protein binding, and other pathophysiological conditions affect the pharmacokinetic properties of methadone. It is critical for health care providers who treat patients on methadone to have adequate information on the interactions of methadone with other drugs of abuse and other medications. We set out to describe drug-drug interactions as well as physiological and pathophysiological factors that may impact the pharmacokinetics of methadone. Using MEDLINE, we conducted a systematic search for papers and related abstracts published between 1966 and June 2010. Keywords that included methadone, drug-drug interactions, CYP P450 and AGP identified a total of 7709 papers. Other databases, including the Cochrane Database of Systematic Reviews and Scopus, were also searched; an additional 929 papers were found. Final selection of 286 publications was based on the relevance of each paper to the topic. Over 50 such interactions were found. Interactions of methadone with other drugs can lead to increased or decreased methadone drug levels in patients and result in potential overdose or withdrawal, respectively. The former can contribute to methadone’s fatality. Prescribers of methadone and pharmacists should enquire about any new medications (including natural products and over-the-counter medications) periodically, and especially when an otherwise stable patient suddenly experiences drug craving, withdrawal or intoxication.

Folic Acid Transport to the Human Fetus Is Decreased in Pregnancies with Chronic Alcohol Exposure

Background During pregnancy, the demand for folic acid increases since the fetus requires this nutrient for its rapid growth and cell proliferation. The placenta concentrates folic acid into the fetal circulation; as a result the fetal levels are 2 to 4 times higher than the maternal level. Animal and in vitro studies have suggested that alcohol may impair transport of folic acid across the placenta by decreasing expression of transport proteins. We aim to determine if folate transfer to the fetus is altered in human pregnancies with chronic alcohol consumption. Methodology/Principal Findings Serum folate was measured in maternal blood and umbilical cord blood at the time of delivery in pregnancies with chronic and heavy alcohol exposure (n = 23) and in non-drinking controls (n = 24). In the alcohol-exposed pairs, the fetal∶maternal serum folate ratio was ≤1.0 in over half (n = 14), whereas all but one of the controls were >1.0. Mean folate in cord samples was lower in the alcohol-exposed group than in the controls (33.15±19.89 vs 45.91±20.73, p = 0.04). Conclusions/Significance Our results demonstrate that chronic and heavy alcohol use in pregnancy impairs folate transport to the fetus. Altered folate concentrations within the placenta and in the fetus may in part contribute to the deficits observed in the fetal alcohol spectrum disorders.

False-positive meconium test results for fatty acid ethyl esters secondary to delayed sample collection.

BACKGROUND Meconium analysis for fatty acid ethyl esters (FAEEs) is a validated method for identifying heavy prenatal ethanol (EtOH) exposure. This study investigated whether delayed sample collection can result in false-positive test results for FAEEs because of collection of samples potentially contaminated with postnatally produced stool. METHODS Serial excretions were prospectively collected from neonates born to nondrinking mothers to capture the transition from meconium to postnatal stool. These were analyzed for FAEEs using headspace-solid phase microextraction and gas chromatography-mass spectrometry. Experiments involving incubation of samples with glucose or EtOH were performed to explore a potential mechanism of FAEE elevation. RESULTS A total of 136 samples were collected from 30 neonates during their first few days of life (median of 4 samples/baby over a mean period of 68.5 hours postpartum). Although the first-collected meconium sample tested negative for FAEEs in all babies, later samples tested above the 2 nmol/g positive cutoff in 19 of 30 babies. Median time to appearance of FAEE-positive samples was 59.2 hours postpartum. In vitro experiments demonstrated that FAEE levels can be further increased in late samples (likely containing postnatal stool) after incubation with glucose, and that FAEEs are readily formed in meconium in the presence of EtOH. CONCLUSIONS Collection of samples excreted later in the postpartum period can lead to false-positive test results for FAEEs, which could be because of contamination with dietary components of postnatally produced stool and EtOH-producing microorganisms. Clinically, it is critical to collect the earliest possible excretion for determination of FAEEs to ensure that the FAEE content is representative of in utero EtOH exposure.

Detection and quantification of fatty acid ethyl esters in meconium by headspace-solid-phase microextraction and gas chromatography–mass spectrometry

Meconium fatty acid ethyl esters (FAEEs) are currently used as biomarkers to detect heavy prenatal alcohol exposure. We introduce a novel technique to quantify FAEEs in meconium using headspace-solid-phase microextraction (HS-SPME) coupled with gas chromatography-mass spectrometry (GC-MS). This method improves on previous approaches by decreasing sample preparation time, eliminating the need for organic solvents, and reducing the required sample size. Using 50mg of meconium, the detection limits of FAEEs ranged from 0.05 to 0.16 nmol/g and had good reproducibility making it ideal for routine analysis of clinical samples.

An improved method for rapidly quantifying fatty acid ethyl esters in meconium suitable for prenatal alcohol screening.

Fatty acid ethyl esters (FAEEs) are nonoxidative metabolites of ethanol, and elevated levels of FAEE in meconium are a useful biomarker for heavy prenatal alcohol exposure. FAEE in meconium has been recommended as useful and cost-effective for universal screening for prenatal alcohol exposure. To support an efficient universal screening program, an analytical method to detect and quantify FAEE in meconium needs to be accurate, inexpensive, and rapid. The purpose of this study was to develop an analytical method that would satisfy these criteria and to validate this method using established laboratory guidelines. A method was developed and validated to detect and quantify four FAEEs (ethyl palmitate, ethyl linoleate, ethyl oleate, and ethyl stearate) from 0.5 g of meconium using d(5)-ethyl esters as internal standards. The sample undergoes liquid-liquid extraction with heptane:acetone, the heptane layer is isolated and evaporated, and then, the resulting residue undergoes headspace solid-phase microextraction coupled with gas chromatography-mass spectrometry. The detection limits of the four FAEEs ranged from 0.020 to 0.042 nmol/g and are 6- to 25-fold lower than the individual FAEE threshold concentrations (0.5 nmol/g). This method also has good precision with the coefficient of variation ranging from 2.6 to 19.4% for concentrations of individual FAEE between 0.5 and 2.62 nmol/g meconium (n=4). Calculated concentrations of FAEE that underwent extraction from meconium were 100-101% of the expected concentration, demonstrating the accuracy of the method. The peak shape and retention time of each FAEE were unaffected by the presence of the matrix, and there is no carryover at clinically relevant concentrations. This method was also able to produce clean chromatograms from meconium samples that could not be quantified using a previous method because of high chromatographic background. This method provides an optimal approach to detecting and quantifying FAEE in meconium that could be used in a universal screening program for prenatal alcohol exposure.