Accidental intoxications in toddlers: lack of cross-reactivity of vilazodone and its urinary metabolite M17 with drug of abuse screening immunoassays

Context. A pilot study of tricyclic antidepressant (TCA)-specific antibody fragments (TCA Fab) in TCA-intoxicated adults showed a marked increase in serum total TCA concentrations following TCA Fab infusion with no worsening signs of TCA toxicity. TCA Fab pharmacokinetics (PK) was not described in this adult study. The objective of this study was to evaluate the PK of TCA Fab in children with TCA poisoning. Methods. This was an open-label, single-center, dose escalation pilot trial of three patients. Inclusion criteria were documented TCA ingestion with at least one serious complication (QRS prolongation, dysrhythmia, hypotension, seizure, or coma). Patients were assigned to either a low-dose intravenous TCA Fab regimen (15, 30, and 60 mg/kg) or a high-dose regimen (30, 60, and 120 mg/kg) as needed to reverse TCA toxicity. Following the administration of TCA Fab, samples of blood and urine were obtained for PK evaluations. The outcomes of interest were serum and urine TCA concentrations (free and total), serum and urine Fab concentrations, improvement or worsening of TCA toxicity, and adverse effects. Results. Three study patients were 11, 11, and 14 years of age. Two patients received 15 mg/kg of TCA Fab and one patient received a total of 90 mg/kg of TCA Fab (30 + 60 mg/kg). Serum-bound TCA increased significantly following TCA Fab administration with concomitant enhanced urinary elimination. Serum-free TCA concentrations were minimal to undetectable. Fab data were available for two patients. The serum TCA Fab area under the curve was 306.12 mg/L/h for the 15 mg/kg dose and 2,198.10 mg/L/h for the 90 mg/kg dose of TCA Fab. Maximum Fab concentrations correlated with maximum bound TCA in serum. The volume of distribution (VD) of TCA Fab was 0.2–0.3 L/kg. The clearance was 0.036–0.05 L/kg/h and the elimination half-life was 4 h. No adverse effects were observed. Conclusion. The limited PK data from this study are consistent with binding of TCA to TCA Fab and redistribution of TCA from the tissue to serum with subsequent enhanced urinary excretion of TCA. No toxic effects were observed with increased total TCA concentrations and no adverse effects were observed following TCA Fab administration. The small number of patients in this pilot study does not allow for safety or efficacy conclusions.

Background. Animal studies suggest that tricyclic antidepressant antibody fragments (TCA Fab) may be a useful therapy for tricyclic antidepressant poisoning. The objective of this study is to determine if TCA Fab increases total serum TCA levels without raising free serum TCA levels in human overdose patients, indicating that TCA Fab effectively binds TCA. Methods. This was a prospective, dose escalation study of patients with mild to moderate TCA poisoning. Patients were treated with an escalating intravenous infusion totaling 7 or 14 gm of TCA Fab. The outcomes of interest were serum TCA levels (total and free), worsening of TCA toxicity, and adverse effects. Results. Seven patients were treated with Fab. Infusion of TCA Fab was associated with a dramatic increase in total serum TCA levels, while free TCA levels fell in both dosing groups. There were no significant changes in QRS duration, heart rate or mean arterial pressure associated with the Fab Infusion. Worsening of TCA toxicity did not occur despite marked elevation of total serum TCA concentrations. The two patients with the greatest prolongation of QRS showed a prompt shortening in their QRS duration temporally associated with the Fab infusion. Mild wheezing was observed in one asthmatic patient. Conclusions. 1) TCA Fab raises total serum TCA levels while lowering free levels in TCA poisoned patients; 2) no toxic effects were associated with the increase in TCA levels and no severe adverse effects were observed during the hospital course following Fab infusion.

Analysis of benzodiazepines and tricyclic antidepressants in serum using a common solid-phase clean-up and a common mobile phase

We describe a rapid, sensitive procedure for detecting benzodiazepines and tricyclic antidepressants in serum. After the compounds are adsorbed on charcoal and eluted with an organic solvent mixture, the drugs are thin-layer chromatographed and detected by their fluorescence. Because it is so fast and easy (turn-around time of about 1 h), the method can be used for emergency toxicology screening. An analysis requires 1.0 mL of serum, and the limit of detection for each of the drugs is about 0.75 mg/L. The procedure is sensitive enough to allow the use of serum instead of urine for the detection of these drugs, because serum has certain advantages over urine as the sample and better reflects the state of the patient's toxicity.

Objectives Substance use during pregnancy is a significant public health issue. Prenatal substance use increased in the past decade while prenatal cigarette smoking has remained stable. Co-use of tobacco and other drugs is a concern because of potential additive risks. This study aims to describe the prevalence rates of substance use among pregnant women and examine the association between smoking status (nonsmoker, recent quitter and current smoker) and other drug use. Methods In this cross-sectional study, pregnant women (n = 500) were recruited from two obstetric practices to complete three substance use screeners and have their urine tested for 12 different drug classes, including cannabis, opioids and cocaine. Participants were divided into three groups based on survey responses: nonsmokers, recent quitters (smoked in the month prior to pregnancy but not past month) and current smokers (past-month). Results Approximately 29% of participants reported smoking in the month before pregnancy. During pregnancy, 17, 12 and 71% were current smokers, recent quitters and nonsmokers respectively. Overall prevalence of illicit or prescription drug use in pregnancy was 27%. Cannabis was the most common drug used in pregnancy with prevalence of 22%, followed by opioids (4%), cocaine (1%), tricyclic antidepressants (TCAs) (1%), amphetamines (1%), and benzodiazepines (1%). On multivariable logistic regression, smoking in pregnancy was associated with a positive urine drug screen; with adjusted odds ratio (aOR) 4.7 (95% CI 2.6-8.3) for current smokers and 1.6 (95% CI 0.8-3.3) for recent quitters. Factors negatively associated with positive drug screen were second and third trimester pregnancies, 0.5 (0.3-0.9) and 0.3 (0.2-0.6) respectively; and employment, 0.5 (0.3-0.8). Conclusions for Practice Co-use of tobacco and illicit drugs, particularly cannabis, is relatively high during pregnancy. Additional research is needed to understand the health implications of co-use versus use of tobacco only. Given the strong association between smoking and other drug use, clinicians should routinely assess for illicit drug use in women who smoke during pregnancy.

An analytical procedure has been developed for the simultaneous separation and quantitation of amitriptyline (AMI), imipramine (IMI), doxepin (DOX), trimipramine (TRI), desipramine (DES), nortriptyline (NOR), desmethyldoxepin (DMD), and protriptyline (PRO) in serum using N-propionylprocainamide (NPPA) as an internal standard. Serum samples were extracted using Bond Elute C-18 columns. A 5-mu Supelcosil LC-PCN column separated the analytes, using a mobile phase consisting of 10 mmol/L sodium phosphate (pH 7.0):acetonitrile:methanol (28:58:14) by volume at ambient temperature. Column effluents were monitored at 254 and 280 nm. Typical recoveries ranged from 81.8% to 94.0% at 50 ng/ml and from 92.0% to 102.6% at 200 ng/ml. Within-run variations were less than or equal to 10.1% at 50 ng/ml and less than or equal to 4.5% at 200 ng/ml, whereas day-to-day variations were less than or equal to 7.4% at 50 ng/ml and less than 4.8% at 200 ng/ml for n = 10. Calibration curves showed linearity over the concentration range of 25-1,000 ng/ml. Superior resolution (Rs greater than or equal to 1.0) was obtained with this column, which completely separated the eight tricyclic antidepressants (TCAs) and the internal standard in 16 min. Sensitivity limit is 25 ng/ml for all TCAs studied. Phenothiazine tranquilizers interfere with the quantitation of TCAs.

We sought a method for routine therapeutic monitoring of serum tricyclic antidepressants (TCAs) which offered good reproducibility, detection limits, linearity, and specificity, and which was simple, rapid, and inexpensive to perform. The method described utilizes Clin-Elut columns (Analytichem International, Inc., Lawndale, CA 90206) to facilitate the extraction. The analysis is by high pressure liquid chromatography (HPLC) with a CN bonded phase column, a mobile phase of acetonitrile/pH 7.0 phosphate/methanol and detection at 210 nm. This chromatographic system gives short equilibration times, stable calibration curves, high sensitivity and resolution, short retention times, and long column life. The method is useful for determination of amitriptyline, doxepin, imipramine, nortriptyline, nordoxepin, desipramine, and protriptyline. Trimipramine is used as an internal standard for the tertiary amines and protriptyline for the secondary amines. Recovery is linear from 25 ato 1,000 ng/ml. Rubber stoppers of a new formulation in Vacutainer blood collection tubes (Becton-Dickinson, Rutherford, NJ 07070) do not affect serum TCA levels. Sera from 53 psychiatric patients suffering from endogenous depression were analyzed using the procedure presented. The mean serum level of four patients on amitriptyline therapy having complete remission was 201 ng/ml (range, 123-259). The mean serum level of four patients on imipramine therapy rated as having complete remission was 200 ng/ml (range, 145-258). These values compare well with recently published therapeutic ranges.

Tricyclic antidepressants (TCA) are used to treat major depressive disorder and other psychological conditions. The efficacy of these drugs is tied to a narrow therapeutic window. Inappropriately high drug concentrations can result in serious side effects such as hypotension, tachycardia, or coma. As a result, concentrations of tricyclic antidepressants are routinely monitored to ensure compliance and to prevent adverse side effects by dose adjustments. We describe a method for the determination of concentrations of amitriptyline, desipramine, imipramine, and nortriptyline in human serum using high-performance liquid chromatography coupled to a tandem mass spectrometer with electrospray ionization (HPLC-ESI-MS/MS). The method is rapid, requiring only 3.5 min per analysis. The method requires 100 μL of serum. Concentrations of each TCA were quantified by a calibration curve relating the peak area ratio of each TCA analyte to a deuterated internal standard (amitriptyline-D3, desipramine-D3, imipramine-D3, and nortriptyline-D3). The method was linear from ~70 ng/mL to ~1000 ng/mL for all TCAs, with imprecision ≤ 12%.

Depression is a psychiatric condition that affects about 120 million people worldwide and can interfere with independence and productivity in essentially all aspects of daily life. Depression is also associated with risk of self-harm, and ultimately suicide. Antidepressant medications are widely used to treat symptoms of depression. While there are several classes of antidepressants, therapeutic drug management (TDM) is most common for the tricyclic antidepressants (TCAs). TDM of TCAs is important due to wide inter-individual variability in pharmacokinetics, production of active metabolites, and a high risk of drug-drug interactions. In addition, TDM of some TCAs can be used to optimize dose, wherein concentration relationships are recognized for both therapeutic response and potentially life-threatening toxicity. In many clinical scenarios, TDM of TCAs is accomplished by currently available point of care or automated immunoassays that provide a "total" TCA concentration. However, these assays may not be adequately specific to meet the needs of all clinical scenarios, and hence, chromatographic separation and quantification of individual TCA parent drugs and active metabolites that may contribute to the "total" TCA concentration is sometimes required. This chapter describes an analytical method designed to detect and/or quantify clinically significant concentrations of nine TCAs (amitriptyline, nortriptyline, imipramine, desipramine, doxepin, nordoxepin, protriptyline, clomipramine, and norclomipramine) in serum or plasma, using ultra pressure liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). The sample preparation employs a rapid protein precipitation with 50:50 MeOH:acetonitrile, high speed centrifugation, and injection of 5 μL of supernatant onto the instrument, with a 5 min run-time.

BackgroundAdverse childhood experiences (ACEs) and substance use disorder (SUD) are well-known risk factors for psychosis and dramatically affect schizophrenia. In this research, we aimed to measure the prevalence of adverse childhood experiences and substance use disorder in patients with schizophrenia and assess the effect of ACEs on the clinical presentation and overall functioning and the association between them and SUD in patients with schizophrenia. A cross-sectional study included a random sample of 165 schizophrenic patients who were examined by doing drug screen in urine, structured questionnaire to collect Socioeconomic characteristics, history of schizophrenia, structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders-fifth edition, Positive and Negative Syndrome Scale (PANSS), Adverse Childhood Experiences International Questionnaire (ACE-IQ), World Health Organization Disability Assessment Schedule 2.0, compliance rating scale, addiction severity index fifth edition (ASI) for individuals with positive urine drug screen.ResultsOnly 14.4% of the studied patients had no adverse childhood experiences. The prevalence of positive substance abuse screening was 18.2%. There were statistically significant negative correlations between total ACE score and educational level, socioeconomic level, and the onset of schizophrenia. On the other hand, statistically significant positive correlations were found between the total ACE score and PANSS score and ASI score. The first most frequent ACE was significantly associated with female gender, lower education levels, low and middle socioeconomic classes, lifetime substance use, smokers, and positive drug screening. Emotional neglect and contact sexual abuse were significantly associated with positive drug screening. At the same time, Physical abuse was significantly associated with both lifetime substance use and positive drug screening.ConclusionThe current study’s findings indicate that childhood adverse experiences and substance abuse are prevalent problems in patients with schizophrenia. Given that there is an association between both issues, they may affect the symptomatology of the disorder, the prognosis, and the therapeutic plan. It is advised that a greater emphasis on and identification of childhood trauma and drug use disorder may be a necessary step in assessing patients with schizophrenia.

Abnormal blood lactate and base deficit (BD) reflect hypoperfusion and have been documented to predict outcome in trauma. Alcohol and drug use may also induce metabolic acidosis in trauma victims, potentially diminishing the predictive accuracy of lactate and BD. We, therefore, sought to examine the effect of alcohol and drug use on the predictive accuracy of admission blood lactate and BD in trauma. Prospective data were collected on 15,179 patients admitted to the R Adams Cowley Shock Trauma Center over a 3-year period from 1998 to 2000. Patients were stratified by age, gender, race, injury severity score (ISS), Glasgow coma score (GCS), alcohol concentration and illicit drug use. Multiple regression analyses were used to assess admission blood lactate and BD as independent risk factors for mortality, intensive care unit (ICU) admission, and ICU and hospital length of stay (LOS) controlling for alcohol and drug use [cocaine, phencyclidine and methamphetamines] by measured serum concentrations. The mean age of the study cohort was 37 +/- 19 years, mean ISS was 9 +/- 10, mean GCS 14.1 +/- 2.7, 71% were male and 77% sustained blunt trauma. Alcohol testing was completed in 13,102 of 15,179 (86.3%) of patients. Alcohol screen was positive in 27% (n = 3536) of the total cohort tested (n = 13,102) with a mean blood alcohol concentration of 141 +/- 95 mg/dL; 7% (n = 992) had positive drug screens. Increasing injury severity was associated with significantly increased admission blood lactate and BD (p < 0.001). Patients with positive alcohol and drug screens had significantly increased admission blood lactate, BD and injury severity compared with patients with negative alcohol and drug screens (p < 0.01). Patients with positive alcohol and drug screens had a significant increase in admission to the ICU (p < 0.05), but no significant increase in mortality, ICU or hospital LOS compared with patients with negative screens. Multiple logistic and linear regression analyses confirmed admission lactate and BD as significant independent predictors of mortality, ICU and hospital LOS (p < 0.01). These results were unchanged after controlling for alcohol and drug use as covariates in the logistic and linear regression analyses. Alcohol and drug use are common in trauma, but do not impair the predictive accuracy of admission lactate and BD in trauma outcome. Admission lactate and BD are therefore confirmed as significant independent predictors of trauma outcome in patients with acute alcohol and drug use in this largest clinical study to date.

We report two separate sample-preparation procedures and a "high-pressure" liquid-chromatographic method for quantitating nine tricyclic antidepressant drugs: trimipramine, doxepin, amitriptyline, imipramine, desmethyldoxepin, nortriptyline, desipramine, maprotiline, and protriptyline. The drugs are extracted from 1 mL of serum by a single manual hexane extraction or by using DuPont's PREP I Automated Sample Processor. The drugs from either process are chromatographed on a mu-Bondapak-CN column with a mobile phase of acetonitrile/methanol/Na2HPO4, 5 mmol/L (60/15/25 by vol), pH 7.0, at a flow rate of 2.0 mL/min. Absorbance at 254 nm is linear with drug concentration from 25 to 1000 mg/L for each drug. With the manual extraction procedure the detection limit was 10 mg/L, absolute recovery 20-44%, within-run precision (CV) 10.1%, and run-to-run precision 11.1%. The performance of automated sample extraction was better, with a detection limit of 5 mg/l, absolute recovery 72-97%, within-run precision 6.1%, and run-to-run precision 6.6%.

A fast and easy solid-phase extraction method was developed for the determination of amitriptyline, doxepin and their metabolites (nortriptyline and nordoxepin) in porcine serum matrix by high performance liquid chromatography. The spiked serum sample was pretreated with 2% phosphoric acid followed by a simple and rugged SPE procedure using OasisTM HLB extraction cartridges. The SPE method requires only one mL of simple solvent throughout the entire SPE process. High and reproducible recoveries were obtained even though the cartridges ran dry. For five replicate analyses, the average recoveries of parent tricyclic antidepressants and their metabolites were all greater than 94%, and the RSDs were all less than 4.0%.

Rapid isothermal gas—liquid chromatographic determination of tricyclic antidepressants in serum with use of a nitrogen-selective detector

Antidepressants in serum determined by isolation with two on-line sorbent cartridges and liquid chromatography