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

ABSTRACT: Background:Vilazodone is an FDA approved medication used to treat major depressive disorder. The authors describe two cases of accidental vilazodone exposure in toddlers who presented with symptoms similar to amphetamine exposure and also with unexplained positive amphetamine urine immunoassay drug screens. Given a lack of published data on cross-reactivity of vilazodone and its metabolites with drug of abuse screening tests, the authors investigated drug of abuse immunoassay cross-reactivity of vilazodone and metabolites using computational and empirical approaches. Methods:To ascertain the likelihood that vilazodone would cross-react with drug of abuse screening immunoassays, the authors assessed the two-dimensional (2D) similarity of the vilazodone parent molecule and known metabolites to an array of antigenic targets for urine immunoassay drug screens. To facilitate studies of the commercially unavailable M17 metabolite, it was prepared synthetically through a novel scheme. Urine and serum were spiked with vilazodone and M17 into urine (200-100,000 ng/mL) and serum (20-2000 ng/mL) samples and tested for cross-reactivity. Results:Computational analysis using 2D similarity showed that vilazodone and metabolites have generally low similarity to antigenic targets of common drug of abuse screening immunoassays, predicting weak or no cross-reactivity. The M17 metabolite had 2D similarity to amphetamines and tricyclic antidepressants in a range similar to some other compounds exhibiting weak cross-reactivity on these immunoassays. Cross-reactivity testing was therefore performed on two different urine amphetamines immunoassays and a serum tricyclic antidepressant immunoassay. However, actual testing of cross reactivity for vilazodone and the M17 metabolite did not detect cross-reactivity for any urine amphetamines screen at concentrations up to 100,000 ng/mL and for a serum tricyclic antidepressants assays at concentrations up to 2000 ng/mL. Conclusion:While the vilazodone metabolite M17 has weak 2D structural similarity to amphetamines and tricyclic antidepressants, the current study did not demonstrate any experimental cross-reactivity with two different urine amphetamines immunoassays and a serum tricyclic antidepressant immunoassay. Vilazodone ingestions in young children present a diagnostic challenge in their similarity to amphetamine ingestions and the lack of routine laboratory tests for vilazodone. Further work is needed to understand the metabolic profile for vilazodone in children versus adults.

SUBMITTER: Martinez-Brokaw CD

PROVIDER: S-EPMC6379996 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundImmunoassays are widely used in clinical laboratories for measurement of plasma/serum concentrations of steroid hormones such as cortisol and testosterone. Immunoassays can be performed on a variety of standard clinical chemistry analyzers, thus allowing even small clinical laboratories to do analysis on-site. One limitation of steroid hormone immunoassays is interference caused by compounds with structural similarity to the target steroid of the assay. Interfering molecules include structurally related endogenous compounds and their metabolites as well as drugs such as anabolic steroids and synthetic glucocorticoids.MethodsCross-reactivity of a structurally diverse set of compounds were determined for the Roche Diagnostics Elecsys assays for cortisol, dehydroepiandrosterone (DHEA) sulfate, estradiol, progesterone, and testosterone. These data were compared and contrasted to package insert data and published cross-reactivity studies for other marketed steroid hormone immunoassays. Cross-reactivity was computationally predicted using the technique of two-dimensional molecular similarity.ResultsThe Roche Elecsys Cortisol and Testosterone II assays showed a wider range of cross-reactivity than the DHEA sulfate, Estradiol II, and Progesterone II assays. 6-Methylprednisolone and prednisolone showed high cross-reactivity for the cortisol assay, with high likelihood of clinically significant effect for patients administered these drugs. In addition, 21-deoxycortisol likely produces clinically relevant cross-reactivity for cortisol in patients with 21-hydroxylase deficiency, while 11-deoxycortisol may produce clinically relevant cross-reactivity in 11β-hydroxylase deficiency or following metyrapone challenge. Several anabolic steroids may produce clinically significant false positives on the testosterone assay, although interpretation is limited by sparse pharmacokinetic data for some of these drugs. Norethindrone therapy may impact immunoassay measurement of testosterone in women. Using two-dimensional similarity calculations, all compounds with high cross-reactivity also showed a high degree of similarity to the target molecule of the immunoassay.ConclusionsCompounds producing cross-reactivity in steroid hormone immunoassays generally have a high degree of structural similarity to the target hormone. Clinically significant interactions can occur with structurally similar drugs (e.g., prednisolone and cortisol immunoassays; methyltestosterone and testosterone immunoassays) or with endogenous compounds such as 21-deoxycortisol that can accumulate to very high concentrations in certain disease conditions. Simple similarity calculations can help triage compounds for future testing of assay cross-reactivity.

Project description:BACKGROUND:Guidelines recommend endotracheal intubation in trauma patients with a Glasgow coma scale (GCS) < 9 because of the loss of airway reflexes and consequential risk of airway obstruction. However, in patients with acute alcohol intoxication guidelines are not clear. Thus, we aimed to determine the proportional incidence of intubation in alcohol intoxication and compare the clinical characteristics of intubated and non-intubated patients, as well as reasons for intubation in all patients and in the subgroup of patients with reduced GCS (< 9) but without traumatic brain injury. METHODS:We performed a retrospective analysis of all consultations to an urban ED in Switzerland that presented with an acute alcohol intoxication between 1st June 2012 and 31th Mai 2017. Patient and emergency consultations' characteristics, related injuries, intubation and reason for intubations were extracted. As a subgroup analysis, we analysed the patients with a GCS < 9 without a traumatic brain injury. RESULTS:Of 3003 consultations included from 01.06.2012 to 31.05.2017, 68 were intubated, leading to a proportional incidence of 2.3% intubations in alcohol-intoxication. Intubated patients had a lower blood alcohol concentration (1.3 g/kg [IQR 1.0-2.2] vs. 1.6 g/kg [IQR1.1-2.2], p = 0.034) and less often suffered from chronic alcohol abuse (1183 [39.4%] patients vs. 14 [20.6%], p = 0.001) than non-intubated patients. Patients with trauma were intubated more often (33 patients [48.5%] vs. 742 [25.3%], p < 0.001). In subgroup analysis, 110/145 patients (74.3%) were not intubated; again, more intubated patients had a history of trauma (9 patients [25.7%] vs. 10 [9.1%], p = 0.011). CONCLUSIONS:Intubation in alcohol-intoxicated patients is rare and, among intoxicated patients with GCS < 9, more than two thirds were not intubated in our study - without severe complications. Trauma in general, independent of the history of a traumatic brain injury, and a missing history of chronic alcohol abuse are associated with intubation, but not with blood alcohol concentration. Special caution is required for intoxicated patients with trauma or other additional intoxications or diseases.

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

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