Severe Clinical Toxicity Research Articles

Ten years outcomes after SABR in central and ultracentral primary lung tumors

PurposeSABR performed for central and ultracentral lung tumors is associated with increased toxicity but limited data is available on late toxicities. We studied toxicity in patients followed-up ≥ 2 years post-SABR at a single-institution. MethodsAll patients were treated using VMAT for a primary or recurrent central lung cancer between 2008–2015. 60 Gy was delivered in 8 or 12 fractions. Grade ≥ 3 clinical and radiological bronchial toxicity was scored. Multivariable Cox regression models were used to estimate hazard ratios. ResultsOf 127 eligible patients, 63% were treated with 8 fractions. Median tumor diameter was 4.4 cm (range 1.3–12.0). Median overall survival was 25.0 months (95% CI 16.5–33.5); 4% developed isolated local recurrences. The actuarial 5-year rate for severe clinical toxicity was 34.1% (95% CI 21.2–44.9). Both clinical toxicity and fatal lung haemorrhage were most observed when tumors were located ≤ 1 cm from the trachea or main bronchi (46% of all cases). The 5-year actuarial rate of radiological bronchial toxicity was 37.5% (95% CI 21.5–50.2). Multivariable analysis revealed that a performance score of 2 or 3 (HR 3.6; 95% CI 1.7–7.8), and tumor location ≤ 1 cm from the trachea or main bronchi (HR 4.3; 95% CI 1.2–14.9) were significant predictors for severe clinical toxicity. ConclusionThe actuarial rates for both severe clinical and radiological bronchial toxicity after central SABR was approximately 35% in patients surviving 5 years. Patients with tumors located ≤ 1 cm from the trachea or main bronchus were at the highest risk for severe clinical toxicity.

Abstract 2648: In vivo efficacy and preclinical safety profile of NN3201, an anti-cKIT antibody-drug conjugate, for treating SCLC and AML

Abstract Overexpression and activating mutations of cKIT are associated with tumor aggressiveness and poor prognosis in various cancer patients such as small cell lung cancer (SCLC), gastrointestinal stromal tumor (GIST), acute myeloid leukemia (AML), and mastocytoma. Since small molecule inhibitors including imatinib frequently have a limited therapeutic application due to eventual drug resistance and severe adverse events, we developed the cKIT-directed antibody-drug conjugate (ADC), NN3201, for the treatment of wild-type and mutant cKIT-positive cancers. NN3201 is an ADC conjugate of the antimitotic payload MMAE to the fully human 2G4 antibody, directed against cKIT, via the cysteine re-bridging technology ThioBridge® at a drug-to-antibody ratio (DAR) of 4. NN3201 displayed preferable biophysical properties and broadly potent in vitro antitumor activities across various cKIT-positive tumor cell lines. NN3201 exhibited potent in vivo antitumor activities in cKIT-positive tumor cell line xenograft and patient-derived tumor xenograft models of SCLC and AML, representing robust and durable antitumor responses. Furthermore, in a single-dose toxicity study with cynomolgus monkey, no significant or severe clinical toxicity signs were observed in animals dosed at 1, 2, and 3 mg/kg. Even though a decrease in reticulocyte, red cell mass (hemoglobin and red blood cell), neutrophil, and monocyte counts, along with bone marrow recovery and reticulocyte compensatory mechanism, red blood cell and white blood cell recovery were observed from day 14 in the low and medium dose groups and day 21 in the high dose group, dose-dependently. These preclinical results suggest that NN3201 is a potential therapeutic agent for the treatment of cKIT-positive cancers and support the further clinical evaluation in SCLC and AML. Citation Format: Han-Jik Ko, Sung Tae Kim, Jin Gu Cho, Jin-Ock Kim, Jung Tae Lee, Sang Gyu Park. In vivo efficacy and preclinical safety profile of NN3201, an anti-cKIT antibody-drug conjugate, for treating SCLC and AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2648.

An illicit drug early warning system in Victoria, Australia: The role of forensic toxicology in clinical casework

In response to the evolving threat of illicit substance use in Australia, public health bodies and advisory committees have called for an enhanced public health response including greater visibility related to community illicit drug use, particularly novel psychoactive substances (NPS). Victorian state government agencies recommended the development of a state-wide illicit drug early warning system (EWS), utilising data-sharing collaborations between emergency physicians, forensic laboratories, researchers, and health services. Current monitoring modalities utilised in Australia, such as surveys, wastewater monitoring and coronial investigations, lack the specificity and/or responsiveness required for an effective EWS. Clinical toxicity observed in patients presenting to emergency departments (EDs) following exposure to an illicit drug provides an objective and timely measure of harm. Although illicit drug EWS exist in other jurisdictions, not all utilise high-quality forensic analysis and instead rely on patient-reported exposure. However, there is evidence demonstrating poor correlation between reported exposure and forensic analytical findings. The Emerging Drugs Network of Australia Victoria (EDNAV) was therefore created to provide a clinical registry collecting high-quality clinical and analytical data from Emergency Department (ED) illicit drug presentations, combined with a multi-disciplinary expert team to analyse registry data and provide intelligence to a state illicit drug EWS. The EDNAV is a Human Research Ethics Committee (HREC) approved project created in conjunction with a pilot project utilising data from wastewater analysis, syringe residue analysis and ED illicit drug presentations to provide health authorities with intelligence on community drug use. Patients 16 years of age or older presenting to one of eleven EDNAV project EDs with reported or suspected illicit drug related toxicity requiring a venipuncture as part of their standard clinical care are eligible for registry inclusion. Blood samples from cases are transferred weekly to the Victorian Institute of Forensic Medicine (VIFM) Toxicology Department. Overnight liquid chromatography-tandem mass spectrometry (LC-MS/MS) screens for 327 common pharmaceuticals and illicit substances (including ∼80 NPS), followed by a secondary NPS specific screen targeting 268 NPS. The NPS specific screen is actively updated based on emerging drug intelligence and literature reports. The HREC approved waiver of patient consent to include deidentified clinical and analytical data into a purpose built secure on-line (REDCap platform) registry. Forensic and clinical toxicologists/emergency physicians produce intelligence reports based on EDNAV registry data, which are provided to department of health policy officers to identify triggers and/or threats that lead to interventions designed to reduce community harm. There were 700 ED illicit drug presentations included in the EDNAV registry during the period September 2020–February 2022 (71% male, median age 33 years). Eighty-seven percent of patients arrived in ED via ambulance. Overall clinical acuity was high with 22% Australasian triage category 1 (require immediate treatment), and 62% category 2 (require treatment within 10 minutes), while 47% of patients were classified as having moderate, and 41% severe clinical toxicity. In additional to traditional illicit substances, novel substance detections included illicit benzodiazepines ( n = 10), cathinones ( n = 9), synthetic cannabinoid receptor agonists ( n = 6), and opioids ( n = 3). Forensic analyses revealed that in over 90% of cases there were different and/or additional drugs detected in comparison to the reported exposure, suggesting significant drug adulteration, drug substitution or under-reporting and highlighting the potential limitations of illicit drug EWS that do not utilise high-quality forensic analysis. Three public health alerts have been released in Victoria as the result of EDNAV registry intelligence, involving detections of N-ethylpentylone, 25B-NBOH, and paramethoxymethamphetamine. The EDNAV registry project has highlighted the critical role of a high-quality forensic analytical service in an illicit drug EWS in the state of Victoria.

Iatrogenic medication errors reported to the Victorian Poisons Information Centre.

Iatrogenic medication errors are a cause of medical morbidity and mortality. They result in significant cost to the Australian healthcare system each year. There is limited Australian evidence describing the iatrogenic errors occurring within the hospital system. To examine and describe iatrogenic medication errors occurring in Victorian healthcare settings through the analysis of referrals to a state Poisons Information Centre (PIC). A retrospective review of iatrogenic medication errors reported to the Victorian PIC (VPIC) from community and hospital healthcare settings from January 2015 to December 2019. Over a 5-year period, 357 iatrogenic errors were identified, 63% (n = 224) of which occurred in a hospital setting. The remaining errors occurred in a community healthcare setting. One in five patients were symptomatic from the medication error at the time of the call to the VPIC, and a change in management was required in 45% (n = 165) of all cases. Five percent (n = 17) of patients developed moderate to severe clinical toxicity as determined by the recorded poisoning severity score, and 88% (n = 18) of these required critical care management. Incorrect medication dosing accounted for 62% (n = 221) of errors. Common medication dosing errors included: double dose (51%, n = 114), incorrect medication administered (14%, n = 49), incorrect route (9%, n = 31), incorrect patient (6%, n = 22) and adult dose given to a child (4%, n = 15). Iatrogenic errors are occurring in the Victorian health care system. These errors can result in serious morbidity. Identification of causative factors and investment in preventative strategies will likely reduce associated morbidity and healthcare costs.

Reviving chloroquine for anti-SARS-CoV-2 treatment with cucurbit[7]uril-based supramolecular formulation

The wide-spreading SARS-CoV-2 virus has put the world into boiling water for more than a year, however pharmacological therapies to act effectively against coronavirus disease 2019 (COVID-19) remain elusive. Chloroquine (CQ), an antimalarial drug, was found to exhibit promising antiviral activity in vitro and in vivo at a high dosage, thus CQ was approved by the FDA for the emergency use authorization (EUA) in the fight against COVID-19 in the US, but later was revoked the EUA status due to the severe clinical toxicity. Herein, we show that supramolecular formulation of CQ by a macrocyclic host, curcurbit[7]uril (CB[7]), reduced its non-specific toxicity and improved its antiviral activity against coronavirus, working in synergy with CB[7]. CB[7] was found to form 1:1 host-guest complexes with CQ, with a binding constant of ∼104 L/mol. The CQ-CB[7] formulation decreased the cytotoxicity of CQ against Vero E6 and L-02 cell lines. In particular, the cytotoxicity of CQ (60 μmol/L) against both Vero E6 cell line and L-02 cell lines was completely inhibited in the presence of 300 μmol/L and 600 μmol/L CB[7], respectively. Furthermore, the CB[7] alone showed astonishing antiviral activity in SARS-CoV-2 infected Vero E6 cells and mouse hepatitis virus strain A59 (MHV-A59) infected N2A cells, and synergistically improved the antiviral activity of CQ-CB[7], suggesting that CB[7]-based CQ formulation has a great potential as a safe and effective antiviral agent against SARS-CoV-2 and other coronavirus.

Toxicity from illegitimate slimming agents – a 10-year case series at a tertiary toxicology laboratory in Hong Kong

Context This retrospective case-series study aims to provide an overview of the clinical, biochemical and analytical findings in patients who presented with toxicity related to the use of illegitimate slimming agents in Hong Kong from the perspective of a tertiary referral toxicology laboratory. Methods All clinical cases referred to the Hospital Authority Toxicology Reference Laboratory, Hong Kong with clinical suspicion of illegitimate slimming agent-related toxicity between January 2008 and December 2017 were reviewed retrospectively. The use of illegitimate slimming agents included the use of (1) deregistered slimming agents, (2) drug analogues that were not registered drugs, (3) registered drugs not approved for the indication of weight reduction (whether prescribed by a doctor or not), and (4) prescription-only slimming agents without a doctor’s prescription. Patients taking registered weight-reducing drugs prescribed by a doctor were excluded. Patient demographics, clinical features, relevant laboratory investigations, and toxicological findings were analyzed. Results From 2008 to 2017, a total of 346 patients were analytically confirmed by our laboratory to have clinical toxicity related to the use of illegitimate slimming agents. The median age of the patients was 27 years and 92.5% of the patients were female. The most common clinical presentations included psychiatric features, sympathomimetic toxicity, hypokalemia, and abnormal thyroid function tests. Fatal or severe clinical toxicity was observed in 10% of the cases. The major classes of drugs detected on our analytical platforms were stimulants (e.g., sibutramine), laxatives (e.g., anthraquinones), diuretics (e.g., hydrochlorothiazide), and thyroid hormones (e.g., animal thyroid tissue). These illegitimate slimming agents were obtained from various sources including the Internet, over-the-counter in community pharmacy, or unspecified local sources. Discussion and conclusions The use of slimming agents is common worldwide; apart from taking registered slimming agents prescribed by registered practitioners, many users obtain slimming agents from various illegitimate sources. The unregulated use of these drugs can be associated with significant clinical toxicity. This study provides a current landscape of illegitimate slimming agent toxicity in Hong Kong to frontline clinicians and other toxicology professionals. Collaboration between clinicians, laboratories, and government authorities would be imperative to prevent further health adversities related to the misuse of these agents.

Pharmacokinetic/Pharmacodynamic Relationship of Enzalutamide and Its Active Metabolite N-Desmethyl Enzalutamide in Metastatic Castration-Resistant Prostate Cancer Patients.

Enzalutamide (ENZA) is an oral androgen receptor inhibitor approved by the Food and Drug Administration and the European Medicines Agency for the treatment of metastatic and nonmetastatic castration-resistant prostate cancer (CRPC). ENZA is extensively metabolized by cytochrome P450 3A4 into N-desmethyl ENZA (NDE), an active metabolite. We aimed to explore the pharmacokinetic/pharmacodynamic relationship for ENZA and NDE in metastatic CRPC patients from a real-world setting. Trough plasma concentration (Ctrough) of ENZA and NDE were assayed using liquid chromatography coupled with UV detection. The relationship between ENZA, NDE, and composite (ENZA with NDE) plasma concentration and requirement of ENZA dose reduction was investigated using the Mann-Whitney test. A survival univariate analysis was conducted to explore association between progression-free survival (PFS), overall survival (OS), and plasma Ctrough (ENZA, NDE, and composite). Twenty-two metastatic CRPC patients treated with ENZA (median age, 75.5 years; 13 patients (59%) with Eastern Cooperative Oncology Group status 0-1) were prospectively included. Mean plasma Ctrough of ENZA and NDE were 12.4 ± 3.0 μg/mL and 8.8 ± 2.1 μg/mL, respectively. Neither PFS nor OS were statistically associated with ENZA, NDE, or composite plasma Ctrough. In 4 patients (18%) who required ENZA dose reduction because of severe clinical toxicity, an increased ENZA plasma Ctrough was observed compared with 18 remaining patients (16.1 ± 2.4 μg/mL vs. 11.6 ± 2.6 μg/mL, respectively; P= .027). The low interindividual variability in ENZA and NDE Ctrough and the lack of relationship with survival do not support the need for plasma drug monitoring. Severe asthenia might be related to higher exposure and could be improved by decreasing ENZA dosing.

Acute side effects after consumption of the new synthetic cannabinoids AB-CHMINACA and MDMB-CHMICA

Introduction: In 2014, the “European Monitoring Centre for Drugs and Drug Addiction” (EMCDDA) reported on 30 novel synthetic cannabinoids (SCs). Among these were indole- and indazole-based valine derivatives with a cyclohexylmethyl side chain (e.g., AB-CHMINACA and MDMB-CHMICA), which represent a new class of SCs.Methods: A prospective observational study of patients treated in emergency departments (EDs) after the intake of SCs was conducted. Clinical and laboratory data were combined and reported to a poison control centre. Serum and/or urine samples of ED patients were analyzed using LC–MS/MS.Results: Forty four patients (39 male, five female, 12–48 years) were included. AB-CHMINACA (MDMB-CHMICA) was identified in 20 (19) serum samples, and in 21 (25) urine samples, respectively. In 19 of the cases, more than one SC was present. Other psychoactive substances (mainly amfetamines) were identified in seven cases, but in five out of these in urine samples only. Based on the Poison Severity Score, severity of poisoning was minor (4), moderate (31) or severe (9). Most frequently reported neuropsychiatric symptoms were CNS-depression (n = 21, 61%), disorientation (n = 20, 45%), generalized seizures (n = 12, 27%), combativeness (n = 8, 18%) and extreme agitation (n = 7, 16%). Duration of symptoms lasting 24 hours or longer occurred in 15 cases (34%).Discussion: The prevalence of certain neuropsychiatric symptoms was higher in our study than in former reports after the intake of SCs of the aminoalkylindole-type (first generation) SCs. In addition, severe poisoning and duration of symptoms were also higher.Conclusions: In this study, the valine derivative AB-CHMINACA and the tert-leucine derivative MDMB-CHMICA (“third generation of SCs”) seem to be associated with more severe clinical toxicity than was previously reported in patients exposed to earlier generation SCs such as JWH-018. However, this observation needs to be confirmed with a larger cohort of patients with analytically confirmed abuse of third generation SCs. The rapid turnover of SCs on the drug market together with the occurrence of SCs such as AB-CHMINACA and MDMB-CHMICA is alarming, especially because of the unexpectedly high frequency of neuropsychiatric symptoms.

Pancytopenia and Severe Gastrointestinal Toxicities Associated with 5-Fluorouracil in a Patient with Thymidylate Synthase (TYMS) Polymorphism

5-Fluorouracil (5-FU) is one of the most commonly used chemotherapeutic agents in solid tumors, including colon, gastric and breast cancers. The pharmacogenetic syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency leading to severe toxicity after administration of 5-flourouracil (5-FU) and capecitabine has been well-recognized. However, the data about the association of the target enzyme, thymidylate synthase (TYMS) with the toxicity of these agents is limited. A 50-year-old Caucasian woman with T2N2M0 Stage IIIB squamous cell rectal cancer after local surgical excision initiated 5-FU therapy with mitomycin-C and radiation therapy in the adjuvant setting. Following the first treatment with 5-FU, she developed grade III mucositis and grade IV neutropenia which delayed her second dose of therapy. Following her second dose of 5-FU, she again developed grade III mucositis, grade II diarrhea, pancytopenia, fever, and rectal bleeding requiring hospitalization. She was treated with blood and platelet transfusion, pegfilgrastim, IV antibiotics, and supportive therapy. Due to her severe clinical toxicity following chemotherapy involving 5-FU, we tested her for both DPD deficiency andTYMS polymorphisms. The patient was found to be homozygous for the TYMS polymorphism 5’TSER genotype 2R/2R*f, which has been associated with increased 5-FU drug sensitivity and susceptibility to 5-FU toxicity. Our case report further underlines the fact that TYMS polymorphism not only predicts response to 5-FU by relating to intratumoral-TYMS mRNA expression but also the toxicity in these patients receiving fluoropyrimidines. In brief, TYMS genotype variations present a dilemma in 5-FU-driven cancer therapy- overexpression leads to decreased drug sensitivity and poor prognosis, while underexpression leads to the manifestation of toxic drug effects that may halt therapy altogether. Future prospective translational studies in a larger population are warranted to validate its role as a predictive and prognostic factor.

Comparison of trapping profiles between d-peptides and glutathione in the identification of reactive metabolites

Qualitative trapping profile of reactive metabolites arising from six structurally different compounds was tested with three different d-peptide isomers (Peptide 1, gly–tyr–pro–cys–pro–his-pro; Peptide 2, gly–tyr–pro–ala–pro–his–pro; Peptide 3, gly–tyr–arg–pro–cys–pro–his–lys–pro) and glutathione (GSH) using mouse and human liver microsomes as the biocatalyst. The test compounds were classified either as clinically “safe” (amlodipine, caffeine, ibuprofen), or clinically as “risky” (clozapine, nimesulide, ticlopidine; i.e., associated with severe clinical toxicity outcomes). Our working hypothesis was as follows: could the use of short different amino acid sequence containing d-peptides in adduct detection confer any add-on value to that obtained with GSH? All “risky” agents’ resulted in the formation of several GSH adducts in the incubation mixture and with at least one peptide adduct with both microsomal preparations. Amlodipine did not form any adducts with any of the trapping agents. No GSH and peptide 2 and 3 adducts were found with caffeine, but with peptide 1 one adduct with human liver microsomes was detected. Ibuprofen produced one Peptide 1-adduct with human and mouse liver microsomes but not with GSH. In conclusion, GSH still remains the gold trapping standard for reactive metabolites. However, targeted d-peptides could provide additional information about protein binding potential of electrophilic agents, but their clinical significance needs to be clarified using a wider spectrum of chemicals together with other safety estimates.

Lipid Emulsion Infusion in Resuscitation for Local Anesthetic and Other Drug Overdose

Abstract The use of intravenous lipid emulsions (ILEs) as antidote in local anesthetic systemic toxicity has gained widespread support following convincing data from animal models, and successful case reports in humans. An injection of a simple, intravenous nutritional solution could be acutely life-saving for a patient with severe drug overdose. But dozens of published case reports support this observation, the first ones made more than a decade ago in a rodent model of bupivacaine toxicity. It is even more surprising that such a simple formulation can rapidly reverse severe clinical toxicity from a variety of vastly disparate medications with distinct pharmacodynamics and mechanisms of action. This review will focus on the clinical application of lipid emulsion therapy in resuscitation from drug-related toxicity and will provide an introduction to the development of a method, guidelines for its use, and insights into potential controversies and future applications [1].

Increasing frequency of severe clinical toxicity after use of 2,4-dinitrophenol in the UK: a report from the National Poisons Information Service

Objective2,4-Dinitrophenol (DNP) increases energy consumption by uncoupling oxidative phosphorylation. Although not licensed as a medicine, it is sometimes used by ‘body sculptors’ and for weight loss as a ‘fat burning’...

Intoxications of the new psychoactive substance 5-(2-aminopropyl)indole (5-IT): A case series from the Swedish STRIDA project

Context. 5-(2-aminopropyl)indole (5-IT) is a new psychoactive substance (NPS; “legal high” or “research chemical”) structurally related to indoleamines and substituted phenethylamines and implicated in several fatalities. We describe the clinical characteristics and results of laboratory investigations of 14 analytically confirmed nonfatal cases of 5-IT intoxication within the Swedish STRIDA project. Study design. Observational case series of consecutive patients with admitted or suspected intake of NPS presenting to hospitals in Sweden in 2012. Patients and methods. Blood and/or urine samples were collected from intoxicated patients presenting to emergency departments and intensive care units over the country. Analysis of NPS was performed using an LC–MS/MS multi-component method. Clinical data were collected when caregivers consulted the Poisons Information Centre and also retrieved from medical records. The severity of poisoning was graded retrospectively using the Poisoning Severity Score (PSS). Results. Eleven male and three female patients (age: 21–53 years, median: 27) tested positive for 5-IT in 2012, all cases appearing in April–July. The 5-IT concentration in serum ranged between 0.015 and 0.59 μg/mL (median: 0.22; n = 8) and in urine between 0.005 and 24.7 μg/mL (median: 5.95; n = 12). Five intoxications were indicated to be caused by 5-IT alone, whereas additional psychoactive substances were detected in the other nine cases. Six (43%) of fourteen cases were graded as severe (PSS 3), five (36%) as moderate (PSS 2), and three (21%) as minor (PSS 1) poisonings. In the severe cases, agitation, hallucinations, dilated pupils without light reaction, tachycardia, hypertension, hyperthermia, myoclonus, muscle rigidity, arrhythmias, seizures, rhabdomyolysis, and/or renal failure were noted. Conclusions. The results demonstrated that severe clinical toxicity was commonly present in patients with analytically confirmed 5-IT exposure. The clinical features are consistent with a sympathomimetic toxidrome, and some patients also displayed symptoms associated with serotonin toxicity.

A novel class of bioreponsive nanomedicines for localised reinstatement of bioactivity and specific targeting

BackgroundGram-negative infection is a global health concern. We present a custom-engineered, novel, patented, dextrin-colistin conjugate that can mask the toxicity of colistin; this conjugate allows controlled, enzymatically mediated dextrin degradation (unmasking) and reinstatement of colistin activity at the infected site. In the presence of amylase, the lead candidate EA-4 (1·0 mol% succinoylation, 11·2 % w/w colistin, molecular weight ∼10 300 g/mol) maximally unmasked and was equally effective to the clinical colistin formulation against strains of multidrug resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae (minimum inhibitory concentration ≤4 g/L), but suppression of bacterial viability was six times longer. Here we report ex-vivo and in-vivo activity, pharmacokinetics and pharmacodynamics, and toxicity. MethodsWe used a newly validated two-compartment static dialysis bag model under infinite sink conditions to unmask EA-4 directly in six samples of infected burn wound fluid. We assessed wound versus plasma amylase partitioning with a Phadebas amylase test. We established pharmacokinetics (with high-performance liquid chromatography and ELISA) and toxicity (clinical variables) in an intravenous, escalating-dose Sprague Dawley rat model (35 rats). FindingsSignificant partitioning of amylase to the infected burn fluid occurred, despite normal plasma amylase (∼6·8:1, p<0·05), and controlled EA-4 unmasking was observed (48 h peak 68%, p<0·05). EA-4 showed no in-vivo toxicity even at maximum protocol dose (0·5 mg/L). However, severe clinical toxicity limited colistin dosing to 0·1 mg/L. Substantial improvement in pharmacokinetic variables compared with colistin were recorded—namely, plasma half-life (1·6 vs 0·9 h), clearance (2·8 vs 13·4 mL/min per kg), and last measurable concentration (>24 vs 4 h). InterpretationThese findings support proof of principle for the first bioresponsive macromolecular antibiotic class, which is equally potent to the current clinical alternative, but presents substantially improved toxicity and pharmacokinetic characteristics. Moreover, the ability for localised targeted, enzyme-mediated reinstatement of activity has implications for future design of controlled drug release polymer therapeutic systems. Imminent scale-up studies and testing in man are the next steps. FundingEuropean Union (European Social Fund), STEPS scheme (Government of Malta, EU), Welsh Government.

Severe Clinical Toxicity Associated with Analytically Confirmed Recreational Use of 25I-NBOMe: Case Series: Hill SL, Doris T, Gurung S, et al. Clin Toxicol 2013;51:487–92.

The novel psychoactive substance 4-iodo-2, 5-dimethoxy-N-(2-methoxybenzyl) phenethylamine (25I-NBOMe), first synthesized in 2003, has become increasingly popular on Internet-based drug forums over the past several years. 25I-NBOMe has hallucinogenic and sympathomimetic effects, with an affinity for the serotonin 2a (5HT2a) receptor approximately 10 times that of LSD. Street names for this drug include: “25-I,” “INB-MeO,” “Solaris,” “Smiles,” “N-Bomb,” and “Cimbi-5.” This observational case series described seven cases of analytically confirmed toxicity due to recreational use of 25I-NBOMe in the United Kingdom.

Severe clinical toxicity associated with analytically confirmed recreational use of 25I–NBOMe: case series

Context. 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a N-methoxybenzyl-substituted phenethylamine with potent serotoninergic effects. We describe seven cases of analytically confirmed toxicity due to the recreational use of 25I-NBOMe in the United Kingdom. Case series. Seven patients, all young adult males, presented to hospitals in the northeast of England with clinical toxicity after recreational drug use in January 2013. Clinical features included tachycardia (n = 7), hypertension (4), agitation (6), aggression, visual and auditory hallucinations (6), seizures (3), hyperpyrexia (3), clonus (2), elevated white cell count (2), elevated creatine kinase (7), metabolic acidosis (3), and acute kidney injury (1). LC–MS/MS analysis identified 25I-NBOMe as the main active substance in the plasma of all seven cases. Conclusions. Severe clinical toxicity may occur following recreational use of 25I-NBOMe, with stimulant and serotoninergic features predominating. Clinicians should be alert to this substance, in view of its emergence in Europe as well as in the United States.

Gastrointestinal and Hepatotoxicity Assessment of an Anticancer Extract from Muricid Molluscs

Marine molluscs from the family Muricidae are under development as a potential medicinal food for the prevention of colon cancer and treatment of gynaecological cancers. Here we report the outcome of the first in vivo toxicity assessment on an anticancer extract from a muricid mollusc containing brominated indole derivatives. Mice received the concentrated lipophilic extract by daily oral gavage over a two-week period. Mortality or clinical toxicity symptoms resulting from the extract were not detected during the trial, and there was no difference in the body weight of treated and control mice at the end of the trial. Histological analysis revealed some evidence for mild, idiosyncratic effects on the gastrointestinal tract and liver, including necrosis, fatty change, and inflammation in a small proportion (<40%) of mice. This is likely to result from first-pass hepatic metabolism of tyrindoxyl sulphate combined with second-pass metabolism of indoles. Overall however, oral administration of muricid extract containing brominated indoles does not result in severe clinical toxicity.

Lipid Emulsion Infusion

It seems implausible that an injection of a simple, off-the-shelf, intravenous nutritional solution could be acutely life-saving for a patient with severe drug overdose. Yet, dozens of published case reports support this observation, first made more than a decade ago in a rodent model of bupivacaine toxicity. It is even more surprising that such a simple formulation can rapidly reverse severe clinical toxicity from a variety of vastly disparate medications with distinct pharmacodynamics and mechanisms of action. This review will focus on the clinical application of lipid emulsion therapy in resuscitation from drug-related toxicity and provide an introduction to the development of the method, guidelines for its use and insights into potential controversies and future applications.

Relationship Between Antimetabolite Toxicity and Pharmacogenetics in Turkish Cancer Patients

Antimetabolites may cause severe toxicity and even toxic death in cancer patients. Our aim was to evaluate the relationship between antimetabolite toxicity and pharmacogenetics in patients with severe clinical toxicity or alanine transaminase (ALT) elevation after fluorouracil (5FU), capecitabine or methotrexate administration. Cancer patients with severe antimetabolite toxicity were evaluated for methylenetetrahydrofolate reductase (MTHFR) gene C667T, thymidilate synthase (TS) gene 5' UTR variable number of tandem repeats (VNTR), dihydroprymidine dehydrogenase (DPYD) gene IVS14+1G/A, Xeroderma pigmentosum (XPD) gene Lys751Gln and X-ray repair cross-complementing group 1 (XRCC1) gene Arg399Gln polymorphisms. Eighteen patients were enrolled, with a male/female ratio of 0.8. They had osteosarcoma in methotrexate group (n=7), gastrointestinal malignancies in 5FU group (n=9) and breast cancer in the capecitabine group (n=2). Mucositis and dermatitis occurred in all groups, together with ALT elevation in the methotrexate group and 2 toxic deaths were encountered. DPYD, TS, MTHFR, XPD and XRCC1 gene polymorphism rare allele frequencies were observed to be higher than in the general population. Pharmacogenetics might contribute to tailored therapy.

B-Cell Depletion, Remissions of Malignancy, and Cytokine-Associated Toxicity in a Clinical Trial of T Cells Genetically-Engineered to Express An Anti-CD19 Chimeric Antigen Receptor

Abstract 167▪FN2▪This icon denotes a clinically relevant abstractNew therapies are needed for chemotherapy-resistant B-cell malignancies. Adoptive transfer of T cells genetically-engineered to express chimeric antigen receptors (CARs) that specifically recognize the B-cell antigen CD19 is a promising new approach for treating B-cell malignancies. We are conducting a clinical trial in which patients receive infusions of autologous T cells that are transduced with gamma-retroviruses encoding an anti-CD19 CAR. The CAR is made up of the variable regions of an anti-CD19 antibody, a portion of the CD28 molecule, and a portion of the CD3-zeta molecule. Our clinical protocol consists of cyclophosphamide plus fludarabine chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of high-dose IL-2. We have treated 8 patients on this clinical trial. Four of the patients had chronic lymphocytic leukemia (CLL), and 4 patients had B-cell lymphoma. Anti-CD19-CAR-transduced T cells that specifically recognized CD19-expressing target cells were produced for all patients. The total number of cells administered to each patient ranged from 0.5×107 to 5.5×107 cells per kg of bodyweight. A mean of 54% of the administered cells expressed the anti-CD19 CAR. One patient with CLL obtained a complete remission that is ongoing 15 months after treatment. Five patients obtained partial remissions that are ongoing in 3 patients. One patient with CLL had stable disease. One patient with lymphoma died of culture-proven influenza A pneumonia and is not evaluable for lymphoma response. A striking depletion of CD19+ B-lineage cells occurred in 4 of 8 patients. This B-cell depletion lasted for up to 15 months, and it is ongoing in 3 of 4 patients. Because of the long duration of B-cell depletion, it cannot be attributed to the chemotherapy that the patients received. For example, a patient with follicular lymphoma had a normal level of polyclonal blood B cells before treatment on our protocol. Six months after treatment, he had a blood B cell count of 1/microliter (normal range 61–321 B cells/microliter). A patient with CLL had a regression of adenopathy in the first 32 days after chemotherapy and CAR-transduced T cell administration. Interestingly, this adenopathy continued to substantially regress between 33 and 133 days after chemotherapy ended. CAR-transduced cells were detected in the blood of all 8 patients by quantitative PCR. The percentage of peripheral blood mononuclear cells (PBMC) containing the CAR gene varied widely, but in 2 patients the CAR gene was detected in greater than 0.1% of PBMC more than 90 days after infusion. At early time-points after infusion, CAR-expressing T cells constituted up to 20% of all blood T cells. Patients had significant toxicity during the first 10 days after CAR-transduced T cell infusion. The most prominent toxicity was hypotension. Sharp increases in serum interferon gamma (IFN) and tumor necrosis factor (TNF) occurred in 4 of 8 patients during the first 10 days after cell infusion. In the 4 patients with prominent elevations in inflammatory cytokines, peak serum IFN levels ranged from 865 to 2305 pg/mL, and peak TNF levels ranged from 49 to 118 pg/mL. As measured by an objective sequencial organ failure assessment score, the 4 patients with prominent elevations in IFN and TNF had more severe clinical toxicity during the first 10 days after cell infusion than the other 4 patients who did not have prominent elevations of IFN and TNF. We analyzed PBMC of three patients with elevations of serum IFN and TNF by using an ex vivo assay consisting of a 6-hour incubation of PBMC with target cells followed by intracellular cytokine staining. In all three patients, we detected T cells that produced IFN and TNF in a CD19-specific manner in PBMC samples collected after anti-CD19-CAR-transduced T cell infusions but not in PBMC samples collected before CAR-transduced T cell infusions. This indicates that anti-CD19-CAR-transduced T cells were a source of the elevated serum cytokines. In multiple patients receiving infusions of anti-CD19-CAR-transduced T cells, we have demonstrated elimination of CD19+ B-lineage cells, regressions of malignancy, elevated levels of serum inflammatory cytokines, and CD19-specific T cells that produce inflammatory cytokines ex vivo. These results demonstrate that CAR-expressing T cells can specifically eliminate targeted cells and cause significant cytokine-mediated toxicity in humans. Disclosures:No relevant conflicts of interest to declare.