Short-term treatment with cholestyramine increases long-acting anticoagulant rodenticide clearance from rabbits without affecting plasma vitamin K1 levels nor blood coagulation.

Administration of high dose vitamin K1 (VK1) overcomes coagulopathy and bleeding elicited by acute poisoning with long-acting anti-coagulant rodenticides (LAARs). However, long-term (months) treatment is required due to long LAAR biological half-lives that may lead to poor compliance and recurrent coagulopathy. The half-lives of LAARs are extended by slow metabolism, and similar to warfarin, are thought to undergo enterohepatic recirculation. We now show that treatment with the bile acid sequestrant cholestyramine (CSA) administered concomitantly with VK1 decreases plasma LAAR levels and increases LAAR fecal excretion. Daily CSA treatment for 14 days did not reduce plasma VK1 levels, nor increase prothrombin time. Collectively, these data show that CSA accelerates LAAR clearance from rabbits without adverse effects on VK1 anti-coagulation, and could provide an additional therapeutic option for treatment of LAAR poisoning.

Brodifacoum pharmacokinetics in acute human poisoning: implications for estimating duration of vitamin K therapy.

Standard of care follow-up therapy for patients poisoned by long-acting anticoagulant rodenticides (LAARs) is daily high-dose (up to 100 mg per day) oral vitamin K1 (VK1) for weeks to months to over a year. The availability of CLIA-certified quantitative testing for plasma LAAR concentrations can now assist health care providers in determining when to safely discontinue VK1 therapy. We present estimates of treatment duration required to reach safe concentrations (< =10ng/ml) using serial measurements of plasma brodifacoum (BDF, a potent LAAR) concentrations obtained from patients poisoned after inhaling synthetic cannabinoids containing BDF. We fit the data to zero-order (linear) and first-order (exponential) curves, the latter to account for enterohepatic circulation of BDF. The results show that estimates of therapy duration are significantly longer when exponential clearance is assumed. Accordingly, we recommend that plasma BDF concentrations be monitored simultaneously with international normalization ratio (INR) during follow-up of poisoned patients, and that concentrations be determined after VK1 therapy is discontinued to document persistence of safe concentrations.

Effects of vitamin K1 treatment on plasma concentrations of long-acting anticoagulant rodenticide enantiomers following inhalation of contaminated synthetic cannabinoids.

Background: An outbreak of synthetic cannabinoid (SC)-associated coagulopathy and bleeding in Illinois, USA was determined to be due to inhalation of SC contaminated with brodifacoum (BDF), difenacoum (DiF), and bromadiolone (BDL), highly potent long-acting anticoagulant rodenticides (LAARs). Treatment with high-dose vitamin K1 (VK1) prevented mortality; however, plasma LAAR levels were not measured risking recurrence of coagulopathy and bleeding due to premature discontinuation. The goal of this study was to determine if plasma LAAR levels were reduced following standard of care treatment to normalize coagulopathy.Methods: Blood samples were collected from a cohort of 32 patients, and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis used to quantify plasma LAAR levels including enantiomers.Results: BDF was detected in 31 samples; 30 also contained DiF and 18 contained BDL. Initial plasma levels were 581 ± 87, 11.0 ± 1.9, and 14.9 ± 5.9 ng/mL for BDF, DiF, and BDL, respectively (mean ± SE). At discharge plasma, BDF levels remained elevated at 453 ± 68 ng/mL. Plasma half-lives for BDF, DiF, and BDL were 7.5 ± 1.3, 7.2 ± 1.9, and 1.8 ± 0.3 days, respectively. The half-life for trans-BDF enantiomers (5.7 ± 0.8 days) was shorter than for cis-enantiomers (7.6 ± 1.9 days). BDF half-lives were shorter, and coagulopathy normalized faster in patients receiving intravenous VK1 as compared to oral VK1. Patients prescribed VK1 at discharge had fewer re-admittances.Conclusions: These results demonstrate that plasma LAAR levels at discharge were elevated in poisoned patients despite normal coagulation, and that the route of VK1 administration affected LAAR pharmacokinetics and INR normalization. We propose plasma LAAR levels and coagulation be monitored concomitantly during follow-up of patients with LAAR poisoning. KEY POINTSIn patients treated with high-dose vitamin K1 for LAAR poisoning, plasma levels remained 40-fold above safe levels upon discharge from hospital.LAAR half-lives, normalization of coagulopathy, and readmittances were reduced by treatment with intravenous vitamin K1.

Adherence to Long-Term Follow-Up of Patients with Life-Threatening, Inhaled Synthetic Cannabinoids-Associated Coagulopathy in Chicago.

A large-scale outbreak of life-threatening, inhaled synthetic cannabinoids (Spice/K2)-associated coagulopathy with bleeding complications was recently reported in Illinois. The causative agents were brodifacoum, difenacoum, and bromadiolone, potent, long-acting, 4-hydroxycoumarin anticoagulant rodenticides (LAAR) that were mixed with Spice/K2 products procured and then inhaled by the victims. We report on 3 poisoned patients who reside in underserved, socioeconomically disadvantaged neighborhoods of Chicago that were admitted and treated successfully at two inner-city, tertiary care hospitals in Chicago. The patients were discharged from the hospitals on daily long-term high-dose oral vitamin K1 (VK1), provided free of charge. However, 2 patients were lost to follow-up prior to safe discontinuation of oral VK1 therapy. The third patient was treated and followed successfully for 7 months when VK1 was discontinued. We conclude that prolonged oral VK1 therapy and follow-up of acute, life-threatening LAAR poisoning are variable and present challenges to healthcare providers. Appropriate practice guidelines to improve patient access and adherence to daily high-dose oral VK1 therapy and follow-up should be developed and implemented.

Should Cytochrome P450 Inducers be Used to Accelerate Clearance of Brodifacoum from Poisoned Patients?

A recent multi-state outbreak of life-threatening bleeding following inhalation of synthetic cannabinoids has been attributed to contamination with the long-acting anticoagulant rodenticide (LAAR) brodifacoum, a second-generation, highly potent, long-acting derivative of the commonly used blood thinner warfarin. While long-term treatment with high-dose vitamin K1 restores coagulation, it does not affect brodifacoum metabolism or clearance, and, consequently, brodifacoum remains in the human body for several months, thereby predisposing to risk of bleeding recurrence and development of coagulation-independent injury in extrahepatic tissues and fetuses. This has prompted the evaluation of pharmacological measures that accelerate brodifacoum clearance from poisoned patients. Since the induction of certain cytochrome P450 (CYP) enzymes accelerates warfarin metabolism, using CYP inducers, such as phenobarbital, to accelerate brodifacoum clearance seems plausible. However, unlike warfarin, brodifacoum does not undergo significant metabolism in the liver, nor have the effects of phenobarbital on vitamin K1 metabolism been previously determined. In addition, the safety of phenobarbital in brodifacoum-poisoned patients has not been established. Therefore, we propose that CYP inducers should not be used to accelerate the clearance of brodifacoum from poisoned patients, but that alternative approaches such as reducing enterohepatic recirculation of brodifacoum, or using lipid emulsions to scavenge brodifacoum throughout the body, be considered.

Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro-emulsion.

Triglyceride micro-emulsions such as Intralipid® have been used to reverse cardiac toxicity induced by a number of drugs but reservations about their broad-spectrum applicability remain because of the poorly understood mechanism of action. Herein we report an integrated mechanism of reversal of bupivacaine toxicity that includes both transient drug scavenging and a cardiotonic effect that couple to accelerate movement of the toxin away from sites of toxicity. We thus propose a multi-modal therapeutic paradigm for colloidal bio-detoxification whereby a micro-emulsion both improves cardiac output and rapidly ferries the drug away from organs subject to toxicity. In vivo and in silico models of toxicity were combined to test the contribution of individual mechanisms and reveal the multi-modal role played by the cardiotonic and scavenging actions of the triglyceride suspension. These results suggest a method to predict which drug toxicities are most amenable to treatment and inform the design of next-generation therapeutics for drug overdose.

Rapid cardiotonic effects of lipid emulsion infusion*.

OBJECTIVES: Bolus infusion of lipid emulsion can reverse cardiac pharmacotoxicity caused by local anesthetics and other lipophilic drugs. The mechanisms of this effect are not completely elucidated. The authors test the hypothesis that lipid emulsion infusion exerts direct, positive inotropic effects. DESIGN: Prospective, randomized animal study. SETTING: University research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: Rats anesthetized with isoflurane were given intravenous infusions (9 mL/kg over 1 min) of either 20% soybean oil-based emulsion or saline. MEASUREMENTS AND MAIN RESULTS: Arterial pressure and aortic flow were measured continuously in intact animals. Lipid infusion increased aortic flow and arterial pressure faster and to a greater degree than did the same volume of saline infusion. Isolated rat hearts were studied using an isovolumetric, constant flow, nonrecirculating system. Left ventricular pressure was monitored. The infusion of lipid emulsion in the isolated heart dose-dependently increased rate pressure product, dP/dt, -dP/dt, and myocardial oxygen demand. CONCLUSIONS: Lipid emulsion exerts rapid, positive inotropic and positive lusitropic effects in both intact animal and isolated heart models. We hypothesize that this inotropy and the resulting increase in tissue blood flow contribute to the phenomenon of lipid reversal of cardiac toxicity caused by drug overdose.

Sterically stabilized phospholipid mixed micelles: in vitro evaluation as a novel carrier for water-insoluble drugs.

PURPOSE: Sterically stabilized phospholipid micelles (SSMs) composed of poly(ethylene glycol-2000)-grafted distearoyl phosphatidylethanolamine (PEG(2000)-DSPE) are new and promising lipid-based carriers for water-insoluble drugs. This study investigates and compares sterically stabilized mixed micelles (SSMM), composed of (PEG(2000)-DSPE) plus egg-phosphatidylcholine, with SSM as a novel delivery system for improved solubilization of water-insoluble drugs using paclitaxel as a model. METHODS: Paclitaxel was solubilized in SSM (P-SSM) and SSMM (P-SSMM) by coprecipitation and rehydration with isotonic 0.01M HEPES buffer, pH 7.4. After separation of excess drug by centrifugation, mean particle size and morphology of particles in the supernatant were determined by quasi-elastic light scattering and transmission electron microscopy. The solubilization potentials of SSMM and SSM for paclitaxel were determined by reverse phase high pressure liquid chromatography (RP-HPLC). Cytotoxic activity of paclitaxel in SSMM. SSM, and dimethyl sulfoxide (10% DMSO) was determined against human breast cancer cells (MCF-7). RESULTS: Mean hydrodynamic diameter of P-SSMM and P-SSM were 13.1 +/- 1.1 nm and 15 +/- 1 nm (n = 3), respectively. SSMM solubilized 1.5 times more paclitaxel than SSM for the same total lipid concentration. Solubilized paclitaxel amount increased linearly with an increase in lipid concentration. A therapeutically relevant lipid concentration (15 mM) of SSMM solubilized 1,321 +/- 48 microg/ml of paclitaxel. Paclitaxel in the absence of sufficient SSM aggregated to form lipid-coated crystals. P-SSMM, P-SSM. and paclitaxel in DMSO had comparable cytotoxic activities against MCF-7 cells. CONCLUSIONS: SSMM showed increased solubilization potential compared with SSM while retaining all of its own advantages. Therefore, it can be used as an improved lipid-based carrier for water-insoluble drugs.