Article #1: Pryce G, Baker D. Antidote to cannabinoid intoxication: the CB1 receptor inverse agonist, AM251, reverses hypothermic effects of the CB1 receptor agonist, CB-113, in mice. Br J of Pharmacology 2017;174:3709. 10.1111/bph.13973
Background:
Over the past decade, synthetic cannabinoid receptor agonists (SCRAs, known colloquially as “K2” or “spice”) have been more widely used as recreational drugs. These synthetic agonists work mainly on the CB-1 cannabinoid receptor found primarily in the neocortex, hypothalamus, basal ganglia, hippocampus, and cerebellum. While most cannabis exposures require minimal interventions, SCRAs can cause serious adverse effects and have been associated with deaths. Use of CB-1 receptor antagonists for SCRA toxicity may be effective.
Research Question:
Can cannabimimetic effects be reversed by a CB1 receptor antagonist/inverse agonist?
Methods:
Adult mice were given a dose of a synthetic CB1 receptor agonist (CB-13; 1-naphthalenyl[4-(pentyloxy)-1-naphthalenyl]methanone) known to induce hypothermia and sedation. Antagonized mice were then given the CB1 receptor antagonist/inverse agonist, AM251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide), 20 min after injection with CB-13. The mice were analyzed by measuring hypothermia and visual evidence of hypomotility.
Results:
Six mice receiving the CB1 receptor antagonist AM251 had significantly increased temperature compared to the control (p < 0.05), and hypothermia was reversed within 40 min. The mice given AM251 also had subjective reversal of hypomotility and sedation.
Conclusion:
A CB1 receptor antagonist/inverse agonist reversed CB1-induced hypothermia and sedation in mice.
Critique:
This small, unblinded study was performed on mice where one of the results, hypomotility, was entirely subjective. There was no AM251-only arm, and the use of this agent (with inverse agonist effects) may differ from agents with antagonist effects only. While this may have implications for use in humans, the adverse effects from SCRAs have not been shown to be from CB1 receptor agonism.
Implication for Toxicologists:
There were commercially available CB1 receptor antagonists; however, they were removed from the market due to adverse effects of depression, anxiety, and risk of suicide. Originally, the CB1 receptor antagonists had been marketed for prophylaxis and have not been studied as treatment for intoxication. Further studies are required to evaluate the safety and efficacy of CB1 receptor antagonists (and inverse agonists) for severe synthetic cannabinoid intoxications.
Article #2: Sun S, Jiang Y, Wang R, et al. Treatment of Paraquat-Induced Lung Injury with an Anti-C5a Antibody: Potential Clinical Application. Crit Care Med 2018;46(5):e419. 10.1097/CCM.0000000000002950
Background:
Complement activation has been shown to play a role in the inflammatory response that causes acute lung injury (ALI). Complement is aberrantly activated after paraquat poisoning and is likely implicated in the mechanism for ALI, a major cause of death after paraquat poisoning. C5a interaction with its receptor (C5aR) causes oxidative damage in several disease states. Interference with this signaling has been shown to prevent further oxidative burst and may alleviate further ALI.
Research Question:
Will targeting C5a activity help reduce the inflammatory response and ALI from paraquat?
Methods:
IFX-1, a neutralizing antihuman C5a monoclonal antibody, was administered to paraquat-poisoned cynomolgus macaque monkeys to evaluate the inflammatory response, compared to a sham treatment group, by analyzing complement activation, and post-mortem lung and tissue samples. IFX-1 was also tested by analyzing CD11b expression by granulocytes in serum from patients with paraquat-induced lung damage.
Results:
Compared with healthy subjects, patients with paraquat poisoning (including ALI) had significantly higher concentrations of C5a (p < 0.01) and C5b-9 (p < 0.001). Blood samples were then incubated with or without IFX-1. Samples treated with IFX-1 blocked upregulation of CD11b that is typically mediated by paraquat. After administration of paraquat, cynomolgus macaque monkeys showed typical characteristics of ALI. At 6 h after administration, paraquat monkeys had increased concentrations of all cytokines/chemokines, including C3a, C5a, and C5b-9. Lung tissue from paraquat monkeys also had increased expression of C3aR and C5aR, as well as increased deposition of C3c. After paraquat poisoning, there were decreased levels of lymphocytes and eosinophils and increased levels of neutrophils and monocytes. At 16 h post-paraquat injection, the IFX-1 group had decreased levels of neutrophils (p < 0.001) and monocytes (p < 0.05) and decreased values associated with acute systemic inflammatory response, compared to controls. IFX-1 administration caused significantly decreased concentrations of IL-1β, IL-6, TNF-α, MCP-1, and C5a, but not C3a or C5b-9. Stained lung tissue samples of poisoned monkeys showed an increased number of myeloperoxidase and CD68 positive cells which was significantly lower in the IFX-1-treated group. Necropsy showed less severe damage of the lung tissue, increased expression of pulmonary surfactant, and decreased organ damage in monkeys treated with IFX-1.
Conclusion:
ALI, a serious effect from paraquat poisoning, is mediated by aberrant activation of the complement system, leading to dysregulation and inflammatory damage. This effect can be ameliorated by therapies that target complement activation.
Critique:
In assessing animal models, it is unclear how to apply the results to humans. Additionally, the route of paraquat poisoning for the monkeys was peritoneal injection, not oral. Although IFX-1 showed response in human blood assays, further studies are needed to show safety and efficacy of complement antibodies in humans.
Implication for Toxicologists:
Knowing about alternative and experimental therapies can help toxicologists better understand and, perhaps, treat toxic poisonings. Having an adjunctive therapy that decreases the inflammatory response and subsequent lung injury could be very important in treating paraquat toxicity.
Article #3: Guo S, Manning V, Yang Y, et al. Lofexidine versus diazepam for the treatment of opioid withdrawal syndrome: a double-blind randomized clinical trial in Singapore. J of Substance Abuse 2018;91:1. 10.1016/j.jsat.2018.04.012
Background:
Opioid use and dependence are increasingly important worldwide public health issues. Medication-assisted therapy (MAT) has become a mainstay of treatment, except in places (and countries) where non-opioid medications are used. In Singapore, the current standard pharmacological treatment for opioid withdrawal is 7–10 days of oral diazepam. However, benzodiazepines have a high abuse potential. Another aspect of opioid withdrawal involves noradrenergic hyperactivity, contributing to the recent FDA approval of lofexidine (an alpha-2-adrenergic medication) for the treatment of opioid withdrawal in the USA.
Research Question:
Is lofexidine an effective and safe non-opioid alternative to diazepam in treating opioid withdrawal among inpatients in Singapore?
Methods:
This was a single site, randomized double-blind, placebo-controlled clinical trial at a 14-day inpatient detoxification program (initial 10-day medication treatment followed by 4 days of behavioral counseling). During the 10-day medication period, patients were treated with either lofexidine or diazepam. Consented subjects were 21–55 years of age, had a diagnosis of opioid dependence, a urine drug screen-positive for opioids, and no history of major physical or psychiatric illness (among several other exclusion criteria). Patients were assessed by measuring the Objective Opiate Withdrawal Scale (OOWS) on days 3 and 4. Secondary outcome measurements on days 3 through 10 included retention rates, pupil size, Short Opiate Withdrawal Scale (SOWS) score, and visual analogue scale (VAS) rating for opioid craving. Safety was assessed by monitoring adverse outcomes.
Results:
There were 111 patients enrolled and randomized into the trial (n = 56 lofexidine; n = 55 diazepam) with no significant difference in baseline characteristics between groups. There was no significant difference between SOWS, OOWS, or VAS scores on days 3 and 4. Although not statistically significant, the authors reported lower scores for the lofexidine group on all scales and significantly less changes in pupil size compared to the diazepam group. The lofexidine group had a higher rate of retention, with more participants remaining in treatment from day 7–13. The diazepam group had twice as many patients self-discharged on day 4. However, by day 14, the participants in the lofexidine were only slightly more likely to remain in the treatment program. Although both groups commonly experienced side effects (e.g., lethargy, dry mouth, weakness) almost twice as many lofexidine subjects experienced decreased blood pressure or heart rate, eight of which required a decrease in dose. Three lofexidine patients also reported numbness of mild-to-moderate severity.
Conclusion:
Lofexidine was as effective as diazepam in reducing symptoms of opioid withdrawal.
Critique:
The study did not show a significant reduction in opiate withdrawal symptoms with lofexidine, but rather, the results were comparable between groups. While useful in places where MAT is not available or in patients who would prefer non-opioid medications, further studies are required to determine if lofexidine has improved outcomes.
Implication for Toxicologists:
Lofexidine was approved by the FDA on May 16, 2018. Toxicologist and poison centers should be aware of this and other treatments for opioid withdrawal and their proven efficacies.
Article #4: Schutzmeier P, Baquerizo AF, Castillo-Tandazo W, et al. Efficacy of N,N’bis-(2-mercaptoethyl) isophthalamide on mercury intoxication: a randomized controlled trial. Environmental Health 2018;17:15. 10.1186/s12940-018-0358-1
Background:
Chronic mercury exposure can cause serious effects such as tremor, ataxia, sleep disturbance, and neurologic dysfunction. There are two chelators currently used for treatment: 2,3-dimercapto-1-pro-panesulfonate (DMPS) and dimercaptosuccinic acid (DMSA). However, neither agent is available in some countries with high rates of mercury exposure, such as Ecuador and Indonesia. N,N’bis-(2-mercaptoethyl) isophthalamide (NBMI) is a new chelator developed specifically for binding mercury and shown to improve acute toxicity in rat models.
Research Question:
What are the effects of NBMI on chronic, human mercury poisoning in a pilot study?
Methods:
This was a double-blinded, placebo-controlled pilot study using a gold mining population in Ecuador. After meeting all inclusion and exclusion criteria, 36 subjects were randomized into one of three groups: 100 mg/day NBMI, 300 mg/day NBMI, or placebo. Outcome measurements included the mercury intoxication score (MIS); neuro-motoric functions (CATSYS); mental and physical fatigue, tremor (finger-to-nose test); and mercury urine and plasma concentrations. Adverse outcomes were also recorded.
Results:
The groups differed in baseline characteristics (e.g., age, years of mine work) and urine mercury concentrations. There were no statistical differences in the change in serum mercury concentrations between groups. Unadjusted urine mercury concentrations showed a significant decrease between the 300-mg and placebo groups at 15 days. However, there was no difference when urine levels were adjusted for creatinine, and no significant change in MIS scores, although MIS scores decreased in all groups. There was a statistical decrease in subjective fatigue score between the 300-mg and placebo groups, but no difference between the 100-mg group. There were no serious adverse events.
Conclusion:
The authors concluded that NBMI effectively reduces subjective fatigue at a dose of 300 mg for 15 days. Further studies, with improved outcome variables, are required.
Critique:
This study involved numerous limitations and design flaws, including a very small sample size (n = 36) and important base line differences between groups. The study also did not show a change in either serum or adjusted urine concentrations, although it is possible that 14 days was an insufficient treatment duration. Since NBMI is lipophilic and excreted in feces, it may not result in significant changes in urine concentrations. The outcomes used to show improvements were subjective (e.g., fatigue, coordination) or unique (left versus right handed tremor) with limited internal validity. Further studies are needed to elucidate if NBMI is truly efficacious and safe for human use.
Implication for Toxicologists:
As new chelator agents, such as NMBI, become available, toxicologists must be aware of their effects, efficacy, and safety profiles.
Sources of Funding
None.
Compliance with Ethical Standards
Conflicts of Interest
None.
Footnotes
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