Leo J. Schep

The clinical toxicology of metamfetamine.

Introduction. Metamfetamine is a highly addictive amfetamine analog that acts primarily as a central nervous system (CNS) stimulant. The escalating abuse of this drug in recent years has lead to an increasing burden upon health care providers. An understanding of the drugs toxic effects and their medical treatment is therefore essential for the successful management of patients suffering this form of intoxication. Aim. The aim of this review is to summarize all main aspects of metamfetamine poisoning including epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management. Methods. A summary of the literature on metamfetamine was compiled by systematically searching OVID MEDLINE and ISI Web of Science. Further information was obtained from book chapters, relevant news reports, and web material. Epidemiology. Following its use in the Second World War, metamfetamine gained popularity as an illicit drug in Japan and later the United States. Its manufacture and use has now spread to include East and South-East Asia, North America, Mexico, and Australasia, and its world-wide usage, when combined with amfetamine, exceeds that of all other drugs of abuse except cannabis. Mechanisms of toxicity. Metamfetamine acts principally by stimulating the enhanced release of catecholamines from sympathetic nerve terminals, particularly of dopamine in the mesolimbic, mesocortical, and nigrostriatal pathways. The consequent elevation of intra-synaptic monoamines results in an increased activation of central and peripheral α±- and β-adrenergic postsynaptic receptors. This can cause detrimental neuropsychological, cardiovascular, and other systemic effects, and, following long-term abuse, neuronal apoptosis and nerve terminal degeneration. Toxicokinetics. Metamfetamine is rapidly absorbed and well distributed throughout the body, with extensive distribution across high lipid content tissues such as the blood-brain barrier. In humans the major metabolic pathways are aromatic hydroxylation producing 4-hydroxymetamfetamine and N-demethylation to form amfetamine. Metamfetamine is excreted predominantly in the urine and to a lesser extent by sweating and fecal excretion, with reported terminal half-lives ranging from ∼5 to 30 h. Clinical features. The clinical effects of metamfetamine poisoning can vary widely, depending on dose, route, duration, and frequency of use. They are predominantly characteristic of an acute sympathomimetic toxidrome. Common features reported include tachycardia, hypertension, chest pain, various cardiac dysrhythmias, vasculitis, headache, cerebral hemorrhage, hyperthermia, tachypnea, and violent and aggressive behaviour. Management. Emergency stabilization of vital functions and supportive care is essential. Benzodiazepines alone may adequately relieve agitation, hypertension, tachycardia, psychosis, and seizure, though other specific therapies can also be required for sympathomimetic effects and their associated complications. Conclusion. Metamfetamine may cause severe sympathomimetic effects in the intoxicated patient. However, with appropriate, symptom-directed supportive care, patients can be expected to make a full recovery.

Improvement of the in vitro dissolution of praziquantel by complexation with α-, β- and γ-cyclodextrins

Abstract Although praziquantel (PZQ) is the primary drug of choice in the treatment of schistosomiasis, its poor solubility has restricted its delivery via the oral route. In spite of its poor solubility, PZQ is well absorbed across the gastrointestinal tract, but large doses are required to achieve adequate concentrations at the target sites. Improving the solubility would enable the parenteral route to be used, thereby avoiding significant first pass metabolism. The aqueous solubility of PZQ was improved by forming inclusion complexes with α-, β- and γ-cyclodextrins (CDs). These complexes were assessed and confirmed by solubility analysis, Fourier transform infrared analysis, elemental analysis, differential scanning calorimetry and mass spectrometry. Dissolution of PZQ from the α-, β- and γ-CD complexes was 2.6-, 5- and 8-fold greater, respectively, than that of the pure drug. However, only the β-complex had a stability constant in the optimum range for pharmaceutical use, suggesting that the preferred complex for further development would be a water-soluble β-CD derivative.

The clinical toxicology of gamma-hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol

Introduction. Gamma-hydroxybutyrate (GHB) and its precursors, gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD), are drugs of abuse which act primarily as central nervous system (CNS) depressants. In recent years, the rising recreational use of these drugs has led to an increasing burden upon health care providers. Understanding their toxicity is therefore essential for the successful management of intoxicated patients. We review the epidemiology, mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management of poisoning due to GHB and its analogs and discuss the features and management of GHB withdrawal. Methods. OVID MEDLINE and ISI Web of Science databases were searched using the terms “GHB,” “gamma-hydroxybutyrate,” “gamma-hydroxybutyric acid,” “4-hydroxybutanoic acid,” “sodium oxybate,” “gamma-butyrolactone,” “GBL,” “1,4-butanediol,” and “1,4-BD” alone and in combination with the keywords “pharmacokinetics,” “kinetics,” “poisoning,” “poison,” “toxicity,” “ingestion,” “adverse effects,” “overdose,” and “intoxication.” In addition, bibliographies of identified articles were screened for additional relevant studies including nonindexed reports. Non-peer-reviewed sources were also included: books, relevant newspaper reports, and applicable Internet resources. These searches produced 2059 nonduplicate citations of which 219 were considered relevant. Epidemiology. There is limited information regarding statistical trends on world-wide use of GHB and its analogs. European data suggests that the use of GHB is generally low; however, there is some evidence of higher use among some sub-populations, settings, and geographical areas. In the United States of America, poison control center data have shown that enquiries regarding GHB have decreased between 2002 and 2010 suggesting a decline in use over this timeframe. Mechanisms of action. GHB is an endogenous neurotransmitter synthesized from glutamate with a high affinity for GHB-receptors, present on both on pre- and postsynaptic neurons, thereby inhibiting GABA release. In overdose, GHB acts both directly as a partial GABAb receptor agonist and indirectly through its metabolism to form GABA. Toxicokinetics. GHB is rapidly absorbed by the oral route with peak blood concentrations typically occurring within 1 hour. It has a relatively small volume of distribution and is rapidly distributed across the blood–brain barrier. GHB is metabolized primarily in the liver and is eliminated rapidly with a reported 20–60 minute half-life. The majority of a dose is eliminated completely within 4–8 hours. The related chemicals, 1,4-butanediol and gamma butyrolactone, are metabolized endogenously to GHB. Clinical features of poisoning. GHB produces CNS and respiratory depression of relatively short duration. Other commonly reported features include gastrointestinal upset, bradycardia, myoclonus, and hypothermia. Fatalities have been reported. Management of poisoning. Supportive care is the mainstay of management with primary emphasis on respiratory and cardiovascular support. Airway protection, intubation, and/or assisted ventilation may be indicated for severe respiratory depression. Gastrointestinal decontamination is unlikely to be beneficial. Pharmacological intervention is rarely required for bradycardia; however, atropine administration may occasionally be warranted. Withdrawal syndrome. Abstinence after chronic use may result in a withdrawal syndrome, which may persist for days in severe cases. Features include auditory and visual hallucinations, tremors, tachycardia, hypertension, sweating, anxiety, agitation, paranoia, insomnia, disorientation, confusion, and aggression/combativeness. Benzodiazepine administration appears to be the treatment of choice, with barbiturates, baclofen, or propofol as second line management options. Conclusions. GHB poisoning can cause potentially life-threatening CNS and respiratory depression, requiring appropriate, symptom-directed supportive care to ensure complete recovery. Withdrawal from GHB may continue for up to 21 days and can be life-threatening, though treatment with benzodiazepines is usually effective.

Diethylene glycol poisoning.

Introduction. Diethylene glycol (DEG) is a clear, colorless, practically odorless, viscous, hygroscopic liquid with a sweetish taste. In addition to its use in a wide range of industrial products, it has also been involved in a number of prominent mass poisonings spanning back to 1937. Despite DEGs toxicity and associated epidemics of fatal poisonings, a comprehensive review has not been published. Methods. A summary of the literature on DEG was compiled by systematically searching OVID MEDLINE and ISI Web of Science. Further information was obtained from book chapters, relevant news reports, and web material. Aim. The aim of this review is to summarize all main aspects of DEG poisoning including epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, toxicity of DEG, diagnosis, and management. Epidemiology. Most of the documented cases of DEG poisoning have been epidemics (numbering over a dozen) where DEG was substituted in pharmaceutical preparations. More often, these epidemics have occurred in developing and impoverished nations where there is limited access to intensive medical care and quality control procedures are substandard. Toxicokinetics. Following ingestion, DEG is rapidly absorbed and distributed within the body, predominantly to regions that are well perfused. Metabolism occurs principally in the liver and both the parent and the metabolite, 2-hydroxyethoxyacetic acid (HEAA), are renally eliminated rapidly. Mechanisms of toxicity. Although the mechanism of toxicity is not clearly elucidated, research suggests that the DEG metabolite, HEAA, is the major contributor to renal and neurological toxicities. Clinical features. The clinical effects of DEG poisoning can be divided into three stages: The first phase consists of gastrointestinal symptoms with evidence of inebriation and developing metabolic acidosis. If poisoning is pronounced, patients can progress to a second phase with more severe metabolic acidosis and evidence of emerging renal injury, which, in the absence of appropriate supportive care, can lead to death. If patients are stabilized, they may then enter the final phase with various delayed neuropathies and other neurological effects, sometimes fatal. Toxicity of DEG. Doses of DEG necessary to cause human morbidity and mortality are not well established. They are based predominantly on reports following some epidemics of mass poisonings, which may underestimate toxicity. The mean estimated fatal dose in an adult has been defined as ∼1 mL/kg of pure DEG. Management. Initial treatment consists of appropriate airway management and attention to acid–base abnormalities. Prompt use of fomepizole or ethanol is important in preventing the formation of the toxic metabolite HEAA; hemodialysis can also be critical, and assisted ventilation may be required. Conclusions. DEG ingestion can lead to serious complications that may prove fatal. Prognosis may be improved, however, with prompt supportive care and timely use of fomepizole or ethanol.

Nicotinic plant poisoning

Introduction. A wide range of plants contain nicotinic and nicotinic-like alkaloids. Of this diverse group, those that have been reported to cause human poisoning appear to have similar mechanisms of toxicity and presenting patients therefore have comparable toxidromes. This review describes the taxonomy and principal alkaloids of plants that contain nicotinic and nicotinic-like alkaloids, with particular focus on those that are toxic to humans. The toxicokinetics and mechanisms of toxicity of these alkaloids are reviewed and the clinical features and management of poisoning due to these plants are described. Methods. This review was compiled by systematically searching OVID MEDLINE and ISI Web of Science. This identified 9,456 papers, excluding duplicates, all of which were screened. Reviewed plants and their principal alkaloids. Plants containing nicotine and nicotine-like alkaloids that have been reported to be poisonous to humans include Conium maculatum, Nicotiana glauca and Nicotiana tabacum, Laburnum anagyroides, and Caulophyllum thalictroides. They contain the toxic alkaloids nicotine, anabasine, cytisine, n-methylcytisine, coniine, n-methylconiine, and γ-coniceine. Mechanisms of toxicity. These alkaloids act agonistically at nicotinic-type acetylcholine (cholinergic) receptors (nAChRs). The nicotinic-type acetylcholine receptor can vary both in its subunit composition and in its distribution within the body (the central and autonomic nervous systems, the neuromuscular junctions, and the adrenal medulla). Agonistic interaction at these variable sites may explain why the alkaloids have diverse effects depending on the administered dose and duration of exposure. Toxicokinetics. Nicotine and nicotine-like alkaloids are absorbed readily across all routes of exposure and are rapidly and widely distributed, readily traversing the blood–brain barrier and the placenta, and are freely distributed in breast milk. Metabolism occurs predominantly in the liver followed by rapid renal elimination. Clinical features. Following acute exposure, symptoms typically follow a biphasic pattern. The early phase consists of nicotinic cholinergic stimulation resulting in symptoms such as abdominal pain, hypertension, tachycardia, and tremors. The second inhibitory phase is delayed and often heralded by hypotension, bradycardia, and dyspnea, finally leading to coma and respiratory failure. Management. Supportive care is the mainstay of management with primary emphasis on cardiovascular and respiratory support to ensure recovery. Conclusions. Exposure to plants containing nicotine and nicotine-like alkaloids can lead to severe poisoning but, with prompt supportive care, patients should make a full recovery.

The clinical toxicology of the designer “party pills” benzylpiperazine and trifluoromethylphenylpiperazine

Introduction. Benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) are synthetic phenylpiperazine analogues. BZP was investigated as a potential antidepressant in the early 1970s but was found unsuitable for this purpose. More recently, BZP and TFMPP have been used as substitutes for amfetamine-derived designer drugs. They were legally available in a number of countries, particularly in New Zealand, and were marketed as party pills, but are now more heavily regulated. This article will review the mechanisms of toxicity, toxicokinetics, clinical features, diagnosis, and management of poisoning due to BZP and TFMPP. Methods. OVID MEDLINE and ISI Web of Science were searched systematically for studies on BZP and TFMPP and the bibliographies of identified articles were screened for additional relevant studies including nonindexed reports. Nonpeer-reviewed sources were also accessed. In all, 179 papers excluding duplicates were identified and 74 were considered relevant. Mechanisms of action. BZP and TFMPP have stimulant and amfetamine-like properties. They enhance the release of catecholamines, particularly of dopamine, from sympathetic nerve terminals, increasing intra-synaptic concentrations. The resulting elevated intra-synaptic monoamine concentrations cause increased activation of both central and peripheral α- and 𝛃-adrenergic postsynaptic receptors. BZP has primarily dopaminergic and noradrenergic action while TFMPP has a more direct serotonin agonist activity. Toxicokinetics. There is limited information on the kinetics of these drugs. Following ingestion, peak plasma concentrations are reached after 60 to 90 min. Both drugs would be expected to cross the blood brain barrier and they are metabolized mainly by hydroxylation and N-dealkylation catalyzed by cytochrome P450 and catechol-o-methyl transferase enzymes. In humans, only small amounts of both BZP and TFMPP are excreted in the urine, suggesting a low bioavailability. The serum half-lives of BZP and TFMPP are relatively short with elimination being essentially complete in 44 h for BZP and 24 h for TFMPP. Clinical features. These compounds can cause harmful effects when taken recreationally. Commonly reported features include palpitations, agitation, anxiety, confusion, dizziness, headache, tremor, mydriasis, insomnia, urine retention, and vomiting. Seizures are induced in some patients even at low doses. Severe multiorgan toxicity has been reported, though fatalities have not been recorded conclusively. Management. Supportive care including the termination of seizures is paramount, with relief of symptoms usually being provided by benzodiazepines alone. Conclusions. BZP and TFMP can cause sympathomimetic effects in the intoxicated patient. Appropriate, symptom-directed supportive care should ensure a good recovery.

Ricin as a weapon of mass terror — Separating fact from fiction

In recent years there has been an increased concern regarding the potential use of chemical and biological weapons for mass urban terror. In particular, there are concerns that ricin could be employed as such an agent. This has been reinforced by recent high profile cases involving ricin, and its use during the cold war to assassinate a high profile communist dissident. Nevertheless, despite these events, does it deserve such a reputation? Ricin is clearly toxic, though its level of risk depends on the route of entry. By ingestion, the pathology of ricin is largely restricted to the gastrointestinal tract where it may cause mucosal injuries; with appropriate treatment, most patients will make a full recovery. As an agent of terror, it could be used to contaminate an urban water supply, with the intent of causing lethality in a large urban population. However, a substantial mass of pure ricin powder would be required. Such an exercise would be impossible to achieve covertly and would not guarantee success due to variables such as reticulation management, chlorination, mixing, bacterial degradation and ultra-violet light. By injection, ricin is lethal; however, while parenteral delivery is an ideal route for assassination, it is not realistic for an urban population. Dermal absorption of ricin has not been demonstrated. Ricin is also lethal by inhalation. Low doses can lead to progressive and diffuse pulmonary oedema with associated inflammation and necrosis of the alveolar pneumocytes. However, the risk of toxicity is dependent on the aerodynamic equivalent diameter (AED) of the ricin particles. The AED, which is an indicator of the aerodynamic behaviour of a particle, must be of sufficiently low micron size as to target the human alveoli and thereby cause major toxic effects. To target a large population would also necessitate a quantity of powder in excess of several metric tons. The technical and logistical skills required to formulate such a mass of powder to the required size is beyond the ability of terrorists who typically operate out of a kitchen in a small urban dwelling or in a small ill-equipped laboratory. Ricin as a toxin is deadly but as an agent of bioterror it is unsuitable and therefore does not deserve the press attention and subsequent public alarm that has been created.

Poisoning due to water hemlock

Introduction. Water hemlock, which encompasses a range of species divided across two genera (Cicuta and Oenanthe), are regarded as being among the most poisonous plants both in North America and in the United Kingdom. Despite their toxicity, the literature consists almost entirely of case reports. Aim. The aim of this review is to summarize this literature by covering all aspects of taxonomy and botanical characterization, principal toxins, basic pharmacology including mechanisms of toxicity, and the clinical features, diagnosis, and management of poisoning. Mechanisms of toxicity. The principal toxins, cicutoxin and oenanthotoxin, belong to a group of C17 conjugated polyacetylenes. They act as (noncompetitive) gamma-aminobutyric acid antagonists in the central nervous system (CNS), resulting in unabated neuronal depolarization that can lead to seizures. Ingestion of even a small amount of plant matter may result in severe intoxication. Features. After ingestion, the patient is most likely to experience CNS stimulatory effects including seizures that, in the absence of aggressive supportive care, can result in death. Other features include nausea, vomiting, diarrhea, tachycardia, mydriasis, rhabdomyolysis, renal failure, coma, respiratory impairment, and cardiac dysrhythmias. Management. Treatment consists mainly of prompt airway management and seizure control, plus decontamination if achieved early and after stabilization. In the event of renal failure, the use of hemodialysis has been employed successfully. Conclusions. The ingestion of water hemlock can lead to serious complications that may be fatal. Prognosis is good, however, if prompt supportive care is provided.

Delayed seizure-like activity following analytically confirmed use of previously unreported synthetic cannabinoid analogues

Synthetic cannabinoid use has become widespread, leading to increased burdens on health care providers. Symptoms range from agitation and psychosis to seizures and acute kidney injury. We report a case where a patient was assessed and treated twice within 12 h for seizures following synthetic cannabinoid intoxication. Blood sample determinations showed low concentrations of analogues not previously reported, some of which are legal. Clinicians should be aware that synthetic cannabinoids may cause an array of severe health consequences. Given the ever evolving structure of available analogues, clinicians must also be prepared for other unexpected adverse effects.

The Effect of Cetylpyridinium Chloride (CPC) on the Cell Surface Hydrophobicity and Adherence of Candida albicansto Human Buccal Epithelial Cells in Vitro

AbstractPurpose. This study examined the effects of cetylpyridinium chloride (CPC) on cell surface hydrophobicity (CSH) and adherence of blastospores of Candida albicans(MEN strain) to human buccal epithelial cells (EEC) in vitro. Methods. The effect of CPC treatment of either C. albicans blastospores or BEC on their subsequent adherence was determined using 35SO4 labelled blastospores in association with a Percoll™ gradient. The effects of CPC treatment of blastospores on their CSH was determined using Hydrophobic Interaction Chromatography. Results. Treatment of exponential and stationary phase blastospores with CPC (50 µg mL−1) for 0.5–30 minutes, or with CPC (0.5–50 µg mL−1) for 15 minutes resulted in significant reductions in both blastospore CSH and adherence to BEC in vitro. No correlation was apparent (r < 0.8) between reduced CSH and reduced blastospore adherence following treatment with CPC (0.5–50 µg mL−1). Significantly reduced adherence of C. albicans (stationary or exponential growth phases) to human EEC was also observed following treatment of BEC with CPC (50 µg mL−1) for 0.5–30 minutes or with CPC (0.5–50 µg mL−1) for 15 minutes. Antiadherence effects were observed at both sub and super-minimum inhibitory concentrations of CPC. Conclusions. It is suggested that, whilst the ability of CPC to reduce the CSH of C. albicans may contribute to its reduced adherence to human BEC in vitro, reduced CSH is only one of several possible factors that contribute to the observed antiadherence effects.