Antimalarial drug toxicity: a review

Antimalarial drug toxicity is viewed differently depending upon whether the clinical indication is for malaria treatment or prophylaxis. In the treatment of Plasmodium falciparum malaria, which has a high mortality if untreated, a greater risk of adverse reactions to antimalarial drugs is inevitable. As chloroquine resistance has become widespread, alternative agents may be used in treatment regimens, however, the toxicity of these antimalarial agents should be considered. Quinine is the mainstay for treating severe malaria due to its rare cardiovascular or CNS toxicity, but its hypoglycemic effect may be problematic. Mefloquine can cause dose-related serious neuropsychiatric toxicity and pyrimethamine-dapsone is associated with agranulocytosis, especially if the recommended dose is exceeded. Pyrimethamine-sulfadoxine and amodiaquine are associated with a relatively high incidence of potentially fatal reactions, and are no longer recommended for prophylaxis. Atovaquone/proguanil is an antimalarial combination with good efficacy and tolerability as prophylaxis and for treatment. The artemisinin derivatives have remarkable efficacy and an excellent safety record. Prescribing in pregnancy is a particular problem for clinicians because the risk-benefit ratio is often very unclear.     

Effects of aggregation and solvent on the toxicity of amphotericin B to human erythrocytes.

In aqueous suspensions of amphotericin B (AmB), a polyene antibiotic and antifungal agent, three forms of AmB coexist: monomers, water-soluble oligomers, and non-water-soluble aggregates. The toxicity of the water-soluble self-associated form of AmB compared with that of the non-water-soluble self-associated form was tested by measuring induction of K+ leakage from human erythrocytes, using different suspensions containing the antibiotic and phosphate-buffered saline. These suspensions were obtained from various stock solutions of the antibiotic in dimethyl formamide or dimethyl sulfoxide. Their circular dichroism spectra around 340 nm, indicative of the degree of AmB self-association, were strongly dependent on the concentration of organic solvent in the suspensions. The nonsoluble self-associated form was separated from the water-soluble form by centrifugation. The nonsoluble form was favored by a high concentration of AmB of the stock solution. The kinetics of AmB-induced K+ leakage from human erythrocytes also appeared to be strongly dependent on the AmB concentration of the stock solution being much weaker with concentrated stock solutions. It was concluded that the only form of AmB toxic to human erythrocytes is the water-soluble self-associated form (in contrast with fungal cells on which the monomeric form is also active). This result may be important in the design of new less toxic AmB derivatives and in the understanding of the mechanism of action of liposomal AmB.     

Hydrofluoric acid: a review of toxicity.

Hydrofluoric acid is a toxic substance used widely in both industrial and domestic settings. It can cause severe burns, as well as systemic toxicity. Death has been reported from as little as 2.5% body surface area (BSA) burn involving concentrated acid. Topical and parenteral calcium salts have proven effective therapy for both dermal and systemic manifestations. All emergency physicians should be aware of the unique complications and treatment of these injuries.     

Pneumococcal immune adherence to human erythrocytes

BACKGROUND: Human red blood cells bind various C3b-coated microorganisms via their C3b/CR1 receptor, a phenomenon referred to as immune adherence. The aim of the present study was to measure pneumococcal adherence to human red blood cells by flow cytometry and to study kinetic aspects of this binding. MATERIAL AND METHODS: We quantified pneumococcal adherence to human erythrocytes by FACS analysis and tested the involvement of antibodies and complement activation in this process. RESULTS: Pneumococci are able to bind to human red blood cells in the presence of human serum. Coating with C3b/C4b appeared obligatory for pneumococcal adherence to red blood cells. The ligand on erythrocytes was confirmed to be complement receptor 1. Kinetic studies showed that innate (mannose-binding lectin) and specific immune factors (IgG antibodies) contributed to the binding of C3b-coated pneumococci to human erythrocytes. After initial binding, serum-derived factor I was found to induce bacterial detachment from the erythrocyte. CONCLUSIONS: Pneumococci are able to adhere to red blood cells. Both the classical and lectin complement pathways are important for optimal C3b-coating of pneumococci for immune adherence. Bound pneumococci are detached from red blood cells by factor I. These findings are in line with the hypothesis of immune adherence in which human erythrocytes are able to bind pneumococci and target the bacteria to the reticulo-endothelial system in the spleen.     

Hydrocarbon toxicity: A review

Context. Clinical effects of hydrocarbon exposure have been reported since 1897. These substances are ubiquitous, and their exposures are common. The specific hydrocarbon and route of exposure will determine the clinical effect, and an understanding of this is helpful in the care of the hydrocarbon-exposed patient. Objective. To complete a comprehensive review of the literature on hydrocarbon toxicity and summarize the findings. Methods. Relevant literature was identified through searches of Medline (PubMed/OVID) and Cochrane Library databases (inclusive of years 1975–2013), as well as from multiple toxicology textbooks. Bibliographies of the identified articles were also reviewed. Search terms included combinations of the following: hydrocarbons, inhalants, encephalopathy, coma, cognitive deficits, inhalant abuse, huffing, sudden sniffing death, toluene, renal tubular acidosis, metabolic acidosis, arrhythmia, dermatitis, and aspiration pneumonitis. All pertinent clinical trials, observational studies, and case reports relevant to hydrocarbon exposure and published in English were reviewed. Chronic, occupational hydrocarbon toxicity was not included. Results. Exposure to hydrocarbons occurs through one of the following routes: inhalation, ingestion with or without aspiration, or dermal exposure. Inhalational abuse is associated with central nervous system depression, metabolic acidosis, and arrhythmia. The exact mechanism of the CNS depression is unknown, but experimental evidence suggests effects on NMDA, dopamine, and GABA receptors. Chronic toluene inhalation causes a non-anion gap metabolic acidosis associated with hypokalemia. Halogenated hydrocarbon abuse can cause a fatal malignant arrhythmia, termed “sudden sniffing death”. Individuals who regularly abuse hydrocarbons are more likely to be polysubstance users, exhibit criminal or violent behavior, and develop memory and other cognitive deficits. Heavy, long-term use results in cerebellar dysfunction, encephalopathy, weakness, and dementia. Neuroimaging may demonstrate leukoencephalopathy in these cases. Acute exposures improve with cessation of exposure. Electrolyte and fluid replacement will improve metabolic acidosis. Arrhythmias are precipitated via catecholamine surge, and beta blockers are presumed protective. Aspiration of hydrocarbons causes a potentially fatal pneumonitis. Symptoms may include cough, wheezing respiratory distress, and hypoxia. Bilateral interstitial infiltrates may be delayed for several hours after the development of pneumonitis. Treatment consists of supportive care, supplemental oxygen, and may require intubation and admission to an intensive care unit in severe cases. Unfortunately, aspiration pneumonitis remains a leading cause of poisoning mortality in children. Dermal exposure can cause dermatitis, chemical burns, and defatting injury. Oral exposure can cause local irritation as well as vomiting, diarrhea, and abdominal pain. Conclusion. Acute hydrocarbon exposure can result in a wide array of pathology, such as encephalopathy, pneumonitis, arrhythmia, acidosis, and dermatitis. Intentional inhalational and accidental ingestion exposures with aspiration lead to the greatest morbidity and mortality.     

Treatment of cocaine cardiovascular toxicity: a systematic review

Introduction: Cocaine abuse is a major worldwide health problem. Patients with acute cocaine toxicity presenting to the emergency department may require urgent treatment for tachycardia, dysrhythmia, hypertension, and coronary vasospasm, leading to pathological sequelae such as acute coronary syndrome, stroke, and death. Objective: The objective of this study is to review the current evidence for pharmacological treatment of cardiovascular toxicity resulting from cocaine abuse. Methods: MEDLINE, PsycINFO, Database of Abstracts of Reviews of Effects (DARE), OpenGrey, Google Scholar, and the Cochrane Library were searched from inception to November 2015. Articles on pharmacological treatment involving human subjects and cocaine were selected and reviewed. Evidence was graded using Oxford Centre for Evidence-Based Medicine guidelines. Treatment recommendations were compared to current American College of Cardiology/American Heart Association guidelines. Special attention was given to adverse drug events or treatment failure. The search resulted in 2376 articles with 120 eligible involving 2358 human subjects. Benzodiazepines and other GABA-active agents: There were five high-quality (CEBM Level I/II) studies, three retrospective (Level III), and 25 case series/reports (Level IV/V) supporting the use of benzodiazepines and other GABA-active agents in 234 subjects with eight treatment failures. Benzodiazepines may not always effectively mitigate tachycardia, hypertension, and vasospasm from cocaine toxicity. Calcium channel blockers: There were seven Level I/II, one Level III, and seven Level IV/V studies involving 107 subjects and one treatment failure. Calcium channel blockers may decrease hypertension and coronary vasospasm, but not necessarily tachycardia. Nitric oxide-mediated vasodilators: There were six Level I/II, one Level III, and 25 Level IV/V studies conducted in 246 subjects with 11 treatment failures and two adverse drug events. Nitroglycerin may lead to severe hypotension and reflex tachycardia. Alpha-adrenoceptor blocking drugs: There were two Level I studies and three case reports. Alpha-1 blockers may improve hypertension and vasospasm, but not tachycardia, although evidence is limited. Alpha-2-adrenoceptor agonists: There were two high-quality studies and one case report detailing the successful use of dexmedetomidine. Beta-blockers and β/α-blockers: There were nine Level I/II, seven Level III, and 34 Level IV/V studies of β-blockers, with 1744 subjects, seven adverse drug events, and three treatment failures. No adverse events were reported for use of combined β/α-blockers such as labetalol and carvedilol, which were effective in attenuating both hypertension and tachycardia. Antipsychotics: Seven Level I/II studies, three Level III studies, and seven Level IV/V case series and reports involving 168 subjects have been published. Antipsychotics may improve agitation and psychosis, but with inconsistent reduction in tachycardia and hypertension and risk of extrapyramidal adverse effects. Other agents: There was only one high level study of morphine, which reversed cocaine-induced coronary vasoconstriction but increased heart rate. Other agents reviewed included lidocaine, sodium bicarbonate, amiodarone, procainamide, propofol, intravenous lipid emulsion, propofol, and ketamine. Conclusions: High-quality evidence for pharmacological treatment of cocaine cardiovascular toxicity is limited but can guide acute management of associated tachycardia, dysrhythmia, hypertension, and coronary vasospasm. Future randomized prospective trials are needed to evaluate new agents and further define optimal treatment of cocaine-toxic patients.     

Epidemiology of human exposure to ultrasound: a critical review

Epidemiologic studies and surveys and widespread clinical usage over 25 years have yielded no evidence of any adverse effect from diagnostic ultrasound. Nonetheless, the inability to find convincing proof of an effect, either from epidemiology or from physicians' experience, does not preclude the possibility of it happening. Statistical reasoning shows that even with large population studies, it is difficult to identify a small increase in the rate of a commonly occurring event. Subtle effects, long-term delayed effects, and certain genetic effects, could easily escape detection.     

Assessment of bilirubin toxicity to erythrocytes. Implication in neonatal jaundice management

BACKGROUND: Neonatal hyperbilirubinaemia remains one of the most common clinical conditions requiring therapeutic intervention. Nevertheless, reliable indicators of bilirubin toxicity are still missing. This prompted us to investigate (a) the progression of cytotoxic events produced by increasing concentrations of bilirubin; (b) the relevance of the membrane lipid package on bilirubin binding to erythrocytes; and (c) the reliability of chloroform extraction compared with albumin extraction to evaluate erythrocyte-bound bilirubin and cytotoxicity. MATERIALS AND METHODS: Morphological alterations, free bilirubin, erythrocyte-bound bilirubin (albumin- and chloroform-extractable), haemolysis and membrane-released lipids, were determined in human erythrocytes at 4 degrees C or 37 degrees C, after 4 h incubation at pH 7.4, with increasing molar ratios of bilirubin to albumin (0.5-5). The reversibility of cytotoxicity by albumin washing was assessed by morphological analysis. RESULTS: Decreased free bilirubin, lower erythrocyte-bound bilirubin concentration by albumin extraction (superficial/non-aggregated bilirubin) and higher values by chloroform extraction (deep/aggregated bilirubin) were observed for 37 degrees C vs. 4 degrees C, at molar ratios > 1. Echinocytosis increased with bilirubin concentration and temperature and was not fully reversed by albumin washing. Haemolysis was already significant at a molar ratio of 1, and was enhanced by temperature at molar ratios 3 and 5 (P < 0.01). The loss of membrane lipids was remarkable at molar ratios > or = 0.5, both at 4 degrees C and 37 degrees C (P < 0.01), although correlation with bilirubin concentration was only significant at 37 degrees C (r = 0.971; P < 0.01). CONCLUSIONS: These results suggest that increased lipid fluidity and high bilirubin concentrations promote membrane bilirubin translocation and toxicity. They also show that albumin is not able to displace the bilirubin located deeply or aggregated within the membrane, which in turn is removed by chloroform. Accordingly, chloroform-extractable rather than albumin-extractable bilirubin is a more accurate parameter to assess erythrocyte-bound bilirubin during severe hyperbilirubinaemia.     

Methamphetamine-induced toxicity: An updated review on issues related to hyperthermia

Reports of methamphetamine-related emergency room visits suggest that elevated body temperature is a universal presenting symptom, with lethal overdoses generally associated with extreme hyperthermia. This review summarizes the available information on methamphetamine toxicity as it pertains to elevations in body temperature. First, a brief overview of thermoregulatory mechanisms is presented. Next, central and peripheral targets that have been considered for potential involvement in methamphetamine hyperthermia are discussed. Finally, future areas of investigation are proposed, as further studies are needed to provide greater insight into the mechanisms that mediate the alterations in body temperature elicited by methamphetamine.     

Bench-to-bedside review: Mechanisms and management of hyperthermia due to toxicity

Body temperature can be severely disturbed by drugs capable of altering the balance between heat production and dissipation. If not treated aggressively, these events may become rapidly fatal. Several toxins can induce such non-infection-based temperature disturbances through different underlying mechanisms. The drugs involved in the eruption of these syndromes include sympathomimetics and monoamine oxidase inhibitors, antidopaminergic agents, anticholinergic compounds, serotonergic agents, medicaments with the capability of uncoupling oxidative phosphorylation, inhalation anesthetics, and unspecific agents causing drug fever. Besides centrally disturbed regulation disorders, hyperthermia often results as a consequence of intense skeletal muscle hypermetabolic reaction. This leads mostly to rapidly evolving muscle rigidity, extensive rhabdomyolysis, electrolyte disorders, and renal failure and may be fatal. The goal of treatment is to reduce body core temperature with both symptomatic supportive care, including active cooling, and specific treatment options.     

Lipid infusion as a treatment for local anesthetic toxicity: a literature review

Local anesthetic toxicity can have catastrophic outcome in an otherwise benign procedure. Introduction of even a small amount of local anesthetic into the bloodstream can cause cardiac arrest in a healthy patient. Most healthcare facilities rely on standard resuscitative techniques to treat such events; however, treatment via infusion of lipid emulsion has been used successfully to stabilize the condition of some patients in a safe, effective, and rapid manner. The online databases consulted included Academic Search Premier, CINAHL, and MEDLINE. The key words included in the search were "Intralipid," "local anesthetic toxicity," "lipid infusion," and "lipid sink." Lipid therapy has shown great promise for the treatment of patients facing cardiovascular collapse due to local anesthetic toxicity. However, the slow adoption of this novel evidence-based practice by healthcare facilities endangers patients who may not receive the best available care when the need is most dire. Current evidence suggests that infusion of lipid emulsion should be considered among the primary treatments for local anesthetic toxicity and be made readily available in every facility's operating or procedure room, and hospital staff should be trained in its use when local anesthetic toxicity is suspected.     

The human gene map: a review

Genes are mapped to human chromosomes using many different methods: by somatic cell hybridization (by far the most fruitful method until now), by taking advantage of gene dosage effect in cases of chromosomal imbalance, and more recently by molecular hybridization which consists of techniques with great potential values. Some 350 autosomal loci have been assigned. They include genetic markers (blood groups), gene clusters such as the Ig, Hb, HLA genes, enzymatic markers, hereditary diseases (the morbid anatomy of the genome), and the recently discovered "micro-deletions" responsible, for instance, of certain types of childhood malignancies. The X- and Y-linked genes are also discussed.     

Chronic acetaminophen toxicity: a case report and review of the literature

Acetaminophen is one of the most frequently used medications in the United States. While usual dosing of acetaminophen is considered harmless, both acute and chronic overdoses can be fatal. The majority of reported cases of chronic acetaminophen toxicity in adults occur in chronic alcohol abusers, patients taking P450-inducing medications, or following massive dosing. We describe a case of toxic hepatitis free of the aforementioned risk factors associated with chronic ingestion of moderately excessive doses of acetaminophen. Our patient ingested approximately 5.0 to 6.5 g of acetaminophen daily for 6 to 8 weeks via multiple medications. The inclusion of acetaminophen in numerous medications combined with the frequency of use of acetaminophen necessitates an increased concern for not only acute but also chronic acetaminophen toxicity.     

Fatal pulmonary toxicity related to the administration of granulocyte colony-stimulating factor in amyloidosis: a report and review of growth factor-induced pulmonary toxicity

We report on a 59-year-old man with renal amyloidosis who died after three doses of granulocyte colony-stimulating factor were administered. Noncardiac pulmonary edema was precipitated by the growth factor. Autopsy revealed amyloid in the lung not visible by plain chest radiograph. Patients with amyloidosis who are candidates for stem cell transplantation and are mobilized with growth factors must be monitored for unexpected pulmonary toxicity. We review the in vitro experimental evidence as well as the clinical data on the pulmonary toxicity of growth factors.     

Bilirubin as a signaling molecule

For long time bilirubin was only considered as a potentially dangerous sign of liver diseases, but it now appears clear that it is also a powerful signaling molecule. Together with potent antioxidant activities that were only reported in the last few decades, many other biological effects have now been clearly described. These include especially profound inhibitory effects on almost all effectors of the immune system, with their clinical consequences in the bilirubin-mediated protection against autoimmune and inflammatory diseases. Separate from these, bilirubin activates various nuclear and cytoplasmic receptors, resembling the endocrine activities of actual hormonal substances. This is true for the “classical” hepatic nuclear receptors, including the aryl hydrocarbon receptor, or the constitutive androstane receptor; and also for some lesser-explored receptors such as peroxisome proliferator-activated receptors α and γ; Mas-related G protein-coupled receptor; or other signaling molecules including fatty acid binding protein 1, apolipoprotein D, or reactive oxygen species. All of these targets have broad metabolic effects, which in turn may offer protection against obesity, diabetes mellitus, and other metabolic diseases. The (mostly experimental) data are also supported by clinical evidence. In fact, data from the last three decades have convincingly demonstrated the protective effects of mildly elevated serum bilirubin concentrations against various “diseases of civilization.” Additionally, even tiny, micromolar changes of serum bilirubin concentrations have been associated with substantial alteration in the risks of these diseases. It is highly likely that all of the biological activities of bilirubin have yet to be exhaustively explored, and thus we can expect further clinical discoveries about this evolutionarily old molecule into the future.