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HISTORY AND EPIDEMIOLOGY
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During the last century there were several outbreaks of toxicity in the United States associated with pharmaceutical additives (Chap. 2). The 1937 Massengill sulfanilamide disaster is the most notorious of these epidemics. Diethylene glycol, an excellent solvent and potent nephrotoxin, was substituted for the additives propylene glycol and glycerin in the liquid formulation of a new sulfanilamide antibiotic because of lower cost.27,64,73 As a result, more than 100 people died from acute kidney failure.27 Outbreaks of acute kidney failure occurred when diethylene glycol was used to solubilize acetaminophen in South Africa, Bangladesh, Nigeria, and Haiti, cough syrup in Panama, and teething powder in Nigera.22,30,75,87,133,143
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In December 1983, a new parenteral vitamin E formulation (E-Ferol) was introduced. It contained 25 units/mL of α-tocopherol acetate, 9% polysorbate 80, 1% polysorbate 20, and water for injection. At the time, no premarketing testing was required for new formulations of an already approved drug. Several months after its release, a fatal syndrome in low-birth-weight infants, characterized by thrombocytopenia, acute kidney injury, cholestasis, hepatomegaly, and ascites, was described.1,119 Thirty-eight deaths and 43 cases of severe symptoms were attributed to E-Ferol. Vitamin E was thought to be the cause and E-Ferol was recalled from the market 4 months after its release. It is now believed that the polysorbate emulsifiers were responsible.1
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Although these additive-related occurrences are rare, relative to the frequency of pharmaceutical additive use, they illustrate the potential of pharmaceutical additive toxicity.
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Pharmaceuticals are labeled specifically to focus attention on the active ingredient(s) of a product, thus giving the misimpression that additive ingredients are inert and unimportant. Additives, or excipients as they are more properly termed, are necessary to act as vehicles, add color, improve taste, provide consistency, enhance stability and solubility, and impart antimicrobial properties to medicinal formulations. Although it is true that most cases of excipient toxicity involve exposure to large quantities, or to prolonged or improper use, these adverse events are nonetheless related to the toxicologic properties of the excipient.
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Prior to selecting the specific additives and quantity necessary for a drug formulation, the drug manufacturer must consider several factors, including the active ingredient’s physical form, its solubility and stability, the desired final dosage form and route of administration, and compatibility with the dispensing container materials. Often, the same active ingredient requires different excipients to impart appropriate pharmacokinetic characteristics to different dosage forms, such as in long-acting and immediate-release formulations. Similarly, multiple-dose injection vials containing the same active ingredients as single-dose vials specifically require the addition of a bacteriostatic xenobiotic not necessary for single-dose vials.
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Unlike requirements for active ingredients, there is no specific US Food and Drug Administration (FDA) approval system for pharmaceutical excipients. As such, the FDA determines the amount and type of data necessary to support the use of a specific excipient on a case-by-case basis. Under current practice, only excipients that were previously permitted for use in foods or pharmaceuticals are defined as generally recognized as safe (GRAS), or “GRAS listed.” All components of a pharmaceutical product, including excipients, must be produced in accordance with current good manufacturing practice standards to ensure purity. The Safety Committee of the International Pharmaceutical Excipients Council developed guidelines for the toxicologic testing of new excipients.172 Because of patent protection laws, it was not until 1985 that manufacturers were required to provide a list of inactive ingredients contained in all pharmaceutical products. Although it is becoming easier to identify pharmaceutical additives in products, information on their effects and the mechanisms by which they cause adverse responses are often unknown or difficult to obtain.
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This chapter summarizes the available literature on commonly used additives associated with direct toxicities (Table 46–1). Data on pharmacokinetics and mechanism of toxicity are presented when data are available. Although many additives are associated with hypersensitivity reactions, including anaphylaxis, these are not discussed because of their nonpharmacologic basis. However, excipients should always be considered as possibly causative in patients who develop hypersensitivity reactions.
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BENZALKONIUM CHLORIDE
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Benzalkonium chloride (BAC, BAK), or alkyldimethyl (phenylmethyl) ammonium chloride, is a quaternary ammonium cationic surfactant composed of a mixture of alkyl benzyl dimethyl ammonium chlorides. Although it is the most widely used ophthalmic preservative in the United States, it is also considered the most cytotoxic (Table 46–2).96,104 Benzalkonium chloride is also used in otic and nasal formulations, and in some small-volume parenteral preparations. The antimicrobial activity of BAC includes gram-positive and gram-negative bacteria, and some viruses, fungi, and protozoa. Because of its rapid onset of action, good tissue penetration, and long duration of action, BAC is preferred over other preservatives. The concentration of BAC in ophthalmic medications usually ranges from 0.004% to 0.01%.104 Strong BAC solutions (>0.1%) can be caustic (Chap. 103).
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Corneal epithelial cells harvested from human cadavers within 12 hours of death were exposed to a medium containing 0.01% BAC.168 The surfactant properties of BAC resulted in intracellular matrix dissolution and loss of epithelial superficial layers. Following exposure to the medium, mitotic activity ceased and degenerative changes to corneal epithelium were noted. During a 24-hour observation period, epithelial cell cytokinetic or mitotic activity did not occur. Patients with compromised corneal epithelia are at increased risk for the adverse effects of BAC.168
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Two case reports demonstrate the potential toxicity of BAC and highlight the difficulty of diagnosing BAC toxicity. A 36-year-old woman complained of decreased vision when she inadvertently switched from Lensrins, a contact lens cleaning solution, to Dacriose, an isotonic boric acid solution preserved with BAC. After 3 days, she had inflammation, pain, and decreased visual acuity. Examination of the cornea revealed many superficial punctate erosions of the epithelium. An in vitro experiment identified significant binding of BAC to soft contact lenses.59 In the second case, a 56-year-old man diagnosed with keratoconjunctivitis sicca was treated with topical antibiotics and artificial tears containing BAC. Following one year of continual use, the patient developed intractable pain, photophobia, and extensive breakdown of the corneal epithelium. Not suspecting the BAC-containing products, the patient continued to use the artificial tears solution for another 9 years despite continued pain and decreasing visual acuity. Replacement with a preservative-free saline solution resulted in resolution of pain, photophobia, and corneal changes.104 Furthermore, there are newer ophthalmic medication preservatives available (eg, polyquaternium-1, stabilized oxychloride complex, sodium perborate, Sof Zia), which in studies are less toxic than BAC.4
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A case series of corneal endothelial injury following the inadvertent intraocular use of balanced salt solution (BSS) preserved with BAC instead of preservative-free BSS in 12 patients undergoing phacoemulsification, a surgical technique to remove cataract lenses. The BSS was instilled in the anterior chamber. The operating room had run out of preservative-free BSS and, unbeknownst to the surgeon, it was replaced with the BAC-containing BSS, which contained 0.013% BAC. This is in excess of recommended concentration for intraocular use and is associated with corneal endothelial injury and edema. Within 48 hours of instillation of the BSS, the visual acuity in all 12 patients was limited to only being able to count fingers at 2 feet. This persisted in 11 of the patients at a 6-month follow-up evaluation after the instillation of the BSS. One patient had improvement at 6 months of visual acuity to 20/120 and 20/30 without and with pinholes, respectively.106
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Nasopharyngeal and Oropharyngeal Toxicity
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Human adenoidal tissue was exposed to oxymetazoline nasal spray preserved with BAC at concentrations ranging from 0.005 to 0.15 mg/mL for 1 to 30 minutes.16 Irregular and fractured epithelial cells occurred at all concentrations; however, these findings developed earlier and more frequently with the higher concentrations. The number of beating ciliary bodies also decreased as the duration and the concentrations increased. Benzalkonium chloride decreases the viscosity of the normal protective mucous lining of the naso- and oropharynx, resulting in cytotoxicity.
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Administration of one of 3 nasal corticosteroid sprays (beclomethasone dipropionate, flunisolide, budesonide) preserved with either 0.031% or 0.022% BAC in the right nostril of rats twice daily for 21 days caused squamous cell metaplasia and a decrease in the number of goblet cells, cilia, and mucus.17 No histologic changes occurred in rats receiving any of the preservative-free steroids or in tissue exposed to 0.9% sodium chloride solution administered into the left nostril as the control. Similarly, in another study, epithelial desquamation, inflammation, and edema occurred when 0.05% and 0.10% BAC was applied hourly to the nostrils of rats for 8 hours.99 No lesions developed in the nostrils of rats receiving 0.01% BAC.
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In an in vitro study, cultured human nasal epithelial cells were exposed to varying concentrations of BAC compared with another preservative, potassium sorbate (PS), with phosphate-buffered saline (PBS) as a control. Cell viability was greatly reduced at the higher concentrations of BAC compared with no decrease in cell viability in the PS or PBS groups. Additionally, at concentrations used clinically, loss of microvilli, destruction of cell membranes, and poor cytoskeletal alignment demonstrated by electron microscopy occurred.84
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An in vitro study of human nasal mucosa exposed mucosa to either fluticasone or mometasone preserved with either BAC or PS at various concentrations with subsequent measure of ciliary beat frequency. Although PS did not affect ciliary beat frequency at any concentration, BAC adversely affected ciliary beat frequency. At lower concentrations, BAC slowed ciliary beat frequency and brought it to standstill at higher concentrations.85 Another in vitro study in human nasal epithelial comparing budesonide, fluticasone propionate, azelastine hydrochloride, or levocabastine hydrochloride preserved with either BAC or PS at various concentrations showed similar results.92
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Polyquaternium-1 (PQ), an alternative detergent preservative to BAC, is reported to be less toxic to various cell types. In an in vitro study of cultured human corneal and conjunctival cells exposed to various topical glaucoma medications preserved with either BAC with concentrations ranging from 0.001% to 0.005% or PQ 0.04% with other arms using BSS as “live” control and 70% methanol and 0.2% saponin as “dead” controls, PQ had less cytotoxicity to both cell types compared to BAC.5 In an in vivo murine model comparing BAC concentrations 0.1% and 0.5% and PQ 0.1% and 0.5% to control BSS showed decreased tear production, increased corneal punctate lesions, increased in conjunctival injection, corneal neovascularization, and stromal inflammation in BAC compared to PQ and BSS.100 It is important to note that both of these studies5,100 involving PQ were funded by the manufacturer.
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Benzyl alcohol (benzene methanol) is a colorless, oily liquid with a faint aromatic odor that is most commonly added to pharmaceuticals as a bacteriostatic (Table 46–3). In 1982, a “gasping” syndrome, which included hypotension, bradycardia, gasping respirations, hypotonia, progressive metabolic acidosis, seizures, cardiovascular collapse, and death, was first described in low-birth-weight neonates in intensive care units.23,66 All the infants had received either bacteriostatic water or sodium chloride solution containing 0.9% benzyl alcohol to flush intravenous catheters or in parenteral medications reconstituted with bacteriostatic water or saline.23,66 The syndrome occurred in infants who had received more than 99 mg/kg of benzyl alcohol (range, 99–234 mg/kg).66 The World Health Organization (WHO) currently estimates the acceptable daily intake of benzyl alcohol to be not more than 5 mg/kg body weight.25
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In adults, benzyl alcohol is oxidized to benzoic acid, conjugated in the liver with glycine, and excreted in the urine as hippuric acid. Preterm babies have a greater ability to metabolize benzyl alcohol to benzoic acid than do term babies, but are unable to convert benzoic acid to hippuric acid, probably because of glycine deficiency. This results in the accumulation of benzoic acid (Fig. 46–1).66 A fatal case of metabolic acidosis was reported in a 5-year-old girl who received 2.4 mg/kg/h diazepam preserved with benzyl alcohol for 36 hours to control status epilepticus. Elevated benzoic acid concentrations were identified in serum and urine samples. The estimated daily dosage of benzyl alcohol was 180 mg/kg.66,107
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Benzyl alcohol is believed to have a role in the increased frequency of cerebral intraventricular hemorrhages and mortality reported in very-low-birth-weight (VLBW) infants (weight <1,000 g) who received flush solutions preserved with benzyl alcohol.83 An increased incidence of developmental delay and cerebral palsy was also noted in the same VLBW patients, suggesting a secondary damaging effect of benzyl alcohol.14
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There are several case reports of transient paraplegia following the intrathecal or epidural administration of chemotherapeutics or analgesics containing benzyl alcohol as a preservative.10,41,74,149 The local anesthetic effects are most likely responsible for the immediate paraparesis and limited duration of effects, rather than actual demyelination of nerve roots. In a rat study, lumbosacral dorsal root action potential amplitudes were measured after exposure to 0.9% or 1.5% benzyl alcohol solutions in either 0.9% sodium chloride solution or distilled water.74 Rats exposed to all benzyl alcohol solutions for less than one minute had inhibited dorsal root action potentials. This was attributed to the local anesthetic effects of benzyl alcohol as function was 50% to 90% restored after rinsing the nerves with 0.9% sodium chloride solution. Chronic intrathecal exposure to benzyl alcohol 0.9% over 7 days resulted in scattered areas of demyelination and early remyelination. The 1.5% benzyl alcohol solution–exposed dorsal nerve roots showed greater changes, with widespread areas of demyelination and fatty degeneration of nerve fibers.
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Chlorobutanol, or chlorbutol (1,1,1-trichloro-2-methyl-2-propanol), is available as volatile, white crystals with an odor of camphor. Chlorobutanol has antibacterial and antifungal properties and is widely used as a preservative in injectable, ophthalmic, otic, and cosmetic preparations at concentrations up to 0.5% (Table 46–4). Chlorobutanol also has mild sedative and local anesthetic properties and was formerly used therapeutically as a sedative–hypnotic.20 The lethal human chlorobutanol dose is estimated to be 50 to 500 mg/kg.128
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Central Nervous System Toxicity
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Chlorobutanol has a chemical structure similar to trichloroethanol (Fig. 72–1), the active metabolite of chloral hydrate, and is believed to exhibit similar pharmacologic properties. Central nervous system depression was reported in a 40-year-old alcoholic man who chronically abused Seducaps (formerly available in Australia and several other countries), a nonprescription hypnotic containing chlorobutanol as the active ingredient.20 On admission to the emergency department, he had drowsiness, dysarthria, slurred speech, and occasional episodes of myoclonic movements. His peak serum chlorobutanol concentration was 100 mcg/mL, decreasing to 48 mcg/mL over 2 weeks, with a half-life of 3 days based on serial declining concentrations. This is similar to human volunteer pharmacokinetic data following oral administration of chlorobutanol demonstrating an elimination half-life of 10.3 ± 1.3 days.170 His speech abnormality resolved after 4 weeks. Only chlorobutanol was detected in the patient’s urine or serum. In a second case, a possible central nervous system depressant effect from chlorobutanol was suggested in a 19-year-old woman treated with high doses of intravenous morphine preserved with chlorobutanol.47 She received approximately 90 mg/h of chlorobutanol for several days. Her peak serum chlorobutanol concentration was 83 mcg/mL, a concentration similar to that in the previous case report;20 however, the coadministration of morphine precludes the effects being attributed to chlorobutanol alone.
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Ketamine is neurotoxic when administered intrathecally to animals.116,117 The potential neurotoxic effects of chlorobutanol as a preservative in ketamine compared with preservative-free ketamine was studied in rabbits.117 Forty rabbits were given 0.3 mL intrathecally of either 1% preservative-free ketamine, 1% ketamine, 0.05% chlorobutanol, or 1% lidocaine as control. The rabbits were observed and hemodynamically monitored for 8 days and then euthanized. Histologic evaluation of the spinal cord as well as for blood–brain barrier lesions was performed. Seven of the 10 rabbits given intrathecal chlorobutanol showed both white and gray matter histologic changes as well as diffuse blood–brain barrier injury. No histologic changes were seen in either ketamine groups or the lidocaine group, and only one rabbit in each ketamine group had blood–brain barrier injury. These results suggest that chlorobutanol should not be administered intrathecally.117
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A case series of 5 patients were given intra-arterial papaverine preserved with 0.5% chlorobutanol,155 which is used to prevent cerebral vasospasm in patients with subarachnoid hemorrhage. Immediately after administration of papaverine in either the left, right, or bilateral anterior cerebral arteries, patients had an acute deterioration in neurologic status. Subsequent brain magnetic resonance imaging identified selective gray matter toxicity in the territories treated with papaverine. Postmortem brain histology in one patient also identified gray matter changes. The authors state the absence of white matter changes is not consistent with ischemic infarction but suggest direct toxic effect of either the papaverine or chlorobutanol. The manufacturer of the papaverine stated that no other reports had been made and the papaverine used came from 2 different lots; therefore, it is unclear if an unidentified independent variable caused these effects, but the authors caution using intra-arterial papaverine in patients with subarachnoid hemorrhage.155
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Chlorobutanol is a commonly used preservative in ophthalmic preparations and is less toxic to the eye than benzalkonium chloride.132 Chlorobutanol increases the permeability of cells by impairing cell membrane structure.168 An in vitro experiment using corneal epithelial cells harvested from human cadavers demonstrated arrested mitotic activity following chlorobutanol exposure.168 At the commonly formulated concentration of 0.5%, chlorobutanol can cause eye irritation, most likely due to cellular contraction of epithelial microfilaments, cessation of normal cytokinesis, cell movement, and mitotic activity.50 Degeneration of human corneal epithelial cells specifically manifested as membranous blebs, cytoplasmic swelling, and occasional breaks in the external cell membrane has also occurred at this concentration.50
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In general, there are 3 types of commercial intravenous lipid drug-delivery systems available: lipid emulsion, liposomal, and lipid complex (Table 46–5). Lipid emulsions are immiscible lipid droplets dispersed in an aqueous phase stabilized by an emulsifier (eg, egg, soy lecithin). Liposomes differ from emulsion lipid droplets in that they are vesicles composed of one or more concentric phospholipid bilayers surrounding an aqueous core. Lipophilic drugs are formulated for intravenous administration by partitioning them into the lipid phase of either an emulsion or liposome. Liposomes are capable of encapsulating hydrophilic xenobiotics within their aqueous core to exploit lipid pharmacokinetic properties.162 Attaching a therapeutic drug to a lipid to form a lipid complex is another way to take advantage of lipid pharmacokinetics.
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Lipid drug-delivery systems are biocompatible because of their similarity to endogenous cell membranes. They are created with stable lipid membranes resistant to hydrolysis or oxidation, to decrease toxicity, and to enhance therapeutic efficacy by altering drug pharmacokinetic and pharmacodynamic parameters. The biodistribution, and the rate of release and metabolism of a drug incorporated in a lipid drug-delivery system, is regulated by the type and concentration of oil and emulsifier used, pH, drug concentration dispersed in the medium, the size of the lipid particle, and the manufacturing process.134,162 Intravenous formulations are usually isotonic and have a pH of 7 to 8.162
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The rate of clearance of a lipid drug-delivery system from the blood depends on its physicochemical properties and the molecular weight of the emulsifier. Electrically charged lipid carriers are removed more rapidly than neutral particles.26,134 Smaller lipid particle size and high-molecular-weight emulsifiers decrease clearance. “Stealth” liposome formulations incorporate a polyethylene glycol coating that prevents rapid detection and clearance of liposomes by the reticuloendothelial system, prolonging circulation time.134 Active drug targeting is achieved by conjugating antibodies or vectors to side chains on the emulsifier.26,134 For a therapeutic drug available in more than one lipid drug-delivery systems (eg, amphotericin B), it is important to note that any change in the lipid formulation can alter the pharmacokinetic, pharmacodynamic, and safety parameters of the drug; consequently, they are not equivalent dosage formulations (Chap. 54).
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The physicochemical properties of lipid emulsions not only affect the therapeutic drugs carried by them, but the lipids themselves also have direct pharmacologic effects on the central nervous182 and immune systems.103 Lipid fatty acid mediators affect the membrane receptor channels of N-methyl-D-aspartate (NMDA) receptors, potentiating synaptic transmission.120,122,136,165 Dogs given a medium-chain triglyceride emulsion intravenous infusion developed dose-related central nervous system metabolic and neurologic effects, accompanied by electroencephalographic changes consistent with encephalopathy observed when serum octanoate concentration reached 0.5 to 0.9 mM.120 In an in vitro model, 3 of 9 lipid emulsions tested (Abbolipid, 20% soya and safflower oil; Intra-lipid, 20% soya oil; and Structolipid, 20% structured triglycerides) demonstrated a dose-related activation of cortical neuronal NMDA receptor channels.182 The lipid source for all but one (Omegaven, 10% fish oil) of the emulsions tested was made up solely or partially by soya oil. The authors could not explain why the other 6 lipid emulsions did not induce membrane currents. Adequate control for the nonlipid constituent contribution of these emulsions is lacking. In another in vitro study, the same authors found that NMDA-induced neuronal currents are reduced by an unknown factor in the aqueous portion of Abbolipid.183 This suggests that lipid emulsions pharmacologically enhance the anesthetic effect of hypnotics such as propofol. The clinical relevance of these studies remains to be determined.
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Triglycerides in parenteral nutrition emulsions are implicated in altering the immune system, leading to an increased susceptibility to infection,58,180 and altering lung function and hemodynamics in patients with acute respiratory distress syndrome.103 Phospholipid activation of phospholipase A2 may be an initiating cause.58,103,180 However, it is not clear if these immunologic effects are a consequence of factors other than the lipid in the emulsion.
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The parabens, or parahydroxybenzoic acids, are a group of compounds widely employed as preservatives in cosmetics, food, and pharmaceuticals because of their bacteriostatic, fungistatic, and antioxidant properties (Table 46–6).150 A survey conducted by the FDA identified the parabens as the second most common ingredients in cosmetic formulations, with water being the most common.108 Parabens are often used in combination, because the presence of 2 or more parabens are synergistic.107 Methylparabens and propylparabens are most commonly used.150 Pharmaceutical paraben concentrations usually range from 0.1% to 0.3%.144
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Widespread usage of parabens since the 1920s demonstrates a relatively low order of toxicity.108 However, because of their allergenic potential they are currently considered less suitable for injectable and ophthalmic preparations.144 Based on long-term animal studies, the WHO has set the total acceptable daily intake of ethylparabens, methylparabens, and propylparabens to be 10 mg/kg body weight.144 In addition to allergic reactions, parabens have the potential to cause other adverse effects. Bilirubin displacement from albumin-binding sites occurred with administration of methylparaben- and propylparaben-preserved gentamicin when serum parabens concentrations were 3 to 15 mcg/mL.43 Gentamicin alone has no effect on bilirubin displacement.109 Spermicidal activity was demonstrated in an in vitro study of human semen specimens exposed to local paraben concentrations of 1 to 8 mg/mL.160 Possible interference with conception and potential adverse effects on fertility were not investigated in this paper. However, other investigators show a direct toxic effect of parabens on sperm mitochondrial function.166 Sperm require an enormous amount of ATP to adequately fertilize ova.
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Concerns have arisen regarding the potential estrogenic and anti-androgenic effects of the parabens and their common metabolite, p-hydroxybenzoic acid. Xenobiotics with these effects are commonly referred to as endocrine disrupting substances. It has been suggested that methylparaben is less toxic than butyl and benzyl-parabens with regard to oxidative stress and resultant cytotoxicity.44,153 The clinical significance of these effects is not elucidated.34,45,141,142,175 There is a focus on the role of parabens and the development of breast cancer due to the estrogenic effects of parabens. In a study of breast tissue following mastectomies of women with primary breast cancer, concentrations of parabens were highest in the axillary region compared to other more medial regions. These authors suggest there may be a role of using cosmetics and deodorants under the arm increasing local estrogenic effects on breast tissue.12,77
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Phenol (carbolic acid, hydroxybenzene, phenylic acid, phenylic alcohol) is a commonly used preservative in injectable medications (Table 46–7). Phenol is a colorless to light pink, caustic liquid with a characteristic odor. When exposed to air and light, phenol turns a red or brown color.40 Phenol exerts antimicrobial activity against a wide variety of microorganisms, bacteria, mycobacteria, and some fungi and viruses.40 Phenol is well absorbed from the gastrointestinal tract, skin, and mucous membranes and is excreted in the urine as phenyl glucuronide and phenyl sulfate metabolites.40 Although there are numerous reports of phenol toxicity following intentional ingestions or unintentional dermal exposures (Chap. 103), adverse reactions to its use as a pharmaceutical excipient are uncommon, most likely because of the small quantities used.40
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Systemic toxicity from cutaneous absorption of phenol is reported. Ventricular tachycardia was observed in an 11-year-old boy following application of a chemical peel solution containing 88% phenol in water and liquid soap. The solution was applied to 15% of his body surface area for the treatment of xeroderma pigmentosum. Immediately following the onset of the ventricular tachycardia, the phenol-treated areas were irrigated, an infusion of 0.9% sodium chloride solution was begun, and 2 intravenous lidocaine boluses were given followed by a lidocaine infusion. The dysrhythmia persisted for 3 hours. The urinary phenol concentration the following day was 58.9 mg/dL.173 In a similar case, multifocal premature ventricular contractions were observed in a 10-year-old boy after application of a chemical peeling solution of 40% phenol, 0.8% croton oil in hexachlorophene soap, and water for the treatment of a giant hairy nevus.181 The premature ventricular contractions were refractory to intravenous lidocaine but resolved with intravenous bretylium. No phenol concentrations were obtained to confirm systemic absorption. In a case series of 181 patients undergoing chemical face peeling with phenol-based solutions, 12 demonstrated cardiac dysrhythmias. This occurred more commonly in patients with comorbid diabetes mellitus, hypertension, or treatment with antidepressants.101 Both lidocaine and propranolol treatment and pretreatment are reported to abate these dysrhythmias.101 However, these are anecdotal reports and have not been formally studied sufficiently to support recommending their use.21,70,169 Despite the risk of toxicity, phenol chemical peels are still used in some cases because phenol penetrates deep into tissues, providing both long-lasting and good cosmetic results. Most commonly, phenol chemical peels are used for deep acne scars and other severe skin disorders.
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A 9-year-old girl sustained partial-thickness burns over 17% of her body following the topical administration of Creolin, which contains phenolic compounds. The Creolin was applied by her mother to delouse the patient. Creolin is not intended for human use and is generally used as deodorant cleanser for bathrooms, kennels, and barns. The child had 8 ounces poured onto her hair, which then flowed onto her neck, chest, back, left shoulder, and upper arm. Within minutes she became obtunded, requiring endotracheal intubation by paramedics. In the emergency department, she had sinus tachycardia with brief runs of ventricular tachycardia. She was decontaminated with soap and water, low-molecular-weight polyethylene glycol and ethanol. The patient experienced a mild elevation of hepatic aminotransferases and had dark-green–black urine while in the intensive care unit. This resolved and the patient was extubated and discharged to home on hospital day 4.177
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Drowsiness, respiratory depression, and blue-colored urine were noted in a 6-month-old infant 12 hours after topical application of magenta paint over most of the body for seborrheic eczema.146 Magenta paint (also known as Castellani paint) was widely used for seborrheic eczema and contained 4% phenol, magenta, boric acid, resorcinol, acetone, and ethanol. Further investigation found that phenol was detected in urine samples of 4 of 16 other infants with seborrheic eczema who had approximately 11% to 15% of their body surface area painted with magenta paint for 2 days.
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Polyethylene glycols (PEGs; Carbowax, Macrogol) include several compounds with varying molecular weights (200–40,000 Da).140 They are typically available as mixtures designated by a number denoting their average molecular weight. Polyethylene glycols are stable, hydrophilic substances, making them useful excipients for cosmetics and pharmaceuticals of all routes of administration (Table 46–8). Pegylation, a process that modifies the pharmacokinetics of therapeutic liposomes and proteins (eg, peginterferon-α), is the most recent application of PEG. At room temperature, PEGs with molecular weights less than 600 Da are clear, viscous liquids with a slight characteristic odor and bitter taste. Polyethylene glycols with molecular weights higher than 1,000 Da are soluble solids and range in consistency from pastes and waxy flakes to powders.140 Commercially available products used for bowel-cleansing preparations and whole-bowel irrigation are solutions of PEG 3350 sometimes combined with electrolytes and known as PEG electrolyte lavage solution (Antidotes in Depth: A2).
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The solid, high-molecular-weight PEGs are essentially nontoxic. Conversely, low-molecular-weight PEG exposures cause adverse effects similar to the chemically related toxic alcohols ethylene and diethylene glycol (Special Considerations: SC9).30
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High-molecular-weight PEGs (>1,000 Da) are not significantly absorbed from the gastrointestinal tract, but low-molecular-weight PEGs are absorbed when taken orally.49,156,157 Topical absorption also occurs when PEGs are applied to damaged skin.24,163 Once in the systemic circulation, PEGs are mainly excreted unchanged in the urine;49 however, low-molecular-weight PEGs (eg, PEG 300, PEG 400) are partially metabolized by alcohol dehydrogenase to hydroxyacid and diacid metabolites. The pharmacokinetics of intravenously administered PEG 3350 Da has not been studied; however, it did not appear to have any systemic effects when unintentionally given by this route.145
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In rats fed various PEGs (200, 300, and 400) in their drinking water for 90 days, a solution of 8% PEG 200 produced renal tubular necrosis in all of the animals, followed by death within 15 days; however, a 4% PEG 200 solution resulted in only 2 of 9 rats dying within 80 days. A 16% PEG 400 solution killed all animals within 13 days; however, both 8% and 4% PEG 400 solutions had no observable effect except for a decrease in kidney weight when compared to control animals.158 A canine study administering daily high-dose PEG 400 intravenously, up to 8.45 g/kg/day, failed to show serious renal toxicity. However, edema of kidney cells and increased glomerular volume occurred at these dosages, but were reversible.105 Acute tubular necrosis was reported with oliguria, azotemia, and an anion gap metabolic acidosis following oral and topical exposures to low-molecular-weight PEGs (200 and 300). Acute kidney failure occurred in a 65-year-old man with a history of alcohol abuse and a seizure disorder after ingestion of the contents of a lava lamp containing 13% PEG 200.51 About 48 hours after admission (approximately 50–72 hours post ingestion), the patient became oliguric with an anion gap metabolic acidosis and acute kidney failure. Blood sampling confirmed traces of the lava lamp fluid; none was detected in the urine. After clinical complications from ethanol withdrawal and aspiration pneumonitis, the patient was discharged 3 months later with residual kidney dysfunction attributed to the PEG component of the lamp contents. Acute tubular necrosis was noted at autopsy of 6 burn patients treated with a topical antibiotic cream in a PEG 300 base.24,163 Mass spectrometry detected hydroxyacid and diacid metabolites in serum and urine samples. Oxalate crystals were seen in the urine of 2 cases. These effects were reproduced with the topical application of PEG for 7 days to rabbits with full-thickness skin defects.163
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There are reports of neurologic complications, such as paraplegia and transient bladder paralysis, following intrathecal corticosteroid injections containing 3% PEG as a vehicle.15,19 In an in vitro experiment, rabbit vagus nerves were exposed to concentrations of PEG 3350 ranging from 3% to 40% for one hour.15 A total of 3% and 10% PEG had no effect on nerve action potential amplitude or conduction velocity. Doses of 20% and 30% PEG significantly slowed nerve conduction and had varying effects on the amplitudes of action potentials. Forty percent PEG completely abolished action potentials. These changes were reversible and thought to be related to PEG-induced osmotic effects. The administration of PEG 1800 is a potential therapy for spinal cord injury by repairing damaged axons through cellular fusion of damaged cells following the short-term (2 minutes) application, in a guinea pig model. This increases compound action potential conduction.154 Interestingly, administering a similar dose of PEG continuously for 25 minutes decreased compound action potentials approximately 64% in both damaged and nondamaged isolated mammalian spinal cords, suggesting dose-response toxicity.38
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Another study in an ex vivo experiment of isolated injured spinal cords of Wistar rats showed combining hyperthermia (40°C) with various PEGs (400, 1000, and 2000) greatly improved compound action potential recovery compared to these PEGs at 25°C and 37°C. The lower-molecular-weight PEG 400 was the most effective. This occurs through PEG rapidly sealing damaged neuronal membranes.95
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Fluid, Electrolyte, and Acid–Base Disturbances
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Hyperosmolality was reported in 3 patients with burn surface areas ranging from 20% to 56% following repeated applications of Furacin, a topical antibiotic dressing containing 63% PEG 300, 32% PEG 4000, and 5% PEG 1000.24 Polyethylene glycol produces an osmotic effect that is greater than expected for its molecular weight.151 It is theorized that PEG increases osmolality by sequestering water through hydrogen binding, which reduces the availability of water to interact with solutes, thus increasing the chemical and osmotic activity of the solute. Hyperosmolality following the administration of a PEG-containing substance supports systemic PEG absorption.
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Two cases of metabolic acidosis were reported following administration of therapeutic dosages of an intravenous nitrofurantoin solution containing PEG 300.164 Similarly, an otherwise unexplained increased anion gap was reported in 3 patients being treated with a topical PEG-based burn cream.24 Metabolism of the lower-molecular-weight PEGs by alcohol dehydrogenase to hydroxyacid and diacid metabolites explained the metabolic acidosis.80
++
++
Propylene glycol (PG), or 1,2-propanediol, is a clear, colorless, odorless, sweet, viscous liquid employed in numerous pharmaceuticals (Table 46–9), foods, and cosmetics. Propylene glycol is used as a solvent and preservative with antiseptic properties similar to ethanol. The WHO has set the daily allowable intake of PG at a maximum of 25 mg/kg,184 or 1.75 g/day for a 70-kg person.
++
++
Propylene glycol is rapidly absorbed from the gastrointestinal tract following oral administration and has a volume of distribution of approximately 0.6 L/kg.118,160 When applied to intact epidermis, the absorption of PG is minimal. Percutaneous absorption occurs following application to damaged skin (eg, extensive burn surface areas). Approximately 12% to 45% of PG is excreted unchanged in the urine,48 the remainder is hepatically metabolized sequentially by alcohol dehydrogenase to lactaldehyde, which is metabolized further by aldehyde dehydrogenase to lactic acid. Lactic acid is also formed by another metabolite, methylglyoxal.131 Lactic acid is reduced to pyruvate catalyzed by lactate dehydrogenase.131 The terminal half-life of propylene glycol is reported to be between 1.4 and 5.6 hours in adults and as long as 16.9 hours in neonates.48,162
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Cardiovascular Toxicity
++
Intravenous preparations of phenytoin contain 40% PG to facilitate the dissolution of phenytoin. Nine years after intravenous phenytoin became available, several deaths were attributed to the rapid administration of phenytoin used for the treatment of cardiac dysrhythmias.65,171,195
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Cardiovascular effects reported in these cases included hypotension, bradycardia, widening of the QRS complex, increased amplitude of T waves with occasional inversions, and transient ST segment elevations. Studies in cats110 and calves71 confirmed PG as the cardiotoxin. Bradycardia and depression of atrial conduction were not observed in cats pretreated with atropine, or in those with vagotomy following rapid intravenous infusion of PG, suggesting that these effects are vagally mediated.110 Amplification of the QRS complex was noted in these same pretreated cats, also suggesting a direct cardiotoxic effect of PG. Similar results were reported in calves pretreated with atropine that received oxytetracycline in a PG vehicle.71
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Infants appear to have a decreased ability to clear PG when compared with older children and adults.111 An increased frequency of seizures was reported in low-birth-weight infants who received 3 grams of PG daily in a parenteral multivitamin preparation.111 Seizures developed in an 11-year-old boy receiving long-term oral therapy with vitamin D dissolved in PG.8 Serum, electrolytes, and blood glucose were normal. Seizures abated after the product was discontinued. Propylene glycol possesses inebriating properties similar to ethanol. Central nervous system depression was reported following an intentional oral ingestion of a PG-containing product.118
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A formerly available oral solution protease inhibitor amprenavir (Agenerase) had a black-box warning added to the product information for its high PG (550 mg/mL) vehicle content.148 The recommended daily dosage of amprenavir supplied 1,650 mg/kg/day of PG. A 61-year-old man experienced visual hallucinations, disorientation, tinnitus, and vertigo after receiving a 750-mg dose (474 mg/kg PG) of amprenavir solution.91
++
Otic preparations contain up to 94% PG in solutions and 10% in suspensions as part of their vehicles.54 In animal studies, application of high concentrations of PG (>10%) to the middle ear produced hearing impairment124,125,178 and morphologic changes, including tympanic membrane perforation, middle ear adhesions, and cholesteatoma.124,125,190 Although the effects of PG in the human middle ear have not been studied, all medications applied to the external ear canal are contraindicated in patients with perforated tympanic membranes.
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Fluid, Electrolyte, and Acid–Base Disturbances
++
Patients receiving continuous or large intermittent quantities of medications containing PG develop high PG concentrations, particularly those with renal or hepatic insufficiency.29,48 Propylene glycol–induced electrolyte and metabolic disturbances are evidenced by hyperosmolarity, and an elevated osmolar gap attributed to the osmotically active properties of PG. In most cases, both an elevated anion gap and elevated lactate concentration are present. Metabolic acidosis and hyperlactatemia result from PG metabolism.28 These adverse effects are typically reported with intravenous preparations such as lorazepam,7,76,86,192 diazepam,186 etomidate,174 nitroglycerin,48 pentobarbital,121 pediatric multivitamins,67 and topical silver sulfadiazine.13,55,98,185
++
Systemic absorption of PG from topical application of silver sulfadiazine cream55 resulted in hyperosmolality in patients with burn surface areas greater than 35% of their body.13,55,98,185 In one study, 9 of 15 burn patients had osmolar gaps (>12) after application of the cream.98 Similarly, a 3-year-old boy with extensive second- and third-degree burns over 60% body surface area developed a persistent elevated osmolar gap and metabolic acidosis with elevated lactate for approximately 20 days following application of silver sulfadiazine cream. Other potential etiologies were excluded. The osmolar gap and metabolic acidosis both resolved within 24 hours of discontinuing silver sulfadiazine.185
++
Hyperosmolarity occurred in 5 infants receiving a parenteral multivitamin that provided a daily PG dose of 3 g.67 After 12 days, one premature infant had a PG concentration of 930 mg/dL and an osmolar gap of 136. Anion gap and lactic acid concentrations were normal. Eleven intubated children aged 1 to 15 months who were receiving continuous lorazepam infusions over 3 to 14 days accumulated serum PG concentrations of 17 to 226 mg/dL; however, increases in osmolar gap or serum lactate concentrations were not significantly different from baseline.35 This was attributed to normal renal function and the low cumulative PG doses received (mean, 60 g).
++
A 72-year-old man died following the ingestion of the contents of a cold/hot therapy gel pack, which contained more than 99% of propylene glycol. Six hours after ingestion, he had an elevated osmolar gap accompanied by acute kidney injury. At 12 hours, he became comatose and an anion gap acidosis with a normal L-lactate concentration. He was found to have a very elevated D-lactate concentration, which was attributed to the PG ingestion. This patient had an extensive medical history and the course was complicated by multiorgan failure and death.94
++
Several small studies have found a strong correlation between elevated PG concentrations and increased osmolar gap measurements in critically ill patients receiving intravenous lorazepam and/or diazepam.7,187,191,192 An osmolar gap greater than 10 is suggested as a marker for potential PG toxicity.191 An osmolar gap of 20 corresponds to a serum PG concentration of approximately 48 mg/dL.7 These authors provide a formula to estimate PG concentrations based on the osmolar gap: [PG] = (–82.1 + [osmol gap × 6.5]). This equation should be used cautiously, as larger, more comprehensive studies are needed to validate it. In addition, elevated anion gap measurements and lactate concentrations occur. As PG toxicity mimics sepsis in these critically ill patients, sepsis should be excluded as the etiology of increased lactate, hypotension, and worsening renal function when considering PG toxicity. Hemodialysis is effective in removing PG and correcting acidemia. The administration of fomepizole should be considered with elevated PG concentrations to prevent further metabolism to lactic acid.135,194
++
Human proximal tubular cells exposed in vitro to PG concentrations of 500 to 2,000 mg/dL exhibited significant cellular injury and membrane damage within 15 minutes of exposure.127 Repeated exposure for up to 6 days produced dose-dependent toxic effects at lower concentrations (76, 190, and 380 mg/dL).126
++
The chronic administration of PG contributes to proximal tubular cell damage and subsequent decreased kidney function. In a retrospective study of 8 patients who developed elevations in serum creatinine concentration while receiving continuous lorazepam infusions, serum creatinine rose within 3 to 60 days (median, 9 days).192 The magnitude of serum creatinine rise was found to correlate with the serum PG concentration and duration of infusion. Serum creatinine decreased within 3 days of discontinuing the infusion. Patients with chronic kidney disease are at greater risk for accumulating PG because 45% of PG is eliminated unchanged by the kidneys;48 the remainder is metabolized by the liver. Caution should be used when prolonged administration of a PG-containing medication is necessary in the presence of renal or hepatic dysfunction.127
++
There are reports of propylene glycol–induced renal tubular necrosis. Daily PG vehicle dosages of 11 to 90 g/day over 14 days was associated with rising serum creatinine concentrations (0.7–2.1 mg/dL), elevated serum lactate concentrations, osmolar and anion gaps, and a serum PG concentration of 21 mg/dL.193 Urine sediment analysis revealed numerous granular, muddy-brown-colored casts and no eosinophils, suggesting an acute renal tubular necrosis. Kidney biopsy and electron microscopy showed extensive dilation of the proximal renal tubules, with swollen epithelial cells and mitochondria. Numerous vacuoles containing debris were also noted. A kidney biopsy of another case with a serum PG concentration of 30 mg/dL showed disrupted brush borders of the proximal renal tubules after a sudden rise in serum creatinine concentration (3.1 mg/dL), nonoliguric kidney failure, and metabolic acidosis. This was attributed to an average daily PG dose of 70 g for 17 days.76
++
++
Sorbitol (D-glucitol) is widely used in the pharmaceutical industry as a sweetener, moistening agent, and as a diluent (Table 46–10). Sorbitol occurs naturally in the ripe berries of many fruits, trees, and plants, and was first isolated in 1872 from the berries of the European mountain ash (Sorbus aucuparia).129 It is particularly useful in chewable tablets because of its pleasant taste. In addition, it is widely used by the food industry in chewing gums, dietetic candies, foods, and enteral nutrition formulations. Sorbitol is approximately 50% to 60% as sweet as sucrose.129
++
++
Unlike sucrose, sorbitol is not readily fermented by oral microorganisms and is poorly absorbed from the gastrointestinal tract. Any absorbed sorbitol is metabolized in the liver to fructose and glucose.129 Sorbitol has a caloric value of 4 kcal/g and is better tolerated by diabetics than sucrose; however, because some of it is metabolized to glucose, it is not unconditionally safe for people with diabetes and is obviously not “dietetic.”129
++
There is a concern of potentially fatal toxicity for individuals with hereditary fructose intolerance (HFI) receiving sorbitol-containing xenobiotics.56 Hereditary fructose intolerance is an autosomal recessive disorder caused by a deficiency of fructose-1,6-bisphosphonate aldolase in the liver, kidney, cortex, and small intestine.93 This results in the accumulation of fructose-1-phosphate, which prevents glycogen breakdown and glucose synthesis causing hypoglycemia. The prevalence of HFI is most commonly reported to be one in 20,000 persons, but can range between one in 11,000 and one in 100,000.2,90,93
++
There are reports of death following the prolonged administration of sorbitol, fructose, or sucrose in individuals with HFI.39,152 Dietary exclusion of fructose, sucrose, and sorbitol prevents the adverse effects. This condition should not be confused with the more common disorder of dietary fructose intolerance, which is caused by a defect in the glucose-transport protein 5 system. This defect leads to the breakdown of fructose to carbon dioxide, hydrogen, and short-chain fatty acids by colonic bacteria, resulting in abdominal pain and bloating.102 This latter syndrome is a potential cause of chronic abdominal pain in childhood.69 Dietary fructose intolerance symptoms are minimized by limiting sorbitol, fructose, and sucrose in the diet.
+++
Gastrointestinal Toxicity
++
In large dosages, sorbitol causes abdominal cramping, bloating, flatulence, vomiting, and diarrhea. Sorbitol exerts its cathartic effects by its osmotic properties, resulting in fluid shifts within the gastrointestinal tract. Iatrogenic osmotic diarrhea is reported following administration of many different liquid medication formulations containing sorbitol.82,112 In a human volunteer study, 42 healthy adults ingested 10 g of a sorbitol solution. Sorbitol intolerance was detected in up to 55% of participants.89 One theoretical explanation for why all participants did not experience the gastrointestinal adverse effects is unrecognized dietary fructose intolerance. Diarrhea resulting from sorbitol-containing medications is common and often overlooked as a possible etiology.56,82 Ingestion of large quantities of sorbitol (>20 g/day in adults) is not recommended (Antidotes in Depth: A2).129
++
++
Thimerosal (Merthiolate, Mercurothiolate), or sodium ethylmercurithiosalicylate, is an organic mercury compound that is approximately 49% elemental mercury (Hg°) by weight.147,179 It is metabolized to ethylmercury and thiosalicylate. Thimerosal has a wide spectrum of antibacterial activity at concentrations ranging from 0.01% to 0.1%; however, higher concentrations are sometimes also used topically as an antiseptic.123,147 Thimerosal has been widely used as a preservative since the 1930s in contact lens solutions, biologics, and vaccines, particularly those in multidose containers (Table 46–11). The use of thimerosal, which is necessary for the production process of some vaccines (eg, pertussis, influenza), leaves trace amounts in the final product.11 High-dose thimerosal exposure resulted in neurotoxicity and nephrotoxicity. Although concerns exist regarding infant exposure to low-dose thimerosal through vaccinations and its effects on neurodevelopment, including possible links to causes of autism,18 these concerns are unfounded (Chap. 95).46
++
++
Because specific guidelines for ethylmercury exposure have not been developed, regulatory guidelines for dietary methylmercury exposure were applied to monitor ethylmercury exposure from injected thimerosal-containing vaccines. Methylmercury is a similar, but more toxic, organic mercury compound (Chap. 95). Maximum daily recommended methylmercury exposures range from 0.1 mcg Hg/kg (US Environmental Protection Agency {EPA}) to 0.47 mcg Hg/kg (WHO).3,32,37
++
An FDA review of thimerosal-containing vaccines revealed that some infants, depending on the immunization schedule, vaccine formulations, and infant’s weight, might be exceeding the EPA exposure limit of 0.1 mcg Hg/kg/day for methylmercury. Over the first 6 months of life, a total cumulative dose of up to 187.5 mcg Hg total from thimerosal-containing vaccines was possible. The US Public Health Service and the American Academy of Pediatrics jointly responded by recommending the preemptive reduction or removal of thimerosal from vaccines wherever possible.3,31 The WHO and European regulatory bodies have similar recommendations.57 To date, thimerosal has been removed from most US-licensed immunoglobulin products. All vaccines routinely recommended for children younger than 7 years are either thimerosal-free or contain only trace amounts (<0.5 mcg Hg/dose), with the exception of some inactivated influenza vaccines. Multidose vials requiring thimerosal preservative remain important for immunization programs in developing countries because of a lack of ability to consistently refrigerate vaccines. Although efforts continue to eliminate all sources of mercury exposure, complete elimination of thimerosal from all vaccines is unlikely in the near future.11 When a thimerosal-containing vaccine is the only alternative, the benefits of vaccination far exceed any theoretical risk of mercury toxicity.130
++
Prior to thimerosal use in pharmaceuticals, evidence for its safety and effectiveness was provided in several animal species and in 22 humans.139 Only limited data exist on infant mercury exposure from thimerosal-containing vaccines. Clinical studies that assess the effects of thimerosal exposure on neurodevelopment and renal and immunologic function are lacking. Based on a comprehensive review of epidemiologic data from the United States,36,60,63,167,179 Denmark,114,115 Sweden,161 and the United Kingdom,6,81 the Institute of Medicine’s Immunization Safety Review Committee,130 the Global Advisory Committee on Vaccine Safety,189 and the European Agency for the Evaluation of Medicinal Products52 have all concluded that no causal relationship exists between thimerosal-containing vaccines and autism. Continued surveillance of autistic spectrum disorders as thimerosal use declines will be conducted to evaluate any associated trends.
++
Limited pharmacokinetic data exist for thimerosal and ethylmercury. Once absorbed, thimerosal breaks down to form ethylmercury and thiosalicylate. Some ethylmercury further decomposes into inorganic mercury in the blood, and the remainder distributes into kidney and, to a lesser extent, brain tissue.114,115 Because of its longer organic chain, ethylmercury is less stable and decomposes more rapidly than methylmercury, leaving less ethylmercury available to enter kidney and brain tissue.114 Ethylmercury crosses the blood–brain barrier by passive diffusion.115 Intracellular ethylmercury decomposes to inorganic mercury, which accumulates in kidney and brain tissues.115 The half-life of thimerosal is estimated to be about 18 days.115 Thimerosal is eliminated in the feces as inorganic mercury (Chap. 95).138
+++
Mercury or Thimerosal Toxicity
++
A case report described a 44-year-old man who ingested 5 g (83 mg/kg) of thimerosal in a suicide attempt; within 15 minutes, he began vomiting spontaneously. Gastric lavage was performed and chelation therapy begun with dimercaptopropane sulfonate. Gastroscopy revealed a hemorrhagic gastritis. Acute kidney injury was noted on the day of admission and persisted for 40 days. Four days after admission, the patient developed fever and a maculopapular exanthem attributed to thimerosal. The patient also developed an autonomic and ascending peripheral polyneuropathy that persisted for 13 days. Chelation therapy was continued for a total of 50 days with dimercaptopropane sulfonate followed by succimer. Elevated blood and urine mercury concentrations persisted for more than 140 days. The patient was discharged 148 days following the ingestion with only sensory defects in his toes. No other neurologic sequelae were noted.137
++
Oral absorption of thimerosal resulted in the fatal poisoning of an 18-month-old girl from the intra-otic instillation of a solution containing 0.1% thimerosal and 0.14% sodium borate. Tympanostomy tubes placed one year earlier allowed the irrigation solution to flow through the auditory tube into the nasopharynx, and subsequently to be swallowed and absorbed through the oral mucosa and gastrointestinal tract. A total of 1.2 L of solution (500 mg Hg) was instilled over a 4-week period, resulting in severe mercury poisoning. Four days after admission, the serum mercury concentration was 163 mcg/dL. The patient also received 1.7 g of boric acid. It is unclear what contribution, if any, the boric acid made to the serum mercury concentration. Chelation therapy with N-acetyl-D-penicillamine was initiated on day 51. Despite increased urinary mercury concentrations following administration of the N-acetyl-D-penicillamine, her neurologic function and blood mercury concentrations remained unchanged. The child died 3 months after admission. An autopsy was not performed.147
+++
Intramuscular Administration
++
Urine mercury concentrations of 26 patients with hypogammaglobinemia, who received weekly intramuscular immunoglobulin G (IgG) replacement therapy preserved with 0.01% thimerosal, were studied. The dosages of IgG ranged from 25 to 50 mg/kg, containing 0.6 to 1.2 mg of mercury per dose.72 The total estimated dose of mercury administered ranged from 4 to 734 mg over a period of 6 months to 17 years. Urine mercury concentrations were elevated in 19 patients, ranging from 31 to 75 mcg/L; however, no patients had clinical evidence of chronic mercury toxicity.72
++
Six cases of severe mercury poisoning resulting in 4 deaths were reported following the intramuscular administration of chloramphenicol preserved with thimerosal. A manufacturing error produced vials containing 510 mg of thimerosal (250 mg Hg) instead of 0.51 mg per vial. Two adults received 4 and 5.5 g of mercury each and 4 children received 0.2 to 1.8 g each. All 6 patients had extensive tissue necrosis at the site of injection. Fever, altered mental status, slurred speech, and ataxia were noted. Autopsy identified widespread degeneration and necrosis of the renal tubules; however, creatine kinase concentrations were not reported, so pigment-induced nephrotoxicity cannot be excluded. Elevated mercury concentrations were found in the injection site tissues, and in the kidneys, livers, and brains.9
+++
Topical Administration
++
Thirteen infants were exposed to 9 to 48 topical applications of a 0.1% thimerosal tincture for the treatment of exomphalos. Analysis for elevated mercury concentrations was performed in 10 of 13 infants who unexpectedly died. Mercury concentrations were determined in various tissues from 6 of the infants. Mean tissue concentrations in fresh samples of liver, kidney, spleen, and heart ranged from 5,152 to 11,330 ppb, suggesting percutaneous absorption from these repeated topical applications.53
+++
Ophthalmic Administration
++
Nine patients undergoing keratoplasty were exposed to a contact lens stored in a solution containing 0.002% thimerosal.188 After 4 hours, the lens was removed and mercury concentrations of the aqueous humor and excised corneal tissues were determined. Mercury concentrations were elevated in both aqueous humor (range, 20–46 ng/mL higher) and corneal tissues (range, 0.6–14 ng/mL higher) as compared with eyes that had not been fitted with contact lenses. Only residual amounts of mercury remained on the contact lenses after 4 hours of wear. The authors noted that although the aqueous humor concentrations were in the same range as those measured in 10 patients with vision loss from systemic mercury poisoning (11–104 ng/mL), adverse effects did not occur.
++
A possible drug interaction between orally administered tetracyclines and thimerosal was reported to result in acute, varying degrees of eye irritation in contact lens wearers using thimerosal-containing contact lens solutions who started treatment with tetracycline.42
++
The benefits of pharmaceutical excipients include improved xenobiotic solubility, stability, and palatability, antimicrobial activity, the availability of various dosage forms, the provision of products with long-term storage, and the availability of multiple-dose packaging. Although excipients are essential and effective, they are suggested to possess no pharmacologic or toxicologic properties but are actually responsible for severe—and sometimes fatal—adverse effects.
The toxicity of pharmaceutical excipients should be evaluated in patients requiring high doses or prolonged administration of any medication containing excipients, particularly those additives known to have toxicities.
Under circumstances in which there is no option but to continue treating a patient with a particular xenobiotic, switching to a preservative-free product, or to another brand without the offending excipient, should obviate the need for discontinuation of an effective xenobiotic. In addition to inherent toxicities, many excipients are also responsible for allergic reactions.
In the majority of cases, pharmaceutical excipients are safe and effective, and their benefits far exceed their potential for adverse effects when properly administered.
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