Expert Opinion - Ototoxic Drugs

Review
Anti-infectives
1. Introduction 2. Anatomy and physiology of the inner ear 3. Aminoglycoside antibiotics 4. Other ototoxic drugs
Understanding drug ototoxicity: molecular insights for prevention and clinical management
Joshua G Yorgason, Jose N Fayad & Federico Kalinec
Ear Institute, Gonda Department of Cell and Molecular Biology, 2100 W. 3rd Street, Los Angeles, CA 90057, USA
House
Expert Opin. Drug Saf. Downloaded from www.informahealthcare.com by Newcastle University on 09/08/09 For personal use only.
5. Ototoxic drugs in pregnancy, infancy and childhood 6. Clinical management 7. Conclusion 8. Expert opinion
Ototoxicity is a trait shared by aminoglycoside and macrolide antibiotics, loop diuretics, platinum-based chemotherapeutic agents, some NSAIDs and antimalarial medications. Because their benefits in combating certain life-threatening diseases often outweigh the risks, the use of these ototoxic drugs cannot simply be avoided. In this review, the authors discuss some of the most frequently used ototoxic drugs and what is currently known about the cell and molecular mechanisms underlying their noxious effects. The authors also provide suggestions for the clinical management of ototoxic medications, including ototoxic detection and drug monitoring. Understanding the mechanisms of drug ototoxicity may lead to new strategies for preventing and curing drug-induced hearing loss, as well as developing new pharmacological drugs with less toxic side effects.
Keywords: aminoglycoside, auditory system, drug ototoxicity, hair cells, inner ear, vestibular system Expert Opin. Drug Saf. (2006) 5(3):383-399
1. Introduction
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Drug ototoxicity is defined as a temporary or permanent inner ear dysfunction after drug exposure, resulting in a hearing and/or balance disturbance. It represents one of the main preventable causes of deafness, an outcome that can perhaps be most directly influenced by healthcare professionals. Although the use of ototoxic drugs in humans should be avoided, this is not always possible because the benefits of these drugs in combating life-threatening diseases often outweigh the risks. Understanding the current clinical and basic information about drug ototoxicity may help healthcare workers to better manage patients who may require these medications and who may develop ototoxic symptoms. Case reports and clinical studies identify the relevance of these drugs in the healthcare setting. Extensive research in animal models, as well as cell and molecular research, provides further insights into drug ototoxicity and could lead to novel therapies to prevent or ameliorate drug-induced hearing loss and balance disturbances. Here, the authors review the current clinical and basic research literature on drug ototoxicity. Suggestions for the clinical management of ototoxic medications, including an emphasis on ototoxicity detection and drug monitoring are given. The authors hope this information will help healthcare professionals in the clinical setting, and encourage further basic and clinical research on drug ototoxicity.
2. Anatomy
and physiology of the inner ear
Sound travels along the outer ear canal to the tympanic membrane and is then transmitted, via the bones of the middle ear, to the inner ear where the sensory organs reside (Figure 1a). The inner ear contains six anatomically separate sensory epithelia.
10.1517/14740338.5.3.383 2006 Informa UK Ltd ISSN 1474-0338
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Five of them (two maculi and three cristae) are part of the vestibular system, which control balance (Figure 1b). The auditory epithelium is located in the cochlea (Figure 1b,c). The human cochlea is a coiled tube, 30 mm long, divided into 3 parallel ducts: the scala vestibuli, the scala tympani, and the scala media (Figure 1c,d). The scala tympani and the scala vestibuli, which are connected at the cochlear apex, contain perilymph, a medium similar to cerebrospinal fluid. The scala media houses the auditory epithelium, commonly known as the organ of Corti. The scala media contains endolymph, a fluid with high levels of potassium (K+) ions. Consequently, the electrical potential of the endolymph is 80 90 mV higher than that of the perilymph (Figure 1e). This difference in perilymphendolymph electrical potential is called the endocochlear potential (EP), and it is essential for cochlear function. In order to maintain the EP, K+ ions are pumped into the scala media by cells of the stria vascularis, located in the lateral wall of the cochlear duct (Figure 1d,e). The organ of Corti is a thin epithelium composed of sensory and supporting cells (Figure 1f). The sensory cells are called hair cells (HCs) because they have an apical bundle of stereocilia. There are 3500 inner hair cells (IHCs), arranged in a single row, and 12,000 outer hair cells (OHCs) distributed in three parallel rows. The IHCs are the primary sensory receptors, providing afferent input to the CNS. The OHCs, in contrast, are responsible for frequency discrimination and signal amplification. IHCs and OHCs are arranged tonotopically, with the basal and apical ends of the cochlea detecting and encoding high and low frequency sounds, respectively. The HC stereocilia are connected by short extracellular links that maintain the integrity of the bundle, and by specialised tip-links that connect the tips of the shorter stereocilia to the body of their longer neighbours. Sound-induced deflection of the hair bundles increases or decreases the stress on the tip-links and regulates the gating of a small number of mechanosensitive ion channels in the stereociliar membrane. These channels regulate the electrical potential across the plasma membranes of IHCs and OHCs by controlling the flow of K+ and Ca2+ ions into the cells. In IHCs, these electrical changes induce release of neurotransmitters, initiating a cascade of signals that proceed along the auditory nerve to the hindbrain and ultimately to the auditory cortex via the central auditory pathways. In OHCs, the plasma membrane contains a semicrystalline array of a protein called prestin, which alters its conformation in response to changes in membrane potential. Simultaneous conformational changes in hundreds of thousands of prestin molecules lead to significant changes in cell length (shortening and elongation) that follows cycle-by-cycle the sonic stimulus. These changes in OHC length increase 100-fold the peak amplitude of organ of Corti vibrations, enhancing hearing sensitivity by 40 60 dB. The electrically-induced changes in OHC length are termed OHC electromotility, and the resulting amplification of the movement of the cochlear partition is known as cochlear amplification.
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The activity of OHCs can be detected by otoacoustic emissions (OAEs) testing.

3. Aminoglycoside
antibiotics
The ototoxicity of aminoglycoside (AG) antibiotics is well established. The clinical use of AG antibiotics, first developed to treat tuberculosis, has evolved to include the treatment of a number of bacterial infections that do not respond to classic penicillin-like drugs, the so-called -lactam antibiotics. All AGs are either produced by a variety of soil fungi, Actinomycetes, or synthetically derived from their products. Those belonging to the Streptomyces family are identified with the suffix mycin (e.g., streptomycin), whereas those from the Micromonospora family contain the suffix micin (e.g., gentamicin) [1]. The suffix of synthetic drugs usually reflects the drug from which they were derived (e.g., the suffix kacin in amikacin and other derivatives of kanamycin) [2]. AGs are bactericidal in a multistep pattern of action, including plasma membrane disruption, drug uptake and intracellular binding to ribosomal subunits and other cellular machinery [3]. Protein translation is thus inhibited, undermining vital organism functions and leading to an excess of toxic intermediate metabolite proteins. AGs are especially effective against Gram-negative bacteria, such as Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. Many AGs are also synergistic with -lactam antibiotics against Gram-positive organisms. Although AGs affect both cochlear and vestibular function, they can predominantly cause damage to the vestibular system (e.g., gentamicin, streptomycin), to the cochlea (e.g., neomycin, kanamycin, amikacin), or affect both systems equally (e.g., tobramycin). The overall incidence of AG ototoxicity in patients has been estimated at 7.5%, but the incidence of specific cochlear or vestibular toxicity depends on the drug [4]. For example, the incidence of cochlear and vestibular toxicity for gentamicin are 8 and 14%, respectively, whereas for amikacin they are 5 and 13%, respectively [4].
3.1 Early AGs: streptomycin, dihydrostreptomycin, neomycin and kanamycin
The first AG antibiotic, streptomycin, was isolated in 1944 [5] and it has been mainly used in the treatment of tuberculosis. The use of dihydrostreptomycin, a streptomycin derivative which proved to be more cochleotoxic and less predictable, has been discontinued [6]. Neomycin, which is potently toxic primarily to the cochlea, was restricted to topical use. Kanamycin, an AG structurally similar to neomycin and equally ototoxic [7], was commonly used against severe Gram-negative organisms since the early 1960s until it was found to be ineffective against pseudomonal infections [8]. Although it is indicated for severe infections of sensitive organisms, in multi-drug tuberculosis regimens and for hepatic encephalopathy, kanamycin has essentially been replaced by newer AGs that have better antipseudomonal activity [9].
Expert Opin. Drug Saf. (2006) 5(3)
Yorgason, Fayad & Kalinec
Figure 1. Anatomy of the inner ear. a) Sound is conducted through the outer ear to the tympanic membrane, and via the bones of the middle ear to the inner ear. Artwork courtesy of House Ear Institute. b) The inner ear includes the vestibular and the auditory systems. The vestibule contains five sensory epithelia, three cristae and two maculi. The auditory epithelium, named organ of Corti, is located inside the cochlea. Modified from von Ebner. c) Section through a human cochlea. Image kindly supplied by Dr Fred Linthicum. d) Second turn of a guinea-pig cochlea. Note the stria vascularis on the lateral wall of the cochlear duct, and the organ of Corti between the scala tympani and the scala media. e) Diagram of a section through one turn of the cochlea. The ST and the SV are filled with perilymph, whereas the SM contains endolymph. The organ of Corti sits on top of the basilar membrane and potassium ions are pumped into the scala media by the stria vascularis. Note that only the apical surface of the organ of Corti cells are in contact with the endolymph. Modified from N Slepecky, in: The Cochlea, Dallos, Popper & Fay (Eds.), New York, Springer (1996) with permission. f) Artistic representation of the organ of Corti. Note the single row of IHCs and the three rows of OHCs. Modified from DJ Lim, Hear. Res. (1986) 22:117-146 [225] with permission. g) Scanning electron microscopy of the surface of the guinea-pig organ of Corti from above, with the tectorial membrane removed. Note the hair bundles of IHCs and OHCs. Scale bar = 10 m. h) Similar to g. In this case, however, the cochlea belongs to a newborn guinea-pig exposed to gentamicin in uterus. OHCs have been lost and supporting cells have repaired the epithelial surface.
BM: Basilar membrane; IHC: Inner hair cell; OHC: Outer hair cell; SC: Supporting cell; SM: Scala media; ST: Scala tympani; SV: Scala vestibule; TM: Tectorial membrane.
3.2 Modern AGs: gentamicin, tobramycin, amikacin and netilmicin
Gentamicin is currently the drug of choice for the treatment of many serious bacterial infections because of its low cost, its reliable activity against all but the most resistant Gram-negative aerobes, and its synergism against Gram-positive bacteria such as Staphylococcus aureus [10]. Like other AGs, it is nephrotoxic and ototoxic and is almost entirely excreted unchanged by the kidneys [11]. Hence, patients with poor renal function are more at risk of its side effects. One prospective study showed that 39% of patients exposed to gentamicin developed ototoxicity, and the majority had good recovery after one year, as measured by horizontal canal vestibulo-ocular function [12]. Like streptomycin, gentamicin is more vestibulotoxic than cochleotoxic, and this feature is used advantageously to treat Menieres disease (a syndrome of episodic attacks of dizziness, or vertigo, accompanied by aural fullness and mild transient hearing loss) [13]. Gentamicin is administered intratympanically for unilateral Menieres disease, whereas streptomycin is given intramuscularly to treat bilateral Menieres disease. A recent meta-analysis showed that therapeutic doses of intratympanic gentamicin for Menieres
disease was not likely to be cochleotoxic [14]. Transmastoid labrynthectomy is a surgical alternative reserved for medically intractable cases of Menieres disease because, unlike intratympanic gentamicin, it results in total hearing loss on the side of surgery [15]. One downside to gentamicin is that it has become ineffective against some strains of bacteria, especially Pseudomonas and Serratia marcescens. Strains of Pseudomonas aeruginosa that were resistant to gentamicin, neomycin and kanamycin, were found to be sensitive to tobramycin, which apparently has greater intrinsic antipseudomonal activity and is preferred over other AGs in treating gentamicin-resistant strains [16]. Tobramycin is used in intravenous form, which is most likely to cause toxicity, to treat susceptible strains of bacteria causing severe infections including peritonitis, septicemia and meningitis [1]. Its topical use for eye infections, on the other hand, is regarded as safe because of poor systemic penetration. Tobramycin is also used in aerosolised inhaled form to treat pseudomonal respiratory infections in cystic fibrosis patients because it provides high doses to the lungs but keeps systemic serum concentrations low. One clinical study showed that this inhaled form was not associated with hearing loss [17], and
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another report showed that tobramycin causes transient tinnitus, or ringing in the ears, in some patients [18]. Amikacin, a semisynthetic AG derived from kanamycin but less ototoxic, is also particularly effective against Pseudomonas and other gentamicin-resistant Gram-negative bacteria [6]. Netilmicin, a semisynthetic AG antibiotic available in the UK but not in the US, has broad coverage of Gram-negative organisms and is synergistic with -lactam antibiotics, probably more so than other AGs [11]. It is fast-acting and effective at relatively low concentrations, features that theoretically could prove less ototoxic. However, at least one prospective, randomised, blinded study in humans suggests that netilmicin is no less ototoxic than gentamicin and amikacin [19]. In another prospective clinical trial of 89 patients, 26% of those treated with netilmicin showed decreased auditory thresholds compared with 11% of those given tobramycin [20]. A clinical trial in 202 patients showed no difference in ototoxicity between netilmicin and amikacin, but that netilmicin was less effective against Pseudomonas and more likely to cause nephrotoxicity [21]. The relative ototoxicity of AGs based on cochlear perfusion studies and correlated with a number of animal and clinical observations is, from most to least ototoxic, as follows: neomycin > gentamicin tobramycin > netilmicin amikacin [22]. With increasing use of tobramycin and amikacin, there is a growing problem of bacterial resistance to these medications. This has lead to a re-emergence of streptomycin to fight severe gentamicin-resistant strains of enterococci, as in endocarditis [23], and to treat tuberculosis resistant to isoniazid and rifampin [24]. Newer pharmacological agents with less resistance and hence broader coverage, such as isepamicin, are also being developed [25]. Because all AGs have been shown to have some degree of ototoxicity, it is likely that the very molecular makeup necessary for their antimicrobial actions is also responsible for their mechanism of toxicity. Until drug research resolves this dilemma, AGs will have to be prescribed cautiously and monitored closely. Some studies suggest that certain patients may have a genetic predisposition to AG ototoxicity. Clinical cases have reported profound hearing loss after a single parenteral injection of AG, which has been linked to an adenosine-to-guanosine substitution at position 1555 in mitochondrial DNA (mtDNA 1555G) [26-29]. This mutation has been found in Chinese, Japanese, Arab-Israeli and North American families, and up to 17 20% of the patients with AG-induced hearing loss could be carriers of this mutation. This mutation, however, cannot explain the cell and tissue specificity of AG toxicity because other cells containing the identical mitochondrial mutation including vestibular hair cells are not more susceptible to AGs. A new important role for AGs is being actively investigated after the discovery that gentamicin has the ability to induce translational read-through of stop codons [30-33]. Thus, gentamicin (and perhaps other AGs) might be useful in the treatment of some forms of cystic fibrosis, Duchenne muscular dystrophy and other conditions associated with premature
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stop codon mutations in specific proteins [30,34-37]. The expected increase in use of AGs for gene therapy calls for an equal increase in awareness of the potential ototoxicity of these drugs in this new clinical setting.
topical medications: neomycin and others Neomycin is a broad-spectrum AG restricted to topical use because of its potent ototoxicity and nephrotoxicity [4]. In addition to its Gram-negative coverage, it is also effective against Staphylococcus aureus, and is the major component of many otic preparations [38]. Neomycin is currently used topically to treat otitis externa and to prevent it postoperatively, but is not recommended in the setting of tympanic membrane perforation. Neomycin is also used for topical applications in a variety of infections of the skin and mucous membranes, to suppress intestinal flora preoperatively and to treat hepatic encephalopathy. Otoxicity after ototopic AG administration can occur. A recent literature review of cochleotoxicity and vestibulotoxicity in topical AGs found 24 and 54 cases, respectively, for gentamicin and 11 and 2 cases, respectively, for neomycin [39]. In the absence of ototoxic drugs, sensorineural hearing loss is a complication of chronic suppurative otitis media [40], which histologically correlates with cochlear hair cell damage [41]. This clinical occurrence lends even greater argument to using non-toxic topical medications in cases of infection with risk of round window membrane drug exposure, such as with tympanic membrane perforation, or with otorrhea after myringotomy placement. Quinolone otic solutions, such as ofloxacin 0.3%, have been shown to be comparable to solutions containing AGs in the treatment of otitis externa and chronic suppurative otitis media and in the relief of subsequent otalgia and otorrhea [42]. They have thus far not been reported to cause ototoxicity, and are an ideal alternative for avoiding iatrogenic ototoxicity in the treatment of middle and outer ear infections [43], although they have less Gram-positive coverage than AGs. Topical solutions containing known ototoxic drugs should only be administered when safer alternatives cannot be used, such as in severe drug allergies.
3.4 Cell 3.3 Ototoxic
and molecular mechanisms of AG ototoxicity The cell and molecular mechanisms of AG toxicity, as well as the reasons behind their tissue and cell specificity and toxicity gradients, are still unknown. At clinical doses, only the proximal tubule renal cells, cochlear OHCs and vestibular type 1 hair cells are affected. In the cochlea, AG-induced OHC death progresses from the base to the apex of the organ of Corti. In the vestibular organ, the initial cell damage occurs in the apex of the cristae and the striolar regions of the maculi, and then progresses to the periphery. These toxicity gradients are not associated with differences in drug exposure, because they were also detected in organotypic cultures [44-47]. AG antibiotics are poorly absorbed from the digestive tract and only a fraction of the administered drug reaches the bloodstream. They arrive rapidly to the inner ear via the
bloodstream, and remain present at low concentrations (one-tenth of the peak serum levels) for > 30 days in animal models [48]. Despite their fast access to the inner ear, AG ototoxicity usually takes several days of treatment, even weeks, to develop. The interaction between AGs and their cellular targets has been under considerable scrutiny. AGs are known to block a variety of ion channels and membrane receptors [49-55]. Animal studies, however, indicate that drug uptake and accumulation inside the cells is necessary, although not sufficient, for AG toxicity [56,57]. For instance, it was shown that practically all inner ear cell types incorporate AGs [56,58,59], with some cells incorporating even more than hair cells and for several months without any evidence of drug-induced damage [59]. In cells, AGs localise largely inside endosomal and lysosomal vacuoles and the Golgi complex, but they are also found disperse in the cytosol and inside the nucleus. Thus, it is generally accepted that AGs are selectively incorporated by inner ear sensory cells via endocytosis, accumulate in lysosome-like intracytoplasmic vesicles and, once drug accumulation exceeds the vesicles capacity after many AG doses, the vesicle membrane is disrupted and the AG diffuses into the cytoplasm [58,60,61]. Other results, however, suggest the existence of a fast uptake mechanism, with slow elimination in absence of toxicity, involving membrane channels in inner ear cells [62,63], as well as in kidney cells [64,65]. These results do not rule out endocytosis, but rather indicate the AG incorporation may involve more than one single mechanism. Several molecular models have been proposed to explain AG ototoxicity. One of them involves the reversible binding of AGs to the cells plasma membrane, energy-dependent uptake of the drug, and subsequent binding of the drug to phosphatidylinositol biphosphate (PIP2), the precursor of important second messengers such as diacylglycerol and inositol triphosphate [66,67]. Although the excellent correlation between the ototoxicity of different AGs and their binding to PIP2 supported the idea of a crucial role of these lipids in the AG-activated toxic mechanisms [68], the reported lack of effect of AGs on the synthesis of inositol phosphates [69] casted doubts about its relevance to AG ototoxicity. Recently, however, the recognised ability of certain PIP2 products, such as arachidonic acid, to serve as electron donors in the generation of reactive oxygen species (ROS) has renewed the interest in the role of these molecules in AG ototoxicity. A considerable body of evidence supports the idea that ROS are an important component of the mechanism of AG cell toxicity [70-75]. Gentamicin, for instance, has the ability to catalyse the formation of free radicals by a mechanism that may involve the formation of a complex with iron [76,77]. In addition, iron chelators have been shown to ameliorate AG-induced cochleo- and vestibulo-toxicity [78,79]. It has been proposed that AGs may harbour two binding domains, one for iron and another for inositol phosphates (see previous paragraph), bringing the reactants in close proximity for an efficient transfer of electrons [80].
Although antioxidant therapy has been used successfully in the treatment of some pathologies involving ROS, it is still controversial as a tool for preventing both ototoxic and nephrotoxic AG effects. One of the major problems is that different types of ROS are generated at different cell compartments, and specific antioxidants are required for their efficient chemical neutralisation before becoming dangerous to the cell [81,82]. Thus, the right antioxidant must be in the right place at the right time to be effective. Most importantly, ROS also act as signals or mediators of changes in cell function, proliferation and differentiation [83,84]. The balance of oxidants, antioxidants and redox status within cells is important in the regulation of gene expression even in the absence of cellular stress [84]. Hence, an excess of antioxidants could be negative for the cellular function by modulating intracellular ROS levels in a way that interferes with normal molecular processes [81]. Thus, pharmacological antioxidants should be used only when required and aimed at specific populations of ROS [81]. Experimental evidence strongly suggests that, at clinical doses, AGs induce hair cell apoptosis [46,85-87]. Higher concentrations, in contrast, may trigger other mechanisms of cell death [88]. It has been shown in vitro that caspase inhibitors promote hair cell survival after exposure to AG antibiotics [86,89-92]. Frequently, however, blocking the default apoptotic programme does not prevent cell death, only delays it. Cell death is finally achieved via alternative caspase-independent, or even necrosis-like, routes [93,94]. Therefore, additional studies are required to demonstrate the usefulness of caspase inhibitors as an otoprotective therapy. By far, the two most common agents used to investigate AG ototoxicity are neomycin and gentamicin. A number of studies suggest that the noxious effects of neomycin would be mediated by c-Jun N-terminal kinase (JNK) MAPKs [95-97]. In vitro studies also indicated that neomycin-induced apoptosis of hair cells would be mediated by the mitochondrial cell death pathway [92,98]. Most importantly, overexpression of an antiapoptotic member of the Bcl2 protein family significantly increased hair cell survival following neomycin exposure in organotypic cultures of the adult mouse utricle, suggesting that the expression level of Bcl2 is important for the regulation of neomycin-induced hair cell death [98]. Gentamicin-induced apoptosis, in turn, would be mediated by Ras/Rho GTPases [99], involve calpains [100], ROS and a PKC-dependent fall of intracellular scavenging abilities [101,102], but would be independent of the apoptotic receptor Fas [103]. Gentamicin-induced apoptosis would be prevented by L-carnitine [104], leupeptin [100], the antibiotic minocycline [105], Toxin B from Clostridium difficile [99], and the antioxidants N-acetyl-L-cysteine, glutathione and vitamin C [106]. Interestingly, JNK [99,107,108] and ERK1/2 MAP kinases [104], as well as members of the Bcl2 protein family [104] have been associated with gentamicin-induced apoptosis. As they have also been reported as participating in the neomycin-activated responses, their precise role in AG ototoxicity deserves a closer scrutiny.
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4. Other
ototoxic drugs
4.1.3 Cell and molecular mechanisms of vancomycin and erythromycin ototoxicity
Although AGs are the most commonly used ototoxic drugs, many other medications have been found to have similar side effects. These other drug classes predominantly cause cochlear toxicity, ranging from tinnitus to temporary hearing loss to permanent hearing impairment. For this reason, the term ototoxicity will refer to cochleotoxicity in this section of the review.
4.1 Antibiotic
and antimalarial drugs
4.1.1 Vancomycin
Although vancomycin ototoxicity has been reported since its emergence as an effective treatment of methicillin-resistant Gram-positive bacilli, clinical studies have not corroborated these claims. Early cases of ototoxicity were explained by the impurities of initial preparations of the drug [109], and subsequent case reports have been clouded by patient exposure to known ototoxins, mainly AG antibiotics [110,111]. Prospective clinical trials have also shown that therapeutic vancomycin administration does not lead to ototoxicity [112,113]. Studies on infants who were exposed to vancomycin prenatally, found no signs of ototoxicity after birth [114]. One study showed that vancomycin can increase nephrotoxicity in patients concomitantly taking gentamicin, but significant ototoxicity was not reported [115]. Vancomycin-induced nephrotoxicity leading to renal dysfunction will result in increased levels of known ototoxins, thereby confounding this presumed synergistic effect. For this reason alone, and until further research clarifies the role of vancomycin in potentiating the ototoxic effects of AG antibiotics, vancomycin should be avoided in the setting of AG treatment.
4.1.2 Erythromycin
Experiments in guinea-pigs have shown that exposure to vancomycin in moderate (150 mg/kg/day) and high doses (300 mg/kg/day) does not lead to significant ototoxic effects. In contrast, exposure to gentamicin and neomycin, used as control experiments, results in substantial hearing loss [122]. However, although vancomycin alone may not cause ototoxicity, it may augment gentamicin-induced hearing loss [123,124]. The mechanism underlying erythromycin ototoxicity is not known, and very little research has been aimed at its elucidation. Guinea-pig studies indicated that erythromycin, when delivered into the middle ear, is able to kill cochlear hair cells [125]. A more recent study about the ototoxic effects of erythromycin, however, failed to detect any effect on hair cells as indicated by transiently evoked otoacoustic emissions (TEOAEs) in the guinea-pig [126]. In contrast, two newer macrolides, azithromycin and clarithromycin, induced a reversible reduction of TEOAE responses attributable to a transient dysfunction of OHCs [126]. This result could be explained as a transient reduction on EP associated with a direct effect of these drugs on the stria vascularis.
4.1.4 Quinine
Erythromycin, a widely used macrolide antibiotic, was first reported to be ototoxic in 1973 [116]. Clinical trials have shown that 4 g/day of erythromycin more likely leads to reversible tinnitus or hearing loss [117], but that doses below 2 g/day do not lead to symptoms or auditory threshold changes [118]. A recent histopathological study described oedema of stria vascularis throughout both cochlea in the temporal bone of a woman who developed bilateral hearing loss after receiving 4 g/day i.v. erythromycin for 6 days [119]. Newer macrolides, azithromycin and clarithromycin, may also be ototoxic. A few cases of tinnitus and hearing loss after high daily doses of azithromycin to treat Mycobacterium Avium complex infections in immunocompromised patients have been reported [120]. Proposed guidelines to prevent macrolide-induced ototoxicity include limiting the maximum dose to 1.5 g/day in patients with renal failure, obtaining pre- and post-treatment audiograms in at-risk patients, and avoiding co-administration with other known ototoxic drugs [121].
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With the abundance of chloroquinine-resistant Plasmodium falciparum infections, quinine, in spite of its known ototoxicity, is becoming the standard treatment for malaria. The syndrome of acute quinine toxicity Cinchonism named after the cinchona tree indigenous to parts of South America from where quinine was isolated classically presents with headache, nausea, vertigo, tinnitus, deafness, blindness and dysphoria. The mechanism of its ototoxicity is thought to be multifactorial. The end result of quinine exposure in humans has been reported as a reversible high frequency hearing loss [127]. A recent clinical study showed that 10 out of 10 patients with Plasmodium falciparum malaria and 9 out of 12 healthy controls developed reversible high frequency hearing loss after quinine administration [128]. The reversible nature of quinine ototoxicity permits physicians to recognise symptoms early, and to replace it with alternative medication.
4.1.5 Cell and molecular mechanisms of quinine ototoxicity
Perfusion of artificial perilymph containing quinine at varying concentrations into the guinea-pig cochlea significantly reduces several electrical responses to high-intensity (98 dB SPL) and low-intensity (68 dB sound pressure level [SPL]) tone bursts, but not the EP [129]. These results suggest that quinine might be antagonising HC neurotransmitters, and supports the notion that quinine acts at a Ca2+-activated K+ channel or an ATP-sensitive K+ channel in the HCs [129]. Studies showing that quinine directly affects the mechanical tuning of the basilar membrane [130], changes the length of isolated OHCs [130] and damages the lateral cisternae of the OHC [131] led to the hypothesis that this drug also
targets the OHC motility mechanism. This hypothesis was further supported by data indicating that quinine significantly increases OHC length and diameter while decreasing the force generated by the cells [132]. Quinine also affects OAEs in a reversible, dose-dependent manner [133]. Altogether, these results suggest that quinine may have multiple targets, affecting ion channels, antagonising neurotransmitters and impairing cochlear amplifier performance. Effects of quinine on cochlear spiral ganglion neurons and/or their presynaptic processes were also suggested [133,134].
4.2 Nonsteroidal
4.2.1 Salicylate
anti-inflammatory drugs and naproxen
NSAIDs act therapeutically by inhibiting the cyclooxygenase pathway of arachidonic acid metabolism, leading to a decrease in prostaglandins and other pro-inflammatory molecules. Salicylic acid (salicylate), or aspirin, arguably the most widely used NSAID, has long been shown to cause tinnitus and reversible hearing loss. Specifically, high doses of salicylate have been shown to cause tinnitus, decreased acoustic sensitivity, and altered sound perception. With moderate salicylate doses, these symptoms develop and may or may not persist over the initial days of treatment but high doses may produce symptoms within hours of initiation. In the absence of pre-existing hearing loss, salicylate typically causes bilaterally symmetric mild-to-moderate hearing loss, which may be flat or more pronounced at high frequencies. Hearing usually recovers in 24 72 h after the final salicylate treatment [135]. Clinical trials have shown that hearing loss from aspirin administration is correlated with serum salicylate levels, and with increasing doses [136,137]. Tinnitus and reversible hearing loss have been seen in both acute intoxication, as well as in long-term use and accumulation of the drug [138]. Naproxen, another NSAID, in a few rare case reports has been implicated in sudden irreversible sensorineural hearing loss [139,140]. This uncommon entity, if real, would involve a different mechanism that aspirin ototoxicity.
4.2.2 Cell and molecular mechanisms of salicylate ototoxicity
impaired electromotile response [142,143]. A consistent body of anatomical and physiological data indicates that salicylate could be affecting OHCs and their ability to influence the mechanical response of the organ of Corti. For example, salicylate has been reported to decrease [144-146] and increase [147] OAEs in different animal models. Perfusion of millimolar salicylate solutions in the scala tympani of the guinea-pig cochlea results in changes compatible with a reduction in OHC electromotility [148,149]. Moreover, salicylate could be affecting the performance of the OHC molecular motor protein, prestin, either indirectly through changes in its lipidic environment in the plasma membrane [150], or via a direct prestin-salicylate interaction [151,152]. Salicylate alters spontaneous single-neuron activity, a change that could reflect a physiological manifestation of tinnitus [153,154], increases the spontaneous activity of the auditory nerve [155,156], and changes the average spectrum of cochleoneural activity [157,158]. A recent hypothesis suggests that salicylate-induced tinnitus could be associated with an activation of cochlear N-methyl-D-aspartate (NMDA) receptors, a variety of cell receptors mediating glutamatergic responses known to be involved in synaptic repair after excitotoxicity and protection of hair cells from ototoxicity induced from AGs, ischaemia and acoustic trauma [159]. This hypothesis is supported by independent results indicating that salicylate selectively potentiates NMDA-mediated responses in cultured mice type I spiral ganglion neurons [160]. Therefore, in addition to OHCs, auditory neurons and neurotransmitters could also be targets of salicylate toxicity in the auditory system.
4.3 Loop
4.3.1 Furosemide
diuretics and etacrynic acid
As with other drugs, salicylate pharmacokinetics and uptake from serum into perilymph vary across species, complicating the correlation between results in animal models and clinical manifestations in humans [135]. Consistent with human studies, research in animal models indicates that salicylate induces changes in hearing sensitivity accompanied by changes in the suprathreshold characteristics of hearing [135]. Because of the temporary nature of salicylate ototoxicity, no significant cochlear damage is expected as a consequence of salicylate treatment. Acute (4 24 h after a single 500 mg/kg dose) and extended (24 h to 6 weeks after 7 consecutive 375 mg/kg/day doses) treatments revealed no significant salicylate-induced cochlear changes in guinea-pigs [141]. Other studies, however, showed increased endoplasmic reticulum vacuolisation and stereocilia bending in HCs, as well as an
Furosemide and etacrynic acid (EA) are classified as loop diuretics because they exert their effects in the thick ascending limb of the Loop of Henle in the kidney, inhibiting sodium and water reabsorption and thereby increasing diuresis. Furosemide is one of the most commonly used diuretics for treating congestive heart failure and its symptoms, pulmonary and peripheral oedema. EA is used less commonly, usually for patients who poorly respond to furosemide. Both of these diuretics have been reported to cause reversible hearing loss, most frequently when used together with AGs [11]. A temporal bone study of a patient with sudden hearing loss after receiving both furosemide and EA but no AGs, did not show loss of HCs on both light and electron microscopy [161]. This finding perhaps relates to the reversible mechanism of loop diuretic toxicity to the inner ear. Ototoxicity from furosemide alone seems to occur at very low rates when given in high daily doses [162]. Cases of ototoxicity after concomitant AG and furosemide administration have been reported [163]. Until clinical studies confirm this interaction in humans, loop diuretics and AGs should not be combined in patients if possible.
389
4.3.2 Cell
and molecular mechanisms of loop diuretic ototoxicity
EA has been shown to decrease the EP [164], to interfere with strial adenylyl cyclase and Na+/K+ ATPase activity [165], and to inhibit the Na+-K+-2Cl- co-transport system [70]. Recent studies, however, suggest that all these changes could actually be secondary to EA-induced ischaemia in the stria vascularis and spiral ligament [166]. Ischaemia could also be the cause of the morphological changes reported in early studies (see [167] for a review of early studies). Furosemide has been reported as inducing changes in the oxygen tension in the perilymphatic fluid, which could also be associated with stria vascularis ischaemia [168]. Its effects on the response of the chinchilla basilar membrane to tones and clicks could reflect a transient impairment of OHC motor function because of a reduction in the EP [169]. Consistently with an indirect effect of furosemide on OHC motility, light and electron microscopy studies after furosemide application found no permanent damage of OHCs, but confirmed the presence of strial oedema as well as degeneration and atrophy of intermediate cells [170]. Moreover, exposure of isolated guinea-pig OHCs to furosemide results in no appreciable changes in OHC motility [171]. Interestingly, similar experiments showed that OHC motility is indeed affected by EA [171]. These results and others, such as the reduction of the ototoxic effects of furosemide but not those of EA, by pretreatment with organic acids, suggest that furosemide and EA ototoxicity could be mediated by different mechanisms [172]. EA and furosemide have been reported to potentiate the ototoxic effects of AG antibiotics [173-176]. EA could be potentiating AG ototoxicity by facilitating the entry of the antibiotics from the systemic circulation into the endolymph [177]. Interestingly, a more recent study suggests that late dosing of EA could actually protect cochlear hair cells from the ototoxic effect of AG antibiotics [178]. The authors suggested that EA-induced disruption of the bloodlabyrinth barrier at the stria vascularis, at a time when the gentamicin concentration is higher in the cochlea than in the blood, might actually permit the efflux of the AG from the cochlear fluids to the blood, decreasing the risk of HC damage [178].
4.4 Chemotherapy 4.4.1 Cisplatin
with high doses of carboplatin, in contrast, has shown to cause hearing loss associated with cumulative carboplatin blood levels [182].
4.4.2 Cell and molecular mechanisms of cisplatin ototoxicity
agents and carboplatin
Cisplatin is a chemotherapeutic agent used in many anticancer regimens. Carboplatin, a cisplatin derivative, although less efficacious against many cancers, including head and neck tumours and oesophageal cancer, has proven comparable to cisplatin against ovarian cancer as well as against small-cell and non-small cell lung cancer [179]. In a clinical study of 69 patients receiving cisplatin, 20 30% of patients, depending on the dose, experienced irreversible high-frequency hearing loss [180]. Another study showed that cisplatin toxicity seems to correlate more with the single dose amount than cumulative levels [181]. Chemotherapy
390
In guinea-pigs, cisplatin has been shown to potentiate AG- [121] and furosemide-induced ototoxicity [183]. Cisplatin has been shown to cause IHC and OHC damage, typically in the basal turn of the cochlea, as well as degeneration of the stria vascularis and spiral ganglion [184]. Severe to profound hearing loss and vestibular dysfunction can result from cisplatin treatment [185]. Cisplatin ototoxicity, just like aminoglycoside ototoxicity, could be mediated by ROS [186-190] and by activation of a signalling pathway involving the MAP-kinases ERK1/2 [191]. In vitro studies on auditory cells suggest that cisplatin induces an early but transient increase in caspase-8 activity, a delayed increase in caspase-9 activity, and the involvement of Bid and Bax, pro-apoptotic members of the Bcl2 family, but the precise apoptotic pathway has yet to be elucidated [192]. Cisplatin-induced apoptosis in these cells is inhibited by the T-type calcium channel blocker flunarizine, but this effect would probably be associated with direct inhibition of lipid peroxidation and mitochondrial permeability transition rather than with modulation of intracellular calcium levels or ROS production [193]. The list of potential chemoprotective agents against cisplatin ototoxicity includes -lipoic acid, glutathione, ebselen, 4-methylthiobenzoic acid, D-methionine, diethyldithiocarbamate, superoxide dismutase and L-carnitine [186-189,194,195]. Interestingly enough, a recent study indicates that a superoxide dismutase-mimetic antioxidant protects cochlear HCs from gentamicin but not cisplatin toxicity [102]. This result strongly suggests that cochlear HC toxicity from cisplatin and gentamicin are mediated by different pathways. OHCs are the major cochlear target of carboplatin in every animal model investigated except the chinchilla. In chinchillas, carboplatin is considered a selective IHC toxin [196-199]. Carboplatin has also been reported to preferentially damage vestibular type-I HCs and type-I spiral ganglion neurons in this animal model [200-203]. Several lines of evidence suggest that free radicals may contribute to carboplatin-induced sensory cell damage in chinchillas as well as in other animal models [204-207]. D-Methionine [208], -lipoic acid [209] and sodium thiosulfate [210] have been reported as ameliorating carboplatin ototoxicity, whereas neurotrophin 4/5 promotes the survival of spiral ganglion neurons but does not protect the HCs [206]. It has been recently suggested that carboplatin might cause tinnitus by producing oxidative stress within the inferior colliculus or by loss of inhibition within the inferior colliculus resulting from cochlear damage [211]. This could lead to a compensatory gain and enhanced responses in neurons within the auditory cortex. In addition, protective agents may prevent tinnitus by preventing damage to the cochlea, thereby obviating the development of disinhibition within central auditory pathways [212].
5. Ototoxic
drugs in pregnancy, infancy and
childhood
Newborns may have some developmental protection from some ototoxic drugs. A large prospective study of streptomycin, kanamycin and gentamicin in newborns showed that the rate of ototoxicity and nephrotoxicity was no different compared to controls [213]. Under severe conditions, however, neonates also appear to be susceptible to ototoxins. A study of 547 preterm infants showed a 1.5% incidence of severe progressive bilateral hearing loss associated with perinatal complications and total dose of ototoxic drugs, mainly AGs and furosemide [214]. In children, topical AGs may be safe at low doses given for short periods. For example, a study of 446 children who received two weeks of topical AGs after myringotomy and tympanoplasty tube placement showed no incidence of ototoxicity by audiometry three months later [215]. Clearly more studies are necessary to better define AG ototoxicity in children. The apparent developmental protection from ototoxicity in infants does not seem to apply to all ototoxins. Cisplatin, for example, has been shown to be ototoxic in children in a dose-dependent fashion [216]. One study estimated the incidence of bilateral hearing loss in children who received cisplatin chemotherapy to be as high as 61% [217]. Hence, ototoxicity in the paediatric population cannot be overlooked. All known ototoxic drugs should be dosed by body weight according to paediatric source recommendations, and monitoring for signs of ototoxicity should be as important in children as in adults.
6. Clinical
patients treated with AGs or cisplatin, both known to cause permanent ototoxicity because the presence of symptoms may already indicate irreversible impairment. Cochleotoxicity can first be detected clinically as tinnitus perceived by the patient. It can then progress to mild hearing loss, perceived by the patient and detected on physical exam with the Rinne and Weber tuning fork tests. Mild-to-severe hearing loss should be documented by audiometry, if possible. Vestibulotoxicity may first be perceived by the patient as vertigo, nausea and balance difficulties. It can be confirmed on physical exam with by presence of nystagmus, and by electronystagmography testing [221]. Early recognition of signs and symptoms of ototoxicity is essential to stop the causative agents in a timely fashion to minimise ototoxicity. This is particularly relevant for the drugs mentioned whose toxic effects are reversible.
monitoring and treatment Because screening for subclinical ototoxicity may not be cost-effective, or even possible in an emergent setting, the emphasis of ototoxicity prevention should be placed on the monitoring of levels of known ototoxic drugs, especially those requiring high daily doses. Although once-daily dosing of AGs was proven to be as efficacious compared to multiple-daily dosing at fighting infections, meta-analyses in children and adults have not shown any difference in ototoxicity incidence in this comparison [222,223]. A prospective clinical study showed that cumulative drug levels of gentamicin do not correlate with vestibulotoxicity [12]. One retrospective observation of 33 patients with long-term gentamicin vestibulotoxicity, showed that ototoxicity occurred even at recommended dose ranges and did not correlate with serum peak and trough levels [224]. This study also illustrates the importance of close follow up in patients having received AG therapy. Symptoms of ototoxicity in all but one patient were not recognized, symptoms of ototoxicity in all but one patient were not recognised prior to hospital discharge, but did develop within 1 3 weeks after initiation of gentamicin therapy [224]. Six of these patients had elevated creatinine levels which may have contributed to the ototoxicity [224]. This emphasises the importance of carefully observing renal function when using ototoxic drugs. Every effort should be made to keep AG levels below recommended peak and trough values to minimise any subsequent hearing or balance side effect. Matz and Rybak provide a table of suggested doses and desirable serum levels of AGs for drug monitoring [11]. Serum levels of AGs and all other ototoxic drugs should be monitored according to standard pharmacological recommendations for each drug. Patients who have sustained only high-frequency hearing loss or mild-to-moderate hearing deficits secondary to ototoxic medications will benefit from rehabilitation with hearing aids (HAs). Those with profound hearing loss from drug ototoxicity may benefit from cochlear implants. Patients with vestibular deficits can also undergo rehabilitation, receiving sedation and antinausea medications to treat their symptoms.
391
6.2 Drug
management
of ototoxicity Prior to use of AGs, if the clinical scenario allows it, patients should undergo audiometry. Repeat audiograms should be obtained thereafter for preventative monitoring or as symptoms present. Patients with reduced hearing, a history of drug ototoxicity, renal insufficiency, and who are taking other known ototoxic drugs are at greater risk of ototoxicity, and may benefit from more frequent subclinical ototoxicity testing when the use of AGs can not be avoided. One study used baseline and follow-up audiometry to track cisplatin-induced ototoxicity in cancer patients. Hearing loss in tracked patients was detected mainly at high frequencies [218]. Similarly, audiometry could be used more routinely to detect subclinical AG or cisplatin ototoxicity, and at the bedside using insert earphones, paying particular attention to high frequency hearing changes (correlating to OHC dysfunction) [219]. OAE testing, which is sensitive to OHC changes, is an effective tool for measuring hearing in newborns [220]. OAEs may also prove an effective measure of initial subclinical OHC damage from ototoxic drugs, and may be used in comatose patients, as in severe meningitis, to detect and perhaps prevent AG ototoxicity. These subclinical detection techniques may be particularly beneficial in at-risk
6.1 Detection
7. Conclusion
To emphasise the problem at hand, AG ototoxicity occurs at doses necessary for antimicrobial efficacy. AGs should be used judiciously, to treat severe infections that are not responsive to safer alternative medications. Similar care should be given when prescribing other known ototoxic medications. Blood levels of these drugs should be monitored to avoid toxic levels and early detection of ototoxicity symptoms should be emphasised to minimise toxic effects. Professional awareness and improved clinical decision-making will promote prevention of drug-induced ototoxicity. Continued research, on the other hand, is necessary to understand the cell and molecular mechanisms underlying the ototoxic effects of AGs and other common medications. Elucidation of these mechanisms will facilitate the development of safe and effective clinical approaches for the prevention and amelioration of drug-induced ototoxicity.
8. Expert
opinion
Patients who have suffered sensorineural hearing loss as a result of ototoxic medication administration, usually benefit from the use of assistive listening devices such as HAs or cochlear implants. HAs are electronic devices that amplify sound and deliver it as sound pressure in the external auditory canal to the tympanic membrane. There are many different types of HAs (analogue and digital) and they vary in size. Newer generation HAs are equipped with multiple, directional microphones and circuitry that allow for noise cancellation, thereby improving hearing in noisy places. Cochlear implants are electronic devices designed to electrically stimulate the auditory nerve directly, bypassing the middle and inner ear structures. They are indicated for patients who have suffered severe to profound sensorineural hearing loss. Candidacy is established by medical and audiological evaluations. Surgery is done under general Bibliography
Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
1.
anesthesia, usually in the ambulatory setting. It entails insertion of the active electrode into the cochlea via the round window, and placement of the remaining electronics under the skin. The patients hearing is activated four weeks later, once the surgical swelling has resolved. The patient attends a few sessions to adjust the levels of electrical stimulation, and is then given several listening programmes to choose from. Consequently, a significant number of patients will enjoy limited phone conversations, improving their quality of life. In addition to alleviating permanent symptoms of drug-induced ototoxicity, efforts should emphasise disease prevention. Unfortunately, despite years of research, no simple preventive strategies against drug-induced hearing loss are currently available. The lack of knowledge about the cell and molecular mechanisms of drug ototoxicity clearly contributes to this deficit in clinical practice. Because these mechanisms are very difficult to study in animal models, more simple systems with enough biological complexity are required. High-information-content systems, such as organotypic cultures and cell-based assays, have begun to emerge as useful tools to study pathways, mechanisms and effects of ototoxic drugs, and they are already important tools for ototoxicity screening studies. In addition, the use of high-throughput screening methods with these simpler models could enormously increase the chances of elucidating the mechanisms activated by ototoxic and otoprotective drugs. This knowledge, in turn, will be crucial for designing experiments on animal models or in clinical trials aimed at identifying effective strategies for preventing drug ototoxicity in humans.
Acknowledgements
This work was made possible by Grants 005220 and 005335 from NIDCD-NIH, and the support of House Ear Institute. The authors would like to thank Drs Anne Anglim and Paul Webster for critically reading the manuscript.
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Joshua G Yorgason1 MD, Jose N Fayad2 MD & Federico Kalinec3 PhD Author for correspondence 1Research Associate, House Ear Institute, Gonda Department of Cell and Molecular Biology, 2100 W. 3rd Street, Los Angeles, CA 90057, USA 2Associate, House Ear Clinic, Co-Director, Department of Histopathology, House Ear Institute, Eccles Temporal Bone Laboratory, 2100 W. 3rd Street, Los Angeles, CA 90057, USA 3Head, Section on Cell Structure and Function, House Ear Institute, Department of Cell and Molecular Biology, 2100 W. 3rd Street, Los Angeles, CA 90057, USA Tel: +1 213 353 7030; Fax: +1 213 273 8088; E-mail: fkalinec@hei.org
Affiliation
Current status of electronystagmography testing. Otolaryngol. Head Neck Surg. (1999) 120(3):419-426.
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and physiology of the inner ear

10.1517/14740338.5.3.383 2006 Informa UK Ltd ISSN 1474-0338

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Expert Opin. Drug Saf. (2006) 5(3)

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Expert Opin. Drug Saf. (2006) 5(3)

Expert Opin. Drug Saf. (2006) 5(3)

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Expert Opin. Drug Saf. (2006) 5(3)

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Expert Opin. Drug Saf. (2006) 5(3)

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Expert Opin. Drug Saf. (2006) 5(3)

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Expert Opin. Drug Saf. (2006) 5(3)

Yorgason, Fayad & Kalinec

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Expert Opin. Drug Saf. (2006) 5(3)

Expert Opin. Drug Saf. (2006) 5(3)

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