Drug-Induced Ocular Side Effects: Clinical Ocular Toxicology, 7e Wiley A. 14
Brie Hoffler
He received his formal medical education at Oregon Health and Science University, the University of Chicago School of Medicine, Johns Hopkins School of Medicine and Moorfields Eye Hospital at the University of London. He is the founder of the Casey Eye Institute which is part of Oregon Health and Science University. He is the author or co-author of 15 medical textbooks on the eye and well over 200 peer review scientific articles. He also founded the "National Registry of Drug-Induced Ocular Side Effects" which is a clearinghouse of information on adverse ocular events associated with drugs, chemicals and herbals. In 2008 he co-authored his first non-medical book, Retirement Rx (published in paperback as Retire Right). He has served as national President in multiple scientific organizations and as an associate editor and referee on multiple peer-review scientific journals.
Drug-Induced Ocular Side Effects: Clinical Ocular Toxicology, 7e Wiley A. 14
Download Zip https://urllie.com/2yVfCB
Do not consider this brief discussion exhaustive, as many other drugs and categories may have dry eye as a side effect. While these drug categories are the most common offenders in producing dry eye problems, exceptions exist in every drug category. No one can possibly remember all of the potential ocular adverse events associated with each medication. Fortunately, there are many resources available to help us with this information.
Ocular instillation toxicity studies (OITSs) are one of general toxicity studies. Yet, OITSs have a unique characteristic that the test article is directly administered as eye drops to the target organ. Compared with general toxicity studies aiming systemic exposure, the study design of OITSs is somewhat distinctive in selecting test species, dosing formulation, administration volume/frequency and ocular examinations. After the administration of eye drops, the exposure level is high in the ocular surface, whereas the bioavailability in the eye balls, especially in the posterior segment, is low. In contrast to the general toxicity studies aiming systemic exposure, the absolute systemic exposure level in OITSs is generally low, while the systemic bioavailability is relatively high. These pharmacokinetic features determine the profiles of local and systemic toxicities in OITSs. Systemic toxicities are more often found in animals of relatively small body size, and are in most cases related with pharmacological actions. Current progress in ophthalmologic imaging technologies enables advanced safety evaluation using imaging biomarkers. Bioanalysis detecting drug levels present in blood in trace amount leads to a detailed safety assessment of systemic toxicity and yields accurate safety margins. Recognizing the peculiar characteristics of OITSs, toxicologists need to propose an appropriate study design and strategy of safety evaluation. Further discussion may be awaited on rationales for testing both sexes, and for conducting separated toxicity studies to evaluate systemic toxicity. This mini-review provides insight regarding current status and points to consider of OITSs.
Drug-induced neoplastic changes are a frequent phenomenon in in vivo safety studies, particularly in rodents exposed up to life time. For example, foci of altered hepatocytes are considered putative pre-neoplastic lesions that can occur spontaneously or be induced by chemicals or drugs56. Progression of these foci to hepatocellular neoplasms has been reported, but increases in foci in rodents do not necessarily lead to tumours in carcinogenicity studies57. A non-genotoxic nicotinic α7 receptor partial agonist drug candidate, RG3487, was found to induce foci of altered hepatocytes and subsequently tumours in rats58, potentially precluding human clinical studies. However, the hepatocyte alterations observed in rats were not seen in the liver of mice or dogs. To assess human relevance, primary rodent, canine and human stem cell and patient-derived 3D cell model phenotypic assays were used to explore potential mechanisms of neoplasia. Rodent phenotypic models were found to recapitulate the in vivo effect whereas human and canine models clearly showed an absence of effect, and the study revealed drug-induced effects that were not relevant in humans, such as nuclear receptor-driven liver proliferation in rodents but not in human models58. These data supported the progression of RG3487 into clinical trials.
In the late 1980s and early 1990s, drug-induced ventricular repolarization/QTc interval prolongation and the appearance of rare but potentially fatal cardiac arrythmias called torsade de pointes (TdP) was identified, and several drugs were removed from the market193. Subsequently, it was discovered that these drugs (for example, terfenadine194,195) were delaying cardiac repolarization by inhibiting the cardiac potassium current, IKr, through the hERG channel. In 1997, early guidance on how to evaluate ventricular repolarization was published by CPMP (Committee for Proprietary Medicinal Products)196 and in 2005, the ICH S7B guidance document was issued197, introducing the functional IKr assay as a key component of the preclinical testing strategy alongside a preclinical in vivo QTc assay. The guidance triggered substantial activity within the pharmaceutical industry and service and technology providers that led to the development and implementation198 of a plethora of preclinical platforms and assays194. Preclinical IKr/QTc assessment has been crucial for clinical candidate selection in industry, and has been successful, as it led to a low prevalence of QTc-prolonging drugs in clinical trials, and no newer drugs have been removed from the market owing to unexpected QTc prolongation199.
Eye exposure to the organophosphorus (OP) irreversible cholinesterase inhibitor sarin results in long-term miosis and impaired visual function. We have previously shown that tropicamide is better at ameliorating this insult than topical atropine or cyclopentolate. However, to minimize side effects associated with repeated tropicamide applications and high treatment doses, we evaluated the effects of oximes (ChE re-activators) alone and combined with tropicamide at ameliorating OP-induced ocular impairments. Rats were topically exposed to sarin, followed by topical treatment with various oximes alone or in combination with tropicamide. Pupil width and light reflex were measured by an infrared-based digital photograph system, while visual performance was assessed by employing the cueing version of the Morris water maze (MWM). KEY RESULTS: Oxime treatment following sarin ocular exposure induced a slow persistent pupil widening with efficacy in the order of HLö-7 > HI-6 > obidoxime = TMB-4 = MMB-4. In the light reflex test, the ability of the iris to contract following oxime treatment was mostly impaired at 1 h and was back to normal at 4 h following sarin exposure. All oxime treatments ameliorated the sarin-induced visual impairment as tested in the visual task (MWM). The combined topical treatment of tropicamide with an oxime induced a rapid improvement in pupil widening, light reflex and visual performance, and enabled a reduction in tropicamide dose. CONCLUSIONS AND IMPLICATIONS: The use of tropicamide combined with an oxime should be considered as the topical treatment of choice against the toxic effects of ocular OP exposure.
Experimental studies for treatment of endophthalmitis in rabbit eyes with intraocular antibiotics like penicillin and sulphonamides were reported as early as the 1940s [11]. Intravitreal penicillin was found to have a favourable though limited effect on traumatic endophthalmitis in these studies. In the 1970s, Peyman and associates reported the safety and efficacy of various intravitreal antibiotics in experimentally induced endophthalmitis in rabbit eyes and established the recommended doses of various intravitreal antibiotics in human eyes [12],[13]. Favourable results of treatment of acute postoperative endophthalmitis with intravitreal antibiotics - vancomycin for staphylococcal endophthalmitis and aminoglycosides for Gram-negative endophthalmitis - were reported during the 1970s [13]-[15]. However, as the macular toxicity of aminoglycoside antibiotics became known, ceftazidime, a third-generation cephalosporin, has become the preferred alternative [16]. In recent times, alternate antibiotics like intravitreal piperacillin-tazobactam have been studied both in animal models and clinically especially in cases of Enterobacter species and multidrug-resistant Pseudomonas endophthalmitis with favourable outcomes and have emerged as a useful alternative to ceftazidime [17]-[19].
Status of ocular inflammation: In a non-inflamed eye, the anterior route is poorly efficient, and hence, antibiotics (vancomycin, aminoglycosides, erythromycin and rifampicin) eliminated by this route show long half-life values. Thus, drugs eliminated through the anterior route have a faster clearance in an inflamed eye [25]. For drugs mainly eliminated by the posterior route (beta-lactams, cephalosporins and clindamycin) in the case of an inflamed eye, the drug clearance is retarded due to compromise of the retinal pigment epithelial (RPE) pump or the active transport. Thus, their half-life is extended [24],[28]-[30].
Indiscriminate and injudicious use and abuse of antibiotics have led to the development of resistant bacterial strains. These include the ocular and nasopharyngeal flora as well as pathogenic organisms like those causing keratitis and other ocular infections. Endophthalmitis caused by these organisms is associated with more severe clinical course and worse visual outcomes [60]-[62]. This problem of emergence of resistance to standard antibiotic therapy has forced clinicians to continually evaluate the best intraocular antibiotics available for the treatment of bacterial endophthalmitis. In such situations, the choice of antibiotics is judiciously guided by culture results and sensitivity patterns of the causative organism. However, it is also known that in vitro resistance need not be mirrored with in vivo sensitivity and routinely administered antibiotic doses provide intraocular drug concentrations which are much higher than the MICs of most pathogens [61],[62]. Knowledge of pharmacokinetics, susceptibility patterns and minimum inhibitory concentration serves to properly predict the in vivo efficacy of antibiotics against target pathogens [62].
aa06259810