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Ramsey DJ, Kwan JT, Sharma A. Keeping an eye on the diabetic foot: The connection between diabetic eye disease and wound healing in the lower extremity. World J Diabetes 2022; 13:1035-1048. [PMID: 36578874 PMCID: PMC9791566 DOI: 10.4239/wjd.v13.i12.1035] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/27/2022] [Accepted: 11/18/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetic eye disease is strongly associated with the development of diabetic foot ulcers (DFUs). DFUs are a common and significant complication of diabetes mellitus (DM) that arise from a combination of micro- and macrovascular compromise. Hyperglycemia and associated metabolic dysfunction in DM lead to impaired wound healing, immune dysregulation, peripheral vascular disease, and diabetic neuropathy that predisposes the lower extremities to repetitive injury and progressive tissue damage that may ultimately necessitate amputation. Diabetic retinopathy (DR) is caused by cumulative damage to the retinal mic-rovasculature from hyperglycemia and other diabetes-associated factors. The severity of DR is closely associated with the development of DFUs and the need for lower extremity revascularization procedures and/or amputation. Like the lower extremity, the eye may also suffer end-organ damage from macrovascular compromise in the form of cranial neuropathies that impair its motility, cause optic neuropathy, or result in partial or complete blindness. Additionally, poor perfusion of the eye can cause ischemic retinopathy leading to the development of proliferative diabetic retinopathy or neovascular glaucoma, both serious, vision-threatening conditions. Finally, diabetic corneal ulcers and DFUs share many aspects of impaired wound healing resulting from neurovascular, sensory, and immunologic compromise. Notably, alterations in serum biomarkers, such as hemoglobin A1c, ceruloplasmin, creatinine, low-density lipoprotein, and high-density lipoprotein, are associated with both DR and DFUs. Monitoring these parameters can aid in prognosticating long-term outcomes and shed light on shared pathogenic mechanisms that lead to end-organ damage. The frequent co-occurrence of diabetic eye and foot problems mandate that patients affected by either condition undergo reciprocal comprehensive eye and foot evaluations in addition to optimizing diabetes management.
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Affiliation(s)
- David J Ramsey
- Department of Ophthalmology, Lahey Hospital and Medical Center, Burlington, MA 01805, United States
- Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, United States
| | - James T Kwan
- Department of Ophthalmology, Lahey Hospital and Medical Center, Burlington, MA 01805, United States
- Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, United States
| | - Arjun Sharma
- Department of Ophthalmology, Lahey Hospital and Medical Center, Burlington, MA 01805, United States
- Department of Ophthalmology, Tufts University School of Medicine, Boston, MA 02111, United States
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Vorel ES, Mehta JJ, Russo ME, Muego MP, Borek RC, Kelly JA, Greenfield ME. A 7-Year-Old With Persistent Fever and Cough. Pediatrics 2022; 150:189214. [PMID: 36017677 DOI: 10.1542/peds.2021-050751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/05/2022] [Indexed: 11/24/2022] Open
Abstract
A previously healthy, fully immunized 7-year-old girl presented with a 7-week history of daily fevers and a worsening cough with persistently elevated inflammatory markers. Before admission, she had an unrevealing outpatient workup by infectious disease, rheumatology, pulmonology, and otorhinolaryngology for her fever and other symptoms. Multiple courses of antibiotics had no effect, but brief courses of steroids seemed to modestly alleviate her symptoms. At an outside hospital, a computed tomography neck and chest scan revealed mediastinal lymphadenopathy. She was subsequently transferred to the authors' institution. Her examination was notable for a febrile, tired-appearing girl in respiratory distress with a muffled voice and inspiratory stridor. Her laboratory tests revealed leukocytosis with left shift, microcytic anemia, and hypoalbuminemia, as well as elevated inflammatory markers, ferritin, and fecal calprotectin. Her peripheral smear, uric acid, and lactate dehydrogenase were all within normal limits. Infectious study results, including blood and urine cultures, cytomegalovirus serologies, and Bartonella serologies were negative. On the second read of her outside computed tomography imaging, her lymphadenopathy was felt to be nonpathologic. Based on a recommendation by rheumatology, an ophthalmologic examination was obtained, which revealed bilateral anterior uveitis; however, rheumatologic laboratory test results returned negative. Her fevers continued, and inflammatory markers remained elevated despite antibiotics. On day 6 of hospitalization, she developed worsening respiratory distress, necessitating intubation and transfer to the ICU. Repeat laryngoscopy and bronchoscopy revealed severe purulent tracheitis; however, throat cultures remained sterile. Her clinical deterioration without identification of an offending organism prompted additional evaluation for a systemic etiology.
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Affiliation(s)
| | - Jay J Mehta
- Department of Pediatrics.,Division of Rheumatology.,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Michael E Russo
- Department of Pediatrics.,Division of Infectious Diseases.,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Melissa P Muego
- Department of Pediatrics.,Division of Pulmonary and Sleep Medicine.,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ryan C Borek
- Division of Otolaryngology, Department of Pediatric Surgery.,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Janice A Kelly
- Department of Pediatrics.,Division of Gastroenterology, Hepatology, and Nutrition.,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Morgan E Greenfield
- Department of Pediatrics.,Division of General Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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Chiquet C, Aptel F, Creuzot-Garcher C, Berrod JP, Kodjikian L, Massin P, Deloche C, Perino J, Kirwan BA, de Brouwer S, Combette JM, Behar-Cohen F. Postoperative Ocular Inflammation: A Single Subconjunctival Injection of XG-102 Compared to Dexamethasone Drops in a Randomized Trial. Am J Ophthalmol 2017; 174:76-84. [PMID: 27810317 DOI: 10.1016/j.ajo.2016.10.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 10/21/2016] [Accepted: 10/22/2016] [Indexed: 10/20/2022]
Abstract
PURPOSE To evaluate the efficacy and safety of XG-102 (brimapitide) compared to dexamethasone eye drops in the treatment of postoperative ocular inflammation. DESIGN Multicenter, randomized, parallel group, double-masked, noninferiority clinical trial. METHODS Patients who underwent anterior and posterior segments combined surgery or glaucoma surgery or complex posterior segment surgery were eligible to participate. Patients were administered a single subconjunctival injection of 250 μL XG-102 90 μg (n = 47) or 900 μg (n = 48) or placebo (n = 50) at the end of ocular surgery. Subconjunctival injection for each group (XG-102 90 μg, XG-102 900 μg, or placebo) was followed by eye drops instilled 4 times per day for 21 days with placebo, placebo, or dexamethasone solution, respectively. The primary outcome measure was anterior chamber cell grades at day 28 comparing XG-102 900 μg with dexamethasone. RESULTS The anterior cell grades for both XG-102 groups were noninferior to dexamethasone (-0.054 anterior cell grade [95% confidence interval -0.350-0.242]; P < .001 for noninferiority) for XG-102 900 μg and -0.086 anterior cell grade (95% confidence interval -0.214-0.385; P = .003 for noninferiority) for XG-102 90 μg. Rescue medication was introduced for 10 (21%), 7 (15%), and 2 (4%) patients allocated to the XG-102 90 μg, XG-102 900 μg, and dexamethasone groups, respectively. The difference between XG-102 90 μg and dexamethasone was statistically significant (P = .013). The number of patients for whom adverse events were reported and the nature of the events reported was similar between the 3 treatment groups. CONCLUSIONS A single subconjunctival injection of XG-102 at the end of ocular surgery is noninferior to dexamethasone eye drops in the treatment of postoperative ocular inflammation.
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Farkouh A, Frigo P, Czejka M. Systemic side effects of eye drops: a pharmacokinetic perspective. Clin Ophthalmol 2016; 10:2433-2441. [PMID: 27994437 PMCID: PMC5153265 DOI: 10.2147/opth.s118409] [Citation(s) in RCA: 127] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
When administering eye drops, even when completely correctly applied, several routes of absorption are possible and excess amounts can sometimes cause an unwanted systemic bioavailability of the drops when not completely absorbed into the eye. Furthermore, the concentration of active ingredients in such medicinal preparations is usually very high, so that despite the correct application of the recommended dose, considerable amounts may be absorbed in an unwanted manner through various routes. Children are subject to a much higher risk of systemic side effects because ocular dosing is not weight adjusted and physiological development (eg, liver status) differs from that of adults. There is a lack of information about pediatric dosing in the current literature. This review summarizes the most important clinically relevant systemic side effects that may occur during ophthalmic eye treatments. In this review, we discuss general pharmacokinetic considerations as well as the advantages, disadvantages, and consequences of administering drugs from some important drug groups to the eye.
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Affiliation(s)
- Andre Farkouh
- Division of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna
| | - Peter Frigo
- Department of Gynecologic Endocrinology and Reproductive Medicine, Medical University of Vienna
| | - Martin Czejka
- Division of Clinical Pharmacy and Diagnostics, Faculty of Life Sciences, University of Vienna; Austrian Society of Applied Pharmacokinetics, Vienna, Austria
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Seif Barghi T, Kobarfard F, Hashemian A, Zebardast J. Long Term and Intensive Use of Ophthalmic Topical Corticosteroids and the Risk of Positive Doping Test in Athletes: A Case Report. Asian J Sports Med 2015; 6:e24621. [PMID: 26448853 PMCID: PMC4594141 DOI: 10.5812/asjsm.24621] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 11/17/2014] [Indexed: 12/04/2022] Open
Abstract
Introduction: We express the detection of the prohibited substance prednisone, prednisolone in player’s urine sample by long and intensive use eye steroid drops. Case Presentation: In a rare case in Iranian football, a player’s urine sample had corticosteroids. After all investigations, it was demonstrated that systemic effects can be induced by using long-term of ophthalmic prednisone. Conclusions: It seems to be required to investigate the systemic effects on long term and excessive use of topical corticosteroid drops can have on the result of the sample analysis and showing positive results.
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Affiliation(s)
- Tohid Seif Barghi
- Sports Medicine Research Center, Tehran University of Medical Sciences, Tehran, IR Iran
- Medical Committee, Football Federation Islamic Republic of Iran (FFIRI), Tehran, IR Iran
- Corresponding author: Tohid Seif Barghi, Sports Medicine Research Center, Tehran University of Medical Sciences, Tehran, IR Iran. Tell: +98-2188630227-8, Fax: +98-2188003539, E-mail:
| | - Farzad Kobarfard
- Department of Medicinal Chemistry, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
| | - Ahmad Hashemian
- Medical Committee, Football Federation Islamic Republic of Iran (FFIRI), Tehran, IR Iran
| | - Jayran Zebardast
- Msn Student of Electronic Learning in Medical Education, Tehran University of Medical Sciences, Tehran, IR Iran
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Proksch JW, Lowe ER, Ward KW. Ocular pharmacokinetics of mapracorat, a novel, selective glucocorticoid receptor agonist, in rabbits and monkeys. Drug Metab Dispos 2011; 39:1181-7. [PMID: 21441467 DOI: 10.1124/dmd.111.039099] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Mapracorat is a selective glucocorticoid receptor agonist in development for the treatment of a variety of ocular diseases. The purpose of this investigation was to evaluate the ocular pharmacokinetics of mapracorat after topical dosing over a range of dose levels in rabbits and monkeys. Mapracorat was administered over a range of doses from 0.01 to 3000 μg/eye (rabbit) or 50 to 3000 μg/eye (monkey). All animals received a single instillation, and monkeys also received repeated (three times per day for 4 days) instillations. At predetermined intervals through at least 24 h after dosing, ocular tissues and plasma were collected and analyzed for mapracorat by liquid chromatography-tandem mass spectrometry. Mapracorat was rapidly absorbed and widely distributed into ocular tissues after topical ocular administration, with measurable levels sustained through ≥24 h. In both species, mapracorat concentrations were highest in tears followed by conjunctiva and cornea, with lower levels observed in iris/ciliary body and aqueous humor. Mapracorat concentrations in conjunctiva, cornea, and iris/ciliary body increased linearly with increasing dose levels. Ocular exposure was higher after repeated dosing to monkeys than after a single dose. Systemic exposure to mapracorat was low after a single administration, with an average maximal concentration of ≤2.0 ng/ml at the highest dose tested (3000 μg/eye). In comparison with the traditional glucocorticoids, dexamethasone (0.1%) and prednisolone acetate (1%), mapracorat (3%) demonstrated similar or higher levels in ocular tissues with lower systemic exposure. The favorable pharmacokinetic profile of mapracorat supports further clinical investigation and suggests that a convenient daily dosing regimen may be efficacious for this novel ophthalmic anti-inflammatory therapy.
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Affiliation(s)
- Joel W Proksch
- Pharmaceutical Research and Development, Bausch & Lomb, Inc., Rochester, NY 14609, USA.
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Bahar I, Rosenblat I, Erenberg M, Eldar I, Gaton D, Avisar R, Weinberger D. Effect of Dexamethasone Eyedrops on Blood Glucose Profile. Curr Eye Res 2009; 32:739-42. [PMID: 17882705 DOI: 10.1080/02713680701573704] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
PURPOSE To evaluate the effect of dexamethasone eyedrops on blood glucose. METHODS Two hundred eighty-five patients who underwent cataract surgery were prospectively randomized to receive treatment with topical dexamethasone or diclofenac for 1 month. A capillary blood sample was collected before surgery, immediately after, 1 week later, and 1 month later. RESULTS A significant increase in blood glucose levels was noted only in the diabetic dexamethasone group, from 170 +/- 55.5 (mg/dl) before surgery to 229 +/- 76.8 (mg/dl) 1 month later (p = 0.05, 95% confidence interval of -13 to -83.2). The latter level was significantly higher than the 1-month level in the diabetic patients treated with diclofenac drops (198.4 +/- 66.5 mg/dl, p = 0.038). CONCLUSIONS Postoperative dexamethasone eyedrops have a greater effect on the blood glucose profile of diabetic patients than on nondiabetic patients. Clinicians should be alerted to this risk and may initiate appropriate follow-up in this patient subgroup.
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Affiliation(s)
- Irit Bahar
- Department of Ophthalmoogy, Golda Campus, Petah Tiqwa 14900, Israel.
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Abstract
A 3-week-old infant developed buphthalmos and glaucoma after a 1-week course of topical steroid drops. The glaucoma resolved after cessation of the medication. This report underscores the sensitivity of infants and very young children to steroid-related intraocular pressure rises.
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Affiliation(s)
- Kelly A Hutcheson
- Children's National Medical Center and George Washington University School of Medicine, Washington, DC 20010, USA.
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Abstract
Some eyedrops, gels or ointments may cause adverse effects as serious as those observed with systemic therapies. Because of their relatively poor penetration into eye tissue, ophthalmic drugs usually contain high concentrations of their active ingredient. Asking patients about these drugs to prevent interactions is useful when prescribing a new systemic treatment. Conversely, it is advisable to ask about ophthalmic drugs during the etiological investigation of possible iatrogenic effects.
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Affiliation(s)
- Marc Labetoulle
- Service d'ophtalmologie, CHU de Bicêtre, Le Kremlin-Bicêtre (94), Assistance Publique--Hôpitaux de Paris.
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Abstract
Corticosteroids, used prudently, are one of the most potent and effective modalities available in the treatment of ocular inflammation. However, they can produce a plethora of adverse ocular and systemic events. In order to optimise and target drug delivery, whilst minimising systemic adverse effects, a diverse range of local ophthalmic preparations and delivery techniques have been developed. Topical drops and ointments remain the primary methods for administration of ocular corticosteroids. However, ocular penetration of topical corticosteroid drops depends upon drug concentration, chemical formulation of corticosteroid, and composition of the vehicle, therefore, apparently small modifications in preparations can produce a more than 20-fold difference in intraocular drug concentration. Periocular injections of corticosteroids continue to have a useful, but limited, therapeutic role and longer acting, intraocular delayed-release devices are in early clinical studies. Although newer corticosteroids with lesser pressure elevating characteristics have been developed, corticosteroid-induced ocular hypertension and glaucoma continue to be significant risks of local and systemic administration. Posterior subcapsular cataract, observed following as little as 4 months topical corticosteroids use, is thought to be due to covalent binding of corticosteroid to lens protein with subsequent oxidation. Inappropriate use of topical corticosteroid in the presence of corneal infections also continues to be a cause of ocular morbidity. Other risks of locally administered ophthalmic corticosteroids include: tear-film instability, epithelial toxicity, crystalline keratopathy, decreased wound strength, orbital fat atrophy, ptosis, limitation of ocular movement, inadvertent intraocular injection, and reduction in endogenous cortisol. This extensive review assesses the therapeutic benefits of locally administered ocular corticosteroids in the context of the risks of adverse effects.
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Affiliation(s)
- Charles N J McGhee
- Discipline of Ophthalmology, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand.
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