Shigeru Kinoshita, MD, PhD

Shigeru Kinoshita, MD, PhD

Personal Profile Shigeru Kinoshita, MD, PhD Over the course of his career, Shigeru Kinoshita, MD, PhD, has built a reputation in the global ophthalmic ...

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Personal Profile Shigeru Kinoshita, MD, PhD Over the course of his career, Shigeru Kinoshita, MD, PhD, has built a reputation in the global ophthalmic community as an innovative researcher and a pioneering spirit, particularly in the fields of corneal wound healing and ocular surface reconstruction. In the 1980s, during a cornea fellowship at Harvard Medical School, Dr. Kinoshita discovered the centripetal movement of the corneal epithelial cells and demonstrated the importance of the limbal epithelium, work that led to our current understanding of corneal stem cells. Since then, Dr. Kinoshita has continued to pursue a variety of research interests, while also working in the department of ophthalmology at the Kyoto Prefectural University of Medicine, where he has held the titles of professor and chairman since 1992. Dr. Kinoshita was instrumental in developing an eye research program at Kyoto that has led to the development of new surgical and medical interventions for some of the most challenging eye conditions.

THE OCULAR SURFACE What were your circumstances growing up and what experiences formed your outlook on the world? SHIGERU KINOSHITA, MD, PHD I was raised in an upper middle class family in Osaka, Japan. My father was a businessman whose work was unrelated to medicine, and my mother was a typical Japanese housewife. At the age of 18, I felt honored to gain acceptance into Osaka University Medical School. While at medical school, I became a member of the university sailing club, and I would often spend all day at sea learning navigation, seamanship, and racing. That experience gave me a deep re©2010 Ethis Communications, Inc. All rights reserved.


spect for nature, and it taught me both self-reliance and how to work successfully as a member of a team. Our sailing team was very successful and we won many regattas against sailing teams from other universities in Japan, ultimately winning a coveted position in the national championship race. TOS Why did you choose medicine and then ophthalmology? KINOSHITA I was in my second year of senior high school when my class went on a field trip to the anatomy department at Osaka University Medical School. While there, my classmates and I had the opportunity to view a human cadaver. That experience had a big impact on me and may have, in some way, influenced my decision to enter medicine. Additionally, because the Osaka University Medical School is centrally located in the city of Osaka, I would often pass by the university campus on my way around the city. Like many universities worldwide, the campus is old and the buildings have wonderful architecture, both of which help to create a beautiful and serene atmosphere in which to study. I suppose that those aspects also drew me to the university, in addition to the school’s reputation as an excellent institution of higher learning. As I entered my sixth and last year of medical school, my plan was to specialize in cardiovascular surgery, but one day early that year I chanced to talk with Dr. Yasuo Tano, who was

then a resident in the ophthalmology department at Osaka University Medical School and two years my senior. (He subsequently became its chairman.) Dr. Tano was imbued with a deep passion for the field of ophthalmology, and it was during that conversation that he strongly urged me to join his department, which I ultimately did. TOS How did you become interested in the ocular surface? KINOSHITA While a resident in Osaka, I saw many devastating ocular surface disorders that, at the time, could not be successfully treated. That prompted my interest in the ocular surface and the development of effective treatments for ocular surface diseases. TOS How did your cornea fellowship at Harvard Medical School come about? KINOSHITA Near the end of my residency at Osaka University Medical School, I had a strong desire to continue my education in cornea, preferably in the United States. At the time, Boston was the primary center for those with an academic interest in cornea, and I began to think about and research the possibility of going there, in the process learning about the Massachusetts Eye and Ear Infirmary and the Retina Foundation (now the Schepens Eye Research Institute). In the course of my research I also came across a 1977 paper by Prof. Richard A. Thoft entitled “Conjunctival Transplantation.” I was fascinated by Thoft’s discussion of the treatment of chemical injury, which at the time was a puzzle. Nobody knew then how to treat chemical injury or Moorens ulcer, and little thought had been directed towards


PERSONAL PROFILE / Shigeru Kinoshita, MD, PhD

the biological background of those conditions. When I read Thoft’s paper, I was impressed by both his surgical procedure and his basic knowledge of corneal biology. I decided to try to contact him directly. As fate would have it, Japan was the host country of the International Congress of Ophthalmology in 1978, and both Thoft and his colleague Judith Friend were in Japan to attend the meeting. I had the opportunity to meet and speak with Prof. Thoft, which started me on a journey that culminated with my fellowship at Harvard Medical School.

KINOSHITA At Harvard, Prof. Thoft asked me to work on a project related to corneal epithelium. At the time, nobody knew what happened to donor corneal epithelial cells once they were grafted to a recipient. To be honest, I did not know why Prof. Thoft was so keenly interested in those cells. Initially, I thought that there was indirect evidence for the persistence of donor corneal epithelial cells in the form of a late immune reaction to those cells. However, Prof. Thoft insisted that I prove the persistence of the donor corneal epithelial cells. When I performed sex-chromosome experiments on the donor cells, I discovered that donor corneal epithelial cells are somehow diluted by the host epithelial cells without any immunological reaction. Those studies led to the concept of centripetal movement, the slow but continuous movement of epithelial cells from the periphery to the center of the cornea. I was truly amazed that I had discovered direct evidence of this centripetal movement. Nobody at the time knew how important the limbal epithelial cells were, and we went on to perform additional experiments that provided us with much more data about limbal epithelial cells. This was the starting point of my research into the location of corneal epithelial stem cells.

KINOSHITA I had two mentors during my early academic life—a mentor in Japan and a mentor in America—both of whom greatly influenced the course of my work. The first of these was Prof. Reizo Manabe at Osaka University Medical School, who taught me through daily conversation the importance of individual diversity and freedom. Prof. Manabe was a very progressive individual by Japanese standards, as he did not insist on strict “top-down” instruction from teacher to student, thus freeing me to think independently. Of course, he insisted that his students learn the basics and understand the benefits of working together as a team, yet any time that I approached him with an independent research idea, he would tell me to follow that course—not explicitly encouraging the new direction but not discouraging it either. Interestingly, that experience somewhat mirrored my relationship with my second mentor, Prof. Thoft, during my years at Harvard. Prof. Thoft taught me the importance of honesty and purity of mind in science, traits that help keep a person in awe of nature. Both of my mentors allowed me to freely explore new ideas and to work independently. Their support allowed me to move in new directions with confidence, and that gift has stayed with me to the present day and made possible my best work. I now try to instill that same sense of freedom in my research students. Finally, I must mention one other scientist who greatly influenced the course of my work: J. Wayne Streilein, who was also at Schepens Eye Research Institute. Prof. Streilein would often come to Japan, especially to the city of Kyoto, and we had many wonderful chances to talk about our research, as well as other developments in eye research. Those conversations always brought a certain type of happiness to me, as he taught me about the great enjoyment that can be obtained from the wonder and curiosity of science.

KINOSHITA I became Chairman of the department of ophthalmology at Kyoto Prefectural University of Medicine in 1992, and at that time, my foremost desire was to make our department international. From 1992 to now our motto has been “Be international!” I wanted to cultivate a very strong team on both the clinical and research sides, and since the beginning of my tenure at this institution, we have been able to recruit bright, young freshmen residents. Every year has brought 10 new members to the department, many of whom are eager to be involved in eye research. A number of those individuals have stayed on with our department. Initially, I orchestrated the development of cornea research and then gradually expanded our focus to include research related to glaucoma, vitreous/retina, refractive surgery, and ocular plastic reconstruction.

TOS What people and events were most influential in setting the course of your work?

TOS Can you describe the way ocular surface research is done at Kyoto Prefectural University of Medicine?

TOS What do you hope to accomplish through your work as vice president of the Asia Cornea Society? Please briefly

TOS Can you describe the course of your work on the ocular surface?

TOS What do you enjoy most about being at Kyoto Prefectural University of Medicine? What are the biggest challenges? KINOSHITA What I enjoy most is the research side of our work, my personal interest lying in the direction of translational research. I initially thought that I enjoyed clinical work more than research, but the research we have conducted here has led to new surgical and medical treatments, and this has been very gratifying for me. The biggest challenge is gaining the funding that is crucial to the continuation of our research. TOS What are your goals for ocular surface research at Kyoto Prefectural University of Medicine? KINOSHITA Although our department treats all eye-related diseases, we try to challenge ourselves by tackling the most devastating eye diseases, like Stevens-Johnson Syndrome. What we have learned from taking on the most terrible of eye diseases has helped us meet challenges with other diseases.



PERSONAL PROFILE / Shigeru Kinoshita, MD, PhD AZASITE® (azithromycin ophthalmic solution) 1%

explain the work of the International Committee for Classification of Corneal Dystrophies. KINOSHITA Well, in answering the first part of the question, please allow me to first say that Prof. Donald Tan has been doing a spectacular job over the past few years in his capacity as the President of the Asia Cornea Society. As Vice President, my aim is to work alongside Prof. Tan in our mutual goal of promoting a global sharing of new and effective treatments for corneal and ocular surface diseases, especially among Asian countries. As to my work with the International Committee for Classification of Corneal Dystrophies, it is centered on our attempt to obtain a worldwide consensus about the classification of such dystrophies. I have personally learned a great deal about corneal dystrophies from our meetings. Credit for much of the group’s success should go the committee chair, Jayne Weiss, MD, who is professor of ophthalmology at Wayne State University in Detroit, Michigan. TOS What do you consider your greatest professional achievement? KINOSHITA I suppose that my greatest professional achievement would have to be the findings derived from the sex chromatin project that I conducted many years ago at Harvard University. That project was some of my first work, and it resulted in the discovery of the centripetal movement of corneal epithelial cells, which provides us with such a wonderful foundation for the corneal epithelial stem cell theory. TOS When you are not working, what do you enjoy doing? KINOSHITA In my free time, I enjoy reading and watching television, as well as visiting museums, all of which help to clear my mind of day-to-day work-related problems. TOS In your opinion, what are some of the most pressing questions researchers must answer to advance the study of ocular surface diseases? KINOSHITA Ocular surface diseases have historically been important and pressing issues, and they will continue to be so in the future. These disorders present important questions that we researchers need to solve. Over the years, my personal research interest has gradually shifted from the anterior side of the cornea to the posterior side. In my opinion, continued research needs to be conducted on corneal endothelial cells and why donor corneal endothelial cell density decreases over time, an area of research related to corneal endothelial cell biology. This is a key question that is still unresolved, and if we can answer this question, then the success rate of managing corneal endothelial diseases will certainly improve. W


Sterile topical ophthalmic drops Initial U.S. Approval: 2007 BRIEF SUMMARY Before prescribing, please consult the full prescribing information. INDICATIONS AND USAGE AzaSite is indicated for the treatment of bacterial conjunctivitis caused by susceptible isolates of the following microorganisms: CDC coryneform group G* Haemophilus influenzae Staphylococcus aureus Streptococcus mitis group Streptococcus pneumoniae *Efficacy for this organism was studied in fewer than 10 infections. DOSAGE AND ADMINISTRATION The recommended dosage regimen for the treatment of bacterial conjunctivitis is: Instill 1 drop in the affected eye(s) twice daily, eight to twelve hours apart for the first two days, and then instill 1 drop in the affected eye(s) once daily for the next five days. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Topical Ophthalmic Use Only NOT FOR INJECTION. AzaSite is indicated for topical ophthalmic use only and should not be administered systemically, injected subconjunctivally, or introduced directly into the anterior chamber of the eye. Anaphylaxis and Hypersensitivity With Systemic Use of Azithromycin In patients receiving systemically administered azithromycin, serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy. Although rare, fatalities have been reported. The potential for anaphylaxis or other hypersensitivity reactions should be considered, since patients with a known hypersensitivity to azithromycin or erythromycin were excluded from study. Growth of Resistant Organisms With Prolonged Use As with other anti-infectives, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If super-infection occurs, discontinue use and institute alternative therapy. Whenever clinical judgment dictates, the patient should be examined with the aid of magnification, such as slit-lamp biomicroscopy, and where appropriate, fluorescein staining. Avoidance of Contact Lenses Patients should be advised not to wear contact lenses if they have signs or symptoms of bacterial conjunctivitis. ADVERSE REACTIONS The most frequently reported ocular adverse reaction in patients receiving AzaSite was eye irritation. This reaction occurred in approximately 1% to 2% of patients. Other adverse reactions associated with the use of AzaSite were reported in less than 1% of patients and included: burning, stinging and irritation upon instillation, contact dermatitis, corneal erosion, dry eye, dysgeusia, nasal congestion, ocular discharge, punctate keratitis, and sinusitis. In addition to adverse events reported from clinical trials, the following events have been identified during post approval use of AzaSite. Eye: blurring, eyelid swelling, itching, pain, visual acuity reduction. General: allergic reactions including facial swelling, hives, periocular swelling, rash, urticaria. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B. Reproduction studies have been performed in rats and mice at doses up to 200 mg/kg/d. The highest dose was associated with moderate maternal toxicity. These doses are estimated to be approximately 5000 times the maximum human ocular daily dose of 2 mg. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman. Pediatric Use The safety and effectiveness of AzaSite solution in pediatric patients below 1 year of age have not been established. The efficacy of AzaSite in treating bacterial conjunctivitis in pediatric patients one year or older has been demonstrated in controlled clinical trials. Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients. STORAGE AND HANDLING Store unopened bottle under refrigeration at 2°C to 8°C (36°F to 46°F). Once the bottle is opened, store at 2°C to 25°C (36°F to 77°F) for up to 14 days. Discard after the 14 days. PATIENT COUNSELING INFORMATION Patients should be advised to avoid contaminating the applicator tip by allowing it to touch the eye, fingers, or other sources. Patients should be directed to discontinue use and contact a physician if any signs of an allergic reaction occur. Patients should be told that although it is common to feel better early in the course of the therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by AzaSite or other antibacterial drugs in the future. Patients should be advised not to wear contact lenses if they have signs or symptoms of bacterial conjunctivitis. Patients are advised to thoroughly wash hands before using AzaSite. Rx only Inspire Pharmaceuticals Inc. Licensee of InSite Vision Incorporated Manufactured by Catalent Pharma Solutions, LLC U.S. PAT NO. 5,192,535; 6,239,113; 6,569,443; 6,861,411; 7,056,893; and Patents Pending AZA-0301 Revised: 11/2008