The preparation of HEMA-MPC films for ocular drug delivery

There is a need to prolong drug residence time using a biocompatible formulation in the subconjunctival space after surgery to treat glaucoma. Drug releasing discs were prepared with 2-(hydroxyethyl)methacrylate (HEMA) and 2-methacryloyl-oxyethyl phosphorylcholine (MPC). The ratio of bound water (Wb) to free water (Wf) ratio increased from 1:0.3 to 1:6.8 with increasing MPC (0 to 50%, w/w). The optimal balance between water content, SR and mechanical strength were obtained with 10% MPC (w/w) hydrogels. Water-alcohol mixtures were examined to facilitate loading of poorly soluble drugs, and they showed greater hydrogel swelling than either water or alcohol alone. The SR was 1.2 ± 0.02 and 3.3 ± 0.1 for water and water:ethanol (1:1) respectively. HEMA-MPC (10%) discs were loaded with dexamethasone using either water:ethanol (1:1) or methanol alone. Drug release was examined in an outflow rig model that mimics the subconjunctival space in the eye. Dexamethasone loading increased from 0.3 to 1.9 mg/disc when the solvent was changed from water:ethanol (1:1) to methanol with the dexamethasone half-life (t½) increasing from 1.9 to 9.7 days respectively. These encouraging results indicate that HEMA-MPC hydrogels have the potential to sustain the residence time of a drug in the subconjunctival space of the eye

Влияние разгрузочных медикаментозных проб на стереометрические характеристики зрительного нерва при первичной открытоугольной глаукоме

PURPOSE: To evaluate the changes of optic nerve head (ONH) stereometric parameters during drug-induced stressrelief tests in patients with primary open-angle glaucoma. METHODS: 165 people (222 eyes) were examined. 135 patients (186 eyes) had open-angle glaucoma diagnosis of different severity (early, moderate, advanced). Also 30 healthy controls (36 eyes) were included. Patients' mean age was 62±8.2 years. Groups were standardized by sex, age and range of the original corneal-compensated IOP (21-30 mmHg), as well as by length of the anterior-posterior axis of the eye. All people underwent standard ophthalmologic examination including visometry, biomicroscopy, gonioscopy, ophthalmoscopy and and Humphrey visual field assessment. Corneal hysteresis (CH), corneal resistance factor (CRF), corneal-compensated IOP (lOPcc), and Goldmann-related IOP (lOPg) were measured using ocular response analyzer (ORA). The length of the anterior-posterior axis of the eye was measured using A-scan ultrasound biometry (Ocuscan RxP, “Alcon" USA). Confocal laser scanning ophthalmoscopy (Heidelberg Retina Tomoghaph) HRT Ill was used to evaluate ONH stereometric parameters. RESULTS: ONH rigidity coefficient (RC) was formulated according to the analysis of changes in ONH stereometric parameters as a result of drug induced stress-relief tests. RC coefficient was calculated according to the following formula: RC = (AIOP/Acup volume) / 100. According to this formula, the coefficient modulus increase indicates growing rigidity of ONH structures. RC value of the healthy control group was 3.0+1.4 mm Hg/mm3. In patients with early glaucoma RC did not differ from the control group and equaled 3.3+1.0 mm Hg/mm3. It may be indicative of maintaining resilience of the structures of the optic nerve head and the surrounding tissue in early glaucoma. Significant changes of ONH stereometric parameters were found in patients with moderate glaucoma during drug-induced stress-relief test; CR increased significantly and amounted to 5.7+1.1 mm Hg/mm3 and showed a positive correlation with disease duration (r=0.4; p=0.006). Advanced glaucoma patients group revealed the highest possible CR value (8.6+3.6 mm Hg/mm3), which may indicate a marked increase in the rigidity of ONH structures and surrounding tissues. CONCLUSION: ONH rigidity coefficient (RC) significantly reflects the degree of IOP reduction effect on ONH cup volume; RC value increase may serve as a risk factor for glaucoma progression. Based on our research results we can recommend including RC calculation into complex examination of primary open-angle glaucoma patients. RC may be a possible prognostic factor for evaluating glaucomatous optic neuropathy progression.ЦЕЛЬ. Изучить влияние разгрузочных медикаментозных проб на стереометрические характеристики зрительного нерва у пациентов с установленным диагнозом первичной открытоугольной глаукомы (ПОУГ) I-III стадий. МЕТОДЫ. Всего обследовано 165 человек, 222 глаза; из них 135 пациентов, 186 глаз с установленным диагнозом ПОУГ I-III стадий и 30 пациентов, 36 глаз - группа контроля. Средний возраст пациентов составил 62±8,2 года. Группы были стандартизированы по полу и возрасту, диапазону исходного роговично-компенсированного ВГД (21-30 мм рт.ст.), по длине переднезадней оси глаза (ПЗО). Проводили стандартное офтальмологическое обследование, включавшее визометрию, биомикроскопию, гониоскопию, офтальмоскопию и компьютерную статическую периметрию Humhprey. Исследование вязкоэластических свойств фиброзной оболочки глаза и внутриглазного давления (ВГД) с помощью динамической двунаправленной аппланации роговицы выполняли на приборе Ocular Response Analyzer (ORA) («Reichert», США). Длину ПЗО глаза измеряли с помощью ультразвукового А-сканирования на приборе Ocuscan RxP («Alcon», США) в режиме 10 МГц. Для оценки стереометрических характеристик головки зрительного нерва (ГЗН) использовали конфокальную лазерную сканирующую офтальмоскопию (Heidelberg Retina Tomoghaph) HRT Ill. РЕЗУЛЬТАТЫ. На основании полученных данных в ходе проведения разгрузочных проб для оценки биомеханических свойств головки зрительного нерва предложен коэффициент объемной ригидности головки зрительного нерва (КР ГЗН), который рассчитывали по формуле: КР ГЗН = (ДВГД/Добъема экскавации ДЗН)/100. В соответствии с данной формулой увеличение модуля коэффициента свидетельствует о росте ригидности структур головки зрительного нерва. У пациентов группы контроля КР ГЗН составил 3,0±1,4 мм рт.ст./мм3. У пациентов с начальной стадией ПОУГ КР ГЗН достоверно не различался с группой контроля и был равен 3,3±1,0 мм рт.ст./мм3, что может свидетельствовать о сохранении способности к восстановлению структур головки зрительного нерва и окружающих ее тканей. У пациентов с развитой стадией глаукомы на фоне разгрузочных медикаментозных проб обнаружены значимые изменения стереометрических параметров; КР ГЗН достоверно увеличился и составил 5,7±1,1 мм рт.ст./мм3 и положительно коррелировал с длительностью заболевания ПОУГ (r=0,4; p=0,006). У пациентов с далеко зашедшей стадией ПОУГ на фоне снижения ВГД при проведении разгрузочных медикаментозных проб выявлены максимально высокие значения КР ГЗН (8,6±3,6 мм рт.ст./мм3), что может свидетельствовать о выраженном увеличении ригидности структур головки зрительного нерва и окружающих ее тканей. ЗАКЛЮЧЕНИЕ. Разработанный коэффициент ригидности головки зрительного нерва достоверно отражает степень влияния снижения ВГД на объем экскавации головки зрительного нерва; повышение его может служить фактором риска прогрессирования глаукомной оптической нейропатии (ГОН). Результаты проведенных исследований позволяют рекомендовать включение в комплекс обследования пациентов с первичной открытоугольной глаукомой расчет коэффициента ригидности ГЗН, который может служить прогностическим фактором для оценки прогрессирования ГОН

Изменения роговицы у больных с первичной открытоугольной глаукомой

For many years people have studied the structure of the eye. This article is devoted to the changes in the structure of the cornea in patients with primary open-angle glaucoma. With the advent of modern technology, which allows the in vivo study of individual structures of the eye, significant changes in the endothelium of the cornea were found in patients with primary glaucoma. In recent years, more attention was being paid to the interrelation of the pathogenesis of glaucoma with the biomechanics of the eye. Therefore, the review gave consideration to such aspects as biomechanical, biochemical features of the structure of the cornea in normal and pathological changes related to primary glaucoma. The cornea is a highly sensitive tunic of the eye. In various pathological conditions of the eye its sensitivity can be greatly reduced or completely disappear, so its definition can be very informative. This article provides information about the condition and the sensitivity changes of the cornea in patients with primary open-angle glaucoma. A decrease in tear production leading to the development of the dry eye syndrome was noted to be a side effect of all hypotensive drops which contain preservative agents. A literature review regarding this question is also provided. This article also presents data about the morphological changes of the cornea related to primary glaucoma according to confocal microscopy.На протяжении многих лет происходило изучение структур глазного яблока на разных уровнях. Обзор посвящен изменениям строения роговицы у больных с первичной открытоугольной глаукомой. С появлением современных технологий, позволяющих прижизненное исследование отдельных структур глаза, были найдены значительные изменения в эндотелии роговицы у больных с первичной глаукомой. В последние годы все больше внимания уделяется взаимосвязи патогенеза глаукомы с биомеханикой глаза. Поэтому в обзоре уделено внимание таким аспектам, как биомеханические, биохимические особенности строения роговицы в норме и при патологических изменениях на фоне первичной глаукомы. Роговица является высокочувствительной оболочкой глазного яблока. При различных патологических состояниях глаза ее чувствительность может значительно сни жаться или полностью исчезать, поэтому ее определение может быть очень информативным показателем при установлении диагноза. В литобзоре содержится информация о состоянии и изменении чувствительности роговицы у пациентов с первичной открытоугольной глаукомы. По данным литературы, в исследованиях последних лет отмечается, что побочным эффектом всех гипотензивных капель, содержащих консервант, является достоверное снижение слезопродукции, приводящее к развитию клинических проявлений синдрома «сухого глаза». Дан обзор литературы по этому вопросу. Также представлены данные о морфологических изменениях роговицы на фоне первичной глаукомы по данным конфокальной микроскопии

Ocular Tissue Engineering

Tissue engineering emerged back in the 1990s as a new concept to overcome the problem of tissue and organ failure. Over recent decades, there has been incredible progress towards the regeneration of tissues such as bone, heart valves, cartilage, cornea, and retina. In terms of ocular tissue engineering, despite the scientific and strategic incentive for reconstructing ocular tissues, there is also a tremendous need for novel therapeutic options in treating numerous eye diseases related to tissue failure. The aim of this Special Issue is to discuss tissue engineering applications of ocular tissues including but not limited to cornea, retina, and lenses

Hyperbaric Medicine

Hyperbaric oxygen is a known therapeutic agent, and treatments using this agent remain a matter of discussion and research. This Special Issue collection will add new knowledge and also offer some not so usual approaches to foster contemporary understanding and potential benefit for patients and scholars

Effect of Intraocular Pressure on Chick Eye Geometry, Finite Element Modeling, and Myopia

In most cases, myopia is characterized by an increase in axial length of the eye, but the exact mechanisms for the axial elongation are still unknown. Higher intraocular pressure (IOP) has been associated with myopia and could be involved in eye enlargement. Also, some investigators have argued that the mechanical stresses generated by the ocular muscles during near work cause the eye to stretch out of shape. The purpose of this work was to investigate the effect of IOP on eye geometry, build a finite element model of the corneo-scleral shell of a chick eye, and verify if the eye could elongate due to increased IOP and hence become myopic. In the present study, myopia was induced in the right eye of chicks using -15 dioptre (D) goggles. The in-vitro pressure-volume curves of normal and myopic chick eyes were obtained using a computer controlled syringe pump and a digital pressure gauge. The axial length and horizontal equatorial diameter of the chick eyes as pressure increased were measured from digital photographs. To build the finite element model, normal chick eyes were frozen, sliced using a microtome, and photographed. The image sequence was aligned using MATLAB software and imported into SolidWorks® and Mimics software packages for three-dimensional (3D) reconstruction. Three 3D models were constructed and imported into Abaqus/CAE® software for finite element analysis. Isotropic, homogeneous, linear elastic and exponentially stiffening material properties were used for the finite element models. The results of the finite element models were compared with the experimental data. The results showed that normal chick eyes elongated in the axial direction and initially contracted in the horizontal equatorial direction as IOP increased. Myopic chick eyes did not elongate as much in the axial direction and did not contract as much in the horizontal equatorial direction compared with normal eyes. The volumetric deformation of myopic eyes was similar to normal eyes suggesting that growth and remodelling of the ocular tissues was involved in experimental myopia in the chick. The 3D reconstructed geometry of a chick eye was similar to a real eye although small geometric inaccuracies were present. The finite element model with isotropic, homogeneous, and exponentially stiffening material properties agreed well with the experimental strains in spite of the fact that the anisotropy of the ocular tissues was not included in the finite element model. This suggests that the oblate geometry of the chick eye was the main parameter dictating its deformation under increased IOP. The natural tendency of chick eyes is to elongate in the axial direction as IOP increases and this suggests that IOP could play a role in myopia onset and progression. The way chick eyes deformed as pressure increased is probably due to their oblate geometry. The finite element model could be used in the future to study the effect of different parameters such as ocular muscle forces and ocular tissues material properties on eye geometry. This way, an eye configuration more prone to eye elongation and myopia could be determined

Research into aqueous humour production and its control within the bovine eye

The isolated, perfused bovine eye model has a long proven track record as an established experimental model allowing the study of the physiology and pharmacology of aqueous humour. Wilson et al, 1993 have shown this model in numerous experiments to provide reproducible results, consistent with in vivo models. Shahidullah et aL (1995, 1999) have since taken the use of the model ftirther showing a number of categories of drugs that reduce aqueous production and hence intraocular pressure. Bradykinin (10-9 to 10-8M) suppressesaqueous humour formation (42-49% reduction). At higher concentrations (3x10-8Mand 10-7M) aqueous production appeared to be increased (8-15% increase).It is possible that suppression of aqueous humour formation persists at higher bradykinin concentrations but at higher concentrations leakage of fluid from the vascular compartment into the chamber of the eye occurs -breakdown of the blood- aqueous barrier. Bradykinin was found to act through the B2 receptor. WIN 64338 (3x10-8M), a B2 receptor antagonist, abolished the effect of bradykininon aqueous humour formation suppression (unpaired t-test: p0.1) suggesting that there is no tonic influence of endogenous nitric oxide in the bovine ciliary epithelium. Bradykinin appears to suppress aqueous humour formation via nitric oxide and cGMP since a soluble guanylate cyclase inhibitor (ODQ) also blocked the bradykinin- induced inhibition of aqueous humour formation (bradykinin (10-9M) alone 42% reduction, in presenceof ODQ (3x10-7M) 4% reduction: unpaired t-test p<0.004). The absence of ascorbate from the perfusate significantly reduced the inhibitory effect of bradykinin on aqueous humour production (bradykinin (10-9M) in presence ofascorbate 42% reduction, bradykinin (10-9M) in absence of ascorbate 5% reduction:unpaired t-test p<0.004). It is possible that the vasodilator effect of bradykinin in the absence of ascorbate (McNeish et al, 2003) may counter the effect on aqueous humour formation. The close parallel between the very low concentrations of bradykinin required to suppress aqueous humour formation and to affect intracellular calcium movements, supports the hypothesis that intracellular calcium plays an important role in aqueous humour formation. It may also suggest a physiological role for bradykinin as a modulator in the ciliary epithelium. (Abstract shortened by ProQuest.

Efecto de la ortoqueratología nocturna en la morfología del epitelio corneal y su relación con la sensibilidad corneal

La ortoqueratología (OK) es un método para la reducción o eliminación temporal de los errores refractivos, que consiste en el empleo de lentes de contacto (LC) rígidas permeables a los gases (RGP) para moldear la zona central de la superficie corneal. Sus efectos en la topografía corneal, la agudeza visual, sensibilidad al contraste, calidad óptica del ojo y propiedades biomecánicas se han investigado ampliamente, pero sólo unos pocos estudios han examinado estos efectos en la morfología de la córnea humana. Al respecto, se han reportado cambios en la densidad celular y en el espesor del epitelio corneal, así como en el espesor del plexo nervioso que subyace bajo el epitelio y en el espesor de la membrana de Bowman. La irreversibilidad de los efectos producidos en el espesor del plexo nervioso sub-basal (PNSB) dio lugar a un estudio más profundo del mismo. Sin embargo, aún no se conocían todos los efectos a nivel del mismo.El origen de esta tesis surgió de la necesidad de un estudio prospectivo que analizase cuantitativamente los cambios producidos en los diferentes estratos del epitelio corneal que, según la bibliografía actual, eran susceptibles de necesitar más investigación. Concretamente en el PNSB, donde se estudiaron los efectos de las lentes de OK en su morfología y en la densidad de las células de Langerhans, así como la posible relación de dichos efectos con una alteración sensorial. Por tanto, el objetivo principal de esta tesis fue cuantificar los cambios producidos en el epitelio corneal por un tratamiento de OK a largo plazo y la reversibilidad de los mismos tras el cese de las LC..

The bovine perfused eye as a model for pharmacological investigations

The isolated perfused eye of many species has become a frequently used model in the study of ocular pharmacology. Due to its availability, cheapness and comfortable size for experimental use the bovine eye provides an attractive model for conducting perfusion experiments. Although initially rejected by Kishida et al. (1985), the bovine perfused eye has been proved to be a valid model for studying aqueous humour dynamics and the pharmacology of various antiglaucoma drugs, including the β-adrenoceptor antagonist, timolol, and the carbonic anhydrase inhibitor, MK-927 (Wilson et al., 1993). A general aim of this study was to develop the in vitro bovine perfused eye, to show whether it is a useful model for experimental work in studying drug mechanisms in the eye, whether from a pharmacodynamic or pharmacokinetic point of view. Pharmacodynamic Study The procedure for dissection and setting up of the constant flow method for the bovine perfused eye was initially described by Wilson and co-workers (1993). Bovine eyes, obtained from the local abattoir, were cannulated via the long posterior ciliary artery and perfused with Krebs' solution. In order to monitor drug effects on intraocular pressure the anterior chamber was cannulated and connected to a water manometer. Since some drugs affect vascular resistance, the arterial perfusion pressure was continuously measured. Drug solutions or vehicles were administered by one of three routes; (i) by addition of drug to the perfusate reservoir at an exact concentration, (ii) as a bolus dose injected intra-arterially or (iii) as a bolus dose injected intracamerally. Constriction of the pupil, in response to pilocarpine (10 -6M), shown by a significant decrease in pupil diameter, indicated that following intra-arterial administration, drugs have access to the anterior segment of the eye, including the iris sphincter and therefore very probably the ciliary muscle, since their arterial supply is common. To investigate the bovine perfused eye as a model for studying intraocular pressure and aqueous humour dynamics, we studied four different drugs known to alter either aqueous humour formation or aqueous humour outflow. The results show that experimentally damaging the cornea, effectively removing the barrier properties of the corneal epithelium, increases the amount of aciclovir absorption in the cornea and aqueous humour compared with the undamaged cornea. The observed increases in absorption of aciclovir following experimental damage are much greater when the drug formulations have hydrophilic properties, such as the PVA film and aqueous gel. From the present work, the formulations can be ranked in order of corneal and aqueous humour absorption of aciclovir: Ointment < PVA Film < Aqueous Gel In this model the level of drug penetration in the cornea and aqueous humour can be measured without the complications associated with in vivo studies. Due to the lack of in vivo factors such as blinking, drug dilution, drainage and conjunctival absorption the levels of absorption found in the present model are likely to be exaggerated. Nevertheless, the bovine perfused eye provides a useful model for pharmacokinetic studies, which is perhaps superior to the isolated corneal preparation nominally used to assess corneal drug absorption since conditions are more physiological and no edge-damage has been inflicted on the cornea