Natural Remedies For Ophthalmic Diseases

Rediscover Your Vision

Heres What Rediscover Your Vision Can Do To Help You: Improve and perfect your eyesight so that you dont need your readers nearby every single time you need to read the newspaper, a report, a book, or a document. Strengthen your eyes and focal muscles, eliminating the painful burning sensation in your eyes at the end of every single day. Use a computer or watch TV without pain and suffering anytime, anywhere, and as long as you want. Improve All aspects of your vision. Whether youre nearsighted or farsighted, the condition can be cured! See road signs from far away, watch a movie, play catch or read a book with just a lamp on, without stressing about carrying your glasses around everywhere! Start your day comfortably, without worrying about taking half an hour to pop your uncomfortable contacts in, or scrambling to find your glasses. Save Thousands and Thousands of dollars. I cant stress enough how expensive glasses and contacts are getting nowadays, and the prices just keep Increasing. If you spend $500 a year on glasses and contacts, imagine how much money youd have to spend on things like vacations and luxuries over the 40-50 years you have to Keep buying them!

Rediscover Your Vision Summary

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Acetazolamide Diamox Diamox Sequels Glaucoma 250 mg PO up to

Qid (immediate-release) or 500 mg PO up to bid (sustained-release). Max 1 g day. Acute glaucoma 250 mg IV q 4 h or 500 mg IV initially with 125 to 250 mg q 4 h, followed by oral therapy. Mountain sickness prophylaxis 125 to 250 mg PO bid to tid, beginning 1 to 2 days prior to ascent and continuing at least 5 days at higher altitude. Edema Rarely used, start 250 to 375 mg IV PO q am given intermittently (every other day or 2 consecutive days followed by none for 1 to 2 days) to avoid loss of diuretic effect. Generic only Tabs, 125, 250 mg. Generic Trade Caps, extended-release 500 mg. > LK 2C +

Nutrient Transporters In The Normal And Cataractic Lens

Age-Related Nuclear (ARN) Cataract - a Transport Problem As the world's population ages, ARN cataract has become the leading cause of blindness. It is characterized by a drastic decline in GSH concentration in the nucleus of the lens, but not the cortex, exposing the centre of the lens to the damaging effects of oxygen radicals, causing protein aggregation, increased light scattering and ultimately nuclear cataract (65). However, unlike diabetic cataract, in ARN cataract there appears to no significant morphological changes to the cellular architecture of the lens. Biochemically, however, extensive modifications to proteins in the lens nucleus are observed that include oxidation of methionine residues and sulfhydryl groups, insolubilization of crys-tallins, and protein cross-linking to form mixed disulphides, all of which contribute to light scattering (66). Oxidative damage is a key feature of ARN cataracts. In the transparent lens, a robust oxygen-radical scavenger system which...

C aAdrenoceptor Agonists and Antagonists for the Treatment of Glaucoma

It has also been postulated that imidazoline receptors may be involved in some of the actions of clonidine-like imidazolines in glaucoma (41-43). Radioligand-binding assays provide no evidence for the presence of imidazoline binding sites in the ciliary body of the rabbit (36). However, it is possible that an imidazoline receptor located at another ocular or extraocular site may contribute to the ocular hypotensive actions of those clonidine-like imidazolines that interact with both a2-adrenoceptors and imidazoline I1-receptors, such as moxonidine. when an a-adrenoceptor agonist is used for the treatment of glaucoma. Even agents such as UK 14,304, which have a reasonable degree of selectivity for a2- versus a1-adrenoceptors, can produce an initial, short-lived increase in intraocular pressure (46), which probably results from a1-adrenoceptor activation produced by the high local concentrations achieved immediately following topical administration. Hence the design of even more...

Protective Role of Antioxidants in Eye Health

For over 60 years, vitamin A has been associated with good eyesight. It is essential for forming the retinal photoreceptor pigments which are the basis of vision. Vitamin A deficiency causes eye tissue to shrink and harden, leading to over-sensitivity to bright light, dry and inflamed eyes and eyelids, and finally to night blindness. Vitamin A deficiency is still the prime cause of child blindness in developing countries. It is also associated with advanced AMD (Seddon et al., 1994). Seddon et al. (1994) studied the effect of antioxidant supplementation in patients with an advanced form of AMD. In those subjects given a multivitamin-mineral antioxidant supplement containing vitamin E (400 mg day 1), vitamin C (500 mg day 1), selenium (250 g day 1) and p-carotene (9 mg day 1), distance visual acuity stabilized over a 18 month period whereas in those given placebo it declined. The supplements successfully halted or reversed the degenerative macular changes in 60 of subjects. This study...

Applications of Polysaccharide Nano Microparticles in Ophthalmologic Therapy

Nanomedicine offers potentially safe and successful treatment regimens for ocular disorders especially when polysaccharides are used, because micro nanoparticles based on this kind of natural polymers are able to persist at the surface of the eye to give prolonged drug delivery. Many efforts have been focused on increasing the corneal penetration of drugs with the final goal of improving the therapeutic outcome of treatments of different ocular diseases. These attempts involve the use of colloidal drug delivery systems, such as liposomes, biodegradable nanoparticles and nanocapsules. One of the main disadvantages of this class of materials is represented by the short residence time of the colloidal carrier systems in the ocular mucosa, an important aspect for the therapy of extraocular diseases, such as keratoconjunctivitis sicca or dry eye disease. Consequently, the researchers are looking at designing a mucoadhesive carrier system with improved drug delivery properties to the ocular...

Age Related Eye Diseases Cataract and AMD

Cataract and AMD are common eye diseases and the leading causes of vision impairment and blindness among older individuals worldwide. In the United States, > 1.6 million individuals have AMD (age > 60 y) and > 20 million have cataract (age > 65 y) (20). In less developed countries, the prevalence of cataract and AMD is even higher and occurs earlier in life than in developed countries (21). To date, no medical treatment against these eye diseases is available and although cataract surgery has become a frequent and successful intervention in elderly people, the only available treatment for AMD, i.e., laser photocoagulation, is not applicable to most patients and is of limited benefit. As an antioxidant, vitamin E is thought to protect eye tissues such as the lens and retina against oxidative damage from sunlight, cigarette smoke, or by-products of metabolism, and thus to prevent age-related eye diseases.

Evolution of Contact Lenses

In 1508, Leonardo da Vinci conceived the concept of the contact lens. It was not until 1887 that scleral contact lenses were fabricated by Dr. A. E. Fick, a physician in Zurich F. A. Mueller, a maker of prosthetic eyes in Germany and Dr. E. Kalt, a physician in France. Muller, Obrig, and Gyorry fabricated contact lenses made from polymethyl methacrylate (PMMA) in the late 1930s. K. Tuohy filed the patent for contact lens design in 1948, which were made of PMMA material (371). Although they were safe and effective, these lenses were uniformly uncomfortable, thus suppressing their potential growth for contact lens wear. Lenses made from polyhydroxyethyl methacrylate (HEMA), the so-called soft lenses or hydrophilic lenses were introduced in 1970. Since then, significant technological advances have been made in the lens materials, lens fabrication, and lens designs (372). Consequently, a phenomenal growth in lens wearers necessitated the need for, and development of, lens care products....

Composition of Contact Lenses

Contact lenses are broadly classified as PMMA, RGP, and soft hydrogel (HEMA) lenses. Dyes may be added during polymerization or after fabrication to improve lens handling or to change the color of the lens wearer's eyes. Lenses made from numerous polymers are available today (374). In soft hydrogel lenses, HEMA is a commonly used monomer. However, to avoid infringement of existing patents, many comonomers, as, for example, methyl methacrylic acid or a blend of comonomers, are used. Comonomers produce changes in the water content or ionic nature of lenses that is significantly different from HEMA lenses. For example, addition of acrylic acid in HEMA increases the water content and ionic nature of lenses. Some lenses are made from n-vinylpyrrolidone and have high water contents. Such lenses have pore sizes that are much larger than low water content lenses. Cross-linkers, such as ethyleneglycol dimethacrylate, and initiators as, for example, benzyl peroxide, in appropriate amounts are...

Contact Lens Care Products

Contact lenses are optical devices that are either fabricated from preformed polymers or polymerized during lens manufacture. The main purpose of contact lenses is to correct defective vision, and they are generally referred as corrective lenses. However, due to the recent advances in material manufacturing, reduction in fabrication cost, and their availability in many colors, they are extensively used to change the appearance of the eye. For this application, they are called cosmetic lenses. Contact lenses used medically for the treatment of certain corneal diseases are called bandage lenses.

Ophthalmological

Pilocarpine is used in the treatment of glaucoma, where it is instilled into the eye usually as a 0.5-4 solution. An ocular insert (ocusert pilo-20) that releases 20 Xg of pilocarpine per hour over 7 days also is marketed for the control of elevated intraocular pressure. Pilocarpine usually is better tolerated than are the anticholinesterases and is the standard cholinergic agent for the treatment of open-angle glaucoma. Reduction of intraocular pressure occurs within a few minutes and lasts 4-8 hours. The ophthalmic use of pilocarpine alone and in combination with other agents is discussed in Chapter 63. The miotic action of pilocarpine is useful in reversing a narrow-angle glaucoma attack and overcoming the mydriasis produced by atropine alternated with mydriatics, pilocarpine is employed to break adhesions between the iris and the lens.

Eye health

Eye health is an area in which nutraceutical supplements are increasingly used, and they are now widely available at opticians. They are taken to maintain healthy sight, to improve a condition or to delay disease progression. Visual impairment and blindness are common in the elderly. As we age, visual performance decreases. This usually occurs slowly before the age of 50 years and accelerates after reaching 50. One study, carried out to identify the causes of vision loss in a large sample of visually impaired people aged 75 years or over in Britain in 2004,1 found that in 52.9 of people the main cause of visual loss was age-related macular degeneration (AMD). Another study using pooled findings from three continents found AMD to be present in 0.2 of the combined population aged 55-64 and in 13 of those over 85 years.2 Numerous age-related disorders, including visual problems, have been linked to the cumulative effects of oxidative stress. The retina is particularly susceptible to...

Cataract

Opacification of the ocular lens, or cataract, occurs when lens proteins (crystallins) precipitate. This may result from an accumulation of modified (e.g., glycated) or oxidatively damaged lens proteins. The whole lens contains high amounts of vitamin E with a gradient found from the (outer) epithelium and cortex decreasing to lower amounts in the (inner) nucleus (22). A protective effect of vitamin E on cataractogene-sis was found in several animal studies in which vitamin E successfully delayed the progression of chemically induced cataracts (23-26). Numerous epidemiologic studies have examined the associations between dietary vitamin E intake, supplement use, and blood vitamin E levels in relation to risk of different forms of cataract. As reviewed extensively by Taylor and Hobbs (27), most recent studies, whether retrospective or prospective, found an inverse association between vitamin E intake and risk of cataract, primarily on cortical rather than nuclear cataract. A recently...

Cataracts

Age-related cataract is the world's leading cause of blindness. In the USA it is prevalent in 40 of adults aged over 75 years and cataract extraction is one of the most common types of surgery in the elderly.6 Development occurs when oxidatively damaged protein deposits form on or in the lens, clouding vision.6 Studies have indicated that people who eat more fruit and vegetables are less likely to develop a cataract. A prospective study has shown specifically that spinach consumption was inversely related to cataract development. This was followed by three prospective studies showing intake of lutein and zeaxanthin to be inversely associated with cataract development, with a 20-50 risk reduction.6 Two large epidemiological studies looking at dietary intake of these carotenoids and cataract development found people in the highest quintile of dietary intake to have less chance of developing cataracts by 20 compared with people in the lowest quintile of dietary intake.5

Aquaporin Expression In Ocular Tissuesindirect Evidence For A Role In Eye Physiology

Figure 1 summarizes the sites of fluid transport (panel A) and AQP protein expression (panel B) in the eye. Expression of AQP0 (MIP) in lens fiber has been known for many years, where its involvement in lens transparency and cataracts is well established. Mutations in AQP0 are associated with congenital cataracts in humans (10). However, the mechanisms by which AQP0 deficiency produces cataracts remain unknown. Aquaporin 1 is expressed strongly in endothelial cells and keratocytes in cornea, as well as in nonpigmented ciliary epithelium and in the epithelium at the anterior surface of the cornea. Aquaporin 3 is expressed throughout the corneal and conjunctival epithelium at the ocular surface. Aquaporin 5 is strongly expressed at the corneal epithelium as well. Aquaporin 4 is expressed in M ller cells in retina, and colocalizes with AQP1 in nonpigmented ciliary epithelium. The ocular expression pattern of AQPs provides indirect evidence for their possible involvement in intraocular...

Ocular Roles Of Aquaporins Outside Of The Cornea

The ciliary epithelium is a tissue bilayer consisting of pigmented ciliary epithelia (PCE) and non-pigmented ciliary epithelia, whose apical surfaces are juxtaposed, and basolateral surfaces face the ciliary body and aqueous humor, respectively. The principal determinants of intraocular pressure (IOP) are the rates of aqueous fluid production by the ciliary epithelium and aqueous fluid drainage (outflow) in the canal of Schlemm. Aqueous fluid production involves near-isosmolar water secretion across the ciliary epithelium into the posterior aqueous chamber. Aqueous fluid is drained by pressure-driven bulk fluid flow into the canal of Schlemm and across the sclera. Non-pigmented ciliary epithelial cells coexpress AQP1 and AQP4 (30-33), suggesting their involvement in aqueous fluid production. An initial study on human ciliary epithelial cell cultures reported AQP1 protein expression and partial sensitivity of fluid transport to Hg2+ and AQP1 small interfering RNA (siRNA), suggesting...

Summary And Perspective

Multiple AQPs are strongly expressed in ocular tissues, where they appear to serve a variety of functions related to epithelial fluid secretion, regulation of tissue water content, cell migration and proliferation, and neural signal transduction. Small-molecule modulators of AQP function or expression might thus be exploited clinically. At the ocular surface, AQP3 or AQP5 upregulation could accelerate wound healing and reduce corneal edema. Corneal endothelial AQP1-inducers might also reduce corneal edema and associated opacity. Induction of lens AQPs might slow cataract-related opacification. Inhibition of AQP1 AQP4 represents a possible strategy for reducing intraocular pressure associated with glaucoma. In the retina, AQP4 inhibitors might offer neuroprotection following retinal ischemia. These possibilities will require experimental verification in large animal model experiments when nontoxic AQP-selective modulators

Involvement Of Ion Transport Mechanisms In Mediated Receptor Control Of Corneal Epithelial Cell Renewal And Volume

Even though the contribution of epithelial ion transport activity to deturgescence is much less than that of its endothelial counterpart, the epithelial component is required for the preservation of the integrity of the epithelial layers during exposure to anisosmotic stresses. Anisosmotic insults to the cornea frequently occur during activities of daily life, e.g., swimming or bathing, as well as from contact lens wear and ocular diseases such as dry eye syndrome (DES), as result of which, afflicted individuals experience chronic exposure to hypertonic tears. The physiological disturbances induced by such anisosmotic stresses are, very likely, counteracted by regulatory volume-response activation, such activity having been described in cultured corneal epithelial cells. Two different types of regulatory volume activations have been described for such an in vitro system. Exposure to a hypotonic challenge induces regulatory volume decrease (RVD) behavior, which acts to restore isotonic...

Ion Transport By Ciliary Epithelium

Secretion is electrically neutralized by Na+ entry from the blood plasma (44). Subsequent studies have demonstrated that the rate of HCO3- accession to the posterior chamber is very rapid and the administration of acetazolamide, a carbonic anhydrase inhibitor (CAI), decreases the accumulation of HCO3- in the aqueous humor (72-74). This finding is consistent with the measurement of the steady-state HCO3- concentration in the aqueous humor as compared to its concentration in the blood plasma (75). It has been shown that, in species like rabbit and guinea pig, the HCO3- concentration in the aqueous humor is higher than that of the blood plasma, suggesting the presence of an active HCO3- transport into the eye. The excess HCO3- is necessarily accompanied by a deficit of Cl- in the aqueous humor (8, 75), because of the demands of electroneutrality and isotonicity. Thus, in those species, the aqueous humor is alkaline. In contrast, primates such as the monkey and human secrete acidic...

Role Of Membrane Transporters In The Normal And Diabetic Lens

Diabetic Cataract a Problem with Lens-Volume Regulation Diabetics have a high incidence of cortical cataract and develop cataracts several years earlier than the general population (40). The morphological and biochemical changes associated with diabetic cataract have been extensively studied. Morphologically, diabetic cataract manifests itself as a discrete zone of tissue liquefaction in the outer cortex of the lens, surrounded by relatively normal fibre cells (Fig. 3A). This is an intriguing damage phenotype, when one considers that lens fibre cells are extensively coupled by gap junctions (41, 42). Using a diabetic rat model, Bond et al. (43), subsequently showed that this tissue liquefaction was initiated by the swelling of individual fibre cells within this Fig. 3. Dysfunction of volume regulation is an initiating factor in diabetic cataract. Confocal images of equatorial sections taken from rat lenses made diabetic by injection with streptozotocin. (A) One month post-injection, a...

Lens Osmoregulation And Opacification

It has been suggested that endogenous digitalis-like factors could be associated with the development of cataract (28) and in this respect it is interesting that Lichtstein and his coworkers detected a higher amount of digitalis-like factor in human cataractous lenses than in transparent human lenses (27). In the Nakano mouse, a strain that results from an autosomal recessive single gene mutation (29), there is evidence that associates a different type of endogenous Na,K-ATPase inhibitor with cataract formation (30). Nakano cataract develops in parallel with an increase of lens sodium and loss of potassium, together with an increase of lens calcium and water (31). The Nakano lens contains an Na,K-ATPase inhibitor with the characteristics of a small polypeptide that is capable of inhibiting not only lens Na,K-ATPase, but also Na,K-ATPase in brain and retina (32). An endogenous Na,K-ATPase inhibitor peptide has also been reported in the lens of the ICR f rat, a...

Macular Degenerations Associated With The Abca4 Gene

Advances in molecular genetics have led to the identification of genes and genetic mutations that are unequivocally linked to various visual diseases (1-11) and visual physiology (12-16). Human genetic studies have correlated mutated forms of the ABCA4 gene with several inherited visual diseases, including STGD (17-21), FFM (21-23), AMD (17,24-26), autosomal recessive retinitis pigmentosa (arRP) (20,27-29) and cone-rod dystrophy (arCRD) (30-33). Stargardt disease and its adult onset variant, FFM, are autosomal recessive disorders that affect approximately 1 in 10,000 persons, while AMD is the leading cause of blindness in persons over the age of 75. These diseases are characterized by a progressive loss of central vision and atrophy of the retinal pigment epithelium (RPE). Histopathological studies in patients withSTGD, FFM, and arCRD show an accumulation of lipofuscin fluorophores within the RPE cells (34-36). Evidence suggests this accumulation of lipofuscin is cytotoxic, leading to...

Glutamate Transporters And Retinal Disease

Overactivation of glutamate receptors, or glutamate excitotoxicity, has been implicated in many retinal diseases, including ischemic damage resulting from stroke, diabetic retinopathy, retinitis pigmentosa, glaucoma and retinal damage as a side effect of cancer treatment. This section will discuss recent investigations into the involvement of glutamate transporters in the pathogenesis of these diseases. Interruption of adequate blood supply to the retina results in ischemic tissue damage. This can occur in central retinal artery or vein occlusion, carotid artery disease, stroke, heart disease, and possibly glaucoma (see below). Much of the retinal neuronal damage caused by ischemia is thought to be due to glutamate-mediated excitotoxic-ity (44). Retinal neurons possess metabotropic and ionotropic glutamate receptors, and excessive activation of ionotropic glutamate receptors primarily N-methyl D-aspartate (NMDA) receptors leads to the entry of calcium ions into the cell and calcium...

Transporter Expression In The

Treatment of many eye diseases, such as corneal keratitis, conjunctivitis, dry eye, eye allergies and glaucoma, relies on topically applied medication. Some of these drugs exert their effect at the ocular surface, while others may need to penetrate across the epithelial lining of the cornea and or conjunctiva to reach their target sites within the eye. Expression and function of corneal and conjunctiva transporters, in particular peptide and amino acid transporters, have been thoroughly reviewed in 2003 by Dey et al. (4). Table 1 lists many transporter proteins identified as existing in cornea and conjunctiva, as well as other tissues in the eye.

Factors Impacting Ocular Transporters And Metabolizing Enzymes

Timolol undergoes CYP2D6-mediated hepatic metabolism following oral administration. In ophthalmology, timolol is used to treat ocular hypertension. Adverse events, specifically excessive P-blockade, are associated with ophthalmic timolol therapy and relate to the patient's CYP2D6 genotype (57,58). The mechanism proposed to underlie this event involves systemic absorption of topically applied timolol, such that exposure levels exceed a critical point. These high exposure levels may result from a poorly metabolizing patient phenotype and or competitive inhibition of CYP2D6-mediated The effect of hepatic polymorphic enzyme phenotype has been investigated for arylamine acetylation in the rabbit eye. Aminozolamide undergoes arylamine acetyl-transferase metabolism in the corneal epithelium and iris-ciliary body of rabbits (48). However, in vitro and in vivo ocular acetylation activity do not correlate with hepatic acetylation phenotype (49). Flestolol metabolism by carboxylesterase has been...

Nanotechnology In Retinal Prostheses

Prostheses for vision restoration in visually impaired patients with degenerative disorders like ARMD, retinitis pigmentosa and glaucoma are based on one of three techniques stimulation of the visual cortex, stimulation of optic nerve, and stimulation of retinal cells (53). The visual prostheses can be broadly classified into cortical and retinal implants, which are further discussed below.

Nanotechnology For Gene Delivery To The

The various nanosystems discussed in this chapter can potentially be used for gene therapy. Gene therapy is a promising therapeutic approach for the treatment of a wide array of inherited and acquired disorders. Clinical use of gene therapy is limited by effective gene delivery in vivo. An ideal gene-delivery vector should be nontoxic, efficiently taken up by target cells, should protect the plasmid cargo against enzymatic degradation, and be conducive to gene expression. A number of viral vectors on the nanometer lengthscale have been shown to result in successful intraocular gene expression. The viral vectors have the drawback of limited carrying capacity, immunogenicity, and tox-icity. Therefore, a number of nonviral nanosystems are currently being investigated. In the eye, gene delivery has potential applications in treating various disorders including neovascular and non-neovascular retinal degenerative disorders, glaucoma, and corneal graft rejection among others. Nanosystems of...

Nanosystems And Fundamentals Of Nanotechnology

From Ophthalmology Research Ocular Transporters in Ophthalmic Diseases and Drug Delivery Edited by J. Tombran-Tink and C. J. Barnstable Humana Press, Totowa, NJ Unlike the widely investigated positively charged dendrimers, anionic dendrimers are expected to be safer. Indeed, an anionic dendrimer drug-delivery system was shown to be useful in preventing scar tissue formation after glaucoma filtration surgery. Anionic G3.5 PAMAM dendrimers conjugated to glucosamine (an immunomodulator) or glucosamine-6-sulphate (an antiangiogenic molecule), when coadministered subconjunctival , increase the long-term clinical success of glaucoma surgery (8). In this study, which employed a rabbit model, the day 30 bleb survival increased from 30 to 80 with the use of dendrimer formulations.

Regulation Of Aqueous Humor Formation

It has been known that the level of IOP is not constant, but displays diurnal variation. The fluctuation of IOP is observed both in normal and glaucomatous patients, although the latter may demonstrate a more significant variation (165). Rates of aqueous humor secretion have been reported to be 2.61 l min-1 during the day and 1.08 l min-1 at night in normal human subjects (166). However, the diurnal changes in IOP are not synchronous with those in inflow. The IOP of the normal human peaks in the dark-sleep period Among the many potential modulators of aqueous humor secretion, adenosine is proposed to be an important regulator for the modulation of IOP (187, 188). Moreover, adenosine receptors are of particular interest because knockout of A3ARs has recently found to reduce IOP in the living mouse (189). It has been demonstrated that the level of adenosine in the aqueous humor correlates with the level of IOP (190). Recently, adeno-sine has been shown to increase the rate of aqueous...

Future Directions

In secretory vesicles, and secondary active transport through the SVCT family of carrier proteins may play a critical role in prevalent ocular pathologies known to lead to blindness. A number of eye diseases where a decreased vitamin C concentration has been reported in compartments such as those containing aqueous or vitreous fluid, or specific ocular tissue and cell types, cannot be explained entirely in terms of reduction of dietary intake. Evidence gathered regarding independent transport pathways and the regulation of DHAA and AA would, however, facilitate efforts in the optimal design of modalities for elevation of vitamin C level in patients through the local or systemic administration of AA or DHAA. Given the known link between vitamin C and the redox status of the cell, potential use of transgenic mice and gene-therapy approaches to combat ocular diseases presents another area for future research. Overexpression of vitamin C transporters under conditions of deficiency of...

Conclusion

As the population continues to age, it is expected that the number of glaucoma patients will increase by 50 by the year 2020 (219). Therefore, more-effective and specific anti-glaucoma therapies are very much needed. This challenge demands a more thorough understanding of the mechanism of aqueous humor formation and its control.

Cyp39a1

Such as diclofenac and propranolol, were reported in the mouse eye (28,29). We recently detected mRNA transcript copies of CYP3A, an enzyme with broad substrate specificity that is involved in the metabolism of more than 50 of commercial drugs, in the rabbit lacrimal gland and conjunctiva (30). We confirmed protein expression of CYP3A in the rabbit lacrimal gland and conjunctiva, in addition to the iris-ciliary body (31). Furthermore, we detected the protein expression of CYP1A, CYP2D and NADPH reductase in the rabbit lacrimal gland, conjunctiva, iris ciliary body and choroid-retina (31). The mRNA and protein of CYP4B1, an enzyme involved in arachidonic and retinoic acid metabolism, were detected in the rabbit corneal epithelium (32). Finally, gene expression of CYP1B1, an enzyme involved in retinoic acid biosynthesis and linked to primary congenital glaucoma (33), was detected in the human ciliary body, iris, a nonpigmented ciliary epithelial cell line, and at lower levels in the...

Disease

Cataract When ocular metabolism at a specific site becomes saturated, reactive and or toxic metabolites could be formed locally and cause tissue damage. This pathophysiological mechanism may explain the observation of cataract formation following an overdose of acetaminophen in mice (90). When mice received an overdose of acetaminophen in the presence of the CYP1A1 1A2 inhibitor, diallyl sulfide, cataract development was prevented (91). The protective effect of diallyl sulfide presumably results from inhibition of biotransformation of acetaminophen to the reactive metabolite N-acetyl-p-benzoquinone (NAPQI) by CYP1A1 1A2. Mice injected intracamerally with NAPQI develop cataracts (92). 3-hydroxy-3-methyl-glutaryl- (HMG-)CoA reductase inhibitors, commonly referred to as statins, are widely prescribed as oral drugs to lower plasma low-density lipoprotein cholesterol levels. A strong relationship between systemic exposure levels and the cata-ractogenic potential of this class of compounds...

Instrumental Methods Introduction

The instrumental assessment of clarity and opalescence provides a more discriminatory test that does not depend on the visual acuity of the analyst. Numerical results are more useful for quality monitoring and process control, especially in stability studies. For example, previous numerical data on stability can be projected to determine whether a given batch of dosage formulation or active pharmaceutical ingredient will exceed shelf-life limits prior to the expiry date.

Free Radicals As A Cause Or Consequence Of Cell Damage

Oxidative stress, rather than being the primary cause of disease, is a secondary complication, but in some cases it has a significant role in the pathophysiology. For instance, oxidative stress arising from exposure to environmental stressors such as irradiation or chemicals can be a major source of pathophysiological change leading to disease initiation and progression. Examples are diseases of the lung, eye, and skin where significant involvement of free radical-mediated tissue injury is indicated. Such environmental diseases comprise, e.g., UV-induced cataract, toxic dermatitis caused by oxidizing chemicals, asbestosis, silicosis, and tobacco smoke- and diesel exhaust particle-associated health problems 19 . It is clearly evident that many genetic diseases, such as thalassemias, hereditary hemochromatosis, and cystic fibrosis, are also accompanied by an imbalance in the cellular redox state (oxidative stress), which may have an influence on the disease phenotype. Research in this...

Cranial Nerve Examination

Testing the patient's papillary response to light, visual acuity, and visual field evaluation is essential to evaluate cranial nerve II. Conjugate gaze should be observed superiorly, inferi-orly, laterally, and medially, with the presence or absence of nystagmus noted, to test cranial nerves III, IV, and VI. The trigeminal nerve is evaluated by bilateral light touch and pinprick sensation over the forehead (cranial V1), the maxillary process (cranial V2), and the

Effects of Ageing and Antioxidant Status on Immune Functions

The cumulative effects of free radical damage throughout the life span are graphically seen in the pigmented age spots of the elderly which are a consequence of lipid oxidation. Oxidative damage to the lens of the eye is associated with cataract formation and increased concentrations of free radical-mediated peroxides are seen in several other tissues in the aged. Cumulative oxidative damage visible in the skin and cataracts of the elderly can also be seen in deposits of oxidized lipids in blood vessels (atherosclerosis) and organs. The overall increased oxidative stress associated with ageing is thought to also adversely affect many aspects of immune responses (Bendich, 1995, 1996).

Preventing Trauma During Electroshock Therapy

CONTROL OF MUSCLE SPASMS Agents that act in the CNS to block spasms are considered in Chapter 20. Two peripherally-acting agents are used, botulinum toxin (see Chapter 6) and dantrolene. Botulinum toxin A (BOTOX), by blocking ACh release, produces flaccid paralysis of skeletal muscle and diminished activity of parasympathetic and sympathetic cholinergic synapses. Inhibition lasts from several weeks to 3-4 months, and restoration of function requires nerve sprouting. Uses of BOTOX in dermatology and ophthalmology are described in Chapters 62 and 63.

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Other conditions in which ephedra is contraindicated are anxiety disorders, angle-closure glaucoma, prostate adenoma with residual urine volume, pheochromocytoma, and thyrotoxicosis (Gruenwald et al. 1998). Known medications that may interact adversely with ephedrine include heart glycosides, halothane, guanethidine, MAO inhibitors, secale alkaloids, and oxytocin. Addiction and Dependence

Subconjunctival Drug Delivery Systems

Sustained release dosage forms may extend the drug retention in the subconjunctival space. This can be achieved by using polymeric inserts. After subconjunctival placement of an insert the free drug concentration in the subconjunctival space determines the driving force of drug absorption from the depot to systemic circulation and to the eye via the scleral route (Fig. 2). For example, biodegradable polylactide-co-glycolide inserts have been used to deliver 5-fluorouracil for 2 weeks after subconjunctival placement (Villain et al., 1992). The application of the system is to increase the success rate of glaucoma filtering surgery (Smith et al., 1992 Villain et al., 1992) 5-fluorouracil is released from the system for 2-3 weeks. In the case of solid inserts mechanical loss from the subconjunctival space is minimal and drug absorption into the eye is determined by the drug release, scleral absorption, and systemic absorption (Fig. 2). In practice remarkable prolongation of drug activity...

Preparations And Dosage

TOXIC REACTIONS AND ADVERSE EFFECTS Antipsychotic drugs have a high therapeutic index and are generally safe agents. Most phenothiazines, haloperidol, clozapine, and queti-apine can be used over a wide range of dosages (Table 18-3). Although occasional deaths from overdoses have been reported, fatalities are rare in patients given medical care unless the overdose is complicated by concurrent ingestion of alcohol or other drugs. Adverse effects often are extensions of the many pharmacological actions of these drugs. The most important are those on the cardiovascular, central and autonomic nervous systems, and endocrine system. Other dangerous effects are seizures, agranulocytosis, cardiac toxicity, and pigmentary degeneration of the retina, all of which are rare (see below). Therapeutic doses of phenothiazines may cause faintness, palpitations, and anticholinergic effects including nasal stuffiness, dry mouth, blurred vision, constipation, worsening of glaucoma, and urinary retention...

Sympathomimetics Stimulants

Although the literature is limited by number of subjects, duration, and trial design, there is some evidence to support the use of methylphenidate (5-15 mg two to four times daily), donepezil (5-10 mg daily), and modafinil (200-400 mg daily) for the pharmacologic management of opioid-induced sedation and fatigue (Larijani et al. 2004, Reissig and Rybarczyk 2005). Potential adverse effects can include overstimulation (e.g., anxiety, insomnia, and even paranoia), appetite suppression, exacerbation of motor abnormalities (e.g., tics, dyskinetic movements), and confusion. Contraindications for stimulant use include glaucoma, poorly controlled hypertension, arrhythmias, and cardiovascular disorders, anorexia, seizure disorders, and hyperthyroidism. Methylphenidate is a schedule II medication under federal regulatory control caution is advised in patients with current or preexisting substance use disorders, especially prior stimulant abuse (e.g., cocaine).

Tricyclic Antidepressants

Unfortunately, the adverse effects of the TCAs may limit their utility (Table 5-7). Amitriptyline and imipramine have more troublesome side effects than the secondary-amine TCAs (e.g., nortriptyline and desipramine). TCAs are contraindicated in patients with closed-angle glaucoma, recent myocardial infarction, cardiac arrhythmias, poorly controlled seizures, or severe benign pros-tatic hypertrophy.

Delivery to the Vitreous and Posterior Segment

The most direct means of delivering drug to the vitreous humor and retina is by intravitreal injection. While this method of administration has been associated with serious side effects, such as endophthalmitis, cataract, hemorrhage, and retinal detachment (198), aggravated by the conventional need for serial injections further increasing the risk, intravitreal injection continues to be the mode of choice for treatment of acute intraocular therapy and has become the standard of care for providing treatment of several chronic ocular diseases, such as age-related macular degeneration (AMD) and associated retinal edema. For example, Lucentis (ranibizumab), injected monthly, can be highly effective in decreasing the thickness of the edematous retina in AMD patients.

Herbert Oelschlger and Andreas Seeling

Some groups of drugs, e.g., anti-infectives, are undergoing a process of continual development. In contrast, the local anesthetics that are indispensable to attain freedom from pain in diagnostic and therapeutic interventions tend to be a rather quiescent group. Compared to general anesthetics, there are major regional differences in their proportional share in anesthetic techniques that vary between 5 and 70 . Despite the introduction of medical hypnosis, dental medicine is absolutely dependent on local anesthetics. Temporary abolition of pain sensation by chemical substances was achieved thanks to the Vienna ophthalmologist Karl Koller, who experimented with cocaine at the suggestion of Sigmund Freud.

Dietary Supplementation For Ocular Health

One of the exciting pharmaceutical opportunities afforded when exploring formulations for ocular applications is the direct visual observation and measurement of the consequences of dosage design on therapeutic activity. The disadvantages of treating such an intricate organ are often outweighed by the advantages of its accessibility and the prospect of monitoring a pharmacological benefit of therapeutic intervention. With investigation of impacts of environment and nutrition on ocular health, short-term observations are now replaced by long-term monitoring of the gradual and progressive changes over many years. While pathological conditions are still observable, such as deposits in the retina known as drusen, or changes in gross physiological state measured by visual acuity, or tissue and cellular structure and function by novel technologies such as OCT (285-289) and electroretino-grams (ERGs) (290,291), respectively, discovering underlying biochemical etiologies poses the same...

Physiological and Biochemical Barriers to Controlled Release Drug Delivery

The eye offers different kinds of barriers, such as rapid drainage of delivered drugs and a combination of lipophobic and hydrophobic barriers. Strategies of drug retention include the use of hydrogels, viscosity-imparting agents, and ointments. Other strategies, such as suspension formulations, inclusion of penetration enhancers, bioadhesive polymers, phase-transition agents, colloidal systems, liposomes, nanoparticles, and prodrugs, have been applied to deliver drugs through this organ. The different delivery devices include inserts, minidisks, and contact lenses.63 Improving the tolerability of and compliance with ophthalmic drug delivery systems is also a major focus in formulation technology.

Agerelated macular degeneration

Age-related macular degeneration (AMD) is the most common cause of blindness and vision impairment in Americans over the age of 60 years.33 Zinc is present in relatively high concentrations in the retina, and lower retinal and serum zinc levels have been associated with macular degeneration in primates.34 However, scientific evidence that zinc intake is associated with the development or progression of AMD is limited. Observational studies have not demonstrated clear associations between dietary zinc intake and the incidence of AMD.35 37 A randomized controlled trial found that supplementation with 200mg day of zinc sulfate (81mg day of elemental zinc) for 2 years reduced the loss of vision in patients with AMD.38 However, a later trial using the same dose and duration found no beneficial effect in patients with a more advanced form of AMD in one eye.39 A large randomized controlled trial of daily antioxidant (500 mg of vitamin C, 400 IU of vitamin E and 15 mg of -carotene) and...

Applications in ophthalmic solutions

All povidone types have applications in ophthalmic solutions 83-86,102, 267, 354 . Povidone K 17, povidone K 25 and povidone K 30 are usually used in eye drops while the higher-molecular type, povidone K 90, is preferred for contact lens solutions 87,88,203,382 . It is usually added to these dosage forms in concentrations between 2 and 10 and performs the functions shown in Table 101. Table 102. Sodium perborate effervescent tablet for cleaning contact lenses 382 The use of povidone K 30 in effervescent cleaning tablets for contact lenses is an indirect ophthalmic application. Table 102 shows the composition of a perborate cleaning tablet taken from the literature.

Types of Lens Care Products

Contact lens care products can be divided into three categories cleaners, disinfectants, and lubricants. Improperly cleaned lenses can cause discomfort, irritation, decrease in visual acuity, and giant papillary conjunctivitis (GPC). This latter condition often requires discontinuation of lens wear, at least until the symptoms clear. Deposits can also accumulate preservatives from lens care products and produce toxicity and can act as a matrix for microorganism attachment to the lens (386). Thus, cleaning with the removal of surface debris, tear components, and contaminating microorganisms is one of the most important steps contributing to the safety and efficacy of successful lens wear (387).

Topical Protein Administration To The

There are several reasons why proteins are not administered as eyedrops administered liquid is rapidly cleared from the ocular surface, resulting in a contact time that is limited to a few minutes or even less. Still, ocular drop instillation is widely used in the treatment of glaucoma and other diseases with low-molecular-weight drugs (e.g., prostaglandins, b-blockers, a-2 agonists). These small, hydrophobic drugs are able to partition into the cornea epithelium at adequate rates to allow pharmacologically relevant levels of ocular drug absorption. However, larger molecules like proteins and larger peptides are (> 10 kDa) are typically quite hydrophilic and do not readily partition into the corneal epithelium (14). Paracellular permeation of therapeutic proteins and peptides across the corneal epithelium is very slow because of the tight junctions. Hamalainen et al. estimated the paracellular space of the corneal epithelium with polyethylene glycol permeation studies and subsequent...

Antioxidant Vitamins and CoQ10 in Diabetes in Relation to Vascular Disease

Are lower in diabetes and CHD (Mateo et al., 1978 Noto et al., 1983). Free copper ions are known to catalyse ascorbate oxidation and substances such as aldos reductase inhibitor may block such reactions by binding free copper ions (Jiang et al., 1991). Zinc deficiency is associated with insulin resistance, and zinc therapy is capable of modulating insulin action (Kinlaw et al., 1983). Zinc may work as an antioxidant through superoxide dismutase. Zinc deficiency may also decrease the zinc copper ratio and thereby increase the adverse effects of copper ions on oxidant stress in diabetes. There is no evidence that once oxidative damage occurs, it can be reversed. Modification of long-lived extracellular proteins and structural changes in tissues rich in proteins are associated with the development of complications in diabetes such as cataracts, microangiopathy, atherosclerosis and nephropathy.

Betaadrenoceptor blocking drugs

Other uses Beta-blockers have been used to alleviate some symptoms of anxiety, probably patients with palpitation, tremor, and tachycardia respond best (see also section 4.1.2 and section 4.9.3). Beta-blockers are also used in the prophylaxis of migraine (section 4.7.4.2). Betaxolol, carteolol, levobunolol, metipranolol, and timolol are used topically in glaucoma (section 11.6).

AAdrenoceptor Agonists and Antagonists

Drugs interacting with the a-adrenoceptors come from a variety of different chemical classes, including the quinazoline a1-adrenoceptor antagonists for hypertension and benign prostatic hyperplasia (BPH), the imidazoline a2-adrenoceptor agonists for hypertension, glaucoma, and several applications within the central nervous system, and the phenethylamine and imidazoline a1-adrenoceptor agonists, which are commonly used as nasal decongestants. There is currently great interest in the design of a1-adrenoceptor

What Should We Conclude from All This

There are also dangers to extreme supplementation. Oxidative stress is implicated in the pathogenesis of many degenerative diseases, including cardiovascular disease, cancer, AMD, cataracts, and neurodegenerative diseases. In in vitro and animal studies, antioxidants (including vitamins E, C, (3 -carotene, and flavonoids) show antioxidant activity and plausible mechanisms of action in biological systems. This is especially so in ex vivo lipoproteins and cell culture experiments. Observational studies consistently show a relationship between diets rich in antioxidant-containing fruits and vegetables and reduced risk for chronic diseases such as cancer and heart disease. However, despite this evidence, clinical trials of single antioxidant micronutrient supplementation, and some multivitamin supplements, continue to show inconclusive results. In most of these studies, results either show an effect or are null with regard to efficacy. Very few studies, the ATBC and CARET studies most...

Medicinal Uses Of Prostaglandins

Despite their widespread occurrence and a very considerable research effort, the use of prostaglandins or prostaglandin analogues themselves in medicine, has been limited. Among the reasons for this are the length of syntheses, problems in achieving selectivity and their rapid metabolism. Some applications include the use of prostaglandins E2 and F2 (dinoprostone 5.44 and dinoprostol 5.46) in the induction of childbirth, misoprostol 5.50 in the treatment of peptic ulcers and latanoprost 5.51 in the treatment of glaucoma.

Tricyclic And Tetracyclic Drugs Introduction

The tricyclic antidepressant agents hold an important place in the history of treatments for depression. They were the first class of antidepressant compounds to be widely used in depression and remained the first-line treatment for more than 30 years. The observation of their activity led to theories of drug action involving norepinephrine and serotonin. Indeed, this psychopharmacological bridge suggested that alterations of these neurotransmitters might cause depression (Bunney and Davis 1965 Prange 1965 Schildkraut 1965). The tricyclics were extensively studied, and through this study the field developed several principles for the management of depressive illness. For example, in addition to understanding the need for adequate dose and duration during acute treatment, the importance of continuation treatment was described. The adverse events associated with these agents required that psychiatrists become familiar with a variety of syndromes, such as anticholinergic delirium,...

Antioxidant Nutrient Combinations

We were the first research group to report relationships between the risk for cataracts and various indices of antioxidants (for review, see Taylor and Jacques, 1997). However, it is not clear whether the nutrients are acting additively or synergistically. Thus, until this question is resolved (in progress), there may be only limited use to such discussion. Nevertheless, the following are considered to be important data. The first, and perhaps most important, study in terms of revealing the utility of diet indicates a significant fivefold decrease in risk ratio for cataract between persons consuming > 1.5 servings of fruits and or vegetables daily (Jacques and Chylack, 1991) (Fig. 22.3). Relationships between multiple antioxidant nutrients and cataract risk are further supported by multivitamin use data. Leske and co-workers (1991) found that use of multivitamin supplements was associated with decreased prevalence for each type of cataract 60 , 48 , 45 and 30 , respectively, for...

Pain in Eyes Ears Sinuses Eye Pain

Patients may present with pain in the orbit that may or may not be associated with eye movement. Ocular pain and photophobia may be associated with corneal irritation or abrasions. Pain in the eye may also arise from increased intraocular pressure which occurs in glaucoma. Dental pain and temporal giant arteritis can be referred to the eye. Pain from the greater occipital nerve may be referred to the eye and face. If eye pathology is suspected, patients should be evaluated by an ophthalmologist.

Vasculitis and sarcoidosis

Granulomatous vasculitis may complicate the course of chronic sarcoidosis and can be responsible for diffuse encephalopathy with psychiatric presentation and short-term memory deficit. Necrotizing vasculitis occurs in this context and induces ischemic lesions. This angiitic pattern of neurosarcoidosis has been demonstrated histologically in patients with neuro-ophthalmologic manifestations75 and in patients with sarcoid neuropathy (Said et al, unpublished). These cases pose the problem of their border with Wegener's granulomatosis, with which they share many features, but sarcoidosis, even in the cases with granulomatous angiitis, has a more benign course than Wegener's granulomatosis.76,77

Authors recommendations

Because of the well-characterized side effects of TCA, they should not be chosen as the first-line treatment for patients with certain co-morbidities such as known cardiac arrhythmias, electrocardiographic abnormalities, postural hypotension, unexplained falls and balance problems, glaucoma and prostatic hypertophy. All these medical conditions can potentially be exacerbated by the use of TCA in view of their well-known anticholin-ergic properties. Because of the higher prevalence of these disorders among the elderly, alternative first-line medications frequently have to be chosen for this population. These recommendations are in line with those developed by the Diabetic Peripheral Neuropathic Pain Consensus Treatment Guidelines Advisory Board in 2006 105 which were formulated to help guide treatment decisions so that an optimal balance between pain relief and side effects is achieved.

Ability to filter blue light

Increasing numbers of people taking lutein and zeaxanthin supplements for their proposed prophylactic benefits also report improvements in vision, such as higher contrast sensitivity, less glare, and improved colour perception.5 Within cells, lutein and zeaxanthin may selectively bind to tubulin, a structural protein necessary in the formation of the cytoskeleton within axons. This could improve structural integrity and function of the cytoskeleton,5 thus helping maintain eye health and quality of vision.

Outline of chronic infections

Biofilms can form on just about any imaginable surface metals, plastics, natural materials (such as rocks), medical implants, kitchen counters, contact lenses, the walls of a hot tub or swimming pool, human and animal tissue, etc. Indeed, wherever the combination of moisture, nutrients, and a surface exists, biofilms will likely be found as well. Biofilms are characterized by structural heterogeneity, genetic diversity, complex community interactions, and an extracellular matrix of polymeric substances. Biofilms are an important link in the energy budget of many natural communities. Both types of cells produce a polymeric extracellular slime layer which encloses the cells. This complex aggregate of cells and polysaccharide is the biofilm community.

Antifungal Agents for Ophthalmic

*Only natamycin (natacyn) is commercially available for ophthalmic use. The other antifungal drugs must be formulated for the given method of administration. For further dosing information, refer to the Physicians' Desk Reference for Ophthalmology. For additional discussion of these antifungal agents, see Chapter 48.

Use of Anesthetics in Ophthalmic Procedures

Topical anesthetic agents used clinically in ophthalmology include cocaine, proparacaine, and tetracaine drops and lidocaine gel (see Chapter 14). Proparacaine and tetracaine are used topically to perform tonometry, to remove foreign bodies on the conjunctiva and cornea, to perform superficial corneal surgery, and to manipulate the nasolacrimal canalicular system. They also are used topically to anesthetize the ocular surface for refractive surgery using either the excimer laser or placement of intrastromal corneal rings. Cocaine may be used intranasally in combination with topical anesthesia for cannulating the nasolacrimal system. Lidocaine and bupivacaine are used for infiltration and retrobulbar block anesthesia for surgery. Potential complications and risks relate to allergic reactions, globe perforation, hemorrhage, and vascular and subdural injections. Both preservative-free lidocaine (1 ), which is introduced into the anterior chamber, and lidocaine jelly (2 ), which is placed...

Lymphatic Filariasis LF

It is important to understand the different goals in the use of ivermectin for onchocerciasis and for LF. In the former case, treatment is given to provide symptomatic relief of skin and eye disease as well as a possible interruption of transmission. For LF, ivermectin has no direct clinical benefits but its use is to help lower the counts of microfilariae in the blood in order to block transmission. In order to obtain the maximum effect on transmission of LF, it may be necessary to use both ivermectin and albendazole. Finally, there are insufficient data on the beneficial effects of the use of ivermectin in patients with Mansonella perstans, M. ozzardi or M. streptocerca to recommend it over DEC. For patients with loiasis, the risks may outweigh the benefits (Boussinesque et al., 1998).

Other Terminal Structures

The a-Gal epitope (Gala -Ga -4GlcNAc-R, where R can be a glycolipid or glycoprotein) is a common carbohydrate structure expressed in many tissue in most in mammals reviewed in (208) . It is absent from cells and tissues of Old World monkeys, apes, and humans. Absence of the a-gal epitope in these species is accounted for by inactivation of the a1-3GalT locus that remains active in other mammals (27). Species that lack a functional a1-3GalT locus maintain circulating levels of naturally occurring IgM a-Gal antibody. The a-Gal determinants expressed by animal organs are the target of antibody-mediated hyper-acute graft rejection in xenotransplantation. Functions for this glycan have been sought by analysis of mice with targeted mutation of the a1-3Gal-T locus (9) responsible for a-Gal synthesis. These mice are distinguished from wild-type mice only by the absence of a-Gal epitopes on their cells, by the variable presence of anti-a-Gal in their serum, and by cataracts (209, 210)....

Biological Barriers and Fundamentals of Passive Transport

More recently alternative routes of drug administration have been sought and utilized. Scientists are developing technologies to circumvent the constraints imposed on molecular weight, water solubility, and modest hydrophobicity by the conventional transcorneal route. Patents exist for ophthalmically acceptable penetration enhancers. More water-soluble therapeutic agents now in use for glaucoma appear to achieve approximately equal access by both scleral-limbal and transcorneal routes of administration (194,195). Research is ongoing to understand and utilize scleral administration of therapeutic agents the role of hydrostatic pressure on the transport of both water and drug has been investigated to determine the classes of therapeutic agent for which this mode of delivery may be utilized (196-199). One consequence will be the determination of the diminished transport constraints imposed by a barrier from which the hydrophobic layer is absent. Both academic and industrial...

Endogenous Catecholamines

Midodrine And Desglymidodrine

In addition, E is used in the treatment of open-angle glaucoma, where it apparently reduces intraocular pressure by increasing the rate of outflow of aqueous humor from the anterior chamber of the eye. The irritation often experienced on instillation of E into the eye has led to the development of other preparations of the drug that potentially are not as irritating. One such example is dipivefrin. Phenylephrine. (Neo-Synephrine, a prototypical selective direct-acting -agonist) differs from E only in lacking a p-OH group. It is orally active, and its DOA is about twice that of E because it lacks the catechol moiety and thus is not metabolized by COMT. However, its oral bioavailability is less than 10 because of its hydrophilic properties (log P 0.3), intestinal 3'-O-glucuronida-tion sulfation and metabolism by MAO. Lacking the p-OH group, it is less potent than E and NE but it is a selective -agonist and thus a potent vasoconstrictor. It is used similarly to metaraminol and...

Use Of B Antagonists In Other Cardiovascular Diseases

Glaucoma b Receptor antagonists are very useful in the treatment of chronic open-angle glaucoma. Six drugs currently are available carteolol (ocupress, others), betaxolol (betaoptic, others), levobunolol (betagan, others), metipranolol (optipranolol, others), timolol (timoptic, others), and levobetax-olol (betaxon). Timolol, levobunolol, carteolol, and metipranolol are nonselective betaxolol and levobetaxolol are b1 selective none has significant membrane-stabilizing or intrinsic sympathomimetic activity. Topically administered b blockers have little or no effect on pupil size or accommodation and are devoid of blurred vision and night blindness often seen with miotics. These agents decrease the production of aqueous humor, which appears to be the mechanism for their clinical effectiveness. For details of the treatment of glaucoma, see Chapter 63.

Semisolid Dosage Forms Ophthalmic Ointments and Gels

The principal semisolid dosage form used in ophthalmology is an anhydrous ointment with a petrolatum base. The ointment vehicle is usually a mixture of mineral oil and white petrolatum. The mineral oil is added to reduce the melting point and modify the consistency. The principal advantages of the petrolatum-based ointments are their blandness and anhydrous and inert nature, which make them suitable vehicles for moisture-sensitive drugs. Ophthalmic ointments containing antibiotics are used quite frequently following operative procedures, and their safety is supported by the experience of a noted eye surgeon Ramon Castroviejo (350), who, in over 20,000 postsurgical patients, saw no side effects secondary to ointment use. No impediment to epithelial or stromal wound healing was exhibited by currently used ophthalmic ointments tested by Hanna et al. (351). The same investigators have reported that, even if these ointments were entrapped in the anterior chamber and did not exceed 5 of the...

Intraocular Dosage Forms

Ophthalmic surgery has rapidly advanced in the last three decades particularly with the ability of the surgeon to operate in back of the eye. The ophthalmologist can perform vitreoretinal surgery and restore significant visual function in patients with diabetic complications, endophthalmitis, and retinal tears and detachments. Also, significant advances have been made in anterior segment surgery, especially for cataract surgery where replacement of a cloudy or opaque natural crystalline lens with a plastic or silicone intraocular lens can restore visual acuity and allow the patient to achieve a significant improvement in his or her quality of life. These technological advances have placed greater emphasis on the development of products specifically formulated and packaged for intraocular use. This has led to the development of improved irrigating solutions, intraocular injections, viscoelastics, vitreous inserts, and intravitreal injections. Balanced salt solution (BSS ) provided an...

Limited access to the CNS

Clonidine Metabolites

Apraclonidine (Iopidine) and Brimonidine (Alphagan). In addition to its therapeutic use as an antihyperten-sive agent, clonidine has been found to provide beneficial effects in several other situations,47 including glaucoma, spasticity, migraine prophylaxis, opiate withdrawal syndrome, and anesthesia. This has prompted the development of analogs of clonidine for specific use in some of the mentioned areas. Two of such examples are apraclonidine and brimonidine. Apraclonidine does not cross the BBB. However, brimonidine can cross the BBB and hence can produce hypotension and sedation, although these CNS effects are slight compared with those of clonidine. CNS effects of these drugs are correlated well to their log P, pKa, and thus log D value. Both apraclonidine and brimonidine are selective a2-agonists with a1 a2 ratios of 30 1 and 1,000 1, respectively. Brimonidine is a much more selective a2-agonist than clonidine or apraclonidine and is a firstline agent for treating glaucoma....

Ivermectin Stromectol

Onchocerciasis is a serious global health problem which results from infestation by the nematode Onchocerca volvulus,1 The parasite is spread by the bite of the blackfly Simulium spp., which injects immature larval forms of the worms into a human host. Maturation of the larvae usually takes one year. Adult female worms live for up to 15 years and daily produce approximately 1000 larvae (microfilariae), which migrate through the skin causing rash and itching. Microfilariae can migrate over a period of months to the eye where they cause visual impairment and eventually blindness. More than 18 million people become infected annually in Africa and Latin America, and approximately 270,000 lose their eyesight.

M Glyceryl Trinitrate

Sublingual prophylaxis and treatment of angina Buccal prophylaxis and treatment of angina adjunct in unstable angina acute and congestive heart failure Injection control of hypertension and myocardial ischaemia during and after cardiac surgery induction of controlled hypotension during surgery congestive heart failure unstable angina Transdermal see under preparations below Cautions hypothyroidism malnutrition hypothermia recent history of myocardial infarction heart failure due to obstruction hypoxaemia or other ventilation and perfusion abnormalities susceptibility to angle-closure glaucoma metal-containing transdermal systems should be removed before magnetic resonance imaging procedures, cardioversion, or diathermy avoid abrupt withdrawal monitor blood pressure and heart rate during intravenous infusion tolerance (see notes above) interactions Appendix 1 (nitrates) Contra-indications hypersensitivity to nitrates hypo-tensive conditions and hypovolaemia hypertrophic cardiomyopathy...

O Design Of Eicosanoid Drugs

A second major approach has been aimed at delivering the desired agent, either a natural eicosanoid or a modified analog, to a localized site of action by a controlled delivery method. The exact method of delivery may vary according to the desired site of action (e.g., uterus, stomach, lung) but has included aerosols and locally applied suppository, gel formulations, or cyclodextrin complexes. The recent commercial development of prostaglandin PGF-type derivatives for use in the eye to lower intraocular pressure (IOP) in glaucoma (discussed under Prostaglandins for Ophthalmic Use) relies on their potent therapeutic effects coupled with their limited distribution from this site of administration.23

Drugs and Biological Agents Used in Ophthalmic Surgery

Anterior segment gases Sulfur hexafluoride (SF6) and perfluoropropane gases have long been used as vitreous substitutes during retinal surgery. In the anterior segment, they are used in nonexpansile concentrations to treat Descemet's detachments, typically after cataract surgery. These detachments can cause mild-to-severe corneal edema. The gas is injected into the anterior chamber to push Descemet's membrane up against the stroma, where ideally it reattaches and clears the corneal edema. vitreous substitutes The primary use of vitreous substitutes is reattachment of the retina following vitrectomy and membrane-peeling procedures for complicated proliferative vit-reoretinopathy and traction retinal detachments. several compounds are available, including gases, perfluorocarbon liquids, and silicone oil (Table 63-6). With the exception of air, the gases expand because of interaction with systemic oxygen, carbon dioxide, and nitrogen, and this property makes them desirable to temporarily...

Ocular Pharmacodynamics

Drugs that may be chosen for use in the management of glaucoma may be topically applied miotics, such as pilocarpine hydrochloride or nitrate, carbachol, echothiophate iodide, or demecarium bromide epinephrine prodrugs like dipivefrin hydrochloride, nonselective P-adrenergic blocking agents such as timolol maleate and bunolol hydrochloride, and selective P-adrenergic blocking agents such as racemic- or the more potent L-betaxolol hydrochloride, compounds devoid of pupillary effect topically administered carbonic anhydrase inhibitors, such as dorzolamide and brinzolamide prostaglandin analogs of the class PGF2ot, such as latanoprost and travoprost, capable of lowering IOP significantly with little or no inflammatory or vasodilatory response or, they may be orally administered drugs to present an osmotic effect that will lower IOP, such as 50 glycerin or 45 isosorbide. Other drugs administered orally to lower IOP are the carbonic anhydrous inhibitors acetazolamide and methazolamide....

Preservation and Preservatives

In 1953, the FDA required that all ophthalmic solutions be sterile (135). Preservatives are included as a major component of all multiple-dose eye solutions for the primary purpose of maintaining sterility in the opened product through its shelf life. Packaging ophthalmic solutions in the popular plastic eyedrop container has reduced, but not completely eliminated, the chances of inadvertent contamination. There can be a suckback of an unreleased drop when pressure on the bottle is released. If the tip is allowed to touch a nonsterile surface, contamination may be introduced. Therefore, it is important that the pharmacist instruct the patient on the proper method of dispensing from a plastic eyedrop container to minimize the hazards of contamination. The hazard is magnified in the busy clinical practice of the eye care professional where a diagnostic solution there are many, including cycloplegics, mydriatics, and dyes may be used for many patients from the same container. The...

Antiviral Agents for Ophthalmic

ANTIPROTOZOALAGENTS Parasitic infections involving the eye usually manifest themselves as a form of uveitis, an inflammatory process of either the anterior or posterior segments, and less commonly as conjunctivitis, keratitis, and retinitis. In the U.S., the most commonly encountered protozoal infections include Acanthamoeba and Toxoplasma gondii. In contact-lens wearers who develop keratitis, clinicians should be highly suspicious of the presence of Acanthamoeba. Additional risk factors for Acanthamoeba keratitis include poor contact lens hygiene, wearing contact lenses in a pool or hot tub, and ocular trauma. Treatment usually consists of a combination topical antibiotic, such as polymyxin B sulfate, bacitracin zinc, and neomycin sulfate (neosporin), and sometimes an imidazole (e.g., clotrimazole, miconazole, or ketoconazole). In the UK, the aromatic diamidines (i.e., propamidine isethionate in both topical aqueous and ointment forms, brolene) have been used successfully to treat...

Use of Autonomic Agents in the

Autonomic drugs are used extensively for diagnostic and surgical purposes and for the treatment of glaucoma, uveitis, and strabismus. The autonomic agents used in ophthalmology as well as the responses (i.e., mydriasis and cycloplegia) to muscarinic cholinergic antagonists are summarized in Table 63-5 (also see Chapters 6 through 10). Glaucoma Characterized by progressive optic nerve cupping and visual field loss, glaucoma is responsible for the bilateral blindness of 90,000 Americans (half of whom are African American or Hispanic), and about 2.2 million have the disease (1.9 of the population over age 40). Risk factors associated with glaucomatous nerve damage include increased intraocular pressure (IOP), positive family history of glaucoma, African American heritage, and possibly myopia and hypertension. Elevated IOP is a risk factor for glaucoma. Several clinical trials have determined that reducing IOP can delay glaucomatous nerve damage. Although markedly elevated IOPs (e.g.,...

Use of Immunomodulatory Drugs for Ophthalmic Therapy

GLUCOCORTICOIDS Glucocorticoids have an important role in managing ocular inflammatory diseases their chemistry and pharmacology are described in Chapter 59. Currently the glucocorticoids formulated for topical administration to the eye are dexamethasone (decadron, others), prednisolone (pred forte, others), fluorometholone (fml, others), loteprednol (alrex, lotemax), medrysone (hms), and rimexolone (vexol). Because of their anti-inflammatory effects, topical glucocorticoids are used in managing significant ocular allergy, anterior uveitis, external eye inflammatory diseases associated with some infections and ocular cicatricial pemphigoid, and postoperative inflammation following refractive, corneal, and intraocular surgery. After glaucoma filtering surgery, topical glucocorticoids can delay the wound-healing process by decreasing fibroblast infiltration, thereby reducing potential scarring of the surgical site. Glucocorticoids are commonly given systemically and by sub-Tenon's...

Sources of leads and drugs

Chemical Constituent Foxgloves Leaf

Figure 1.6 Examples of some of the drugs in clinical use obtained from plants. Taxol and vincristine are anticancer agents isolated from Taxus breifolia and Vinca rosea Linn, respectively. Pilocarpine is used to treat glaucoma and is obtained from Pilocarpus jaborandi Holmes Rutaceae. Morphine, which is used as an analgesic, is isolated from the opium poppy Figure 1.6 Examples of some of the drugs in clinical use obtained from plants. Taxol and vincristine are anticancer agents isolated from Taxus breifolia and Vinca rosea Linn, respectively. Pilocarpine is used to treat glaucoma and is obtained from Pilocarpus jaborandi Holmes Rutaceae. Morphine, which is used as an analgesic, is isolated from the opium poppy

Vitamin A and Carotenoids

Carotenoids, lycopene in particular, are considered antioxidants because they are effective at quenching singlet oxygen. It is theorized that carotenoids inhibit lipid peroxidation under some conditions, increase communication between cells, therefore lowering cancer risk, increase immune system function, have a role in cardiovascular disease prevention, and lower risk for macular degeneration and cataracts. But it is still unclear if these potential functions are the result of the actual carotenoid or due to synergistic interactions.

Detoxify The Phosphothioate By Phosphatase

Echothiophate iodide is a long-lasting cholinesterase inhibitor of the irreversible type, as is isofluorphate. Unlike the latter, however, it is a quaternary salt, and when applied locally, its distribution in tissues is limited, which can be very desirable. It is used as a long-acting anticholinesterase agent in the treatment of glaucoma.

Anticholinergic Effects

The tricyclics block muscarinic receptors and can cause a variety of anticholinergic side effects, such as dry mouth, constipation, blurred vision, and urinary hesitancy. These effects can precipitate an ocular crisis in patients with narrow-angle glaucoma. The tricyclic and tetracyclic compounds vary substantially in their muscarinic potency (see Table 12-1). Amitriptyline is the most potent, followed by clomipramine. Of the tricyclics, desipramine is the least anticholinergic. Amoxapine and maprotiline also have minimal anticholinergic effects. Anticholinergic effects can contribute to tachycardia, but tachycardia also occurs as a result of stimulation of -adrenergic receptors in the heart. Thus, tachycardia regularly occurs in patients receiving desipramine, which is minimally anticholinergic (Rosenstein and Nelson 1991). become severe. An ocular crisis in patients with narrow-angle glaucoma is an acute condition associated with severe pain. Urinary retention can be associated with...

Prodrugs for ocular delivery

Ocular absorption of a drug can be enhanced substantially by increasing its lipophilicity, which can be achieved with prodrug applications. Key requirements for ocular prodrugs involve good stability and solubility in aqueous solutions to enable formulation, sufficient lipophilic properties to penetrate through the cornea, low irritation profile, and the ability to release the parent drug within the eye at a rate that meets the therapeutic need. Prodrugs were introduced into ophthalmology about 15 years ago when ocular absorption of epinephrine was improved substantially by its prodrug, dipivefrine.74 Currently, it has replaced epinephrine in the treatment of elevated intraocular pressure (IOP) associated with glaucoma. Since the introduction of dipivefrine, numerous prodrugs have been designed to improve the efficacy of ophthalmic drugs, to prolong their duration of action, and to reduce their systemic side effects.

Osmotic Agents And Drugs Affecting Carbonic Anhydrase

The main osmotic drugs for ocular use include glycerin, mannitol (see Chapter 28), and hypertonic saline. Ophthalmologists occasionally use glycerin and mannitol for short-term management of acute rises in IOP. Sporadically, these agents are used intraoperatively to dehydrate the vitreous prior to anterior segment surgical procedures. Many patients with acute glaucoma do not tolerate oral medications because of nausea therefore, intravenous administration of mannitol and or acetazolamide may be preferred. These agents should be used with caution in patients with congestive heart failure or renal failure. Corneal edema is a clinical sign of corneal endothelial dysfunction, and topical osmotic agents may effectively dehydrate the cornea. Identifying the cause of corneal edema will guide therapy, and topical osmotic agents, such as hypertonic saline, may temporize the need for surgical intervention in the form of a corneal transplant. Sodium chloride is available in either aqueous or...

Agents Used to Assist in Ocular Diagnosis

A number of agents are used in an ocular examination (e.g., mydriatic agents and topical anesthetics, and dyes to evaluate corneal surface integrity) to facilitate intraocular surgery (e.g., mydriatic and miotic agents, topical and local anesthetics) and to help in making a diagnosis in cases of aniso-coria and retinal abnormalities (e.g., intravenous contrast agents). The autonomic agents have been discussed earlier. The diagnostic and therapeutic uses of topical and intravenous dyes and of topical anesthetics are discussed below. anterior segment and external diagnostic uses Epiphora (excessive tearing) and surface problems of the cornea and conjunctiva are common external ocular disorders. The dyes fluorescein, rose bengal, and lissamine green are used in evaluating these problems. Available both as a 2 alkaline solution and as an impregnated paper strip, fluorescein reveals epithelial defects of the cornea and conjunctiva and aqueous humor leakage that may occur after trauma or...

Distribution Blood Pressure

Following transcorneal absorption, the aqueous humor accumulates the drug, which then is distributed to intraocular structures and potentially to the systemic circulation via the trabecular meshwork pathway (Figure 63-4). Melanin binding of certain drugs is an important factor in some ocular compartments. For example, the mydriatic effect of a adrenergic receptor agonists is slower in onset in humans with darkly pigmented irides compared to those with lightly pig-mented irides drug-melanin binding is also a potential reservoir for sustained drug release. Another clinically important consideration for drug-melanin binding involves the retinal pigment epithelium accumulation of chloroquine (see Chapter 39) causes a toxic retinal lesion that is associated with decreased visual acuity.

The Targets used for Virtual Screening

Glaucoma is a general eye disease, in which intraocular pressure rises 41 . In open-angle glaucoma, the inner eye fluid drains too slowly from the front chamber of the eye. As a secondary event, it can also affect the optic nerve causing slow progressive loss of vision. It finally leads, if left untreated, to blindness. Inhibition of human Carbonic Anhydrase II (HCA II) in the eye lowers the intraocular pressure by decreasing aqueous production. The crystal structure of the key enzyme has been solved and it was used for elaborate design studies 42-44 . Accordingly our knowledge base in terms of structural data of this enzyme is significant. Furthermore, to our present knowledge the enzyme remains fairly rigid and unchanged upon ligand binding 42 , It consists of a single polypeptide chain of 260 amino acid residues and a zinc at the bottom of a cone-shaped amphiphilic catalytic center (15A deep, 15A wide). The zinc ion is chelated by three histidine residues and in the ligand-free...

Eicosanoid Catabolism

EYE Although PGF2a induces constriction of the iris sphincter muscle, its overall effect in the eye is to decrease intraocular pressure by increasing the aqueous humor outflow of the eye via the uveoscleral and trabecular meshwork pathway. A variety of F prostaglandin-receptor agonists have proven effective in the treatment of open-angle glaucoma, a condition associated with the loss of COX-2 expression in the pigmented epithelium of the ciliary body (see Chapter 63). INHIBITORS AND ANTAGONISTS As a consequence of the important and diverse physiological roles of eicosanoids, mimicking their effects with stable agonists, inhibiting eicosanoid formation, and antagonizing eicosanoid receptors produce noticeable and therapeutically useful responses. As outlined earlier and in Chapter 26, the tNSAIDs and their subclass of selective COX-2 inhibitors are used widely as anti-inflammatory drugs, whereas low-dose aspirin is employed frequently for cardioprotection. LT antagonists are useful...

Ocular Pharmacokinetics And Pharmacology

Pharmacokinetics generally encompasses the process of absorption, distribution, metabolism, and excretion (ADME) of drugs. For the most part, ADME deals with systemically administered drugs that reach their pharmacological target by way of the systemic circulation, that is, blood, following oral or parenteral administration. Ocular pharmacokinetics embraces many features of ADME, but on a smaller scale and specifically applied to the eye. However, owing to the previously discussed unique anatomic, physiological, and barrier properties of the eye and surrounding tissue, ocular pharmacokinetics often can be as difficult to describe and predict as its systemic counterparts. The task is further confounded by the myriad of formulations, routes, and dosing regimens typically encountered in ophthalmology. For a more comprehensive discussion of ocular pharmacokinetics the reader is referred to various review articles (11,15-23). An overview of the principles regulating drug distribution is...

Oxidative Damage to Carbohydrates

Different phenomena relate AGE products to aging (1) pentosidine concentration in the skin is negatively correlated with MLSP in mammals 124 (2) AGE products accumulate in the extracellular matrix during aging 124 (3) dietary restriction reduces glycation in rodents 124-126 (4) sugar-enriched diets decrease rodent longevity 127 and (5) AGE products are linked to different age-related diseases such as Parkinson's disease, cataracts, diabetes, atherosclerosis and Alzheimer's disease 128 .

Ephedra Ma Huang And Related Drugs

Of athletic performance. 'Herbal ecstasy' is also an ephedrine-containing product, which can induce a euphoric state. Ephedra is a small perennial shrub with thin steams. The plant rarely grows over 30 cm tall. Some of the better known species include Ephedra sinica and Ephedra equisentina (collectively called ma huang from China. The German Commission E report recommended against the use of ephedra in patients with high blood pressure, glaucoma or thyrotoxicosis.

Constitutive Activity of GPCRs and Pathophysiology of Disease

Constitutive Activity

In the case of the luteinizing hormone (LH) receptor, activating mutations have been associated with the development of male precocious puberty 14 . Interestingly, a point mutation resulting in constitutive activity of the FSH receptor has been identified as maintaining male fertility after hypophysectomy 15 . In the visual signaling cascade, several mutations have been linked with congenital eye disease. Most importantly, constitutive activity ofthe light sensor rhodopsin may cause retinitis pigmentosa and night blindness 16 .

Ocular Toxicity and Irritation

As mentioned previously (and discussed in detail in section Contact Lens Care Products), contact lens products have specific guidelines that focus on compatibility with the contact lens and biocompatibility with the cornea and conjunctiva (109). These solutions are viewed as new medical devices and require testing with the contact lenses with which they are to be used. Tests include a 21-day ocular study in rabbits, and may include other solutions that might be used with the lens. Additional tests to evaluate cytotoxicity, acute toxicity, sensitization potential (allergenicity), and risks specific to the preparation are also required (99,109,110). These tests are sufficient to meet requirements in the majority of countries, though testing requirements for Japan are currently much more extensive. in IOP and the onset of an acute attack of glaucoma. The formulator should be aware that particulates may originate from raw materials as well as glass fragments produced in glass ampoule...

The Protein Truncation Test PTT

The PTT would be expected to be useful in the diagnosis of disorders to which terminating mutations contribute substantially. It has been used to scan genes related to disease, including familial adenomatous polyposis, hereditary breast and ovarian cancer, Duchenne's muscular dystrophy, and ophthalmic disease.82 A modification of the standard PTT called digital protein truncation to increase its sensitivity to detect mutations was utilized to detect APC mutations in fecal DNA from patients with colorectal tumors. Mutations were identified in 26 of 46 stool samples tested from patients with neoplastic disease, whereas none was identified in stools from 28 control patients who did not have neoplastic

Supplement Efficacy

Cancer, immune function, and cataracts), particularly among the young, the elderly, those with chronic illnesses, low-income populations, and overweight patients.36 But, it is known that high levels of many of the minerals (i.e., iron, zinc, copper, selenium) and some fat-soluble vitamins (i.e., vitamin A and (3 -carotene) can be toxic. However toxic levels can be avoided when multivitamin mineral supplements are taken properly.

Brimonidine

Brimonidine (alphagan), a clonidine derivative and a2 agonist, is administered topically to lower intraocular pressure in patients with ocular hypertension or open-angle glaucoma brimonidine both decreases aqueous humor production and increases outflow (see Chapter 63). Unlike apraclonidine, brimonidine crosses the blood brain barrier and can produce hypotension and sedation, although these effects are slight compared to those of clonidine.

Methylphenidate

Methylphenidate (ritalin, others), structurally related to amphetamine, is a mild CNS stimulant with more prominent effects on mental than on motor activities. However, large doses produce signs of generalized CNS stimulation and convulsions. Its pharmacological properties are essentially the same as those of the amphetamines, including the potential for abuse. Methylphenidate is a schedule Il-controlled substance in the U.S. Methylphenidate is effective in the treatment of narcolepsy and attention-deficit hyperactivity disorder (see below). Racemic methylphenidate is readily absorbed after oral administration and reaches peak concentrations in plasma in 2 hours. The more potent (+) enantiomer has a t122 of 6 hours. Concentrations in the brain exceed those in plasma. The main urinary metabolite is a deesterified product, ritalinic acid, which accounts for 80 of the dose. Methylphenidate is contraindicated in patients with glaucoma.