Martti Liesmaa

EXPERIMENTAL CATARACTS FOLLOWING LONG-TERM ADMINISTRATION OF CORTICOSTEROIDS*

In recent literature there are numerous reports on the development of posterior subcapsular cataracts on patients receiving long-term corticosteroid therapy. Even topical administration of steroids has been sufficient to produce posterior subcapsular lens opacities. Pertinent literature on the subject has been reviewed by Becker (1964) and Straatsma (1964, 1965). Quite recently Frandsen ( 1 965) reported an interesting spontaneous disappearance of such a cataract. Attempts to produce steroid cataracts in laboratory animals have failed so far. Von Sallman and others (1960) treated rats for 16 weeks with daily subcutaneous injections of dexamethasone but the lenses remained clear. Similar results were reported by Spencer and Andelman (1965), who treated rats for 16 weeks with weekly injections of triamcinolone acetonide. Beitman and others (1963, 1964) administered prednisone to 100 chickens for short and long periods of time in high and moderate doses without development of cataracts. It has to be emphasized, however, that in human studies cataract formation has been more common in patients receiving high doses of steroids for long periods (Black and others, 1960; Sundmark, 1963). Hence it appeared tempting to continue animal experiments for longer periods of time than 16 weeks. In this study the lenticular changes observed in rabbits after 41 weeks of systemic betamethasone treatment are being reported.

EXPERIENCE OF THE USE OF INDOMETHACIN IN INFLAMMATORY EYE DISEASES1

In 1963, Shen and his co-workers reported that they had synthetised a new non-steroid, anti-inflammatory agent with an antiedemic, analgetic and antipyretic effect. The first to study the effect of this drug, indomethasin (1-(pchlorobenzoyl)-5-methoxy-2-methylindole-3-acetic acid) were Winter et al. (1963, 1964), Paul and Strottman (1963), Norcross (1963). These and later studies established that indomethacin enhances the action of corticosteroids, making it possible to reduce the steroid dosage for some chronic rheumatoid arthritis patients; in some cases indomethacin has even made it possible to discontinue steroid administration completely. The mechanism of effect of indomethacin is not fully known, but it has been shown that its effect does not resemble that of corticotrophin as adrenalectomised test animals respond to it equally well as intact animals (Winter et al., 1963). Indomethancin had many side effects in the first clinical studies, e. g. headache, giddiness, nausea, vomiting, tinnitus, dyspepsia, and diarrhea. But most of these were found to be due to excessively high doses, as much as 900 mg/ 24 hours even. Hart and Boardman (1964) recommended an initial dose of 25 mg/24 hours to be given postprandially, increased subsequently to 75-100 mg/24 hours, and even to 300 mg/24 hours if there were no side effects. As the authors have found no reports of the effect of indomethacin in eye diseases, they made a trial use of the drug in some eye inflammations.

INCIDENCE OF CONGENITAL ANOMALIES OF THE LACRIMAL PASSAGES.

In the Eye Hospital of the University of Helsinki there has arisen a strong impression that the incidence of congenital anomalies of the lacrimal passages has increased considerably in the course of the last few years. The following is an attempt to assess the actual magnitude of the recent increase. The lacrimal passages develop from an epithelial cord imbedded in the mesenchyme which can be seen as a thickening in the ectoderm a t the naso-optical fissure as early as a t the 7 mm stage of embryonic development (Cassady 1952). A t the 40 mm stage, it starts to become tubular, canalization proceeding downwards from the lower canaliculus. The lacrimal puncta are formed towards the end of foetal life. 73.3 per cent of lacrimal passages are not quite patent at the moment of birth, according to Cassady’s histological studies. Usually, the obstruction lies a t the nasal end of the duct. 111 milder cases, the obstruction is formed by a smooth membrane or epithelial debris. In more severe cases the reason may be defective canalization or a bony anomaly, but multiple stenoses may also be found (Faldi and Miani, 1958). More rarely, lacrimal atresia is caused by the fact that the strands of the canaliculi do not reach the posterior lid edges but remain hypoplastic, or reach the lid edges but do not become tubular (Waardenburg, Franceschetti and Klein, 1961). Defective function of the lacrimal passages was noticed by Kendig and Guerry (1950) in six per cent of newborns. Usually the membrane covering the nasal end of the duct ruptures in the course of the first few weeks before the lacrimal gland begins to function, and no clinical symptoms occur. If this does not happen, however, retention of tears occurs, and sooner or later, a mucopurulent dacryocystitis ensues.

THE EFFECT OF ASCORBIC ACID ON THE INTRAOCULAR PRESSURE AND THE AQUEOUS HUMOUR OF THE RABBIT EYE

The regulation of intraocular pressure obviously depends on several factors. Attention was paid back in the 19th century to the 24-hour variations in intraocular pressure (Huguenin, 1899), and the subject has subsequently been studied extensively (see e. g. Newel1 and Krill, 1965). The 24-hour variation in intraocular pressure might be attributable to the 24-hour fluctuations in adrenal hormones (e. g. Boyd, McLeod, Hassard and Patrick, see Linnkr and Wistrand, 1962). The mechanism of regulation of the pressure, however, is not known. The hypothesis advanced by Linnkr (1 964) is that ascorbic acid might participate in the regulation of intraocular pressure as a corticoid antagonist. The effect of topical administration of ascorbic acid on the intraocular pressure, outflow coefficient and ascorbic, potassium, sodium and protein concentrations of the aqueous humour of rabbits was studied.

THE EFFECT OF SUBCONJUNCTIVAL AND PERORAL HEXAMETHONIUM BROMIDE ON THE INTRAOCULAR PRESSURE OF THE RABBIT EYE

The chemical composition of hexamethonium bromide is hexamethylene1 :6bistrimethyl-ammonium dibromide. The pharmacology of methonium salts began to attract attention at the end of the 1940s (Barlow and Ing, 1948, Paton and Zaimis, 1948, etc.). Restall and Smirk (1950) found that subcutaneous injections of hexamethonium bromide lowered the blood pressure considerably. Campbell and Robertson (1950) also achieved a decrease in blood pressure with the per 0s administration of hexamethonium bromide. However, only c. 10-15 per cent of the substance is absorbed from the gastrointestinal canal, and the peroral dose should therefore be considerably higher than the pareneral dose (Kilpatrick and Smirk, 1952). The maximal lowering effect of hexamethonium on blood pressure emerges */2-1 hour after it has been injected subcutaneously or intramuscularly, and the effect passes off in 4 hours (Morrison and Paton, 1953). Hexamethonium is a typical ganglion-blocking agent (e. g. Meller, 1958). From this derive its other qualities, i. e. peripheral vasodilatation, decline in the tone of the gastrointestinal canal, impairment of visual accommodation and drying of the mouth. The effect of hexamethonium on intraocular pressure was studied by Offret et al. (1963 a and b). They observed a distinct reduction in tension within 2 minutes of its intravenous injection into patients both with normal intraocular pressure and with glaucoma. They found intravenous administration especially suitable during narcosis for eye operations when elevalted intraocular pressure causes an increased risk of complications. They recommended

THE EFFECT OF β-METHASONE ON THE AQUEOUS HUMOUR OF THE RABBIT EYE

It has been suggested that the effects of cortisone and ascorbic acid on intraocular pressure are antagonistic (Linnkr, 1964). I t has been found, furthermore, that cortisone causes cataract, and that the ascorbic acid content is lowered in a cataract lens (Black et al.; 1960, Abrahamson and Abrahamson, 1961, Gordon et al., 1961, Oglesby et al., 1961, Straatsma, 1964, Goldman and Buschke, 1935). As it is obvious that corticosteroids and ascorbic acid have an important role in the function of the anterior part of the eye, we decided to study the effect of a course of subconjunctival corticoids on the ascorbic acid content of the aqueous humour of the rabbit eye. In addition, changes in the mineral and protein contents of the aqueous humour, and in intraocular pressure and the possible formation of cataract were followed.

THE EFFECT OF ALPHA-METHYLDOPA ON THE INTRAOCULAR PRESSURE OF THE RABBIT EYE1

Levo-3-(3,4-dihydroxiphenyl)-2-methylalanine (alpha-methyldopa) has been found to inhibit dihydroxiphenylalanine-decarboxylase (Sourkes, 1954). Enzymatic decarboxylation of dihydroxyphenylalanine (dopa) results in the biosynthesis of noradrenaline and adrenaline. The synthesis of serotonin (5hydroxytryptamine) from 5-hydroxytryptophan follows the same principle (Westermann et al., 1958, Smith, 1960). Glaucoma has been successfully treated with deseril alone, a serotonin antagonist (SHman et al., 1960). On the other hand, it has been found that serotonin increases distinctly in the patients blood during a glaucomatous attack (Siman et al., 1960), and accordingly it has been regarded as an etiologic factor in the elevation of intraocular pressure. In contrast, several ganglion-blocking agents (e. g. guanethidine sulphate and hexamethanium bromide) exert a depressing effect not only on the blood pressure but also on intraocular pressure (Castrkn and Pohjola, 1962 a and b; Offret et al., 1963). Laibson, Krishna and Leopold (1 962) tested alpha-methyldopa, known to be a potent blood pressure drug, on animals. They established thzt intravenously administered alpha-methyldopa on cats (25 mg/kg) caused a lowering of intraocular pressure. Peczon (1965) did not discover the same effect in man when giving 250 mg X 3 orally. In order lto still ascertain the influence of alphamethyldopa on the ocular tension of rabbits Ithe authors decided to study it by giving bigger doses than Laibson et al.

TOPICALLY ADMINISTERED DEMEKASTIGMINE BROMIDE AS A CHOLINESTERASE INHIBITOR1

Demekastigmine bromide is composed of two neostigmine molecules linked by a polymethylene chain. Its chemical name is decamethylenbis-(N-methylcarbamin acid-m-dimethyl-aminophenyl-esterbrommethylate). It is a reversible cholinesterase inhibitor like physostigmine. Two types of parasympathomimetics are used in principle in ophthalmology: those acting on effector cells so as to mimic the action of acetylcholine and those inhibiting the enzyme cholinesterase, which normally hydrolyses the neurohumoral transmitting agent acetylcholine, thus prolonging the effect of locally produced acetylcholine. The former group includes the most commonly used glaucoma drug, pilocarpine, and the latter, among others, demekastigmine bromide. A powerful miotic, demekastigmine bromide is generally used in the treatment of open angle glaucoma, but also for the topical treatment of accommodative esotropia and convergent strabismus as well as myasthenia gravis. Demekastigmine bromide is water-soluble and can be stored at room temperature. As it is a powerful and long-acting cholinesterase inhibitor, its lowering action on intraocular pressure is also of long effect. However, it has the same toxic properties as other long-acting cholinesterase inhibitors. Applied to the eye, it is absorbed from the conjunctiva and, especially if the lacrimal point is not pressed close lege artis after the instillation, it is absorbed even more rapidly from the extensive mucosal surfaces of the nose and the gastrointestinal canal. The detrimental side effects can be divided into local and systemic. The main local side effects are contact dermatitis of the palpebral skin, hyperemia of the conjunctiva, maximal miosis, pupillary block, epithelial cyst of the

THE INFLUENCE OF CORTICOSTEROIDS ON INTRAOCULAR PRESSURE IN RABBITS: III. The immediate influence of massive intravenous doses of betamethasone and dexamethasone on the intraocular pressure of the rabbit eye

A decrease in the intraocular pressure in the rabbit eye after adrenalectomy has been reported (e. g. Friedenwald and Buschke, 1941, LinnCr and Wistrand, 1963). The diurnal variation in intraocular pressure was attributed by Ericson (1958) to fluctuations in the aqueous inflow. Similar variation has been established in the adrenocortical function: the 17-hydroxycorticosteroid content of the plasma rises rapidly early in the morning, drops subsequently in the course of the day and is at its lowest at night (Forsham et al., 1955). This led e. g. Anjou (1961) to consider that the periodicity of adrenocortical secretion regulated by the anterior pituitary might be associated with the variations in the inflow of aqueous humour. LinnCr and Wistrand failed to establish a similar mechanism in rabbits; on giving adrenocortical hormones by way of substitution therapy to bilaterally adrenalectomised rabbits they were unable to demonstrate a significant pressure elevation or change in resistance to outflow during short-term or prolonged treatment. In the previous section (Part 11) of the study on the effect of corticosteroids we found that systemically administered massive doses of betamethasone and dexamethasone were capable of raising intraocular pressure in a part of the test animals. These corticosteroids are intended expressly for intravenous administration. We therefore used them to study the immediate effect of doses more massive than substitution therapy on intraocular pressure in the rabbit eye and on the dynamics of aqueous flow.